E l i a n e P e d r a D i a s , A n a L u i s a F i g u e i r a G o u v ê a , C l a u d i a C a r v a l h a l E y e r
Condylom a acum inatum : its histopathological pattern
Realized at Antônio Pedro University Hospital, Department
of Pathology,
Universidade Federal Fluminense
- Niterói, Brazil.
C o n d y lo m a a c u m in a tu m is o n e o f th e c lin ic a i m a n ife s ta tio n s o f p a p illo m a v iru s in fe c tio n . T h e c la s s ic a l h is to p a th o lo g ic a l fe a tu re s a re a lre a d y k n o w n a n d d o n o t c o n s titu te a d ia g n o s tic p ro b le m . C lin ic a lly , it h a s b e e n c la s s ifie d in to g ro w th o r p ro life ra tiv e , fu ll-e x p re s s io n , a n d re g re s s iv e o r p e rs is te n t p h a s e s , w ith th e h is to p a th o lo g ic a l a s p e c ts o f th e s e d is tin c t p h a s e s b e in g w e ll d o c u m e n te d in ~ q u in e c u ta n e o u s p a p illo m a s . W e h a v e d e s ig n e d a p ro to c o l o f h is to p a th o lo g ic a l a n a ly s is in o rd e r to in v e s tig a te th e p o s s ib ility o f id e n tify in g th e e v o lu tio n a l p h a s e s in h u m a n c o n d y lo m a ta a c u m in a ta . S ix ty c o n d y lo m a ta a c u m in a ta fro m th e file s o f th e D e p a rtm e n t o f P a th o lo g y , U n iv e rs id a d e F e d e ra l F lu m in e n s e , w e re s tu d ie d re g a rd in g k o ilo c y to s is , p a ra c e ra to s is , a c a n to s is , b a s a l c e ll h y p e rp la s ia a n d m o n o -n u c le a r c e ll i-n filtra te . A fte r a -n i-n d iv id u a l a -n a ly s is a -n d c o m p a ris o -n o f th e c a s e s , th e m a i-n d iffe re -n tia l a s p e c ts o f c o -n d y lo m a a c u m i-n a tu m w e re : k o i/o c y to s is , tra n s e p ith e lia l Iy m p h o c y tic in filtra te a n d b a s a l c e ll h y p e rp la s ia . T h u s , c o n d y lo m a to u s le s io n s c a n b e h is to p a th o -lo g ic a lly d iffe re n tia te d in th re e m a jo r p a tte rn s : p ro life ra tiv e , v ira l re p lic a tio n a c tiv ity a n d re g re s s iv e .
U N IT E R M S : C o n d y lo m a a c u m in a tu m , k o ilo c y to s is , h is to p a th o lo g ic p a tte rn , re g re s s io n .
IN T R O D U C T IO N
C
ondylom aclinicaI aculninatumm anifestationsrepresentsof one of the m anythe H um anP apilIom avirus infection (H P V ); it is found m ore
frequently in the genital region and rarely in m ucous
m em branes. 1 -3 F requently associated w ith H P V 6 and 1 1 ,
the incubation period ranges from 3 w eeks to 8 m onths
and occurs particularly in young i~ dividuals.1.3 P rincipal
clinicaI consequences are transm ission to sexual partners
and to the fetus and new born by infected m others, and the
risk of developing squam ous cell carcinom a.3-5 U ntreated
lesions can rem ain unchanged for 1 0 or m ore years, or
m ore rarely, lnay regress spontaneously.2
A d d r e s s f o r c o r r e s p o n d e n c e :
E l i a n e P e d r a D i a s
R u a B r . d e I t a p a g i p e , 4 0 1 B I .2A p t . 2 0 R i o d e J a n e i r o / R J - B r a s i l - C E P 2 0 2 6 1 - 0 0 0
C lassical histopathological features of C ondylom a
acum inatum w ere recognized long ago, and are
characterized by acantosis, papillom atosis, hyperceratosis,
paraceratosis and koilocytosis.ó
-x M any studies have
described its clinicaI aspects and a great variety of lesions.
D ifferent clinicaI classifications have already been
proposed by m any authors, but none have been able to
correlate the clinicaI w ith the histopathological aspects.3,9 ,IO
T he analysis of several biopsies from outpatient
clinics in gynecology and sexual transm itted diseases
(S T D ) allow ed us to observe the differences, bath
quantitative and qualitative, in the various condylom ata
acum inata. T he grow th phase, the full-expression phase,
and the regressive ar persistent phase have been w ell
characterized clinicallyY T hese phases w ere recognized
histopatholagically in equine cutaneous papillom as by
H A M A D A et al.ll T here have been no sim ilar studies in
hum ans. T herefore, in order to identify their differences
and sim ilarities and classify the histopathological
evolutionary phases of condylom ata acum inata, it is
necessary to conduct a histopathological study.
D IA S , E .P ,; A N A L U IS A F IG U E IR A G O U V Ê A ,A ,L .F .; E Y E R , C .C - C o n d y lo m a a c u m in a tu m : its h is to p a th o lo g ic a l p a tte rn
1384
Among the great number of clinicallesions
associated
with papillomavirus
infection,
only flat warts present the
characteristics
of spontaneous
regression.
M any reports
have attempted
to explain this phenomenon,
12-16
and most
of them concurthat
cell-mediated
immunity is responsible
for the effective
regression
of this kind of lesion. This
immune
response
is expressed
by an early infiltration
of
macrophages
and T lymphocytes
CD4+ in the dermis and
later transepitheliaI.
The non-regressing
warts have an
inconspicuous
infiltrate
composed
of T lymphocytes
CD8+.
1 7In 1993,
OKABAYASHI
et aI.,18 using
rabbits,
classified
the lesions
as proliferative
(marked
cellular
proliferation)
and regres,sive (inflammatory
mononuclear
cell
infiltrate
dermal
and
transepithelial).
In 1994,
COLEM AN
et aI. published
their
first
study
on the
regression
of genital warts in closely monitored
patients.
The
main
histopathological
feature
identified
by
COLEM AN
et aI. was a marked, continuous
subepithelial
inflammatory
infiltrate, with prominent dermal infiltration.
Based
on random
observations
and studies on the
regression phenomenon
causing papillomavirus
lesions, we
have designed a protocol to histopathologically
analyze the
condylomata
acuminata, aiming to identify its evolutionary
phases.
M A T E R I A L S A N D M E T H O D S
The parameters
investigated
in the epithelium
were:
koilocytosis
(according
to
M EISELS6),
basal
cell
hyperplasia
(four or more layers of basal cells), acantosis,
hyperceratosis,
and paraceratosis.
Histological
evaIuation
of the dermis
included
the presence
and localization
(dermal, basal epithelial, transepitheliaI)
of mononucIear
cell infiltrate. The investigation
reveaIed extremely
high
leveIs of variation in paraceratosis
and mononuclear
cell
infiltrate,
and this
resuIted
in further
classification
according
to intensity,
being low, medium
and high as
follows:
Paraceratosis
low : condyloma
with few areas of
paraceratosis
in the epithelium.
Paraceratosis m edium : condyloma
with some areas
of paraceratosis
in the epitheIium.
Paraceratosis high: condyloma
with paraceratosis
throughout
the epithelium.
M ononuclear cell infiltrate low : condyloma
with
few Iymphocytes
and histiocytes
in few areas.
M ononuclear
cell
infiltrate.
m edium :
condyloma
with
Iymphocytes
and histiocytes,
with
moderate
distribution,
sometimes
in foci or in a
band-Iike pattern.
M ononuclear cell infiltrate high: condyloma
with
intense lymphocytes
and histiocytes
infiltrate, many times
in a band-like pattern.
After individual
analysis,
the cases were grouped
according to their differences and similarities in an attempt
to establish an evolutionary
cIassification.
W e retrospectively
studied
60 condylomata
acuminata
from the files of
the Department
of
Patho-logy (UFF)
from
January
1994 through
April
1996.
The
selected
60
cases
fulfilled
the
following
requirements:
a) specimens
measuring
not less than 0.5
em
in
length
and
with
sufficient
dermis;
and b)
specimens
not displaying
acute inflammation.
The specimens
were
stained by the H.E.
techni-que and analyzed
as to the
classical
histopathologicaI
aspects
considered
cha-racteristic
of condyloma
acuminatuTÍ1.
F ig u r e 1 - K O I L O C Y T O S I S (@ )c r it e r ia f o r t h e c 1 a s s if ic a t io n o f c o n d y lo m a t a a c u m in a t u m a s V I R A L R E P L I C A T I O N A C T I V I T Y P H A S E ( H e m a t o x ilin a & E o s in a O b je c t iv e 1 0 0 x O c u la r 1 0x ) .
1385
GROUP A (n=16)
T he detailed
histo-pathological analysis of the
cases (F ig.
4 )
show edacantosis, hyperceratosis and
paraceratosis in all cases, and
basal cell hyperplasia in 4 (25
percent). P araceratosis w as
considered m ild or m oderate
in 25 percent of the cases and
intense in 50 percent.
'The
lym phocytic inflam m atory
infiltrate w as seen in all cases
(m ild in 69 and m oderate in
31 percent). D erm is and the
base of the epithelium w ere
to the derm is and the koilocytosis; w hen present, it w as
in a concentration of five or less (F ig. 3).
T hus, according to the predom inant characteristics,
such as koilocytosis, transepithelial m ononuclear cell
inflam m atory infiltrate or transepithelial inflam m atory
infiltrate and the absence of koilocytosis, the cases w ere
further separated in groups A , B and C respectively. T he
rem aining 13 lesions did not m eet any of the criteria and
therefore w ere considered as
belonging to an interm ediate
evolutionary phase and
excluded from the study.
F ig u r a 3 : A B S E N C E o f K O I L O C Y T O S I S a n d T R A N S E P I T H E L I A L L Y M P H O C Y T I C I N F I L T R A T E (@ ), c r it e r ia f o r t h e c la s s if ic a t io n o f c o n d y lo m a t a a c u m in a t u m a s P R O L I F E R A T I V E P H A S E . ( H e m a t o x ilin a & E o s in a O b je t iv a 4 0 x O c u la r 1 0 x ) .
R E S U L T S
T he histopathological
analysis of the 60
condylom ata acum inata
show ed that koilocytosis
and the m ononuclear
inflam m atory infiltration
presented the m ost
prom inent quantitative
differences.
F irst, w e selected the
cases w here koilocytosis - the
histopathological m arker of
the cytopathic effect ofH P V
replication - w as present. T he
koilocyfosis "intensity varies
from rare to very num erous F ig u r e 2 - T R A N S E P I T H E L I A L L Y M P H O C Y T I C I N F I L T R A T E (@ ) c r it e r ia f o r t h e c la s s if ic a t io n
and this variation w as consi- o f c o n d y lo m a t a a c u m in a t u m a s R E G R E S S I V E P H A S E ( H e m a t o x ilin a & E o s in a O b je c t iv e 4 0 x
dered as an evolutionary O c u la r 1 0 x ) .
variation.
G roup
A w as form ed by 16 condylom ata in w hichm ore than five koilocytosis (F ig.1) per section w ere visible.
F rom the other 44 cases, for our purposes
G roup
B ,w e selected 19 condylom as in w hich the transepithelial
inflam m atory infiltrate (F ig. 2) - histopathological m arker
of regression phenom enon - w as the m ost prom inent feature.
G roup
C w as form ed by 12 condylom as in w hichthe inflam m atory infiltrate w as absent or lnild and confined
D I A S , E . P . ; A N A L U I S A F I G U E I R A G O U V Ê A , A . L . F . ; E Y E R , C . C - C o n d y lo m a
\
a c u m in a t u m : it s h is t o p a t h o lo g ic a l p a t t e r n '
1 3 8 6
1 0 0 %
8 0 %
6 0 %
4 0 %
2 0 %
0 %
BH
AC
HC
PC-L
PC-M
PC-A
KlI-L
II-M
lI-A II-D
II-B II-T
II-Abs
BH
= B a s a l H y p e rp la s iaAC
= A c a n to s isHC
H y p e rc e ra to s isPC
= P a ra c e ra to s is K K o ilo c y to s is 11 In fla m m a to ry In filtra te-L = L ig h t -M M o d e ra te
-A
A c c e n tu a te d-B
= B a s a l -T T ra n s e p ith e lia l-Abs
= A b s e n t-D D e rm a l
G R O U P S :
F ig u re 4 - P e rc e n ta g e s re la tiv e to th e v a rio u s h is to p a th o lo g ic a l a s p e c ts id e n tifie d in :
F ig u re 5 - C o n d y lo m a ta a c u m in a tu m w ith v a rio u s k o ilo c y to s is , re p re s e n ta tiv e o f th e V IR A L R E P L IC A T IO N A C T IV IT Y P H A S E . (H e m a to x ilin a & E o s in a O b je c tiv e 1 0 x O c u la r 1 0 x ).
th e m o s t f r e q u e n t lo c a liz a tio n ( 8 8 p e r c e n t) . T h is g r o u p
w a s c o n s id e r e d a s h a v in g th e v ir a l r e p lic a tio n a c tiv ity
( V R A ) p a tte r n ( F ig . 5 ) .
GROUP B (n=19)
I n th is g r o u p , ( F ig . 4 )
b a s a l c e ll h y p e r p la s ia w a s
d e te c te d in 3 2 p e r c e n t.
A c a n to s is , h y p e r c e r a to s is
a n d p a r a c e r a to s is w e r e
o b s e r v e d in a ll c a s e s .
P a r a c e r a to s is w a s m ild in
1 6 p e r c e n t, m o d e r a te in 6 8
p e r c e n t a n d in te n s e in
1 6
p e r c e n t. K o ilo c y to s is w a s
r a r e ly s e e n ( 6 c a s e s /3 2
p e r c e n t) . T h e m o n o n u c le a r
c e ll in f la m m a to r y in f iltr a te
w a s lo c a liz e d in th e d e r m is
a n d e p id e r m is , a n d c o n
-s id e r e d m ild in 3 2 p e r c e n t,
m o d e r a te in 2 6 p e r c e n t a n d
in te n s e in .4 2 p e r c e n t. T h is
w a s c la s s if ie d a s R e g r e s s iv e
( R ) p a tte r n ( F ig . 6 ) .
GROUPC(n=22)
I n th is g r o u p , b o th tr a n s e p ith e lia l in f la m m a to r y
in f iltr a te a n d k o ilo c y to s is w e r e r a r e ly s e e n o r w e r e a b s e n t.
T h e h is to p a th o lo g ic a l a n a ly s is o f th is g r o u p ( F ig . 4 ) h a s
d is p la y e d b a s a l c e ll h y p e r p la s ia , a c a n to s is , h y p e r c e r a to s is
1 3 8 7
Figure 6 - C ondylom ata acum inatum w ith accentuated transepithe.liallym phocytic infiltrate w ithout
koilocytosis (H ), R EG R ESSIVE PH ASE. (H em atoxilina & Eosina O bjective 4 x O cular 10 x).
a n d p a ra c e ra to s is in a ll c a s e s . T h e p a ra c e ra to s is w a s lT Iild
in 8 0 p e rc e n t a n d m o d e ra te in 2 0 p e rc e n t. K o ilo c y to s is
w a s le s s fre q u e n t (1 7 p e rc e n t). M o n o n u c le a r c e ll in filtra te
w a s a b s e n t in 3 3 p e rc e n t, b u t in th e re m a in in g 8 p a tie n ts
lT Io n o n u c le a r c e ll in filtra te w a s lo c a liz e d in th e d e rm is a n d
c la s s ifie d a s m ild . T h is g ro u p w a s c o n s id e re d a s
P ro life ra tiv e (P ) p a tte rn (F ig .7 ).
k o ilo c y to s is in s o m e le s io n s
m a y e x p Ia i n th e n e g a ti v e
re s u lts o b s e rv e d in s tu d ie s
u tiliz in g p ro c e d u re s s u c h a s
im lT IU n o h is to c h e m is try a n d /
o r in s itu h y b rid iz a tio n w ith
th e a im o f v iru s id e n
ti-fic a tio n . K o ilo c y to s is w a s
d ia g n o s e d in a c c o rd a n c e
w ith M E IS E L S ó c rite ria .
T h e p re s e n c e o f a
p e rin u c le a r h a lo , e v e n th o s e
a s s o c ia te d w ith n u c le a r
a lte ra tio n s , m u s t b e
c a re fu lly in te rp re te d . In o u r
o p in io n , th is c a n n o t b e
re g a rd e d a s a n
h is to p a th o lo g ic a l c rite rio n
o f c o m p a tib ility w ith H P V
in fe c tio n . O u r re s u lts h a v e
a ls o d e m o n s tra te d th e
im p o rta n c e o f k o ilo c y to s is in d e fin in g a p a tte rn . In 31 c a s e s
c la s s ifie d a s p ro life ra tiv e o r re g re s s iv e , it w a s id e n tifie d
in o n ly 8 c a s e s (2 6 p e rc e n t - F ig . 4 ).
O u r s tu d y h a s d e lT IO n s tra te d th e e x is te n c e o f a g ro u p
o f le s io n s th a t s h o w h is to p a th o lo g ic a l c h a ra c te ris tic s th a t
d e n o te a ly m p h o c y te -m e d ia te d im m u n o lo g ic a l re s p o n s e
b y th e p a tie n t.
T h e m o rp h o lo g ic a l re g re s s io n p h e n o m e n a in w a rts
is a Ire a d y w e Il d ? c u m e n te d n o t o n Iy in a n im a Is b u t a Is o in
Figure 7 - C ondylom ata acum inatum w ith rare derm is Iym phocytes (@ ), w ithout koilocytosis.
PR O LI FER ATIVE PH ASE. (H em atoxilina & Eosina O bjective 10x O cular 10x).
D ISC U SSIO N
T h e a n a ly s e s o f s p e c
i-m e n s fro i-m 6 0 p a tie n ts w ith
c o n d y lo m a ta a c u m in a ta
s h o w s th a t th e re a re q u a n
-tita tiv e h is to p a th o lo g ic a l
d iffe re n c e s a m o n g th e m .
T h e re la tiv e ly lo w
in c id e n c e o b s e rv e d fo r
k o ilo c y to s is (4 0 p e rc e n t)
w a s e x p e c te d a s k o ilo
-c y to s is re p re s e n ts th e h is to
-p a th o lo g ic a l e x p re s s io n o f
th e c y to p a th ic e ffe c t o f
H P V , a n d th is is e v id e n t
o n ly in le s io n s w ith g re a t
v ira l re p lic a tio n a c tiv ity .
T h e a b s e n c e o r ra rity o f
D IAS, E.P.; AN A LU ISA FIG U EIR A G O U VÊA,A.L.F.; EYER , C .C - C ondylom a acum inatum : its histopathological pattern
1388
h u m a n s.
12-19
0 u r
re su lts a re in a g re e m e n t w ith th e lite ra tu re ,
c o n trib u tin g
to th e h isto p a th o lo g ic a l
c h a ra c te riz a tio n
o f
th e
re g re ssio n
p a tte rn
o f
c o n d y lo m a ta
a c u m in a ta .
H o w e v e r,
th is
q u a n tita tiv e
stu d y
b a se d
o n ly
in th e
h isto p a th o lo g ic a l
a n a ly sis
is su b je c tiv e ,
a n d its e ffic a c y is
q u e stio n a b le .
O n th e o th e r h a n d , th e d istrib u tio n
o f th e IY ln p h o c y tic
in filtra te
is a ln o re p re c ise
c rite ria
w h ic h c o n sid e rs
o n ly
tw o p o ssib ilitie s:
its p re se n c e
o r a b se n c e in d iffe re n t site s.
W e b e lie v e
th a t
th e
b e st
h isto p a th o lo g ic a l
re g re ssio n
m a rk e r
fo r c o n d y lo m a ta
a c u m in a ta
is th e tra n se p ith e lia l
lo c a liz a tio n
o f th e ly m p h o c y tic
in filtra te .
O K A B A Y A S H I
e t a I.,
IXstu d y in g
ra b b it p a p illo ln a s,
c h a ra c te riz e d
a p ro life ra tiv e
p h a se b y a m a rk e d e p ith e lia l
p ro life ra tio n
w h e n c o m p a re d
w ith th e o th e r p h a se s. In o u r
stu d y , w e c h a ra c te riz e d
a g ro u p o f le sio n s b y th e a b se n c e
o f k o ilo c y to sis
a n d tra n se p ith e lia l
ly m p h o c y tic
in filtra te
(G ro u p C ). E m p lo y in g
th e b a sa l c e ll h y p e rp la sia
c rite rio n
- th e
h isto p a th o lo g ic a l
e x p re ssio n
o f p ro life ra tio n
in
sq u a m o u s
c e ll e p ith e liu ln
- w e w e re
a b le to v e rify
its
p re se n c e
in a ll G ro u p
C c a se s (F ig . 4 ), a n d in
2 5a n d
3 2p e rc e n t
o f g ro u p
A a n d
B c a se s,
re sp e c tiv e ly .
T h is
e x p re sse d
d iffe re n c e
w a s a m a jo r c rite ria
fo r c la ssify in g
G ro u p C a s re p re se n ta tiv e
o fth e p ro life ra tiv e
p a tte rn w h ic h
p ro b a b ly
c o rre sp o n d s
to th e e a rly p h a se o fH P V
in fe c tio n .
A c a n to sis
a n d h y p e rc e ra to sis
w e re p re se n t in a ll c a se s
a n d fo r th is re a so n th e y w e re n o t c o n sid e re d
a s p a rtic u la r
c rite ria
fo r a ,n y g ro u p . P a ra c e ra to sis
w a s a lso o b se rv e d
in
a lI
c a se s.
H o w e v e r,
it
w a s
in c o n sp ic u o u s
in
th e
p ro life ra tiv e
p a tte rn
a n d m a rk e d
in th e a c tiv ity
p a tte rn ,
sh o w in g a c le a r re la tio n sh ip
b e tw e e n
th e c y to p a th ic
e ffe c t
o f
H P V
a n d
th e
d istu rb a n c e
in
sq u a m o u s
c e lI
d iffe re n tia tio n
(F ig . 4 ).
P rio r stu d ie s h a v e p rim a rily
e m p h a siz e d
th e c lin ic a I
v a ria tio n s
o f c o n d y lo m a ta
a c u m in a ta ,
a n d se c o n d a rily
th e
id e n tific a tio n
o f th e
v iru s
b y d iffe re n t
te c h n o lo g ic a l
m e th o d s
b a se d
o n
im m u n o p a th o lo g y
a n d
ln o le c u la r
b io lo g y .2 J.7 .x
O u r
stu d y
re su lte d
in th re e
d istin c t
p a tte rn s
o f
c o n d y lo m a
c U ln in a tu ln :
p ro life ra tiv e ,
v ira I
re p lic a tio n
a c ti v ity a n d re g re ssi v e . T h e se p a tte rn s
p ro b a b ly
re tle c t th e
b io lo g ic a l
p h a se
o f th e H P V
in fe c tio n :
o n e
p h a se
o f
in te rfe re n c e
in th e c o n tro l
o f e p ith e liu m
p ro life ra tio n ,
a n o th e r p h a se o f a n in te n se v ira I re p lic a tio n
w ith c y to p a th ic
e ffe c ts
e x p re ssio n
a n d fin a lly ,
a p h a se
c h a ra c te riz e d
b y
th e re g re ssio n
o fth e
a c tio n o fth e
H P V , p o ssib ly
in a n sw e r
to th e h o st d e fe n se .
T h e se
b io lo g ic a l
p h a se s
a re p ro b a b ly
lin k e d
to th e
c lin ic a I e x p re ssio n
p h a se s. H o w e v e r,
it is p o ssib le
th a t th e
d u ra tio n
o f e a c h p h a se
d e p e n d s
o n a n e ffic ie n t
iln m u n e
re sp o n se . A n a c c u ra te h isto p a th o lo g ic
stu d y o f c o n d y lo ln a
a c u m in a tu lT I, b e sid e s
im p ro v in g
th e p re c ise
d ia g n o sis
o f
le sio n s
n o t
p re se n tin g
k o ilo c y to sis,
p e rm its
th e
id e n tific a tio n
o f th e
h isto p a th o lo g ic a I
p a tte rn .
T h e
c o rre la tio n
o f th is p a tte rn
w ith th e e v o lu tio n
tiln e o f th e
le sio n a n d th e re c u rre n c e
h isto ry c o u ld g iv e th e p h y sic ia n
a p ro g n o stic
e v a lu a tio n
b a se d o n th e p a tie n t's
o w n c u rre n t
d e fe n se s.
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