Sydney Gynaecology Oncology Group, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

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1 bs_bs_banner doi: /jog J. Obstet. Gynaecol. Res. Vol. 41, No. 3: , March 2015 Abnormal cervicovaginal cytology, unsatisfactory colposcopy and the use of vaginal estrogen cream: An observational study of clinical outcomes for women in low estrogen states Anthony Richards and Chris Dalrymple Sydney Gynaecology Oncology Group, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia Abstract Aim: To determine the effectiveness of vaginal estrogen cream to improve the rate of satisfactory colposcopy and subsequent smear result in patients in a hypoestrogenic state and an abnormal Papanicolaou smear. To delineate between abnormal smears secondary to atrophy and inflammation from preneoplastic change and suggest an effective treatment strategy to deal with this challenging situation. Methods: Patients with abnormal cervicovaginal smears who were in a low estrogen state (postmenopausal or amenorrheic postnatal) undergoing colposcopy were identified. All patients had an unsatisfactory colposcopy and were treated with vaginal estrogen cream twice per week for 6 weeks and underwent repeat colposcopy, smear and targeted biopsy where required. Results: Fifty-four patients had an abnormal smear and were clinically in a low estrogen state, with four having previously had a hysterectomy. After 6 weeks of vaginal estrogen therapy, 32 out of 50 patients colposcopic examinations were satisfactory. Also, 40 out of 54 patients smears returned to normal after treatment. Of the 14 patients with persistent smear abnormalities, only three were diagnosed with true high-grade pre-invasive disease. Conclusion: The use of vaginal estrogen cream for patients with smear abnormalities and a low estrogen status improves the satisfactory colposcopy rate and improves the accuracy of the prediction of true high-grade pre-invasive disease. This treatment may then reduce the number of patients that require definitive treatment for their screen-detected abnormalities in this patient population. Key words: atrophy, Papanicolaou test, unsatisfactory colposcopy, vaginal estrogen therapy. Introduction The interpretation of cellular atypia in postmenopausal Papanicolaou tests is challenging. Several studies have indicated a poor positive predictive value of an atypical squamous cell high-grade squamous intraepithelial lesion (ASC-H) Papanicolaou test diagnosis for subsequent high-grade dysplasia in the postmenopausal age group. 1 5 It appears conceivable that the hypoestrogenic state characteristically seen after the menopause produces a reactive cytological atypia, which is misinterpreted as either atypical squamous cell of undetermined significance (ASC-US) or ASC-H. This may be caused by coexistent inflammation, Received: March Accepted: July Reprint request to: Dr Anthony Richards, Sydney Gynaecology Oncology Group, Sydney Cancer Centre, Level 6 Gloucester House, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia. anthony.m.richards@gmail.com The Authors

2 Hypoestrogenic state cytological atypia atrophy or infection. Accordingly, the altered hormone levels seen in pregnant, post-partum and contraceptive-use patients theoretically create a similar diagnostic predicament. 6 Moreover, several studies have reported the effect of age and hormonal status on the position of the new squamocolumnar junction (SCJ). 7 9 It is much more likely to be inside the endocervical canal in the postmenopausal group, resulting in a higher incidence of unsatisfactory colposcopy and potentially necessitating operative management for abnormal cervical cytology. The 2001 US guidelines for management of screendetected abnormalities of the cervix makes a statement that a course of intravaginal estrogen followed by a repeat cervical cytology test approximately a week after completing the regimen is acceptable for women with LSIL [low-grade squamous intraepithelial lesion] who have clinical or cytological evidence of atrophy, with a referral for colposcopy if a result of ASC-US or greater is obtained and there are no contraindications to using intravaginal estrogen. 10 The current 2012 American Society for Colposcopy and Cervical Pathology guidelines 11 and the equivalent Australian ones 12 do not have any similar reference. In view of this observation, the present study was designed to assess the effect of the use of vaginal estrogen cream on the outcome of colposcopic examination and subsequent management in patients with a known low estrogen state and abnormal smear cytology. Methods Study population and data collection This prospective study was in those who had undergone colposcopy in the senior author s colposcopy (C. D.) private rooms and public outpatient practice at Royal Prince Alfred Hospital, Camperdown, Australia, between January 2004 and December Institutional ethics committee approval for this study was granted. Eligible patients were those referred with abnormal cervicovaginal cytology and were clinically in a low estrogen state (i.e. postmenopausal >12 months or were postnatal and remained amenorrheic). These patients required full and complete information on cervical cytology and colposcopic findings, with human papillomavirus (HPV) test results and colposcopic biopsy results when performed. Patients were excluded if they were already using estrogencontaining compounds, had contraindications for vaginal estrogen cream or colposcopic evidence of high-grade pre-invasive disease/cervical carcinoma on colposcopy. All patients seen for colposcopy underwent examination by or directly supervised by the senior author. Assessment and intervention During the colposcopic examination and after the application of 5% acetic acid, there was an assessment as to whether the examination was satisfactory. This required that the entire SCJ be fully visualized, and any visible lesion be seen in its entirety. 4 Following the initial colposcopy, identified patients were prescribed vaginal estrogen cream (Ovestin 1 mg/g; Merck Sharp & Dohme, Sydney, NSW, Australia) 0.5 mg twice per week for 6 weeks. The colposcopy and cervicovaginal cytology (including ectocervical and endocervical brush and liquid-based cytology) were repeated, with HPV testing performed in some cases. A biopsy was taken for any areas with colposcopic features suspicious for pre-invasive disease. Appropriate management was conducted based on the results of subsequent biopsies, based on the Australian National Health and Medical Research Council (NHMRC) guidelines. 5 Follow-up All included study subjects underwent at least 2 years of follow-up after entry into the study to ensure no subject developed high-grade disease requiring treatment. Those that had high-grade disease diagnosed during the study received appropriate treatment and follow-up as per the local guidelines. 12 Results For the 7 years between January 2004 and December 2010, 55 eligible patients were identified and managed as per the study algorithm. One patient from September 2010 defaulted and was excluded due to treatment non-compliance. The remaining 54 consisted of nine amenorrheic postnatal patients and 45 postmenopausal patients (four of which had a previous total hysterectomy). The presenting cytology at the initial consultation of patients entered into the study is presented in Table 1. On initial colposcopy, only 16 patients had a satisfactory colposcopy (32% of the patient population), but following treatment with vaginal estrogen cream, 32 patients had a satisfactory colposcopy (64% of the patient population). The information regarding the initial smear result and satisfactory colposcopy is 2014 The Authors 441

3 A. Richards and C. Dalrymple Table 1 Presenting cytological smear result of enrolled patients Postmenopausal Postnatal Total High grade Possible high grade Low grade Possible low grade Total Patients with a vaginal vault smear due to previous total hysterectomy (n = 4). Table 2 Unsatisfactory colposcopy before and after vaginal estrogen use Papanicolaou smear Before estrogen After estrogen High grade 3/3 patients 3/3 patients Possible high grade 6/20 patients 12/20 patients Low grade 6/22 patients 12/22 patients Possible low grade 1/5 patients 5/5 patients Total 16/50 patients 32/50 patients Table 3 Outcomes for patients comparing presenting cytological smear and subsequent smear following vaginal estrogen cream use High grade Possible high grade Low grade Possible low grade Normal High grade Possible high grade Low grade Possible low grade Total Patients with a vaginal vault smear due to previous total hysterectomy (n = 4). Total shown in Table 2. With regard to repeat cytology after 6 weeks of estrogen therapy, 40 out of 54 patients cervicovaginal cytology had returned to normal. Furthermore, of those patients that had persistent Papanicolaou smear abnormalities, there were only three that were high grade or possible high grade. Of interest here, however, was the one patient whose initial smear showed possible low grade and returned as high grade after vaginal estrogen therapy. The data for this is presented in Table 3. When the initial cervicovaginal smear was compared to the final colposcopic diagnosis, only three patients had biopsy-proven evidence of high-grade disease that required treatment (5.6%) with a further 20 patients having evidence of low-grade disease (37.0%). The summary of this data is presented in Table 4. Within the 2-year follow-up interval, only four patients had persistent low-grade changes on colposcopy, with the resolution in all other patients with ongoing use of vaginal estrogen cream. Moreover, none of the patients whose subsequent smear and colposcopy after vaginal estrogen therapy was considered normal developed new disease within the 2-year follow-up period. Human papillomavirus testing was performed on the Papanicolaou smears of 39 out of the 54 patients. Of those whose subsequent smear and colposcopy was considered normal, seven out of 30 (23.3%) were HPV positive, whereas six out of nine (66.7%) patients with an ongoing abnormal Papanicolaou smear and colposcopy were HPV positive. Moreover, of those who had a normal colposcopy and were HPV positive, none of these patients had any further abnormal smear results within the 2-year follow-up period. Discussion The prolonged course of vaginal estrogen allows adequate restoration of local hormone levels and time for any inflammatory effects on the cervical or vaginal mucosa to settle. Once this is achieved, a more satisfactory cytological assessment and more accurate The Authors

4 Hypoestrogenic state cytological atypia Table 4 Comparison of initial smear result and final colposcopic diagnosis High-grade diagnosis Low-grade diagnosis Normal High grade Possible high grade Low grade Possible low grade Total Total VAIN3 on biopsy. Vault low-grade squamous intraepithelial lesion (LGSIL) smear. Vault LGSIL smear (n = 4). colposcopic diagnosis for a directed biopsy (if required) can occur. Previous studies observed an association between oral contraceptive use and the depth of the SCJ. 13,14 They have shown that treatment with relatively high doses of estrogen improved visualization of the transformation zone in patients whose initial colposcopic assessment was unsatisfactory. 13 A small randomized controlled trial 14 of 36 women with dyskaryotic cervical smears and unsatisfactory colposcopy showed that full colposcopic inspection of the transformation zone was possible in a significantly greater proportion of patients treated with oral estrogen than placebo. In these studies, however, there was no comment on the prior estrogen status of the patients. Furthermore, the endpoint of this study was satisfactory colposcopy and not clinical outcome. In the present study, there was a significant improvement in the satisfactory colposcopy rate from 32% to 64% in order to make an accurate colposcopic assessment for the detection underlying pre-invasive cervical pathology. This result is comparable to that shown by other investigators using misoprostol (a prostaglandin E1 analog), with rates of 20% 15 and 78.9%, respectively, 16 with less medication-related side-effect reported. In a large Italian study, postmenopausal women with abnormal Papanicolaou smears (ASC-US or LSIL) and a negative colposcopy (both satisfactory and unsatisfactory) treated with vaginal estrogen replacement therapy for 3 months resulted in only 11.6% (25/215 patients) requiring treatment for high-grade disease. 17 Moreover, 77.7% (167/215) of the patients Papanicolaou smears returned to normal. Our data suggests similar findings with only three patients (5.6%, two postmenopausal and one postnatal) requiring intervention for high-grade disease. Twenty patients had evidence of low-grade disease on colposcopy and/or repeat cervicovaginal smear (37.0%) and 57.4% of patients having a normal colposcopy and smear after vaginal estrogen therapy. These results would indicate that there was a significant level of false-positive smear results, likely secondary to atrophy and inflammation from those patients with a low estrogen state. Those women whose subsequent colposcopy and cervicovaginal cytology returned to normal returned to their general practitioner to have another cervical smear in 12 months time. Moreover, the majority (16/20) of patients with a lowgrade smear and/or colposcopy also reverted to normal with ongoing use of vaginal estrogen cream. To date, there has not been any subsequent abnormal cytology for these patients. Furthermore, only three patients that had a persistently positive smear after vaginal estrogen cream showed evidence of high-grade disease on biopsy. These patients received appropriate management as per Australian NHMRC guidelines. 12 The unique difference between the Italian study and our data is the duration of the use of vaginal estrogen cream. The Italian study protocol required use for 3 months continuously, whereas our protocol required use for 6 weeks. Despite our sample size being smaller and assuming a similar rate of patient compliance to the protocol, our results are comparable. Furthermore, our study included nine patients who were hypoestrogenic due to being amenorrheic after giving birth. Only four of nine postnatal patients had persistent colposcopic abnormalities after estrogen therapy, with only one patient having high-grade disease on biopsy (CIN3) requiring an excision procedure. With regard to HPV testing in our study, the results are interesting. When the patient s smear reverted to negative, regardless of the HPV result, there were no patients who had evidence of high-grade disease. Interestingly, among this group, seven patients had a positive HPV test. None of these patients developed high-grade disease within 2-year follow-up. With respect to those with positive cytology after vaginal estrogen therapy, only three of nine tested positive; all of these patients had low-grade abnormalities and none required treatment for high-grade disease The Authors 443

5 A. Richards and C. Dalrymple In conclusion, an accurate diagnosis and efficient treatment of screen-detected smear abnormalities in patients with a low estrogen state can be facilitated by the short-term use of vaginal estrogen cream for 6 weeks, as shown in our study. It improves the ability to distinguish between benign atrophic/ inflammatory changes and true pre-invasive disease, with a significant reversion rate of smear samples and colposcopic examinations to within normal limits. Estrogen therapy will also increase the likelihood of subsequent colposcopic examination to be satisfactory in a greater number of patients, by causing enough ectropion of endocervical cells so that the entire SCJ can be visualized. As a result of all of these factors, vaginal estrogen cream application will significantly reduce the number of diagnostic excisional procedures required in this subset of patients. Hence, vaginal estrogen therapy should be considered an appropriate interval treatment of patients with smear abnormalities and in a hypoestrogenic state, as a definitive mechanism to determine actual presence of pre-invasive cervicovaginal disease requiring treatment. Disclosure None declared. References 1. Flynn K, Rimm DL. Diagnosis of ASCUS in women over age 50 is less likely to be associated with dysplasia. Diagn Cytopathol 2001; 24: Ghoussoub RA, Rimm DL. Degree of dysplasia following diagnosis of atypical squamous cells of undetermined significance is influenced by patient history and type of follow up. Diagn Cytopathol 1997; 17: Saad R, Kanbour-Shakir A, Erxiong L, Modery J, Kanbour A. Cytomorphologic analysis and histological correlation of high grade squamous intraepithelial lesions in postmenopausal women. Diagn Cytopathol 2006; 34: Abati A, Jaffurs W, Wilder AM. Squamous atypia in the atrophic vaginal smear: A new look at an old problem. Cancer 1998; 84: Saad R, Dabbs D, Korkunsky L, Kanbour-Shakir A, Silverman JF, Kanbour A. Clinical significance of cytologic diagnosis of atypical squamous cells, cannot exclude a high grade squamous intraepithelial intraepithelial lesion in perimenopausal and postmenopausal women. Am J Clin Pathol 2006; 126: Patton AL, Duncan L, Bloom L, Phaneuf G, Zafar N. Atypical squamous cells, cannot exclude a high-grade intraepithelial lesion and its clinical significance in postmenopausal, pregnant, postpartum, and contraceptive-use patients. Cancer 2008; 114: Urcuyo R, Rome RM, Nelson JH Jr. Some observations on the value of endocervical curettage performed as an integral part of the colposcopic examination in patients with abnormal cervical cytology. Am J Obstet Gynecol 1977; 128: Swan RW. Evaluation of colposcopic accuracy without endocervical curettage. Obstet Gynecol 1979; 63: Rochelson B, Krumholz BA. The unsatisfactory colposcopic examination. J Reprod Med 1983; 28: Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for the ASCCP-Sponsored Consensus Conference consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002; 287: Massad LS, Einstein MH, Huh WK et al updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013; 121: National Health and Medical Research Council. Screening to Prevent Cervical Cancer: Guidelines for the Management of Asymptomatic Women with Screen-Detected Abnormalities. Canberra: Commonwealth of Australia, Prendiville WJ, Davies WA, Davies JO, Shepherd AM. Medical dilatation of the non-pregnant cervix: The effect of ethinyl oestradiol on the visibility of the transformation zone. Br J Obstet Gynaecol 1986; 93: Saunders N, Anderson D, Gilbert L, Sharp F. Unsatisfactory colposcopy and the response to orally administered oestrogen: A randomized double blind placebo controlled trial. Br J Obstet Gynaecol 1990; 97: Thanapprapasr D, Wilailak S, Ayudhya NI et al. Can vaginal misoprostol effectively increase rate of a satisfactory colposcopy? A randomized double-blind placebo-controlled trial. Jpn J Clin Oncol 2010; 40: Aggarwal R, Suneja A, Agarwal N, Mishra K. Role of misoprostol in overcoming an unsatisfactory colposcopy: A randomized double-blind placebo-controlled clinical trial. Gynecol Obstet Invest 2006; 62: Piccoli R, Mandato VD, Lavitola G et al. Atypical squamous cells and low squamous intraepithelial lesions in postmenopausal women: Implications for management. Eur J Obstet Gynecol Reprod Biol 2008; 140: The Authors