The aim of this study was to evaluate medical and economic justification of vaginal smears as a part of primary screening for cervical carcinoma and its precursors. Study included 245.048 participants whose VCE (vaginal, cervical, endocervical) smears were examined at Department of clinical cytology of University Hospital Center Osijek from 2003 till 2008. There were 12.639 (5.2%) abnormal findings, and they were divided into three groups: abnormal cells found only in vaginal smear (V), abnormal cells found in vaginal and in at least one other smear (V+) and abnormal cells not found in vaginal smear (C/E). These three groups were analysed in respect to cytological differential diagnosis and age of participants. It was estimated how many women could be additionally included in the screening, if vaginal smear would be included in the Pap test only after 50 years of age. In 6.9% of cytologically diagnosed lesions abnormal cells were found exclusively in vaginal smears (0.35% of all findings). As for squamous cell lesions, 91.2% were mild lesions (ASC and LSIL). Invasive squamous cell carcinoma was not diagnosed exclusively by vaginal smear in either woman under 50 years of age, while in women over 50 years of age it was diagnosed in 2.3% of cases. Exclusively by vaginal smear was diagnosed 3.9% of all AGC and 6.3% of adenocarcinoma, while in 85.0% of glandular epithelium lesions abnormal cells were not found in vaginal smears. Two thirds of adenocarcinoma diagnosed exclusively by vaginal smears were endometrial adenocarcinoma, but that is only 10.3% of all endometrial carcinoma diagnosed by Pap test. Obtained results show that taking of vaginal smears along with cervical and endocervical smears as a part of primary screening for cervical carcinoma and its precursors in women under 50 years of age is not justifiable, since vaginal smear only has a role in detection of endometrial carcinoma that are extremely rare in younger age groups. If vaginal smear would be taken only in women over 50 years of age, additional 37.7% of women under 50, or 25.1% women over 50 years of age could be included in the screening

Darko Čuržik

Ivana Prvulović

Marija Pajtler

Marija Perić

Valerija Miličić-Juhas

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Coll. Antropol. 34 (2010) 1: 69–74Original scientific paperPap Test – With or Without Vaginal Smear?Valerija Mili~i}-Juhas1,4, Marija Peri}1, Marija Pajtler1,4, Ivana Prvulovi}2 and Darko ^ur`ik3,41 Department of Clinical Cytology, University Hospital Center Osijek, Osijek, Croatia2 Department of Clinical Cytology, General Hospital »Dr. J. Ben~evi}«, Sl. Brod, Croatia3 Clinic of Obstetrics and Gynecology, University Hospital Center Osijek, Osijek, Croatia4 University of Osijek, School of Medicine, Osijek, CroatiaA B S T R A C TThe aim of this study was to evaluate medical and economic justification of vaginal smears as a part of primaryscreening for cervical carcinoma and its precursors. Study included 245.048 participants whose VCE (vaginal, cervical,endocervical) smears were examined at Department of clinical cytology of University Hospital Center Osijek from 2003till 2008. There were 12.639 (5.2%) abnormal findings, and they were divided into three groups: abnormal cells foundonly in vaginal smear (V), abnormal cells found in vaginal and in at least one other smear (V+) and abnormal cells notfound in vaginal smear (C/E). These three groups were analysed in respect to cytological differential diagnosis and ageof participants. It was estimated how many women could be additionally included in the screening, if vaginal smearwould be included in the Pap test only after 50 years of age. In 6.9% of cytologically diagnosed lesions abnormal cellswere found exclusively in vaginal smears (0.35% of all findings). As for squamous cell lesions, 91.2% were mild lesions(ASC and LSIL). Invasive squamous cell carcinoma was not diagnosed exclusively by vaginal smear in either womanunder 50 years of age, while in women over 50 years of age it was diagnosed in 2.3% of cases. Exclusively by vaginalsmear was diagnosed 3.9% of all AGC and 6.3% of adenocarcinoma, while in 85.0% of glandular epithelium lesions ab-normal cells were not found in vaginal smears. Two thirds of adenocarcinoma diagnosed exclusively by vaginal smearswere endometrial adenocarcinoma, but that is only 10.3% of all endometrial carcinoma diagnosed by Pap test. Obtainedresults show that taking of vaginal smears along with cervical and endocervical smears as a part of primary screeningfor cervical carcinoma and its precursors in women under 50 years of age is not justifiable, since vaginal smear only hasa role in detection of endometrial carcinoma that are extremely rare in younger age groups. If vaginal smear would betaken only in women over 50 years of age, additional 37.7% of women under 50, or 25.1% women over 50 years of agecould be included in the screening.Key words: cervical screening, Pap test, cervical/vaginal smearIntroductionIn vaginal smear Papanicolaou accidentally discov-ered cells of cervical carcinoma and established new diag-nostic method for detection of cervical carcinoma inearly, asymptomatic and curable stage1–3, and it is afterdiscovery and publication of this revolutionary under-standing that vaginal smear became accepted as ascreening method for detection of premalignant and ma-lignant changes in asymptomatic women. However, al-ready in the first years of application of this method, itwas determined that samples obtained directly from cer-vix using wooden spatula4 were more efficient and easierto analyse than vaginal smears5, and later endocervicalcanal sample was included in routine practice6. Besidethis historical significance, vaginal smear is valuable forhormone status evaluation and detection of infections,and in peri- and postmenopausal women for identifica-tion of carcinoma cells from endometrium, tubes, ovariesand cervix, incidence of which is significantly increasingafter 50 years of age.Experience shows that vaginal smear analysis is time--consuming because this is a part of smear with the mostprominent degenerative changes of the cells and with thehighest number of inflammatory cells and microorgan-isms. In contrast, it contains relatively small number ofcervical cells, among which is hard to find early preinva-69Received for publication July 11, 2009sive lesions. Since more than 90% of neoplastic changesof cervix develop in transformation zone7, sample takendirectly from cervix contains numerous abnormal cells,including those located deeper that do not desquamatespontaneously. Current practice is that LBC Pap testcontains only cervical and endocervical sample taken inone act or separately with two different instruments.Conventional Pap test has been conducted in Croatiafrom the middle of the last century, and it includes sam-ples taken from posterior fornix of vagina (vaginal), fromectocervix (cervical) and from endocervical canal (endo-cervical smear). However, large number of Pap tests withinsufficient number of educated cytotechnologists justi-fies idea of possible exclusion of vaginal sample.The aim of this study was to evaluate medical and eco-nomic justifiability of vaginal smear as a part of primaryscreening.Materials and MethodsThe study included 245.048 participants whose VCE(vaginal, cervical and endocervical) smears were exam-ined as a part of primary screening at Department forclinical cytology of University Hospital Center Osijekfrom 2003 till 2008. Vaginal and cervical samples weretaken using wooden spatula4, while endocervical sampleswere taken using cotton swab or a brush, and were allsmeared on to one slide. Smears were examined by fourcytotechnologists, which daily examine on average 45VCE smears smeared onto one slide. Results were classi-fied in concordance with Croatian modification of Be-thesda 2001 classification8,9, but in data processing diag-noses dysplasia media, dysplasia gravis, carcinoma insitu and carcinoma in situ with possible initial invasionwere observed as one – HSIL. Atypical squamous cell(ASC) diagnosis comprised three diagnoses: atypical squa-mous cells – undefined significance, atypical squamouscells – heavy squamous intraepithelial lesion (HSIL) cannot be excluded and atypical squamous cells – invasive le-sion can not be excluded. In data processing of glandularepithelium lesions, atypical glandular cell (AGC) groupwas observed as a whole, although Croatian modifica-tion9 of Bethesda classification recognises three catego-ries in this group – cases of probable reactive, intra-epithelial or invasive lesions. AGC group and adeno-carcinoma were divided according to origin of colum- narcells into endocervical, endometrial, extrauterine andundefined origin.Abnormal findings were divided into three groups:ones where abnormal cells were found only in vaginalsmear (V), ones where abnormal cells were found in vagi-nal and in at least one other smear (V+) and ones whereabnormal cells were not found in vaginal smear (C/E).These three groups were analysed in respect to cytologi-cal differential diagnosis and age of participants.It was determined how many women could existingcytological team additionally include in the screening, ifvaginal smear should be included in Pap test only after50 years of age. Significance of difference was tested at95% level10.ResultsOut of 245,048 examined smears, 12,639 (5.2%) wereabnormal. Exclusively in vaginal smear, abnormal cellswere found in 870 smears, which make 6.9% of all abnor-mal results (i.e. 0.35% of all results). In combination ofvaginal smear and one other smear, abnormal cells werefound in 3,170 (25.1%) smears, and in 8,599 samples(68%) abnormal cells were not found in vaginal smear(Table 1).Exclusively by vaginal smear it was discovered 7.2%of squamous lesions (14.2% of ASC, 7.4% of LSIL, 2.7% ofHSIL and 1.7% of invasive squamous carcinoma), whilein 66.2% of lesions abnormal cells were not found in vagi-nal smear (65.4% of ASC, 70.3% of LSIL, 57.9% of HSILand 7.8% of invasive squamous carcinoma). In 26.6% oflesions abnormal cells were found both in vaginal andcervical/endocervical smears (Table 2).Exclusively by vaginal smear it was discovered 4.2%of glandular lesions (3.9% of AGC and 6.3% of adenocar-cinoma), while in 85.0% of lesions abnormal cells werenot found in vaginal smear (87.6% of AGC, 56.3% of AISV. Mili~i}-Juhas et al.: Pap Test – With or Without Vaginal Smear?, Coll. Antropol. 34 (2010) 1: 69–7470TABLE 1EPITHELIAL CELL ABNORMALITY PER SMEAR (N=12.639)SmearsTotalV V+ C/EAbnormalcellsSquamous cell lesions819 3014 7526 113597.2% 26.5% 66.3% 100%Glandular cell lesions51 132 1036 12194.2% 10.8% 85% 100%Squamous + Glandular cell lesions0 24 37 610% 39.3% 60.7% 100%Total870 3170 8599 126396.9% 25.1% 68% 100%V – vaginal smear, V+ – vaginal and at least one other smear, C/E – cervical and/or endocervical smearV. Mili~i}-Juhas et al.: Pap Test – With or Without Vaginal Smear?, Coll. Antropol. 34 (2010) 1: 69–7471TABLE 2ABNORMAL SQUAMOUS CELL FINDINGS PER SMEAR (N=11.420)SmearsTotalV V+ C/EAbnormalsquamouscellsASC213 307 981 150114.2% 20.5% 65.4% 100%26% 10.1% 13% 13.1%LSIL535 1622 5097 72547.4% 22.4% 70.3% 100%65.2% 53.4% 67.4% 63.5%HSIL70 1003 1477 25502.7% 39.3% 57.9% 100%8.5% 33% 19.5% 22.3%Squamous cell carcinoma2 104 9 1151.7% 90.4% 7.8% 100%0.2% 3.4% 0.1% 1%Total820 3036 7564 114207.2% 26.6% 66.2% 100%100% 100% 100% 100%V – vaginal smear, V+ – vaginal and at least one other smear, C/E – cervical and/or endocervical smear, ASC – abnormal squamouscells, LSIL – low risk squamous intraepithelial lesion, HSIL – high risk squamous intraepithelial lesionTABLE 3ABNORMAL COLUMNAR CELL FINDINGS PER SMEAR (N=1.280)SmearsTotalV V+ C/EAGCEndocervical28 57 984 10692.6% 5.3% 92% 100%Endometrial18 39 59 11615.5% 33.6% 50.9% 100%Undefined origin1 5 8 147.1% 35.7% 57.1% 100%Extrauterine0 1 0 10% 100% 0% 100%Total47 102 1051 12003.9% 8.5% 87.6% 100%AIS Endocervical0 7 9 160% 43.8% 56.3% 100%AdenocarcinomaEndocervical0 13 3 160% 81.3% 18.8% 100%Endometrial3 21 5 2910.3% 72.4% 17.2% 100%Undefined origin1 12 4 175.9% 70.6% 23.5% 100%Extrauterine0 1 1 20% 50% 50% 100%Total4 47 13 646.3% 73.4% 20.3% 100%V – vaginal smear, V+ – vaginal and at least one other smear, C/E – cervical and/or endocervical smearand 20.3% of adenocarcinoma). In 10.8% of lesions ab-normal cells were found both in vaginal and cervical/en-docervical smears. Out of 6.3% of adenocarcinoma diag-nosed exclusively by vaginal smear, 75% was endometrialadenocarcinoma. However, out of all endometrial adeno-carcinoma, exclusively by vaginal smear was diagnosedonly 10.3% (Tables 1 and 3).Medium age of participants with squamous cell carci-noma was 59,6 years, and of ones with adenocarcinoma itwas 66.6 years. There was neither one participant under50 years of age with invasive squamous carcinoma oradenocarcinoma that were diagnosed exclusively by vagi-nal smear, while squamous cell carcinoma was diagnosedexclusively by vaginal smear in 2.3%, and adenocar-cinoma in 7.3% of participants over 50 years of age (Ta-ble 4).Dividing participants in two groups, regardless ofgrade and type of lesion (squamous or glandular), exclu-sively by vaginal smear was diagnosed 6.6% of lesions inparticipants under 50 years of age, and 8.9% of lesions inparticipants over 50 years of age (Table 5). There wasstatistically significant difference in finding of abnormalcells by vaginal smear among participants under andover 50 years of age (z=–3.629, p=1.42*10–4).Discussion and ConclusionValue of vaginal sample as a part of conventional Pap testis best illustrated by the type of lesion and the age in whichabnormal cells are found exclusively in vaginal smear.In 6.9% of cytologically diagnosed lesions abnormalcells were found exclusively in vaginal smear. As forsquamous cell lesions, 91.2% were mild lesions (ASC andLSIL) (Table 2), which in respect to their biological be-haviour have high probability of spontaneous regressionand/or possibility of later detection. As for invasive squa-mous cell carcinoma, abnormal cells were found exclu-sively in vaginal smear in 1.7% of women, but they wereall over 50 years of age. As for cytological diagnosis HSIL,abnormal cells were found exclusively in vaginal smearin 2.7% of women, and those lesions would not have beendiscovered if vaginal smear had been excluded. However,possibility of incorrect sampling of vaginal smear, whereV. Mili~i}-Juhas et al.: Pap Test – With or Without Vaginal Smear?, Coll. Antropol. 34 (2010) 1: 69–7472TABLE 4ABNORMAL CELL FINDINGS OF THE GRAVEST LESIONS PER SMEAR WITH RESPECT TO AGE OF PARTICIPANTS (N=179)SmearsTotalV V+ C/ESquamous cellcarcinomaUnder 50 years of age0 22 6 280% 78.6% 21.4% 100%Over 50 years of age2 82 3 872.3% 94.3% 3.4% 100%Total2 104 9 1151.7% 90.4% 7.8% 100%AdenocarcinomaUnder 50 years of age0 3 6 90% 33.3% 6.67% 100%Over 50 years of age4 39 12 557.3% 70.9% 21.8% 100%Total4 42 18 646.3% 65.6% 28.1% 100%V – vaginal smear, V+ – vaginal and at least one other smear, C/E – cervical and/or endocervical smearTABLE 5ABNORMAL CELL FINDINGS WITH RESPECT TO AGE OF PARTICIPANTS (N=12.639)SmearsTotalV V+ C/EAgeUnder 50 years of age711 2673 7468 108526.6% 24.6% 68.8% 100%Over 50 years of age159 497 1131 17878.9% 27.8% 63.3% 100%Total870 3170 8599 126396.9% 25.1% 68% 100%V – vaginal smear, V+ – vaginal and at least one other smear, C/E – cervical and/or endocervical smearin one act a smear of posterior fornix and exocervix hasbeen done, can not be excluded.Exclusively by vaginal smear has been detected over-all 4.2% of glandular lesions (3.9% of AGC and 6.3% ofadenocarcinoma), while in 85.0% of lesions abnormalcells were not found in vaginal smear. Since neither oneadenocarcinoma of endocervical origin nor adenocarcino-ma in situ (AIS) was detected in vaginal smear, vaginalsmear has a role in detecting glandular epithelium le-sions of endometrial origin. Out of all endometrial carci-noma that were detected by Pap test, abnormal cellswere found exclusively in vaginal smear in 10.3% ofthem, and since average age of participants with endo-metrial carcinoma in our study was almost 67 (none ofthe participants was under 50 years of age), if we shouldnot had taken vaginal smear to women under 50 years ofage, we would not have missed neither one endometrialcarcinoma.Richart and Vaillant already determined that for wo-men in reproductive age that have extremely low preva-lence of endometrial carcinoma and high prevalence ofcervical neoplasia samples should be taken by techniquesthat provide direct samples from cervix11.Similar results obtained Pajtler et al.12,13, who alsopointed out clinical and economic unjustifiability of tak-ing vaginal smears to women under 50 years of age.From all said can be concluded that taking vaginalsmear along with cervical and endocervical smears as apart of primary screening for cervical carcinoma and itsprecursors to women under 50 years of age is not justifi-able, since vaginal smear only has a role in detection ofendometrial carcinoma that are extremely rare in youn-ger age groups.In respect to age structure, 75.4% of examined popu-lation was under, and 24.6% was over 50 years of age. Ifvaginal smear should be taken only to women over 50years of age, then to 185,109 women only CE smearwould be taken, and CVE smear would be taken to60,299 women. At the same time and with the same staffadditional 92,554 CE smears (37.7%) to women under 50years of age, or 61,703 VCE smears (25.1%) to womenover 50 years of age could be examined without signifi-cant screening quality reduction. Our cytotechnologistsexamine 45 smears daily during 7.5 working hours. Con-sidering the age structure of our patients, they woulddaily spend 112 minutes less for the same amount ofsamples. Average time of waiting for Pap test results inCroatia is 25 days, and the longest is 90 days. Therefore,exclusion of vaginal smear in patients under 50 years ofage would reduce average time of waiting for Pap test re-sults to 18.8 days, and the longest time of waiting to 67.7days.R E F E R E N C E S1. PAPANICOLAOU GN, New Cancer Diagnosis (Race BettermentFoundation, Battle Creek, Michigan 1928). — 2. PAPANICOLAOU GN,TRAUT HF, Am J Opstet Gynecol, 42 (1941) 193. — 3. PAPANICOLAOUGN, TRAUT HF, Comonwealth Found (1943). — 4. AYRE JE, Am JOpstet Gynecol, 51 (1946) 743. — 5. SCHEFFEY LS, RAKOFF EA,HOFFMAN J, American Journal of Obstetrics & Gynecology, 55 (1948)453. — 6. NIEBURGS, H E, Obstet. Gynec, 72 (1956) 511. — 7. JÄRVI K,Cytopatology, 8 (1997) 282. — 8. SOLOMON D, DAVEY D, KURMAN R,MORIARTY A, JAMA, 287 (2002) 2114. — 9. OVANIN-RAKI] A, PAJT-LER M, STANKOVI] T, AUDY-JURKOVI] S, LJUBOJEVI] N, GRUBI-[I] G, KUVA^I] I, Gynaecol Perinatol, 12 (2003) 148. — 10. BARNETRN, Clinical laboratory statistics, 2nd ed (Little-Brown, Boston, 1979). —11. RICHART RM, VALLIANT HV, Cancer, 18 (1965) 1474. — 12. PAJT-LER M, MILOJKOVI] M, Pap test – with or without vaginal smear? In:Proceedings (3rd Croatian Congress of Clinical Cytology, Opatija, 2005).— 13. PAJTLER M, Diagnostic value of cytology in comparison with an-other complementary methods for detection and diagnosis of premalig-nant and early malignant lesions of the uterine cervix. PhD Thesis. InCroat (University of Zagreb, Zagreb, 2001). — 14. MILI^I]-JUHAS V,LON^AR B, MAHOVLI] V, KARDUM SKELIN I, PAJTLER M, Currentorganisation of clinical cytology in Croatia. In: Proceedings (4th Croatiancongress of clinical cytology with international participation, Split, 2009).V. Mili~i}-JuhasDepartment of Clinical Cytology, University Hospital Center Osijek, J. Huttlera 4, 31000 Osijek, Croatiae-mail: valerija.mj@gmail.comPAPA TEST – SA ILI BEZ VAGINALNOG RAZMAZA?S A @ E T A KCilj ove studije bio je procijeniti medicinsku i ekonomsku opravdanost uzimanja vaginalnog razmaza u sklopu pri-marnog probira cervikalnog karcinoma i njegovih prekursora. U studiju je uklju~eno 245.408 ispitanica ~iji su VCE(vaginalni, cervikalni, endocervikalni) razmazi bili pregledani na Odjelu za klini~ku citologiju Klini~kog bolni~kog cen-tra Osijek od 2003. do 2008. godine. Abnormalnih je nalaza bilo 12.639 (5,2%), a podijeljeni su u tri skupine: abnor-malne stanice na|ene samo u vaginalnom razmazu (V), abnormalne stanice na|ene u vaginalnom i bar u jo{ jednomrazmazu (V+) i abnormalne stanice nisu na|ene u vaginalnom razmazu (C/E). Te su tri skupine analizirane u odnosuV. Mili~i}-Juhas et al.: Pap Test – With or Without Vaginal Smear?, Coll. Antropol. 34 (2010) 1: 69–7473na citolo{ku diferencijalnu dijagnozu i `ivotnu dob ispitanica. Procijenjeno je koliko bi se `ena moglo dodatno obuhva-titi probirom ukoliko bi se vaginalni razmaz uklju~io u PAPA test tek nakon pedesete godine `ivota. U 6,9% citolo{kidijagnosticiranih lezija abnormalne su stanice na|ene isklju~ivo u vaginalnim razmazima (0,35% svih nalaza). Kodlezija plo~astog epitela u 91,2% slu~ajeva radilo se o lak{im lezijama (ASC i LSIL). Invazivni plo~asti karcinom isklju-~ivo vaginalnim razmazom nije dijagnosticiran niti u jedne `ene mla|e od 50 godina, dok je u `ena starijih od 50 godinadijagnosticiran u 2,3% slu~ajeva. Isklju~ivo vaginalnim razmazom otkriveno je 3,9% svih AGC i 6,3% adenokarcinoma,dok kod 85,0% lezija `ljezdanog epitela abnormalne stanice nisu na|ene u vaginalnim razmazima. Dvije tre}ine adeno-karcinoma dijagnosticiranih isklju~ivo vaginalnim razmazom ~ini adenokarcinom endometrija, no to je samo 10,3%svih PAPA testom dijagnosticiranih endometralnih karcinoma. Iz navedenih se rezultata mo`e zaklju~iti da `enamamla|im od pedeset godina nema opravdanja uz cervikalni i endocervikalni uzeti i vaginalni razmaz u sklopu primarnogprobira cervikalnog karcinoma i njegovih prekursora, budu}i da vaginalni razmaz ima ulogu jedino u detekciji endo-metralnih karcinoma koji su u mla|im dobnim skupinama izuzetno rijetki. Ukoliko bi se vaginalni razmaz uzimaosamo `enama starijim od 50 godina moglo bi se dodatno pregledati jo{ 37,7% `ena mla|ih od 50 godina, ili 25,1% `enastarijih od 50 godina.V. Mili~i}-Juhas et al.: Pap Test – With or Without Vaginal Smear?, Coll. Antropol. 34 (2010) 1: 69–7474

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