Cvtobrush and endocervical curettarre in the d$gnosis of dysplasia and rnalignaky of the uterine cervix

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1 ACIU Ohstrt Gj~17ewl Scuizrl 1997: 76: Printed in Dmmurk - ull rights reserwd Cojniiqhf 0 4cto 0hrie.r Gi,ir~olScu,id1997 Acta Obstetricia et Gynecologica Scandinavica ISShi ORIGINAL ARTICLE Cvtobrush and endocervical curettarre in the d$gnosis of dysplasia and rnalignaky of the uterine cervix MOGENSEN, MARTIN BAK2, MARGIT DUEHOLM, LARS FROST3. NIELS OLE KNOBLAUCH, SUSANNE THEIL J0RGEN PREST AND HANS svanholm2 From the Departments of Gynecology and Obstetrics, and Pathology, Randers Regional Hospital, Randers, and the 3Depa~ment of Gynecology and Obstetrics, Silkeborg Regional Hospital, Silkeborg, Denmark Acta Obstet Gynecol Scand 1997; 76: Acta Obstet Gynecol Scand 1997 Buckground. The validity of cytobrush and endocervical curettage combined with colposcopically directed biopsies in the diagnosis of cervical dysplasia and malignancy has not been evaluated in randomized trials. We aimed to elucidate the diagnostic validity of the two methods. Methods. A prospective, randomized study of 180 consecutive patients. All patients were examined without anesthesia by colposcopically directed biopsies of the ectocervix and randomly assigned to either cytobrush or endocervical curettage. Patients with SCIN 1 were investigated with the alternative method three months later. Patients with ZCIN 2 had a cone biopsy. Results. One hundred and thirty-one patients were evaluable. The sensitivity of cytobrush and endocervical curettage combined with colposcopically directed biopsies of the ectocervix was 96% and 84% (p=o.os), respectively. The specificities of the two investigations were 95% and 88%, All cytobrush specimens were evaluable but because of a low recovery of endocervical material a diagnosis could not be made in 12% of the patients examined by endocervical curettage. Conclusion. The sensitivity of the combined use of cytobrush and biopsies of the ectocervix was equal to or higher than the sensitivity of endocervical curettage and ectocervical biopsies. The specificities of the two investigations were much alike. All cytobrush specimens were evaluable but a diagnosis could not be performed in 12% of the endocervical curettage specimens because of too little endocervical material. Furthermore, cytobrush is less inconvenient to the patient. Therefore, in the follow-up of patients with cervical dysplasia endocervical curettage may be replaced with cytobrush. Key M.OT~S; cervical dysplasia; cervical intraepithelial neoplasia (CIN); cytobrush; endocervical curettage Submitted 20 October, 1995 Accepted 15 July Colposcopically directed biopsies of the ectocervix combined with endocervical curettage is traditionally used for detection of cervical dysplasia and malignancy. However, this investigation is often in- Abbreviations: CB: cytobrush; CIN: cervical intraepithelial neoplasia; ECC: endocervical curettage; T-zone: transformation zone. conclusive due to an insufficient amount of endocervical tissue (1, 2, 3). Furthermore, endocervical curettage is painful and inconvenient to the patient. Cytobrush has become a widespread method in screening for cervical neoplasia. This led to the present investigation in which patients with an abnormal PAP-smear were examined with co1posc0pically directed biopsies of the ectocervix followed 0 Acta Obstrt Gjnecol Scand 76 (1997)

2 70 s. T. ~ogellsell rt Nl. by a random allocation to endocervical examination by either cytobrush or endocervical curettage. The purpose was to elucidate the use of the two investigations in diagnosing cervical dysplasia and malignancy. and to evaluate if CB can replace ECC in this examination of patients with an abn o r m ;i 1 PAP- smear. Material and methods The current prospective study included 180 nonpregnant patients successively referred to two departments of gynecology (February 1991 to January 1993). The patients had been examined by their general practitioner with a Papanicolaou smear and were referred to the gynecological departments for further examination because the priinary cytological diagnosis was suggestive of dysplasia or malignancy of the uterine cervix. Patients with macroscopic tumor upon examination or with a previous conization or cryocoagulation were excluded from the study. At the gynecological departments colposcopically directed ectocervical biopsies were taken in all patients followed by a random allocation to examination of the endocervical canal by one of two methods: cytobrush examination (CB) (CytobrushTM) or endocervical curettage (ECC) (3 mm sharp curette). The cytobrush samples were fixed on a glass slide with polyethylenglycol isopropylalcohol. The abradates. performed with ECC without anesthesia, were fixed in a specimen box with 9%) neutrally buffered formaldehyde. A histologic preparation with stepsections was made. After a Papanicolaou staining procedure the specimens were evaluated according to the normal clinical routine by one of five pathologists at the Department of Pathology in Randers according to the WHO nomenclature Patients with a negative (ICIN 1) diagnosis or an inadequate CB (no endocervical cell recovery= no columnar cell recovery) or ECC (a low tissue recovery) were examined by the alternative method (biopsies from the ectocervix followed by crossover: previous CB went to ECC and previous ECC went to CB) after two to nine months (median: three months). At the second examination patients with rcin 2 had a cone biopsy and cases with a negative or inadequate result were controlled ac- Table I A 8,s CB+biopsies t 19 neg. crossover ex. ~ 1 I--{ 3 neg. cone biopsies -1 fi 2 pos. cone biopsies 1 I--[ 26 excl. after 1. ex. 1 * of these seven patients there were two patients in the CB group and five in the ECC-group jiiri Oh\tc r (;lllcc(j/ S((lllf/ 76 (1997)

3 ~ Cytobrush versus emlocervical curettuge 7 1 cording to the normal routine of the gynecological departments. Patients with a positive (ICIN 2) diagnosis had a cone biopsy within 3 months. After randomization (Table I), 49 patients (18= 2116 CB and 31=5+26 ECC patients) were excluded: Three patients had a previous conization and one had been cryocoagulated before the start of the study. In one case a stenosis of the endocervical canal made examination impossible. Two patients were examined with a CB although they were randomized to ECC. Seven patients were not conizated in spite of a positive examination result. Thirteen patients with a negative first examination refused the second examination. Furthermore, 22 patients who had CIN 1-3 changes in the cervical punch biopsies only, were cryocoagulated. Thus, in the final calculations we ended up with 72 (50122) patients examined with cytobrush (CB-group) and 59 (301-29) evaluated by endocervical curettage (ECC-group). Fishers exact test was used for statistical analysis. Informed consent was achieved from all patients and the study was approved by the local ethical committee. Results We considered 13 1 patients who underwent examinations according to the study protocol (Table I). The median age in the CB-group was 35 years (range 21-66) and 33 years (range 17-65) in the ECC-group. The transformation zone in the CBand ECC-groups was visible in 31/72 (43%) and 26/59 (44%), respectively. In 32/72 (44%) and 29/59 (49%) of the CB- and ECC-groups the transformation zone was not fully visible. No information concerning the transformation zone was available in 9/72 (13%) and 4/59 (7%) of the CB- and ECCgroup, respectively. In the CB-group (n=72), 50 patients had LCIN 2 at the first examination and 22 had a negative (SIN 1) result. The former group of patients was conizated and the latter group was examined with cervical punch biopsies and ECC three months later. Nineteen patients still had 5CIN 1 changes. CIN 2 or more was diagnosed in three patients who were conizated. The ECC specimen was inadequate in four of the nineteen patients with negative punch biopsies because of a low endocervical cell recovery. In the ECC-group (n=59), 30 patients had a positive result at the first examination; 29 were conizated and one had a hysterectomy because of invasive cancer. CIN 1 or less was demonstrated in 29 cases of whom two were conizated because of anxiety. In three patients with positive and three patients with negative punch biopsies the ECC specimen was inadequate because of a low amount Table II Sensitivity, specificity and predictive values of cytobrush and endocervical curettage combined with colposcopically directed biopsies Cytobrush group Endocervical curettage group Sensitivity 96% (49151) 82% (27133) Specificity 95% (20/21) 88% (23126) Positive predictive value 98% (49150) 90% (27130) Negative predictive value 91% (20122) 79% (23129) The differences in sensitivities and specificities were statistically insignificant (p=0.08 and p=0.78. respectively). Table 111 Diagnoses Diagnoses of either CB group or ECC group at the first examination Normal cells Nonmalignant tissue reactions Non-gradable dysplasia CIN I CIN 2 GIN 3 Dysplasia of columnar epithelium Adenocarcinoma or planocellular carcinoma Inadequate All Cytobrush Endocervical curettage No. Pct. No. Pct At this point only seven of the randomized patients were excluded from the study because of previous conization or cryocoagulation, cervical stenosis or wrong examination, leaving 173 patients. The patients were examined with only one of the two examinations at this stage. of tissue. Three months later, investigation with cervical punch biopsies and cytobrush of 27 patients diagnosed an additional three patients with CIN 2 or more. The last mentioned three patients were conizated in common with one patient with a normal cytologic result, who for other reasons insisted on the surgical procedure. Sensitivity, specificity and predictive values of the results are given in Table 11. A true negative result was defined as 5CINl at the first and second examinations. The diagnoses (Table 111) in the CB- and ECCgroups varied substantially. Normal cells/tissue were diagnosed in 13% and 38Y0, respectively, whereas 63% in the CB-group and 26% in the ECC-group had dysplasia or invasive cancer. Eleven percent of the ECC-group had nongradeable dysplasia and this occurred in none of the CB patients. Furthermore, no diagnosis could be made in 12% of the ECC-group because of a low endocervical cell recovery whereas all CB specimens were adequate for diagnostic purposes. No difference between the CB- and ECC-groups 0 Actti Obsrrt G~netol Scotid ~

4 79 S. T. imogensen et al. concerning the number of positive and negative cone biopsies and the rate of positive (2CIN 2) cervical punch biopsies could be demonstrated. The percentages of positive (LCIN 2) cervical punch biopsies in the CB (76%)) and E:CC group (78?;,) were alike. In nineteen patients with a negative punch biopsy and a positive cone biopsy nine of eleven patients had a positive CB examination and two of eight patients had a positive ECC examination. All of the latter eight patients had a sufficient cell recovery by ECC. Discussion In the present prospective. randomized. investigation we demonstrated that the combined use of cytobrush aiid colposcopically directed biopsies of the ectoccrvix has a higher sensitivity (96%) than endocerc ical curettage combined with colposcopy and biopsies (82%)) in diagnosing cervical dysplasia and malignancy. Both examinations were performed without anesthesia. However, the difference is not statistically significant (p=0.08). The specificities (95%) and 88'%1, respectively) of the two investigations were much alike (p=0.78). Previous studies (1.2.3,) all concluded that cytobrush is more advantageous compared to endocervical curettage in the examination of endocervix for dysplasia. However. no study has reliably demonstrated that CB is statistically significantly better than ECC or that the methods ;are equally c good. The results described by Weitzman et al. (1) and Frost (2) are concordant with ours in respect of the fact that CB diagnoses dysplasias better than ECC. Furthermore, the authors claimed (1) that ECC does not diagnose positive results that are not demonstrated by CB and the pathological staging of the CB-examinations is more concordant with the cone biopsy staging (2). However, in both the cited studies ECC was performed immediately after the CB and this procedure has probably influenced the result. In our study, all patients were examined with cervical punch biopsies and the sensitivity of CB or ECC used alone to diagnose endocervical dysplasia could not be determined. In older women the T-zone is generally situated in the endocervical canal and biopsies obtained from ectocervix may contain normal epithelium whereas the cytobrush or endocervical curettage may detect atypical tissue. The median age in the CB-group was equal to the median age in the ECC-group, and the localization of the T-zone was equal in the two groups. The high and equal percentages of positive punch biopsies in the two groups tended to equalize the sensitivity of the two methods. It has been discussed (4) whether an ectocervix with dysplasia may contaminate the endocervical cell recovery of a CB examination. However, in the 11 patients with negative cervical punch biopsies and a positive cone biopsy, 82%) (9111) were detected by CB and only l8y0 (2/11) by ECC. All of these patients had a sufficient cell recovery by ECC. This indicates that CB detects more endocervical lesions compared with ECC. Furthermore, ECC has a high (120/0) rate of insufficient examinations which increases the number of reexaminations causing discomfort to the patient and increasing economical costs. All CB-specimens were evaluable. ECC requires a histological preparation, where you in spite of step-sections only visualize a minor percentage of the material. CB, on the other hand, only yields a small sample, but all of it is visualized in a single layer. Andersen et a]. (3) made a retrospective study of selected patients who had been evaluated by both CB and ECC before conization. The CB and ECC investigations were false negative in 8.4'%, and 32.00/0, respectively. In accordance with our result the ECC yielded insufficient material in 8% of cases whereas CB provided sufficienl material in all cases. The authors described false positive CB and ECC results in 12.5"/0 and 25.0'%,, respectively. Therefore, it was suggested that a sheath should be used for inserting the CB. Following this suggestion, Gosewehr et al. (4) investigated 39 patients with a sleeved aiid an unsleeved CB. The sleeved CB increased the sensitivity from 89% to 95% and decreased the number of false positive samples from 40%) to 10%. Therefore, the authors recommended the use of the sleeved cytobrush. However, the unsleeved cytobrush examination was performed immediately after the sleeved one and this probably influenced the result of the unsleeved investigation. In conclusion, the present prospective randomized study demonstrated that in combination with colposcopically directed ectocervical biopsies CB had a higher sensitivity than ECC in diagnosing cervical dysplasia and malignancy. However, the difference in sensitivity was insignificant (p = 0.08). In the CB-group all specimens were evaluable whereas 12% of the ECC-group was insufficient due to a low cell recovery. Furthermore. examination with CB is less inconvenient to the patient than ECC. Therefore, CB may replace ECC in the follow up examination of dysplasia found in PAP-smears. References I. Weitzman GA, Korhonen MO, Reeves KO et a]. Endocenical brush cytology. An alternative to endoccrvical curettage'? J Reprod Med 1988; 33: Frost L. Cytobrush in evaluation of cervical dysplasia. Is?.A<,ti/ Oh>tc~t G>.1lc'c(il Sci117tl 76 (1997)

5 Cytobrush versus endocervical curettage 13 cervical curettage necessary? Acta Obstet Gynecol Scand 1990; 69: Andersen W. Frierson H, Barber S et al. Sensitivity and specificity of endocervical curettage and the endocervical brush for the evaluation of the endocervical canal. Am J Obstet Gvnecol 1988: 159: Goseweh; JA, Julian TM, O Connel BJ. Improving the cytobrush as an aid in the evaluation of the abnormal papanicolaou test. Obstet Gynecol 1991; 78: Address for correspondence: Susanne Theil Mogensen, M.D. ~~~~~~~j 22 DK-8270 Hsjbjerg Denmark 0 Acta Ohster Gynecol Scand )