A n to n io C a r lo s P e r e ir a B a r r e tto , B a r b a r a M a r ia Ia n n i
The undetermined form of Chagas' heart disease:
concept and forensic implications
Heart Institute, Hospital das CUnicas da Faculdade
de Medicina da Universidade de Sao Paulo - Sao Paulo, Brazil
T h e u n d e te rm in e d fo rm o f C h a g a s ' d is e a s e is d ia g n o s e d in a s y m p to m a tic s u b je c ts w ith a p o s itiv e b lo o d te s t fo r C h a g a s ' d is e a s e , n o rm a l re s tin g e le c tro c a rd io g ra m , c h e s t X -ra y , b a riu m e s o p h a g e a l a n d la rg e b o w e l ra d io lo g ic a l s tu d ie s . O th e r in v e s tig a tio n m e th o d s a re n o t re c o m m e n d e d fo r id e n tific a tio n o f o th e r o rg a n s d a m a g e le s io n s in th is p h a s e o f th e d is e a s e . W h e n o th e r m e th o d s
o f in v e s tig a tio n w e re e m p lo y e d , c a rd ia c a n d d ig e s tiv e a b n o rm a litie s o f s m a ll m a g n itu d e w e re d e te c te d w ith o u t p ro g n o s tic im p lic a tio n s . T h e s e fin d in g s d o n o t w a rra n t fre q u e n t e x a m in a tio n s o f p a tie n ts w ith u n d e te rm in e d fo rm o f th e d is e a s e e x c e p t fo r th e e le c tro c a rd io g ra m o r if th e p a tie n ts re p o rt o th e r c lin ic a l m a n ife s ta tio n s . T h e b e n ig n c o u rs e o f th e d is e a s e d o e s n o t p re c lu d e a b ility
to w o rk a n d th e s u b je c ts s h o u ld b e c o n s id e re d a p t fo r w o rk in a n y p ro fe s s io n .
U N IT E R M S : C h a g a s ' d is e a s e .
T
he undeterm ined form of the C hagas' disease w as initially described by C arlos C hagas w ho had recognized it as an clinical entity. H e characterized the undeterm ined form as apparently norm al individuals w ho behaved like "potential cardiac disease patients" (2). Later, Laranja et aI. w ould define this entity as a "laboratorial form " (10). This "laboratorial form " includedA d d r e s s fo r c o r r e s p o n d e n c e : A n to n io C a r lo s P e r e ir a B a r r e tto
In s titu to d o C o r a 9 a o d o H o s p ita l d a s C lfn ic a s d a F a c u ld a d e d e M e d ic in a d a U n iv e r s id a d e d e S a o P a u lo
A v . D r . E n e a s d e C a r v a lh o A g u ia r 4 4 S a o P a u lo - S P - B r a s il - C E P 0 5 4 0 0 3 - 0 0 0
infected patients w ho w ith or w ithout an acute phase w ould rem ain asym ptom atic w ith a m arked C hagas' disease positive reaction for m any years or even for the entire life.
o n U C D f o r a lo n g tim e . H o w e v e r , its h ig h p r e v a le n c e in
e n d e m ic z o n e s ( a b o u t 5 0 % o f th e p o p u la tio n ) , m a k e u s
b e lie v e th a t n e a r ly 3 m illio n p e o p le e x is t n o w a d a y s in
B r a z il w ith U C D ( 3 ) . I n th e la s t f e w y e a r s , th e a u th o r s
h a v e o b s e r v e d a g r o w in g in te r e s t in th e u n d e r s ta n d in g o f
U C D . T h is is s p e c ia lly d u e to th e e m e r g e n c e o f n e w
r e s e a r c h to o ls . W ith th e s e to o ls , it is p o s s ib le to s h o w th e
p r e s e n c e o f c a r d ia c a n d d ig e s tiv e in v o lv e m e n t in m o s t o f
c a s e s . T h e s e n e w f i~ d in g s s tir u p d o u b ts a b o u t w h a t is th e
u n d e te r m in e d f o r m o f th e C h a g a s ' d is e a s e . I t a ls o r a is e s
d o u b ts a b o u t th e p r o p e r n o m e n c la tu r e to b e e m p lo y e d in
C h a g a s ' d is e a s e , a b o u t th e m a n n e r s to c o n d u c t
in v e s tig a tio n s in to it. F u r th e r m o r e , it p r o d u c e s d o u b ts
a b o u t th e c o r r e c t m e d ic a l c o n d u c t to b e a d o p te d a n d a b o l! t .
its m e d ic a l la b o r a to r ia l f e a tu r e s . T h e d e f in itio n o f U e D
g iv e n a b o v e is b a s e d o n a c k n o w le d g e d a r b itr a r y c o n d itio n s
w h ic h a r e r e a s o n a b le f o r its d e f in itio n .
E x p e r ie n c e h a s d e m o n s tr a te d , th o u g h , th a t c e r ta in
im p r e c is e p o in ts tu r n in to e v e n le s s p r e c is e c e r ta in a lr e a d y
in e x a c t lim its .
N o t u n c o m m o n ly , to le r a n t e le c tr o c a r d io g r a m
in te r p r e ta tio n s m u s t b e c o n s id e r e d , a s w e ll a s th e a b s e n c e
o f la r g e b o w e ls r a d io lo g ic a l s tu d ie s . T h e s e d if f e r e n c e s
c o u ld c o n tr ib u te f o r th e e v e n tf u l f in d in g o f m a r k e d
a b n o r m a litie s th r o u g h th e u s e o f s o p h is tic a te d in v e s tig a tio n
m e th o d s in in d iv id u a ls w ith a d o u b tf u l a n d im p r e c is e
c h a r a c te r iz a tio n o f C h a g a s ' d is e a s e 's p h a s e . T h e s ta tu s o f
o u r r e s e a r c h g r o u p k n o w le d g e s h o w s u n d o u b te d ly th a t
p e o p le w ith U C D a r e n o t c o m p le te ly n o r m a l. T h e
c o u n tle s s n u m b e r o f la b o r a to r ia l te s ts e m p lo y e d n o w a d a y s
to d e te r m in e a b n o r m a litie s in h e a r t a n d d ig e s tiv e tr a c t
s tu d ie s a llo w s th e v e r if ic a tio n th a t a v a r ia b le p e r c e n ta g e
o f in d iv id u a ls p r e s e n t c h a n g e s in e a c h o n e o f th e e m p lo y e d
m e th o d s . A lth o u g h s h o w in g a n u n r e m a r k a b le
e le c tr o c a r d io g r a m , a s im p le v e c to r c a r d io g r a p h ic s tu d y
r e c o g n iz e s c h a n g e s in m o s t p a tie n ts w ith U C D ( 1 5 ,1 9 ) .
M o s t o f th e s e c h a n g e s a r e n o t s p e c if ic . H o w e v e r , a b o u t
o n e th ir d o f th e s u b je c ts s h o w s in itia l c h a n g e s lik e th o s e
c h a n g e s o b s e r v e d in th e c h r o n ic p h a s e . T h e s e c h a n g e s
b e in g , f o r in s ta n c e , c o n d u c tio n d is tu r b a n c e s a n d in a c tiv e
e le c tr ic a r e a s ( 1 9 ) . E c h o c a r d io g r a p h ic s tu d ie s s h o w n o r m a l
v a lu e s in a ll r e s e a r c h e d p a tie n ts . H o w e v e r , w h e n c o m p a r e d
w ith a g r o u p o f n o r m a l s u b je c ts , th e d im e n s io n s o f th e
h e a r t c h a m b e r s , a lth o u g h w ith in th e n o r m a l r a n g e , th e s e
d im e n s io n s w e r e la r g e r in th e c a r r ie r s o f th e d is e a s e . T h is
is s u g g e s tiv e o f a n in itia l d a m a g e to th e h e a r t c h a m b e r s
( 4 ,1 9 ) . T h e b i- d im e n tio n a l e c h o c a r d io g r a p h y s tu d ie s a llo w
th e v is u a liz a tio n o f th e e n tir e h e a r t c h a m b e r s . T h e s e s tu d ie s
h a v e c o n f ir m e d a n o r m a l g lo b a l c a r d ia c p e r f o r m a n c e a n d
th e v e r if ic a tio n o f r e g io n a l c o n tr a c tib ility a b n o r m a litie s
w ith th e p r e d o m in a n c e o f a p e x h y p o k in e s ia ( 4 ,1 9 ) . T h e
p r e s e n c e o f in f la m m a to r y c h a n g e s in th e m y o c a r d iu m m a y
b e in v e s tig a te d in a n o n - in v a s iv e w a y b y m e a n s o f th e
te c h n e tiu m - la b e le d p y r o p h o s p h a te u p ta k e te s t o r w ith th e
g a lliu m u p ta k e te s t ( 7 ,1 9 ) . T h e la tte r s h o w s a d ia g n o s tic
y ie ld o f 1 0 0 % o f th e in v e s tig a te d c a s e s . I n th e s tr e s s te s t,
d e p r e s s io n o f th e S T s e g m e n t, th e p r e s e n c e o f a r r h y th m ia s
a n d c h r o n o tr o p ic in c o m p e te n c e w a s o b s e r v e d in a v a r ia b le
r a te . I n o u r e x p e r ie n c e , th e s tr e s s te s t w a s a b n o r m a l in
7 2 % o f th e c a s e s ( 9 %
=
c h r o n o tr o p ic in c o m p e te n c e ; 5 0 %=
f a ilu r e to e le v a te th e b lo o d p r e s s u r e a b o v e 4 0 m m H ga n d 5 0 %
=
a r r h y th m ia s ) ( 1 9 ) . T h e d y n a m ice le c tr o c a r d io g r a p h y is tr u ly th e b e s t m e th o d f o r e v a lu a tin g
th e p r e s e n c e o f h e a r t a r r h y th m ia s . T h e c u r r e n t lite r a tu r e
in d ic a te s a v a r ia b le in c id e n c e r a te o f a r r h y th m ia s .
H o w e v e r , it is im p o r ta n t to g iv e e v id e n c e th a t m o s t o f th e s e
s tu d ie s d id n o t in c lu d e c o n tr o l g r o u p s ( 1 6 ,1 9 ) . W h e n
c o m p a r e d to a c o n tr o l g r o u p , th e in c id e n c e o f h e a r t
a r r h y th m ia s in U C D is s lig h tly h ig h e r , b u t th e a r r h y th m ia
is g e n e r a lly b e n ig n in n a tu r e ( 1 ) . A n g io g r a p h ic s tu d ie s
w e r e th e f ir s t ty p e o f in v e s tig a tio n m e th o d to d e m o n s tr a te
r e le v a n t c h a n g e s r e la te d to th e u n d e te r m in e d f o r m o f th e
C h a g a s ' d is e a s e ( 6 ) . T h e d a ta w a s c o n f ir m e d la te r ( 1 4 ) .
V a r ia b le r a te s o f a p e x h y p o k in e s ia a n d e v e n a c tu a l
v e n tr ic u la r a n e u r y s m w e r e r e c o r d e d . F in a lly ,
e n d o m y o c a r d ia l b io p s y s h o w e d h is to lo g ic a l c h a n g e s in
6 0 % o f th e c a s e s s tu d ie d ( 1 3 ,1 8 ) . T h is r a te o f h is to lo g ic a l
c h a n g e s is s im ila r to th e r a te f o u n d in th o s e p a tie n ts
c h r o n ic a lly a f f e c te d b y th e d is e a s e . T h e d if f e r e n c e is th a t
th e h is to lo g ic a l c h a n g e s a r e s ig n if ic a n tly le s s r e m a r k a b le .
M o r e r e c e n tly , a lo n g w ith th e h is to lo g ic a l c h a n g e s ,
im m u n o p a th o lo g ic a l c h a n g e s w e r e r e c o r d e d in 1 0 0 % o f
th o s e s u b je c ts w ith c o n f ir m e d h e a r t f a ilu r e a n d , m o r e
r a r e ly , in th e s u b je c ts w ith th e u n d e te r m in e d f o r m o f th e
d is e a s e ( 8 ) . A ll th e s e d a ta w e r e o b ta in e d e m p lo y in g
d if f e r e n t r e s e a r c h m e th o d s a n d s h o w e d th a t it is p o s s ib le
to id e n tif y , a m o n g s u b je c ts w ith th e u n d e te r m in e d f o r m
o f th e C h a g a s ' d is e a s e , th o s e s u b je c ts w h o a c tu a lly h a v e
h e a r t d a m a g e . T h e s a m e f in d in g w a s id e n tif ie d c o n c e r n in g
th e p r e s e n c e o f d a m a g e in o th e r o r g a n s . E s o p h a g e a l
m a n o m e tr ic s tu d ie s s h o w e d a n a b n o r m a l e s o p h a g e a l
f u n c tio n in 1 0 0 % o f th o s e s u b je c ts d e f in e d a s b e in g U C D
( 1 7 ) . A ll th e s e r e s u lts b r in g f o r w a r d d e ta c h e d
in te r p r e ta tio n s . E a c h in v e s tig a to r s h o w s a c e r ta in
p e r c e n ta g e o f c h a n g e s a n d c o n c lu d e s th a t, a m o n g th o s e
s u b je c ts in c lu d e d in th e u n d e te r m in e d f o r m , th is r a te o f
c h a n g e s r e f le c ts th e p a tie n ts w ith c a r d ia c d is o r d e r s ,
d is c u s s in g th e in v e s tig a tio n m e th o d 's v a lu e in f in a l
c h a r a c te r iz a tio n o f m y o c a r d io p a th y .
T h e a u th o r s d o n o t c o n s id e r th is th in k in g c o r r e c t,
b e c a u s e it d o e s n o t r e g a r d s o m e o f th e d is e a s e 's b a s ic
c lin ic a l s p e c tr u m o f th e c la s s ic c h r o n ic p h a s e , p e r h a p s o n e
c o u ld u n d e r s ta n d th e m b e tte r . C h a g a s ' d is e a s e is
p o ly m o r p h ic , w ith v a r ie d p r e s e n tin g f o r m s . F o r in s ta n c e ,
o n e m a y r e c a ll th a t r ig h t b u n d le b lo c k is f r e q u e n t, b u t is
n o t p r e s e n t in 1 0 0 % o f th e c a s e s . T h is is th e c a s e w ith th e
p r e s e n c e o f a r r h y th m ia s , a p e x a n e u r y s m , m e g a e s o p h a g u s ,
m e g a c o lo n , a m o n g o th e r f in d in g s . H o w e v e r , if a r ig h t
b u n d le b lo c k p o s itiv e r e a c tio n s u b je c t d is p la y s a n
u n r e m a r k a b le e c h o c a r d io g r a m o r h e m o d y n a m ic s tu d y
( w h ic h it is n o t r a r e ) , o n e c o u ld s a y a t b e s t th a t c a r d ia c
f u n c tio n is p r e s e r v e d . H o w e v e r , it is n o t p o s s ib le to s ta te
o n a d e f in ite b a s is th a t n o c a r d ia c d a m a g e is p r e s e n t
b e c a u s e C h a g a s ' d is e a s e is p a te n tly m u ltif o r m in its
p r e s e n ta tio n s . D e s p ite its u n c e r ta in u s e f u ln e s s , e x c e p t f o r
a c a d e m ic in te r e s t, b r o a d e r c lin ic - la b o r a to r ia l e v a lu a tio n s
a r e n e c e s s a r y in th e c h a r a c te r iz a tio n o f u n d e te r m in e d f o r m .
V a r io u s te s ts th a t ta k e in to a c c o u n t th e m u ltip le f e a tu r e s
o f th e C h a g a s ' d is e a s e m a n if e s ta tio n s a r e e m p lo y e d f o r
th e c h a r a c te r iz a tio n o f U C D b e c a u s e o f its c h a r a c te r is tic
p o ly m o r p h ic p r e s e n ta tio n . W ith th a t o b je c tiv e in m in d , th e
a u th o r s e m p lo y e d s e v e r a l m e th o d s in th e s a m e in d iv id u a l
( 1 9 ) . T h e y w e r e s ix te s ts : v e c to r c a r d io g r a p h y , u n i- a n d
b i- d im e n tio n a l e c h o c a r d io g r a p h y , r a d io is o to p e
v e n tr ic u lo g r a p h y , te c h n e tiu m p y r o p h o s p h a te c a r d ia c
m a p p in g , d y n a m ic e le c tr o c a r d io g r a p h y a n d s tr e s s te s t. A s
m e n tio n e d e a r lie r , a v a r ia b le p e r c e n ta g e o f p a tie n ts
p r e s e n te d c h a n g e s in e a c h o f th e s e m e th o d s . W h e n th e y
w e r e a n a ly z e d to g e th e r , th e a u th o r s c o u ld o b s e r v e th a t
1 0 0 % o f th e p o s itiv e s e r u m r e a c tio n s u b je c ts p r e s e n te d a t
le a s t o n e a b n o r m a l te s t. A d d itio n a lly , m o s t o f th e p a tie n ts
( 6 3 % ) d is p la y e d a n a b n o r m a lity in a t le a s t f o u r o u t o f th e
s ix te s ts p e r f o r m e d . O n e m a y c o n c lu d e th a t th e r e is a
s y s te m a tic c a r d ia c a n d e s o p h a g e a l d a m a g e in th e
u n d e te r m in e d f o r m o f C h a g a s ' d is e a s e ( 3 ,1 7 ,1 9 ) . I t is a ls o
p a te n t th a t a ll th e d is o r d e r s d e te c te d b y m e a n s o f th o s e
te s ts e n u m e r a te d a b o v e w e r e a lw a y s o f s m a ll m a g n itu d e .
I t is e v e n ju s tif ia b le to s ta te th a t in th e u n d e te r m in e d f o r m ,
th e c a r d ia c d a m a g e p r o f ile p r o v e s to b e le s s s e v e r e , th e
c a r d ia c d a m a g e p r o v e s to b e p o ly m o r p h ic in f a s h io n th a t
is p o s s ib le to b e d e m o n s tr a te d o n ly th r o u g h m u ltip le n o n
-in v a s iv e m e th o d s . T h is c a r d ia c d a m a g e is s im ila r to th e
c h r o n ic f o r m , b u t w ith a n u n d e te r m in e d p r o g r e s s io n . O n e
m u s t b e c a r e f u l w ith th e p o s s ib le in te r p r e ta tio n o f th is
s ta te m e n t. T h e a u th o r s a r e c o n c lu d in g th a t e v e r y p e r s o n
w ith a p o s itiv e s e r u m r e a c tio n s h o w s c a r d ia c a n d
e s o p h a g e a l d a m a g e . T h is s ta te m e n t is n o t n e w . C a r d ia c
a n d e s o p h a g e a l d a m a g e w a s d e m o n s tr a te d in a n e c r o p s y
s tu d y o f p o s itiv e s e r u m r e a c tio n s u b je c ts d y in g f r o m a n
a c c id e n ta l d e a th . T h e s e s u b je c ts s h o w e d to h a v e c a r d ia c
a n d e s o p h a g e a l c h a n g e s ( d e n e r v a tio n ) ( l I). T h is f in d in g ,
n o w f u lly s u s ta in e d , th a t a ll in d iv id u a ls w ith a p o s itiv e
s e r u m r e a c tio n f o r C h a g a s ' d is e a s e h a v e c a r d ia c d a m a g e
h a s a f u r th e r im p lic a tio n . I t d o e s n o t c h a n g e th e s u b je c ts '
p r o g n o s is , w h ic h h a s r e p e a te d ly b e e n p r o v e d to b e
f a v o r a b le ( 4 ,1 2 ) . L o n g itu d in a l e p id e m io lo g ic a l s tu d ie s in
e n d e m ic z o n e s in d ic a te d th a t a b o u t 5 % o f th e in f e c te d
p a tie n ts s ta r te d to p r e s e n t c lin ic a lly d e m o n s tr a b le
a b n o r m a litie s e v e r y y e a r . T h e s u r v iv a l r a te s tu d ie s o f
in d iv id u a ls w ith C h a g a s ' d is e a s e s h o w e d th a t th e s u r v iv a l
r a te in th e U C D is s im ila r to th e n o r m a l h e a lth y p o p u la tio n
( 9 ) . T h is c le a r ly in d ic a te s th a t th e c o n c e r n f o r h e a r t f a ilu r e
a n d s u d d e n d e a th m u s t a lw a y s b e r e la te d to c h r o n ic f o r m
o f C h a g a s ' d is e a s e . E v e n w ith th e d e m o n s tr a tio n o f
c a r d ia c a n d e s o p h a g e a l in v o lv e m e n t in th o s e p a tie n ts , th e
a u th o r s c o n s id e r th a t th e d e n o m in a tio n " u n d e te r m in e d
f o r m " is th e m o s t c o r r e c t. A lth o u g h b e in g tr u th f u lly a
c h r o n ic f o r m , th e u n d e te r m in e d f o r m h a s p e r h a p s a le s s e r
a g g r e s s i v e p o te n tia l. I t m a y a ls o h a v e a n u n c e r ta in
p r o g r e s s io n a n d c lin ic a l m a n if e s ta tio n s th a t a r e o n ly
p o s s ib le to b e r e c o r d e d o n a u n e q u iv o c a l b a s is th r o u g h
la b o r a to r y te s tin g . T h e u n d e te r m in e d f o r m o f C h a g a s '
d is e a s e s till h a s s e v e r a l in a c c u r a te a n d u n d e te r m in e d
f e a tu r e s . S h o u ld th e c a r in g p h y s ic ia n s u b m it u n d e te r m in e d
f o r m p a tie n ts to m u ltip le e x a m in a tio n s a n d te s tin g ? T h e
a u th o r s ' im p r e s s io n is n e g a tiv e . T h e r e is n o d e f e n s e f o r
th a t. T h e s tu d ie s a lw a y s s h o w e d m ild d a m a g e . S u r v iv a l is
n o t in f lu e n c e d b y th e p r e s e n c e o f o r g a n d a m a g e ( th is h a s
b e e n w e ll d e m o n s tr a te d in e p id e m io lo g ic a l s tu d ie s a n d it
h a s a ls o b e e n p r o v e d b y th e a b s e n c e o f d ir e p r o g r e s s io n
r e p o r ts in s u b je c ts w ith th e u n d e te r m in e d f o r m o f th e
d is e a s e ) .
T h e a u th o r s a r e a ls o a g a in s t th e id e a th a t a p o s itiv e
s e r u m r e a c tio n id e n tif ie s p o te n tia l c a r d ia c p a tie n ts , w h o
c o u ld b e a b a n d o n e d o r w h o c o u ld a ls o n e e d u n r e le n tin g
in v e s tig a tio n s . A c tu a lly , s im ila r ly to w h a t is h a p p e n in g
to d a y w ith A I D S b lo o d te s ts , th e a u th o r s th in k th a t r o u tin e
b lo o d te s ts f o r C h a g a s ' d is e a s e s h o u ld b e p r o h ib ite d . A
p o s itiv e r e s u lt s e r v e s o n ly to la b e l p e o p le w h o in its
m a jo r ity , w o u ld b e p r o d u c tiv e f o r s o c ie ty . C a r d ia c
e x a m in a tio n s w ith e le c tr o c a r d io g r a p h y a r e th e b e s t w a y
to id e n tif y c a r d ia c p a tie n ts , a n d n o t b lo o d te s ts . I n th e
u n d e te r m in e d f o r m , th e a u th o r s b e lie v e th a t th e p a tie n t
m u s t r e c e iv e a m e d ic a l f o llo w - u p . T h e p a tie n t m u s t a lw a y s
b e in f o r m e d a b o u t h is o r h e r d is e a s e 's b e n ig n c h a r a c te r .
T h e y s h o u ld a ls o b e p e r io d ic a lly s u b m itte d to a n
e le c tr o c a r d io g r a p h s tu d y , w h ic h is c o n s id e r e d th e b e s t
la b o r a to r y te s t to in d ic a te th e lik e ly p r o g r e s s io n o f th e
d is e a s e . O th e r la b o r a to r y te s ts m a y b e p e r f o r m e d , u n d e r
th e c a r in g p h y s ic ia n 's c r ite r ia . T h is f u r th e r te s tin g is
g e n e r a lly p e r f o r m e d f o r th e s tu d y a n d e v a lu a tio n o f c e r ta in
s p e c if ic s y m p to m s a n d c o m p la in ts r e p o r te d b y th e p a tie n t,
exam inations in asym ptom atic patients w ith benign diseases (as the undeterm ined form ) usually increase the health care costs, w ithout providing any additional useful inform ation. T he authors can not state that undeterm ined form subjects have a dire disease prognosis, specially for the occurrence of sudden death, heart failure, bundle blocks and arrhythm ias. T hese features are characteristic of the classic chronic phase and the association of these features w ith the undeterm ined form state has not been properly dem onstrated. O n the contrary, it is not accurate to state, based of epidem iological studies, that these patients w ill som eday be sym ptom atic. T hese studies show m any cases rem aining w ith the undeterm ined form for the entire life. A dditionally, those subjects w ith the undeterm ined form w ho present a progression of the disease w ill display in its m ajority a low -grade com prom ise. P rogression to a m ore m alignant form of. the disease is uncom m on. A t InC or, the follow -up of subjects w ith the undeterm ined form during nearly 15 years of its existence, has clearly dem onstrated how absolutely correct the disease benignity concept is. O n the basis of this data and on the basis of the
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