Management of Abnormal Cervical Cytology Screening in Adolescent and Young Women in a Canadian Colposcopy Centre: A Descriptive Analysis

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1 GYNAECOLOGY Management of Abnormal Cervical Cytology Screening in Adolescent and Young Women in a Canadian Colposcopy Centre: A Descriptive Analysis Geneviève Bouchard-Fortier, MD, MSc, 1 Lawrence aszat, MD, MSc, 2,3,4 K. Joan Murphy, MD 1,5 1 Department of Obstetrics and Gynaecology, University of Toronto, Toronto ON 2 Institute for Clinical Evaluative Sciences, Toronto ON 3 Institute of Health olicy, Management and Evaluation, University of Toronto, Toronto ON 4 Dalla Lana School of ublic Health, University of Toronto, Toronto ON 5 Department of Gynecologic Oncology, rincess Margaret Hospital, Toronto ON Abstract Objective: To describe and analyze the management of young women referred for colposcopy at a Canadian comprehensive cancer centre for evaluation of atypical squamous intraepithelial lesion of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). Methods: We conducted a retrospective descriptive study by searching the ecancercare Colposcopy Database at our centre for 15- to 29-year-old females with referral cytology of ASC-US and LSIL who were seen between January 2000 and January Women in three age cohorts ( years, years, and years) were reviewed for risk factors and relevant medical history, cytology and histology results, treatment, and follow-up visits. Results: A total of 407 women met the entry criteria, with 36 women in the group aged, 173 in the group aged, and 198 in the group aged. Ten excisional procedures were performed among the 36 participants in the group aged 15 to 19, with normal histology found in two (20%), low-grade cervical intraepithelial neoplasia (CIN) in four (40%), and high-grade CIN in four (40%). An excisional procedure was performed in 52 of 173 participants in the group aged, with normal histology in 15%, low-grade CIN in 37%, and high-grade CIN in 48%. Among the group aged, 74 of 198 participants had an excisional procedure, with normal histology in 12%, low-grade CIN in 27%, high-grade CIN in 59%, and microinvasive squamous cell carcinoma in one woman (1%). Key Words: Adolescents, young adults, neoplasm regression, spontaneous, papillomavirus infections, cervical intraepithelial neoplasia, uterine cervical neoplasms Competing Interests: None declared. Received on July 13, 2012 Accepted on October 4, 2012 Conclusion: Many women under the age of 25 who were referred with low-grade abnormal cervical cytology underwent treatment(s) and many did not have significant pathology. One case of microinvasive cervical cancer was identified in a patient in the group aged over the nine years of our study. Our results support the safety of developing a more conservative and coordinated approach to cervical cancer screening in adolescent and young women in Canada. Résumé Objectif : Décrire et analyser la prise en charge des jeunes femmes orientées en colposcopie, au sein d un centre anticancéreux canadien d envergure, aux fins de l évaluation d une atypie des cellules malpighiennes de signification indéterminée (ASC-US) ou de lésions malpighiennes intra-épithéliales de bas grade histologique (LSIL). Méthodes : Nous avons mené une étude rétrospective descriptive en effectuant des recherches, dans la base de données ecancercare Colposcopy au sein de notre centre, visant les femmes de 15 à 29 ans qui ont été orientées en colposcopie en raison de résultats cytologiques indiquant une ASC-US ou des LSIL et qui ont obtenu une consultation entre janvier 2000 et janvier Les cas de ces femmes, lesquelles ont été réparties en trois cohortes d âges (15-19 ans, ans et ans), ont été analysés en fonction des paramètres suivants : facteurs de risque et antécédents médicaux pertinents, résultats cytologiques et histologiques, traitement et consultations de suivi. Résultats : Au total, 407 femmes ont répondu aux critères d admissibilité : 36 au sein du groupe des 15 à 19 ans, 173 au sein du groupe des 20 à 24 ans et 198 au sein du groupe des 25 à 29 ans. Dix interventions excisionnelles ont été menées chez les 36 participantes du groupe des 15 à 19 ans : une histologie normale a été constatée dans deux de ces cas (20 %), une néoplasie intraépithéliale cervicale (NIC) de bas grade histologique l a été dans quatre cas (40 %) et une NIC FEBRUARY JOGC FÉVRIER

2 Gynaecology de haut grade histologique l a été dans quatre autres cas (40 %). Une intervention excisionnelle a été menée chez 52 des 173 participantes du groupe des 20 à 24 ans : une histologie normale a été constatée dans 15 % des cas, une NIC de bas grade histologique l a été dans 37 % des cas et une NIC de haut grade histologique l a été dans 48 % des cas. Au sein du groupe des 25 à 29 ans, 74 des 198 participantes ont subi une intervention excisionnelle : une histologie normale a été constatée dans 12 % des cas, une NIC de bas grade histologique l a été dans 27 % des cas, une NIC de haut grade histologique l a été dans 59 % et un carcinome malpighien micro-invasif a été constaté chez une femme (1 % des cas). Conclusion : De nombreuses femmes de moins de 25 ans ont été orientées en colposcopie en raison de résultats cytologiques anormaux de bas grade histologique et ont subi un ou des traitements, et bon nombre d entre elles ne présentaient pas une pathologie significative. Un cas de cancer micro-invasif du col utérin a été identifié chez une patiente du groupe des 25 à 29 ans au cours des neuf années de notre étude. Nos résultats soutiennent l innocuité de l élaboration d une approche plus conservatrice et coordonnée envers le dépistage du cancer du col utérin chez les adolescentes et les jeunes femmes au Canada. J Obstet Gynaecol Canada 2013;35(2): INTRODUCTION ersistent infection with human papilloma virus causes cervical intraepithelial neoplasia and invasive cervical cancer. HV is the most common sexually transmitted infection and has its highest prevalence in adolescents and young women. Approximately 50% of young women will acquire HV within two to three years of initiation of sexual activity. 1-4 Sexual behaviours and physiologic factors account for the high rate of HV acquisition in this population. 2 ersistent oncogenic HV infection is the cause of essentially all cervical neoplasia, pre-invasive or invasive. 5 In Canada, cervical cancer is the second most common cancer in women aged 20 to 44, although the incidence in adolescents and young women remains extremely low. 6 In young women in Canada the incidence of cervical cancer ABBREVIATIONS ACOG American Congress of Obstetricians and Gynecologists ASC-US atypical squamous intraepithelial lesion of unknown significance CIN cervical intraepithelial neoplasia HC2 Hybrid Capture 2 HSIL ICC LEE LSIL STI high-grade squamous intraepithelial lesion invasive cervical cancer loop electrosurgical excision procedure low-grade squamous intraepithelial lesions sexually transmitted infection from 2005 to 2007 was approximately 1.2 per aged and 6 per aged. 7 There were no cases of cervical cancer diagnosed in adolescents aged 15 to 19 in this time period. Furthermore, when comparing current data to data gathered before the implementation of screening programs, the rate of cervical cancer in these age groups has not decreased. 8 Hence screening in this population does not appear to affect the already low incidence of cervical cancer, a finding that is consistent with those in other jurisdictions. 8 Surveillance Epidemiology and End Results data from 2002 to 2006 show the incidence of cervical cancer in the United States to be approximately 1 to 2 cases per adolescents aged. 8 These data and data from 1973 to 1977, before the implementation of screening programs, show that the rate of cervical cancer in this age group has not decreased. 9 Most HV infections in this population are transient. Low-grade squamous intraepithelial lesions, caused by either low-risk or high-risk HV infections, usually regress spontaneously within 36 months, which is due to clearance of the HV infection However, persistent high-risk HV infection is linked to high-grade squamous intraepithelial lesion, CIN, and ICC. 12 Nonetheless, Moscicki et al. showed that HSIL developed in only 3% of young females between the ages of 13 and 22 over a mean follow-up time of 61 months, and in another study they demonstrated that more than two thirds of CIN 2 lesions regress spontaneously in females from the ages of 13 to ,13 Because of the transient nature of most HV infections and the exceedingly low likelihood of their rapid progression to cancer, initiation of screening in the context of an organized screening program for cervical cancer can be safely delayed until after adolescence. In Canada, recommendations to begin screening in adolescence are being replaced by recommendations that more accurately reflect current knowledge of the natural history of HV infections and their relationship to oncogenesis. 14 We hypothesized that a large number of adolescents and young women, referred to our centre for colposcopy, often underwent diagnostic and therapeutic interventions when the likelihood of transient infection was high and the risk of significant pathology was very low. We therefore conducted a retrospective study to describe and analyze the care of adolescents and young women, 15 to 29 years of age, referred to our centre (a Canadian comprehensive cancer centre) for colposcopic evaluation of abnormal cytology demonstrating atypical squamous intraepithelial lesion of unknown significance or LSIL. 150 FEBRUARY JOGC FÉVRIER 2013

3 Management of Abnormal Cervical Cytology Screening in Adolescent and Young Women in a Canadian Colposcopy Centre Table 1. Baseline characteristics, stratified by age Characteristic Referral cytology, ASCUS 9 (25) 41 (24) 57 (29) 0.52 LSIL 27 (75) 132 (76) 141 (71) 0.52 Mean age, yr atients with 1 pregnancy, 10 (28) 35 (20) 44 (22) 0.58 Contraception, Condom and barrier 31 (86) 162 (94) 163 (82) IUD 1 (3) 5 (3) 9 (5) 0.79 OC 11 (31) 68 (39) 74 (37) 0.62 STI, 7 (19) 33 (19) 34 (17) 0.87 Received HV vaccine, 3 (8) 9 (5) 11 (6) 0.69 Tobacco, current or past use, 17 (47) 54 (31) 55 (28) 0.07 Hepatitis, 0 3 (2) 1 (0.5) 0.55 Organ transplant, 0 2 (1) 1 (0.5) 0.70 revious cancer, 0 1 (0.6) HIV positive, 0 1 (0.6) 1 (0.5) > 0.99 OC: oral contraceptive METHODS articipants were enrolled from the ecancercare Colposcopy Clinic Information System, a web-based application with point of care data entry that allows clinicians and researchers to capture, manage, and interrogate colposcopy data on all participants referred to our centre. We selected all women aged 15 to 29 years who were entered in the database between January 2000 and January 2009 with referral cytology of ASC-US or LSIL. For the purpose of our analysis, participants were divided into three age groups: years (group 1), years (group 2), and years (group 3). Risk factors such as reproductive and contraceptive history, previous or current history of genital warts or other STIs, smoking history, HV immunization, previous cancer, and immune compromise were obtained from a standardized history taken at the time of the initial consultation. Referral cytology (ASC-US or LSIL), prior history of abnormal cervical cytology, repeat cytology results, colposcopically directed cervical biopsy, treatment procedures, and associated histology were extracted from the database for our analysis. In some patients, highrisk HV DNA tests using Hybrid Capture 2 (Qiagen Inc., Toronto ON) had been performed in the context of another study. When available, HC2 results were included. We do not currently test women in this age group for HV. We assessed longitudinally the results of colposcopy, repeat cervical cytology, biopsy, endocervical curettage, HV DNA testing, and treatment procedures performed at our centre. Categorical data were analyzed using two-tailed Fisher exact test; < 0.05 was considered significant. The research ethics board of the University Health Network approved this study. RESULTS A total of 407 women were included in the study; 36 (8.9%) were aged (group 1), 173 (42.5%) were (group 2), and 198 (48.6%) were (group 3). Over 73% of participants (300 of 407) were referred for evaluation of LSIL on cytology, and 26% (107 of 407) were referred for evaluation of ASC-US. The baseline characteristics of our population, stratified by age, are summarized in Table 1. In group 1, the rate of previous or current pregnancy of 28% was higher than the rates of 20% and 22% in the other age cohorts, but this difference was not statistically significant ( = 0.58). The majority of adolescents and young women reported using contraception, with 87% of participants (356 of 407) reporting use of condoms. Approximately 20% of participants (74 of 407) had a known history of STI other than cervical HV. Tobacco use, current or past, was FEBRUARY JOGC FÉVRIER

4 Gynaecology Table 2. Results of repeat cytology at initial colposcopy, stratified by age Cervical cytology 36 (100) 170 (98) 193 (97) 0.87 Satisfactory 36 (100) 169 (98) 189 (95) 0.35 Unsatisfactory 0 4 (2) 9 (5) 0.35 Results Normal 12 (33) 65 (38) 58 (30) 0.24 ASC-US 4 (11) 5 (3) 6 (3) 0.08 ASC-H (3) 0.14 LSIL 18 (50) 83 (49) 88 (46) 0.72 HSIL 2 (6) 16 (10) 32 (17) 0.07 Table 3. Results of cervical biopsy and endocervical curettage at initial colposcopy, stratified by age articipants with biopsy 21 (58) 114 (64) 128 (65) 0.68 Normal 7 (19) 57 (33) 62 (31) 0.29 Low-grade CIN 10 (28) 36 (21) 42 (21) 0.62 High-grade CIN 4 (11) 20 (12) 24 (12) > 0.99 articipants with ECC 11 (31) 67 (39) 67 (34) 0.52 Normal 10 (28) 53 (31) 56 (28) 0.90 Inconclusive 0 8 (5) 6 (3) 0.47 Low-grade CIN 1 (3) 4 (2) 4 (2) 0.89 High-grade CIN 0 1 (0.6) 1 (0.5) > 0.99 ECC: endocervical curettage reported in 47% in group 1, 31% in group 2, and 28% in group 3. A trend for higher tobacco use in the younger age group was observed, but the difference between the three age groups did not reach statistical significance ( = 0.07). As expected, the rate of HV immunization was low at 6% (23 of 407). Our population was in relatively good health: only 2% (10 of 407) of participants reported any condition associated with immune compromise. These participants were evenly distributed in groups 2 and 3. At their initial assessment, more than 97% of study subjects had repeat cervical cytology (Table 2). Repeat entry cytology results were normal for 33% in group 1, 38% in group 2, and 30% in group 3. Almost one half of participants in each age cohort had LSIL on their repeat entry cytology. HSIL was present on repeat cytology in 6% of group 1, 10% of group 2, and 17% of group 3. The difference among the groups did not reach statistical significance ( = 0.07). Overall, 65% of participants had a cervical biopsy at the initial visit, and 36% of participants had endocervical curettage (Table 3). High-grade CIN from cervical biopsy was found in 6% of participants with ASC-US or LSIL at entry based on referral or entry cytology in group 1, and in 2% of such participants in group 2. Screening cytology and cervical biopsy were all consistent in group 3. High-risk HV DNA (HC2) testing was available for 30% of study participants, and was positive in 88% of those tested (7 of 8) in group 1, 67% (38 of 57) in group 2 and 78% (46 of 59) in group 3 (Table 4). The difference among the groups was not statistically significant ( = 0.34). 152 FEBRUARY JOGC FÉVRIER 2013

5 Management of Abnormal Cervical Cytology Screening in Adolescent and Young Women in a Canadian Colposcopy Centre Table 4. Results of Hybrid Capture 2 (high-risk HV-DNA) at initial colposcopy, stratified by age articipants with HC2 results 8 (22) 57 (33) 59 (30) 0.44 ositive 7 (88) 38 (67) 46 (78) 0.34 Negative 1 (12) 19 (33) 13 (20) 0.34 Table 5. Distribution of 168 therapeutic procedures, stratified by age No procedures/total no. of procedure Number of procedures 13 (8) 69 (41) 86 (43) 0.65 articipants receiving > 1 procedure 1 (0.6) 5 (3) 6 (4) > 0.99 rocedure Excisional procedure* 10 (6) 52 (31) 74 (44) 0.25 Vaporization 3 (2) 17 (10) 12 (7) 0.25 *Excisional procedure includes LEE and cold knife cone biopsy Table 6. Results of 137 excisional procedures* among participants initially referred with ASC-US and LSIL, stratified by age (n = 10) (n = 52) (n = 74) Normal 2 (20) 8 (15) 9 (12) 0.64 Low-grade CIN 4 (40) 19 (37) 20 (27) 0.48 High-grade CIN 4 (40) 25 (48) 44 (59) 0.33 Cervical squamous cell carcinoma (2) > 0.99 *Excisional procedure includes LEE and cold knife cone biopsy Thirty-eight percent (156 of 407) of all participants had a therapeutic procedure performed and 3% (12 of 407) had more than one treatment. The other participants were followed with serial colposcopy, discharged from colposcopy, or lost to follow-up. Indications for treatment were low-grade or high-grade CIN on completed colposcopic evaluation or discordance between cytology, colposcopy, and histology results; a decision to treat was made by the individual physician. Eighty-two percent of treated participants (137 of 168) underwent an excisional procedure such as LEE or cold knife cone biopsy; the remaining treated patients underwent laser vaporization (Table 5). Excisional procedure histology was normal in 20% of group 1 participants (2 of 10), 15% of group 2 participants (8 of 52), and 12% of group 3 participants (9 of 74) (Table 6). Low-grade CIN was reported in 40% of group 1 participants (4 of 10), 37% of group 2 participants (19 of 52), and 27% of group 3 participants (20 of 74). High-grade CIN was reported in 40% in group 1 (4 of 10), 48% of group 2 (25 of 52), and 59% of group 3 (44 of 74). High-grade CIN appeared to be more common in the older age group, but the difference was not statistically significant ( = 0.33). Microinvasive squamous cell carcinoma was diagnosed on LEE in one participant FEBRUARY JOGC FÉVRIER

6 Gynaecology in group 3. This was an otherwise healthy 25-year-old nulligravida, with a 5-pack-year smoking history, initially referred because of LSIL on cytology. Her pre-treatment cytology and histology showed HSIL and high-grade CIN lesion, respectively. DISCUSSION There is a strong current trend among screening recommendations towards later initiation of screening for cervical cancer and a more conservative approach in the management of cytological abnormalities in young women. Cancer Care Ontario has recently published new cervical screening guidelines for the province of Ontario. Screening initiation at the age of 21 is now recommended regardless of age of initiation of sexual activity. 14,15 In Alberta, initiation of screening is recommended at age 21 or approximately three years after first sexual activity, whichever occurs later. 16 ACOG published cervical cytology screening guidelines in 2010 recommending cervical cancer screening at age 21 regardless of age of initiation of sexual activity. 17 The United States reventive Services Task Force is in agreement with ACOG regarding later initiation of screening. 18 The National Health Service in the United Kingdom states that women under 25 should not be screened in the context of a national program with computerized call and recall. 19 Their recommendations were in part supported by the work of Sasieni et al., who published a case control study in 2009 evaluating the effect of cervical screening on incidence of cervical cancer as a function of age with particular attention to women under ,21 They concluded that screening has minimal or no impact on rates of invasive cervical cancer up to age 30, and should be weighed against the morbidity of testing and treatment in women at low risk of invasive cervical disease due to their young age. In our study, one third of participants were found to have normal (repeat) cytology at their initial colposcopy visit. It is unclear whether this was due to interval spontaneous clearance of their HV infection or to variation among laboratories reporting cytology results. Nonetheless, this finding is consistent with the frequency and transience of low-grade cytology in young women reported in other studies. In a study by Moscicki et al., there was a 61% regression in LSIL after 12 months and 91% after 36 months in females between the ages of 13 and In our study, 13 procedures were performed in 12 patients in the group aged. From the excisional procedures, histology was benign (normal or low-grade CIN on histology) in 60% (6 of 10). We recognize that it has been hypothesized that initial biopsy can eradicate a small lesion before a definitive therapeutic procedure has taken place; in retrospect, however, regardless of the explanation for the lack of histologic abnormality, these procedures were not beneficial. Furthermore, excisional procedures in women of reproductive age are reported to have the potential for significant obstetrical consequences such as cervical stenosis, premature rupture of membranes, preterm delivery, and low birth weight. 22 Those complications should be considered when managing abnormal cervical cytology in women of reproductive age. Similarly, 52% of excisional procedure histology in the group aged was benign (normal or low-grade CIN on histology), as was 40% in the group aged. These findings support a more conservative approach to treatment in the context of an organized program in which there is a high likelihood of adequate follow-up. We had no cases of invasive cancer in the groups aged and. One 25-yearold patient with a smoking history was found to have microinvasive cervical cancer, and this would presumably have been diagnosed at a more advanced stage if screening had not been available until a later age. A small proportion of participants in this study had received the HV vaccine. In Ontario, a publicly funded HV vaccine program was initiated for grade 8 girls in Our study included participants aged 15 and older between 2000 and The majority of them would not have had access to the school-based program. Therefore, if we were to repeat the study today a higher proportion of participants would have been HV-immunized. High-risk HV testing in our population was frequently positive. Our findings confirm those of other studies; the specificity of this test for detecting significant CIN lesions is very poor in young women given the high prevalence of transient high-risk HV infection in this population. In a longitudinal study with a median follow-up of 60 months, only 22% of HV-positive participants aged 13 to 21 developed LSIL. 4 Our data further suggest that incident high-risk HV testing is not a useful strategy for the primary screening of young women for cervical cancer because the presence of the virus on a single test has little clinical significance. ersistence of infection with an oncogenic HV strain is the key factor in developing high-grade CIN and was not addressed in our study. The results from our retrospective observational study should be viewed in light of some important limitations. How the data were retrieved from the database did not allow us to identify pre-treatment cytology and biopsy results. Furthermore, the quality of the data depends on the thoroughness of nurses and physicians who enter data as they see participants, and we did not specifically 154 FEBRUARY JOGC FÉVRIER 2013

7 Management of Abnormal Cervical Cytology Screening in Adolescent and Young Women in a Canadian Colposcopy Centre study the reliability of data input. Also, we were limited to one centre, and differences in practice may be observed between centres. Another limitation is the change in the management of low-grade cytologic abnormalities in adolescents and young women that occurred during the years of the study. New knowledge and updated guidelines in recent years have influenced the management of abnormal cervical cytology in this population We observed more frequent treatment of low-grade CIN in the early years of the study period than in the later years. Finally, our sample size was relatively small when broken down into age cohorts, limiting the statistical power of our study. CONCLUSION As the natural history of HV has become better understood over the last decade, there has been a consistent trend towards more conservative approaches to screening and treatment of low-grade cervical abnormalities prior to age 25 or even later. Guidelines are now beginning to reflect these changes, although uptake in practice appears to be slow. In Canada, cervical screening is separately managed in each province and territory, and recommendations and practices are heterogeneous. Our data show that many young women under age 25 without significant cervical pathology were referred with low-grade abnormal cervical cytology and many underwent potentially morbid treatment(s). One case of microinvasive cervical cancer was identified among the group of women aged over the nine years of our study. We also found that high-risk HV testing had very low specificity in our population and was not helpful in risk stratification or clinical management. 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