81
Sao Paulo Med J/Rev Paul Med 1999; 117(2):81-4. Sheila Jorge Adad, Maria Azniv Hazarabedian Souza, Renata Margarida Etchebehere, João Carlos Saldanha Vera Alice Aguiar Falco, Eddie Fernando Cândido Murta
Original Article
INTRODUCTION
Bra z il le a d s the w o rld in the ra te s o f inc idenc e a nd mo rta lity fro m c ervic a l c a nc er, whic h kills a ppro xima te ly 3 5 0 0 wo me n pe r yea r, ma ny o f fertile a g e. The g rea test numb er o f cases o ccurs in the no rthern and no rtheastern reg io ns, a nd a c c o rding to the la test surveys, the pre ve ntio n pro g ra ms o nly c o ve r a sma ll po rtio n o f Bra z il’s fema le po pula tio n.1 Cervic a l c yto lo g y c o ntinues to b e the mo st a ppro pria te metho d fo r investig ating cervical neo plasia and its p re c urso rs. G re a te r d ia g no stic a c uity is o b ta ined b y c o mb ining c yto lo g y, c o lpo sc o py a nd g uided b io psy metho ds. The idea l wo uld be to have diag no stic ag reement between these metho ds, altho ug h the literature sho ws that cyto -histo lo g ic a l disa g reement va ries fro m 1 1 % to 4 7 %.2 -8 Va rio us fa c to rs ha ve a b ea ring o n this disc o rd: c o lle c tio n, pro c e ssing , re a ding a nd interpreta tio n o f mo rpho lo g ica l a ltera tio ns fro m the c yto lo g ic a l exa m; lo c a tio n a nd extent o f the le sio ns, pro c e ssing , numb e r o f c uts a nd the interpretatio n o f the histo lo g ical sample. Studies have indicated that the g reatest causes o f erro rs in c yto -histo lo g ic a l c o rre la tio n c o me fro m sa mpling o r interpreta tio n pro b lems, o r fro m bo th.7 ,8 The resulting decisio ns have implicatio ns
Cyto-histological corre lation of 219 patie nts
submitte d to surgical tre atme nt due to diagnosis
of ce rvical intrae pithe lial ne oplasia
Disciplines of Special Pathology and Gynecology and Obstetrics.
Faculdade de Medicina do Triângulo Mineiro, Uberaba, Brazil
ABSTRACT
Contex t: Cervic a l c yto lo g y c o ntinues to b e the mo st a ppro pria te metho d fo r investig a ting c ervic a l neo pla sia a nd its prec urso rs. G rea ter dia g no stic a c uity is o b ta ined b y c o mb ining c yto lo g y, c o lpo sc o py a nd g uided b io psy metho ds.
O bjective: To analyz e the diag no stic acuity o f cyto - and histo patho lo g ical exams and causes o f diag no stic erro r. Design: Retro spective study.
Setting: A public tertiary referral center.
Sa mple: Repo rts o n 2 1 9 patients submitted to co ne bio psy and/ o r hysterecto my due to diag no sis o f cervical
intraepithelial neo plasia (CIN ) in the perio d between January 1 9 8 2 and March 1 9 9 7 were reviewed, co mparing . M a in M ea surements: cyto lo g ical and histo lo g ical exams (g uided bio psy and surg ically-remo ved tissue). In cases o f disco rdance, the cyto - and histo lo g ical preparatio ns were reviewed to try to evaluate the causes o f erro rs.
Results: In 1 9 3 cases (8 8 .1 %) there was cyto -histo lo g ical ag reement but no ne in 2 6 (1 1 .9 %). Review o f the
disco rdant cases sho wed that in 2 (0 .9 %) there was invasio n o f the stro mata to a depth g reater than 3 mm, and in 7 (3 .2 %) micro invasio n, unsuspected via cyto lo g y; in 2 (0 .9 %) micro invasio n was suspected via cyto lo g y but no t co nfirmed by the final histo lo g ical exam; and in 1 5 (6 .8 %) there was disag reement abo ut the deg ree o f CIN .
Conclusion: The principal causes o f erro r in the cyto lo g ical exam were the lack o f reliable mo rpho lo g ical criteria fo r micro invasio n, absence o f sampling o f the squamo co lumnar junctio n, and scarcity o f neo plastic cells in the sample. As fo r the histo lo g ical exam, the erro rs were related to inadequate technical pro cessing and
underestimatio n o f fo cal lesio ns.
82
Sao Paulo Med J/Rev Paul Med 1999; 117(2):81-4.
fo r surg ic a l pro c edures, whic h a re no t risk-free a nd ma y a lter the wo ma n’s repro duc tive a nd se x life . This p la c e s a re sp o nsib ility o n the c y to p a tho lo g y la b o ra to ry to re q uire its pro fessio nals to have pro fo und co mpetence and pe rio dic re tra ining , a s we ll a s re q uiring the implementatio n o f a quality co ntro l system.7 The present study wa s perfo rmed with the o b jec tive o f eva lua ting the dia g no stic a c uity o f c yto - a nd histo pa tho lo g ic a l exa ms, a na lyz ing the c yto -histo lo g ic a l c o rre la tio n o f sa mple s o b ta ine d fro m pa tients sub mitted to surg ic a l trea tment fo r c ervic a l intra epithelia l neo pla sia (CIN ) a nd, in c a ses o f dia g no stic c o ne b io psy, investig a ting po ssib le mic ro inva sio n.
METHODS
All p a tie nts se e n b y the G yne c o lo g y a nd O b ste tric s o utp a tie nt se rvic e o f o ur Institutio n a re sub mitte d to trip le c o lle c tio n o f ma te ria l fo r c yto lo g ic a l e xa mina tio n. The ma te ria l is p ro c e sse d a c c o rd ing to Pa p a nic o la o u’ s te c hniq ue a nd re a d ing is p e rfo rme d b y d o c to rs tra ine d a s c y to lo g ists. Pa tie nts p re se nting ma c ro sc o p ic a lte ra tio ns up o n sp e c ula r o r c yto lo g ic a l e xa mina tio n a re se nt to the c o lp o sc o p y se rvic e . The b io p sy is g uid e d b y c o lp o sc o p ic e xa m c a rrie d o ut b y re sid e nts und e r te a c hing sup e rvisio n, a nd the ma te ria l is fixe d in 4 % fo rma ld e hyd e . The re is no sta nd a rd numb e r o f histo lo g ic a l c uts fo r e a c h b io p sy fra g me nt, va rying fro m 1 to 1 0 suc c e ssive c uts a s jud g e d ne c e ssa ry b y the
p a tho lo g ist fo r e a c h c a se . The c o ne b io p sy a nd / o r hyste re c to my sp e c ime ns w ith C IN a re ma rke d w ith se w ing thre a d a t the 1 2 o ’ c lo c k p o sitio n a nd fixe d in 4 % fo rma ld e hyd e ; the c o ne b io p sy o r c e rvix ma te ria l is c ut into p i e c e s o f a b o ut 1 mm i n th i c kn e s s , p e rp e n d i c ula r to th e s urfa c e o f th e e nd o c e rvic a l muc o sa a nd a ll the ma te ria l is p ro c e sse d fo r inc lusio n in p a ra ffin. O ne histo lo g ic a l c ut o f e a c h b lo c k is sta ine d w ith he ma to xylin-e o sin. Ad d itio na l c uts a re ma d e w he n ne c e ssa ry.
Repo rts fro m 2 1 9 patients submitted to co ne bio psy and/ o r hysterecto my fo r diag no sis o f CIN in the perio d between January 1 9 8 2 and March 1 9 9 7 were reviewed, fro m which six patients presented suspected micro invasio n via cyto lo g y. The re sults o f the c y to lo g ic a l a nd histo pa tho lo g ic a l e xa ms (g uide d b io psy a nd surg ic a lly-remo ved tissue) were c o mpa red. In c a se s with disc o rda nc e , the c yto lo g ic a l a nd histo lo g ical preparatio ns were reviewed by 3 cyto lo g ists and 2 patho lo g ists, to try to evaluate the causes o f erro rs.
RESULTS
Ta b le 1 sho w s the c y to -histo lo g ic a l co rrelatio n o f the 2 1 9 cases submitted to co ne bio psy and/ o r hysterecto my. There was cyto -histo lo g ic a l a g reement in 1 9 3 (8 8 .1 %): 1 8 9 cases were CIN III and in 4 cases the suspicio n o f micro invasio n via cyto lo g y was co nfirmed in surg ically-remo ved tissue. In 2 6 cases (1 1 .9 %)
Ta ble 1 - Cyto-histologica l correla tion of 2 1 9 pa tients submitted to surgica l trea tment for cervica l
intra epithelia l neopla sia
Histology CIN o f indeter- CIN I CIN II CIN III Micro invasive Invasive To tal
Cytology minate g rade carcino ma carcino ma
CIN o f indeterminate g rade 0 0 0 1 0 0 1
CIN I 0 0 0 1 0 0 1
CIN II 0 0 0 4 0 1 5
CIN III 2 0 7 1 8 9 7 1 2 0 6
Suspicio n o f micro invasio n 0 0 0 2 4 0 6 Invasive carcino ma 0 0 0 0 0 0 0
83
there was disag reement abo ut the presence o f invasio n o r the deg ree o f CIN : in 2 (0 .9 %) there was invasio n o f the stro mata to a depth g reater tha n 3 mm a nd in 7 (3 . 2 % ) mic ro inva sio n, unsuspected via cyto lo g y; in 2 (0 .9 %) there was the suspicio n o f micro invasio n via cyto lo g y, no t co nfirmed by the histo lo g ical exam; and in 1 5 (6 .8 %) there was disag reement abo ut the deg ree o f C IN , w hic h in 1 1 o f the se w a s o nly a difference o f o ne g rade (CIN II/ III).
DISCUSSION
The review o f the c yto lo g ic a l ma teria l in the 2 c a ses o f c lea r inva sio n o f the stro ma ta sho wed tha t in o ne o f them the dia g no sis wa s prejudic ed b y the sc a rc ity o f a typic a l c ells a nd the a b senc e o f tumo ra l dia thesis, ma king the erro r a ttrib uta b le to the sa mpling . In the o ther c a se , the sme a r w a s a tro p hic a nd d id no t c o nta in sa mp ling fro m the sq ua mo c o lumna r junc tio n (SC J). Ho w e ve r, the re w a s c e llula r differentia tio n a nd a pprec ia b le pleo mo rphism, w hic h sho uld ha ve le d to the susp ic io n o f inva sio n. W e b e lie ve tha t a tro phy c a use s a predispo sitio n to this erro r o f interpretatio n. This reinfo rc es the idea tha t in smea rs o f this type, e stro g e n the ra p y must b e p e rfo rme d b e fo re definitive dia g no sis.9 ,1 0
Co ncerning the 7 cases o f micro invasio n diag no sed via the histo patho lo g ical exam, in which the cyto lo g y underestimated the diag no sis, the review sho wed that in 4 the pro blem was the sampling and in 3 the interpretatio n. In these last 3 cases there was sig nificant pleo mo rphism and cellular differentiatio n, with “ fiber cells” , data whic h c o uld ha ve g iven rise to suspic io ns o f mic ro inva sio n in the initia l c y to lo g ic a l examinatio n. In the 4 cases where there was a failure o f sampling , no mo rpho lo g ical alteratio ns w e re o b se rve d w hic h c o uld sug g e st micro invasio n; in o nly 3 o f these was the SCJ represented in the sampling .
In the 2 cases where micro invasio n was suspected via cyto lo g y but no t co nfirmed by the histo p a tho lo g ic a l e xa m, the re vie w sho w e d alteratio ns which did no t differ sig nificantly fro m
the 4 cases with the suspicio n o f micro invasio n co nfirmed by histo patho lo g ical examinatio n o f the surg ic a lly-re mo ve d tissue . The se finding s co rro bo rate the data in the literature, indicating that there are no reliable mo rpho lo g ical criteria fo r cyto lo g ical diag no sis o f micro invasio n;9 ,1 1 fo r this reaso n, when diag no sing CIN III it may at mo st b e p o ssib le to a d d a n o b se rva tio n questio ning micro invasio n, a pro cedure ado pted in o ur service.
In the 1 5 c a se s w he re the re w a s disag reement reg arding the deg ree o f CIN , the review o f the preparatio ns sho wed that in 6 o f them there was a failure in the cyto lo g ical exam, ma inly c o ming fro m the p re d o mina nc e o f alteratio ns in intermediate cells and scarcity o f atypical deep cells and, less frequently, due to the inflammato ry pro cess and the absence o f SCJ sampling . In the remaining 9 cases the failure c a me fro m e rro rs in inte rp re ta tio n o f the histo patho lo g ical preparatio ns, due to their being fo cal lesio ns o r fro m technical pro blems, creating unc e rta inty re g a rd ing the d e g re e o f C IN . N evertheless, we must emphasiz e that in 1 1 o f these 1 5 cases o f CIN the disag reement was o nly by o ne g rade, which beco mes irrelevant if CIN II and CIN III are g ro uped as hig h g rade intra-epithelial lesio ns, as pro po sed in Bethesda’s classificatio n.1 2
The index o f cyto -histo lo g ical disag reement in o ur material (1 1 .9 %) was similar to that o f Jo nes et al,1 3 Jo ste et al8 and Tritz et al6 and much less than that o f Cavalcanti et al2 and Di Lo reto et al.3 It is po ssible that o ne o f the facto rs which co ntributed to the lo w disag reement in o ur material was the selectio n o f cases submitted to surg ical treatment fo llo wing diag no sis o f CIN (in the vast majo rity g rade III) o r due to suspicio n o f micro invasio n, instead o f using all the ro utine cyto lo g ical preparatio ns.
84
le a rning , a s a lre a d y me ntio ne d b y o the r autho rs.3 ,7 ,1 3 In o ur o pinio n, this review sho uld be do ne befo re instituting therapy so as to avo id unnecessary pro cedures.
REFERENCES
1. Bo letim da co o rdenação de pro gramas de co ntro le de câncer do Instituto Nacio nal do Câncer. INCA/Ministério da Saúde 1997;3:1.
2. Cavalcanti SMB, Zardo LG, Oliveira LHS. Human Papillo ma virus infectio n: co rrelatio n o f co lpo sco py, cyto lo gy, histo patho lo gy and in situ hybridizatio n. J Bras Pato l 1997;33:62-9.
3. Di Lo reto C, Maeda MYS, Utagawa ML et al. Garantia de qualidade em cito pato lo gia: aspecto s da co rrelação cito -histo pato ló gica. Rev Ass Med Brasil 1997;43:195-8.
4. Mikhail EL, Benner B, Kheir SM. The histo patho lo gy o f Papanico -lao u smears in po stmeno pausal wo men: histo patho lo gic findings in 280 po stmeno pausal wo men. Acta Cyto l 1994;38:814.
5. Ro hr LR. Quality assurance in gyneco lo gic cyto lo gy. What is practi-cal? Am J Clin Patho l 1990;94:754-8.
6. Tritz DM, Weeks JA, Spires SE et al. Etio lo gies fo r no n-co rrelating cervical cyto lo gies and bio psies. Am J Clin Patho l 1995;103:594-7.
7. Willco x F, So mer ML, Van Ro y J. Classificatio n o f cervical smears with disco rdance between the cyto lo gic and/o r histo lo gic ratings. Acta Cyto l 1987;31:883-6.
8. Jo ste NE, Crum CP, Cibas ES. Cyto lo gic/histo lo gic co rrelatio n fo r qual-ity co ntro l in cervico vaginal cyto lo gy. Am J Clin Patho l 1995;103:32-34.
9. Go m pe l C, Ko ss LG. Carcino m a m alpighiano invasivo do co lo uterino . In: Cito lo gias gineco ló gicas e suas bases anáto mo -clínicas. São Paulo : Edito ra Mano le Ltda 1997:107-13.
10. Kashimura M, Baba S, Nakamura S, Matsukuma K, Kamura T. Sho rt-term estro gen test fo r cyto diagno sis in po stmeno pausal wo men. Diagn Cyto patho l 1987;3:181-4.
RESUMO
Contex to: A cito lo g ia cervical co ntinua sendo o méto do mais adequado para o rastreamento da neo plasia cervical e seus precurso res. Melho r acuidade diag nó stica é o btida através da asso ciação do s méto do s cito ló g ico , co lpo scó pico e bió psia o rientada. O bjetivo: Analisar a acuidade diag nó stica do s exames cito e histo pato ló g ico e causas de erro diag nó stico . Tipo de estudo: Estudo retro spectivo . Loca l: Centro de referência terciário , público . Am ostra : Fo ram revisto s laudo s de 2 1 9 pacientes submetidas à co niz ação e/ o u histerecto mia po r diag nó stico de neo plasia intra-eptitelial cervical (N IC), no perío do de janeiro de 1 9 8 2 a março de 1 9 9 7 . Va riá veis Estuda da s: Exame cito ló g ico e histo ló g ico (bió psia o rientada e peça cirúrg ica). N o s caso s disco rdantes revisaram-se o s preparado s cito e histo ló g ico s na tentativa de avaliar as causas de erro . Resulta dos: Em 1 9 3 (8 8 ,1 %) caso s ho uve co nco rdância cito -histo ló g ica e em 2 6 (1 1 ,9 %) não . A revisão do s caso s disco rdantes mo stro u que em 2 (0 ,9 %) havia invasão do estro ma em pro fundidade maio r que 3 mm e em 7 (3 ,2 %) micro invasão , não suspeitadas à cito lo g ia; em 2 (0 ,9 %) ho uve suspeita de micro invasão à cito lo g ia, não co nfirmada pelo exame histo ló g ico final e, em 1 5 (6 ,8 %), disco rdância quanto ao g rau de N IC. Conclusã o: As principais causas de erro no exame cito ló g ico fo ram falta de critério s mo rfo ló g ico s seg uro s para micro invasão , ausência de amo strag em da junção escamo -co lunar e escassez de células neo plásicas na amo stra. Q uanto ao exame histo ló g ico , o s erro s fo ram relacio nado s ao pro cessamento técnico inadequado e subavaliação em lesõ es fo cais.
11. Hudso n EA, Gray W. Cervical intraepithelial neo plasia and squa-mo us carcino ma o f the cervix. In: Gray W. Diagno stic cyto patho lo gy. Edinburgh: Churchill Livingsto ne 1995:699-728.
12. Kurman RJ, So lo mo n D. The Bethesda System fo r repo rting cervical/ vaginal cyto lo gic diagno ses. Definitio ns, criteria and explanato ry no tes fo r termino lo gy and specimen adequacy. New Yo rk: Springer-Verlag 1994:81.
13. Jo nes BA, No vis DA. Cervical bio psy-cyto lo gy co rrelatio n. A Co llege o f American Patho lo gists Q-pro bes study o f 22439 co rrelatio ns in 348 labo rato ries. Arch Patho l Lab Med 1996;120:523-31.
ACKNOWLEDGEMENTS
W e thank Mr. David G . Elliff fo r his assistance in translating this manuscript.
Sao Paulo Med J/Rev Paul Med 1999; 117(2):81-4.
Sheila Jorge Ada d - Assistant Pro fesso r
M a ria Azniv Ha za ra bedia n Souza - Assistant Pro fesso r
Rena ta M a rga rida Etchebehere - Medical resident Joã o Ca rlos Sa lda nha - Do cto r
Vera Alice Aguia r Fa lco - Do cto r
Eddie Ferna ndo Câ ndido M urta - Assistant Pro fesso r
Sources of Funding: N o t declared Conflict of interest: N o t declared La st received: 1 5 O cto ber 1 9 9 8 Accepted: 1 8 N o vember 1 9 9 8 Address for correspondence: Sheila Jo rg e Adad
Pato lo g ia Especial Rua G etúlio G uaritá, 1 3 0
