A ntonio F ranco M ontoro, O svaldo G iannotti F ilho, D arcy M archione M onteiro, F lávio F ranco M ontoro, M aria A parecida P inho, M arco T úlio A ssis F igueiredo
H orm onal receptors in m am m ary carcinom a: com parison
betw een quantitative and qualitative m ethods
Fundação
Oncocentro de São Paulo. Breast Clinic at Hospital Alemão Oswaldo Cruz • São Paulo, Brazil
Alternatives to the traditional horm one receptor dosages for prognostic evaluation and clinicai approach to breast cancer have been proposed for im m unohistochem ical determ inations. For correlation purposes, such procedures w ere com pared in 37 patients presenting 5 to 15 years of survival. C onsidering 30 fm /m g as the positivity index, the disagreem ent betw een both m ethods reached 35.1% w ith estrogen and 48.5% w ith progesterone receptors. W hen the positiveness levei w as changed to 20 fm /m g, the discrepancies w ere reduced to 32% w ith ER and increased to 57% w ith PgR . This study leads us to not recom m end the im m unohistochem ical m ethod applied to paraffin sections as an alternative procedure to the dextran-charcoal dosage for prognosis and therapeutic m anagem ent of m am m ary carcinom a.
U N ITER M S: Breast carcinom a. Prognosis. H orm onal receptors assays. C orrelation of m ethods.
IN TR O D U C TIO N
T
h e h o rm o n a l d e p e n d e n c e o fb re a st c a n c e r h a s b e e nk n o w n a n d d isc u sse d fo r o v e r 1 0 0 y e a rs. In 1 8 8 9 ,
S c h in z in g e r I in G e rm a n y , w a s th e first to c a ll
a tte n tio n to th is ~ a c t a n d B e a tso n2 in S c o tla n d , in 1 8 9 6 ,
p re se n te d a p a p e r sh o w in g c a se s o f m a m m a ry c a rc in o m a
re m issio n s a fte r b ila te ra l o o p h o re c to m y . H o w e v e r h is
re su lts d id n o t e x c e e d 3 0 % o f p a tie n ts. A fte r th e la b o ra to ry
iso la tio n o f c o rtiso n e , h o rm o n a l a b la tiv e su rg e ry to c o n tro l
m a m m a ry c a n c e r h a s b e e n e x te n d e d to a lso in c lu d e
a d re n a le c to m y a n d h y p o p h y se c to m y .
M e a n w h ile , e n d o c rin e a d d itiv e tre a tm e n ts w e re
sta rte d a n d su c c e ssiv e ly e stro g e n s, a n d ro g e n s,
A ddress for correspondence:
A ntonio F ranco.M ontoro
P raça A m adeu A m aral, 47
S ão P aulo/S P - B rasil- C E P 01327-010
p ro g e ste ro n e , a n ti-h o rm o n e s lik e ta m o x ife n , a ro m a ta se
in h ib ito rs, a n d re c e n tly L H -R H a n a lo g s, w e re u se d in o rd e r
to c o n tro l b re a st c a n c e r.
A ll th e se a tte m p ts h a d in c o m m o n o n e q u e stio n : to
w h a t p e rc e n ta g e w o u ld th e p a tie n ts re sp o n d to th is
h o rm o n e m a n ip u la tio n ? W ith o u t a se le c tiv e c rite rio n th e
re su lts w e re sim ila r to th o se sh o w ,n b y B e a tso n , ie o n ly
o n e th ird w e re re sp o n siv e .
B y 1 9 7 0 th e re w e re c lin ic a I a n d b io c h e m ic a l p a ra m e te rs
to p re d ic t th e ra p e u tic re su lts th a t w o u ld a llo w th e d ra w in g o f
c o n c lu sio n s re g a rd in g d iffe re n t g ra d e s o f h o rm o n a l
d e p e n d e n c e . A m o n g th e m , th e d ise a se -fre e in te rv a l p ro v e d
to b e w o rth w h ile . W h e n th e tim e e la p se d b e tw e e n th e c u ra tiv e
m a ste c to m y a n d th e frrst re c u rre n c e o f d ise a se w a s lo n g e r
th a n fiv e y e a rs, th e re sp o n siv e n e ss ra te ' to e n d o c rin e
m a n ip u la tio n in c re a se d to tw o th ird s o f th e p a tie n ts.
In th e e a rly se v e n tie s,
J
e n se n3 id e n tifie d th e e stro g e nre c e p to r (E R ) in th e m a m m a ry tu m o r c e ll a s a re lia b le
p a ra m e te r to e v a lu a te th e g ra d e o f h o rm o n e d e p e n d e n c e
rig h t a t th e b e g in n in g o f tre a tm e n t, w ith o u t h a v in g to w a it
fo r fiv e y e a rs o f e v o lu tio n .
M O N TaR a, A.F.;G IAN N O TTI Fo., O .; M O N TEIR O , D .M .; M O N TaR a, F.F.; PIN H O , M .A.; FIG U EIR ED O , M .T.A. - H orm onal receptors in m am m ary carcinom a: com parison betw een quantitative and qualitative m ethods
1 4 7 2
, J e n s e n b e lie v e d th a t th e m a m m a ry c a rc in o m a
h o rm o n a l d e p e n d e n c e w a s p o s itiv e w h e n th e b io c h e m ic a l
d o s a g e s in d ic a te d a re c e p to r a m o u n t a b o v e th re e
fe n to m o le s /m illig ra m o f n e o p la s tic tis s u e . L a te ly , a n o th e r
" e s tro g e n ic d e riv e d m a rk e r h a s b e e n id e n tifie d , th e
p ro g e s te ro n e re c e p to r (P g R ). Its p o s itiv ity in d e x w a s
in itia lly p la c e d a t fiv e frn lm g o f tis s u e4
W ith fu rth e r re s e a rc h p ro g re s s it b e c a m e e v id e n t th a t
th e in d e x o f 3 o r 5 frn lm g w a s to a lo w to c h a ra c te riz e th e
d e g re e o f h o rm o n e d e p e n d e n c e o f th e " n e o p la s tic tis s u e5 •
T h is in d e x w a s g ra d u a lly e le v a te d to 1 0 , 2 0 a n d 3 0 fm /m g .
E v e n ~ e n s e n 6 , a s h is o w n e x p e rie n c e in c re a s e d , c a rn e to th e
c o n c lu s io n th a t 5 0 fm /m g w o u ld b e th e id e a l in d e x to m a k e
a c o rre c t p ro g n o s tic ~ v a lu a tio n a n d p re d ic tio n o f th e ra p e u tic
re s p o n s e to th e e n d o c rin e tre a tm e n t.
M e a n w h ile , in a d d itio n to q u a n tita tiv e m e th o d s fo r
re c e p to r d o s a g e s , im m u n o h is to lo g ic q u a lita tiv e te c h n iq u e s
w e re d e v e lo p e d fo llo w in g th e p io n e e r re s e a rc h s ta rte d b y
P e rts c h u k7• W h e n th e tu m o r re c e p to r c o n te n t w a s n o t
e s ta b lis h e d d u rin g s u rg e ry , s u c h in fo rm a tio n c o u ld
p o s s ib ly b e d e te rm in e d th ro u g h p a ra ffin s e c tio n s . T h u s ,
th e h o rm o n a l d e p e n d e n c e o f b re a s t c a n c e r p o in te d o u t b y
th e re c e p to r p re s e n c e , in b o th e s tro g e n a n d p ro g e s te ro n e
c o n d itio n s , b e in g p o s itiv e o r n e g a tiv e , c o u ld re p re s e n t a n
a lte m a tiv e a p p ro a c h to im p ro v e th e m a m m a ry c a rc in o m a
m a n a g e m e n t.
In th is s tu d y , w e p re s e n t th e re s u lts o f q u a n tita tiv e
b io c h e m ic a l d o s a g e s o fh o rm o n a l re c e p to rs in fro z e n tu m o r
tis s u e a n d q u a Iita tiv e im m u n o h is to c h e m ic a I a n a ly s e s in
p a ra ffin s e c tio n s c a rrie d o u t o n th e s a m e g ro u p o f p a tie n ts .
M A T E R IA L A N O M E T H O O S
O u t o f a s e rie s o f 1 0 0 w o m e n tre a fe d fo r m a m m a ry
c a rc in o m a w ith a n a s y m p to 'm a tic s u rv iv a I o f 5 to 1 5 y e a rs ,
w ith re c e p to r d o s a g e s fo r e s tro g e n a n d p ro g e s te ro n e
(D e x tra n -C h a rc o a l m e th o d ) a n d w ith th e "
im m u n o h is to c h e m ic a l d e te rm in a tio n s o f e s tro g e n a n d
p ro g e s te ro n e a n tib o d ie s (P 2 9 B io g e n e x ), w e s e le c te d 3 7
p a tie n ts p re s e n tin g re lia b le p a ra ffin s e c tio n s .
T h is g ro u p v a rie d in a g e fro m 3 0 to 7 2 y e a rs o ld ; th e
c lin ic a I s ta g e s w e re : C S O : 1 ; C S 1 :9 ; C S 1 1 : 2 1 ; C S 1 1 1 :6
c a s e s . A x illa ry Iy m p h o n o d e m e ta s ta s e s w e re p re s e n t in
1 8 a n d a b s e n t in 1 9 p a tie n ts .
T h e h o rm o n a I re c e p to r v a lu e s ra n g e d fro m z e ro to
" 7 6 2 frn lm g fo r E R , a n d fro m z e ro to 1 ,6 2 9 fm /m g fo r P g R .
T h e p o s itiv e n e s s v a lu e w a s s e t a t 3 0 fm /m g . F o r q u a lita tiv e
d e te rm in a tio n s , th e re s u Its w e re c o n s id e re d a s p o s itiv e o r
n e g a tiv e fo r b o th c o n d itio n s .
T h e m e d ia n s u rv iv a l ra te o fth is s e rie s re a c h e d 1 0 5 .5
m o n th s . It w a s a n a ly z e d fo r p ro g n o s tie p u rp o s e s a n d
c o rre la te d to th e c lin ic a I s ta g e o f d is e a s e a s w e ll w ith th e
a x illa ry s t~ tu s a n d its re c e p to r p o s itiv e n e s s , a c c o rd in g to
b o th q u a n tita tiv e a n d q u a lita tiv e p ro c e d u re s . In c lin ic a I
s ta g e z e ro w ith n o n p a lp a b le tu m o r th e s u rv iv a l ra te w a s
1 2 0 m o n th s . W h e n th e a x illa w a s n e g a tiv e 1 1 3 .7 m o n th s .
In re c e p to r p o s itiv e a b o v e 3 0 fm lm g it w a s 1 1 2 .7 , a n d
o n ly 1 0 9 .4 m o n th s fo r th e p a tie n t p re s e n tin g q u a lita tiv e
p o s itiv e re s u lts .
T h e c o m p a ris o n b e tw e e n th e tw o m e th o d s is s h o w n in
T a b le s 1 a n d 2 . T h e c o n c o rd a n c e ra te fo r E R w a s 6 4 .8 % " a n d
fo r P g R 5 1 % . C o n s id e rin g th a t n u m e ro u s a u th o rs a c c e p t 2 0
fm /m g a s p o s itiv e fo r b o th h o rm o n e re c e p to rs , w e a ls o u s e d
th is in d e x o A s a re s u It, th e e s tro g e n re c e p to r s h o w e d a re d u c tio n
o f d is c re p a n c y fro m 3 5 .1 to 3 2 % . F o r th e p ro g e s te ro n e re c e p to r
th e re w a s a d is c re p a n c y in c re a s e to 5 7 % .
O IS C U S S IO N
Je n s e n3
n o tic e d th a t th e lo n g e r s u rv i v a I a n d b e tte r
re s p o n s e ra te s to h o rm o n a l m a n ip u Ia tio n w e re d ire c tly
p ro p o rtio n a l to q u a n tita tiv e re c e p to r le v e Is . T h e h ig h e r th e
in d e x th e g re a te r th e b e n e fit. S im ila rIy , a d re n a ,Ie c to m y a n d
T a b le 1
C o rre la tio n w ith E R re s u lts . T h e q u a lita tiv e d e te rm in a tio n s d is a g re e d b y 3 5 .1% w ith th e
q u a n tita tiv e d p s a g e s
M e th o d # %
M e th o d # %
D C + IH + 1 4 /2 0 7 0 .0 D C + IH - 6 /2 0 3 0 .0 D C - IH - 1 0 /1 7 5 8 .8 D C - IH + 7 /1 7 4 1 .1 C o n c o rd a n c e 2 4 /3 7 6 4 .8 D is c re p a n c y 1 3 /3 7 3 5 .1
D C : D e x tra n c h a rc o a l d o s a g e IH : Im m u n o h is to c h e m ic a l a s s a y
T a b le 2
C o rre la tio n w ith P g R re s u lts .
F o r th is c o n d itio n th e d is a g re e m e n t re a c h e d 4 8 .5 %
M e th o d # %
M e th o d # %
D C + IH + 3 /1 8 1 6 .6 D C + IC - 1 5 /1 8 8 3 .3 D C - IH - . 1 5 /1 7 8 8 ,2 D C - IH + 2 /1 7 1 1 .7 C o n c o rd a n c e 1 8 /3 5 5 1 .0 D is c re p a n c y 1 7 /3 5 4 8 .5
D C : D e x tra n c h a rc o a l d o s a g e IH : Im m u n o h is to c h e m ic a l a s s a y
S ã o P a u lo M e d ic a i J o u rn a llR P M 1 1 5 (4 ): 1 4 7 1 -1 4 7 4 , 1 9 9 "7 M O N T O R O , A .F .;G IA N N O T II F o ., O .; M O N T E IR O , D .M .; M O N T O R O , F .F .; P IN H O ,
M .A .; F IG U E IR E D O , M .T .A . - H o rm o n a l re c e p to rs in m a m m a ry c a rc in o m a :
1473
c a s t r a t i o n p r o c e d u r e s e x h i b i t i n c r e a s e d r e s p o n s e s w h e n
c o m p a r e d t o e n d o c r i n e a d d i t i v e t h e r a p i e s .
A f t e r t h e i n t r o d u c t i o n o f t h e P g R c o n d i t i o n a s a n o t h e r
m a r k e r f o r b r e a s t c a n c e r h o r m o n a l d e p e n d e n c e e v a l u a t i o n ,
s u c h o b s e r v a t i o n s w e r e c o n f i r m e d 4 ,8 , e s p e c i a l l y b y
O s b o m e 9 , w h o d e m o n s t r a t e d t h a t t h e p r o g e s t e r o n e r e c e p t o r
w a s m o r e s e n s i t i v e t h a n E R a s a p r o g n o s t i c m a r k e r ,
b e c a u s e i t s v a l u e i s i n d e p e n d e n t o f t h e p r e o r p o s t
m e n o p a u s a l s t a t u s , w h i l e t h e E R c o n d i t i o n s h o w s u p o n l y
a f t e r t h e m e n o p a u s e . .
T h e l i t e r a t u r e o n t h e c o m p a r i s o n b e t w e e n t h e
q u a n t i t a t i v e a n d q u a l i t a t i v e m e t h o d s h a s s h o w n d i s c o r d a n t
r e s u l t sl
Q - 1 2 . J a n s s e n s e t a l 1 3 c o n c l u d e d t h a t h i s t o c h e m i s t r y
d e t e r m i n a t i o n s a n d t h e b i o c h e m i c a l d o s a g e s w e r e n o t
c o n c o r d a n t w h e n t h e l a t t e r w e r e c o n s i d e r e d p o s i t i v e a t 1 0
f m / m g o f t i s s u e . O n t h e o t h e r h a n d , P e r t s c h u k e t a l 1 4
u t i l i z i n g t h e s a m e i n d e x 'o f 1 0 'f m / m g f o u n d a 8 0 %
c o n c o r d a n c e b e t w e e n b o t h m e t h o d s . T h e a u t h o r s u s e d o n l y
e s t r o g e n r e c e p t o r s a n d t h e i m m u n o h i s t o c h e m i s t r y t e s t w a s
p e r f o r m e d o n f r o z e n b i o p s y t i s s u e . L e a l e t a l 1 5 u s i n g
i d e n t i c a l m e t h o d s f o u n d 9 2 % i n a g r e e m e n t . P ~ n k o e t a l1 6
h o w e v e r , f o u n d a c o n c o r d a n c e o f 6 3 % a n d c a r n e t o t h e
c o n c l u s i o n t h a t t h e s e l e c t i o n o f p a t i e n t s f o r e n d o c r i n e
t h e r a p y s h o u l d n o t b e m a d e o n t h e b a s i s o f
i m m u n o h i s t o c h e m i s t r y m e t h o d s .
T h e d i v e r s i t y .o f o p i n i o n s a n d c o n c l u s i o n s a b o u t
c o m p a r a t i v e s t u d i e s w a s e x p l a i n e d b y O s b o r n e 1 7 . T h i s
a u t h o r a s s i g n e d t h e s e c o n f l i c t i n g r e s u l t s , e s p e c i a l l y i n
r e l a t i o n t o t h e e s t r o g e n r e c e p t o r s , t o 't h e t u m o r
h e t e r o g e n e i t y , w h e r e h o r m o n e r e s p o n s i v e a n d n o n
-r e s p o n s i v e c e l l s w e r e p r e s e n t i n v a r i a b l e p r o p o r t i o n s . F o r
O s b o m e , t h e s e v a r y i n g f r a c t i o n s w e r e r e s p o n s i b l e f o r t h e
1 5 % t o 3 4 % n o n - c o n c o r d a n c e o f h i s r e s u l t s . H e a d d e d
t h a t t h e c l i n i c a I r e s p o n s e s r e l a t e d t o i m m u n o h i s t o c h e m i s t r y
w e r e n o n - s a t i s f a c t o r y i n 4 0 % o f h i s p a t i e n t s . B o r j e s s o n e t
a l 1 8 c a r n e t o t h e s a m e c o n c l u s i o n . T h o r p e e t a l 1 9 f o u n d t h a t
t h e u n i f o r m i z a t i o n o f t h e t e c h n i q u e s o f c i t o s o l p r e p a r a t i o n
c o n t r i b u t e d t o t h e r e d u c t i o n o f t h e d i f f e r e n c e s s e e n i n t h e
d o s a g e s p e r f o r m e d b y s e v e r a l l a b o r a t o r i e s , e s p e c i a l l y
c o n c e r n i n g t h e p r o g e s t e r o n e r e c e p t o r s .
O z e l l o e t a l 2 0 c o n f r o n t e d t h e q u a n t i t a t i v e m e t h o d w i t h
i m m u n o h i s t o c h e m i s t r y e x e c u t e d i n f r o z e n t i s s u e s , i m p r i n t s
a n d p a r a f f i n b l o c k s e c t i o n s . E x c e p t f o r t h e l a t t e r , t h e r e s u l t s
b e t w e e n t h e t w o m e t h o d s w e r e c o n c o r d a n t .
I t m u s t b e s a i d t h a t o n e r e a s o n f o r d i s a g r e e m e n t
b e t w e e n q u a n t i t a t i v e a n d q u a l i t a t i v e m e t h o d s u s i n g f r o z e n
s e c t i o n s i s t h e l o w i n d e x c r i t e r i o n f o r p o s i t i v e n e s s . P a r I a n d
P o s e y 2 1 v e r i f i e d 8 9 % i n c o n c o r d a n c e w h e n t h e i n d e x f o r
r e c e p t o r s w a s t a k e n a t 3 f e n t o m o l e s . K i n s e l e t a I 2 2u s i n g 1 0
f m / m g a s p a r a m e t e r f o u n d t h e a g r e e m e n t j u s t b e l o w 7 0 % .
F i n a l l y , H a s s o n e t a l 2 3 s t r e s s e d t h a t t h e m a t e r i a l t o b e
s u b m i t t e d e i t h e r t o q u a n t i t a t i v e o r q u a l i t a t i v e m e t h o d s
s h o u l d b e t a k e n e a r l y f r o m t h e b i o p s y f r a g m e n t a n d n o t
f r o m t h e s u r g i c a l s p e c i m e n . B e s i d e s , a f u r t h e r m e a s u r e t o
r e d u c e t h e d i s c r e p a n c i e s i s t h a t t h e t i s s u e s h o u l d b e t a k e n
f r o m d i f f e r e n t a r e a s o f t h e t u m o r . T h i s p r e c a u t i o n a p p l i e s
t o e i t h e r t h e q u a n t i t a t i v e o r t h e q u a l i t a t i v e d e t e r m i n a t i o n s .
C O N C L U S IO N S
O u r s t u d y o f c o r r e l a t i o n b e t w e e n t h e q u a n t i t a t i v e
m e t h o d w i t h d ~ x t r a n c h a r c o a l t e c h n i q u e f o r E R a n d P g R
a n d t h e q u a l i t a t i v e i m m u n o h i s t o c h e m i c a l p r o c e d u r e u s i n g
a n t i b o d i e s a n t i r e c e p t o r s f o r e s t r o g e n a n d p r o g e s t e r o n e o n '
p a r a f f i n s e c t i o n s , r e a c h e d t h e c o n c l u s i o n t h a t t h e
c o n c o r d a n c e b e t w e e n t h e t w o m e t h o d s i s n o t s a t i s f a c t ~ r y .
T h u s , w e d o n o t r e c o m m e n d t h e i m m u n o h i s t o c h e m i c a l
d e t e r m i n a t i o n a p p l i e d t o p a r a f f i n s e c t i o n s a s a n a l t e m a t i v é
t o t h e q u a n t i t a t i v e p r o c e d u r e f o r t h e p r o g n o s t i c e v a l u a t i o n
o f m a m m a r y c a r c i n o m a .
M O N T a R a , A .F .;G IA N N O T T I F o .,o .;M O N T E IR O , D .M .; M O N T a R a , F .F .; P IN H O ,
M .A .; F IG U E IR E D O , M .T .A . - H o r m o n a l r e c e p to r s in m a m m a r y c a r c in o m a :
c o m o a r is o n b e tw e e n Q u a n tita tiv e a n d Q u a lita tiv e m e th o d s
1474
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