Obstetrics & Gynecology:
Cervical Dysplasia in Adolescents
Wright, Jason D. MD; Davila, Rosa M. MD; Pinto, Karen R. MD; Merritt, Diane F. MD; Gibb, Randall K. MD; Rader, Janet S. MD; Mutch, David G. MD; Gao, Feng PhD; Powell, Matthew A. MD
From the Division of Gynecologic Oncology and Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, Department of Pathology and Immunology, and Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri; and Department of Pathology, Baylor University Medical Center, Dallas, Texas.
Address reprint requests to: Jason D. Wright, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes Hospital Plaza, Box 8064, St. Louis, Missouri 63110; e-mail: firstname.lastname@example.org.
Background: Although the incidence of cervical dysplasia in adolescents is increasing, a paucity of data exists regarding the outcomes of adolescents with Pap test abnormalities. We determined the natural history and outcome of adolescents with low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL).
Methods: A review of all women aged 18 years or younger with a cytologic diagnosis of LSIL or HSIL between 1997 and 2003 was performed. Follow-up cytologic and histologic samples were evaluated. The most significant abnormality was recorded for each patient. Rates of regression, persistence, and progression were calculated.
Results: A total of 646 adolescents were identified. Follow-up was available for 477 teenagers with LSIL and for 55 with HSIL. Among adolescents with LSIL, 146 (35%) had negative follow-up. Low-grade abnormalities (atypical squamous cells of undetermined significance, LSIL, and cervical intraepithelial neoplasia grade 1) were seen in 199 (47%), whereas high-grade abnormalities were documented in 77 (18%). After 36 months, 62% had regressed, whereas 31% had progressive dysplasia. For the HSIL cohort, negative follow-up was documented in 12 (21.8%) adolescents, and 15 (27.3%) had low-grade abnormalities, whereas more than one half (50.9%) were found to have a high-grade abnormality. At 36 months, 31% of HSIL subjects had progressed to cervical intraepithelial neoplasia 3.
Conclusion: Adolescents with LSIL and HSIL cytology are at significant risk for progression to high-grade cervical abnormalities. The rate of development of high-grade cervical abnormalities in adolescents is similar to adults. Adolescents with cytologic abnormalities mandate close follow-up.
Level of Evidence: II-3
The introduction of an effective cervical cancer screening program with the Papanicolaou test has resulted in a dramatic decrease in the incidence of invasive cervical cancer in the United States. It is now recognized that most cases of cervical carcinoma are associated with human papillomavirus and develop after a long preinvasive phase.1 The goal of cytologic screening is the detection and eradication of these preinvasive lesions. The lengthy interval from the development of cervical intraepithelial neoplasia until progression to cervical cancer allows for effective screening with cervical cytology. It is estimated that 50 million American women are screened with the Pap test annually.2 Cytologic abnormalities that require further evaluation are diagnosed in 3.5 million of these women.3 Thus, although cervical cancer screening is extremely successful, the diagnosis and management of cervical cytologic abnormalities has become a public health challenge.
A recent consensus panel was convened and developed guidelines for the management of women with cervical cytologic abnormalities.4 Although these guidelines provide a framework for the evaluation and treatment of adult women with cytologic abnormalities, a paucity of data exists regarding the outcome of adolescents and young women with Pap test abnormalities. Several recent reports have suggested that the incidence of cervical dysplasia is increasing within teenage populations.5–7 The increase in the frequency of cervical dysplasia in adolescents is not surprising and is likely related both to increased rates of sexual activity and a rising incidence of human papillomavirus infection in adolescents.8–11 The goal of the present investigation was to determine the natural history and outcome of adolescents with cervical dysplasia. We specifically evaluated adolescents with a cytologic diagnosis of low-grade and high-grade squamous intraepithelial lesions.
MATERIALS AND METHODS
Study approval was obtained from the Washington University School of Medicine Human Studies Committee. A retrospective study to evaluate the outcome and natural history of adolescents with cervical cytologic abnormalities was then performed. A search of the Washington University-Barnes Jewish Hospital cytopathology database was performed to identify all adolescents aged 18 years or younger with a cytologic diagnosis of a low-grade squamous intraepithelial lesion (LSIL) or a high-grade squamous intraepithelial lesion (HSIL) on Papanicolaou sample. Patients with cervicovaginal cytologic samples collected between January 1, 1997, and December 31, 2003, were included in the study cohort. Only subjects with a first cytologic diagnosis of LSIL or HSIL were included in the analysis. Management of each patient was individualized by the treating gynecologist. In general, follow-up consisted of either repeat cytologic sampling or colposcopy with biopsies of any visible lesions. The cytopathology and surgical pathology databases were then queried to identify all follow-up samples for the study subjects. All follow-up information was ascertained from query of pathology databases, outpatient medical records were not reviewed, and no further demographic data were available for the study subjects. All subsequent cervicovaginal cytologic specimens, cervical biopsies, endocervical curettings, and cervical conization specimens were identified.
During the study period all cytologic samples were evaluated by a staff cytopathologist. Before 2001, cytologic specimens were classified according to the diagnostic criteria of the 1988 Bethesda System for the reporting of cervicovaginal tests.12 After 2001 all cytologic preparations were reported using the revised 2001 Bethesda System terminology.13 All histologic specimens were paraffin embedded, routinely processed, and interpreted by a staff pathologist. Standard descriptions of cervical intraepithelial neoplasia 1, 2, and 3 (CIN 1, 2, and 3) and invasive cervical cancer were used to grade the biopsy specimens. Both conventional and liquid-based cytologic preparations were included in the analysis.
Statistical analysis was performed using SAS 9 (SAS Institute Inc., Cary, NC). Two separate statistical analyses were performed. First, the most significant pathology on follow-up was determined for each study subject. For each patient the most significant (highest grade) cytologic and histologic abnormalities were recorded. The adolescents were classified as negative, low grade (atypical squamous cells of undetermined significance [ASC-US], LSIL, or CIN 1) and high grade (HSIL, CIN 2, CIN 3 and adenocarcinoma in situ). The second analysis was performed to estimate the rates of persistence, regression, and progression. Regression was defined as the date of the first of 2 consecutive negative pathologic specimens. Progression was defined as the first date of a documented higher-grade lesion. A subject was classified as having persistent disease if neither of these criteria were met. Time to regression or progression was calculated from the date of the index Pap test until the date of regression or progression. During the study period, excisional procedures were the treatment modality of choice for adolescents with cervical cytologic abnormalities, and ablative therapy was rarely performed at our institution. Patients who underwent an excisional procedure were censored from further analysis on the date of the procedure. For the purpose of calculating total follow-up, the date of the most recent pathologic sample was noted. The cumulative incidence of CIN and persistent SIL were estimated by the Kaplan-Meier method. A value of P < .05 was considered statistically significant.
A total of 646 adolescents with cervical dysplasia were identified. Cytologic or histologic follow-up or both was available for 477 subjects, 55 (11.5%) with HSIL and 422 (88.5%) with LSIL. These 477 patients comprise the study cohort. During the study period 10,090 Pap tests in individuals aged 18 years or younger were reported. The overall incidence of LSIL in our adolescent population was 5.7%, whereas the incidence of HSIL was 0.7%.
The age distribution of the patients at the time of their initial abnormal cytologic sample is displayed in Table 1. The mean age for the LSIL patients was 16.7 years and ranged from 13 to 18 years. The median follow-up for the LSIL cohort was 17.4 months. Conization was ultimately performed on 26 (6.2%) of the adolescents in the LSIL cohort. A follow-up histologic (cervical biopsy, endocervical curettage, or conization) specimen was available for review for 279 (66.1%) of the 422 LSIL patients. Of these adolescents, 103 (36.9%) had no histologic abnormalities, 110 (39.4%) had CIN 1, 38 (13.6%) had CIN 2, and 28 (10.0%) had CIN 3 (Table 2). Only cytologic follow-up was available for the remaining 143 (33.9%) subjects. Of these adolescents, 80 (55.9%) had negative cytology, 23 (16.1%) had ASC, 35 (24.5%) had LSIL, and 5 (3.5%) had HSIL.
The cytologic and histologic follow-up of the adolescents with LSIL was then combined, and the most severe abnormality was recorded. Patients were classified as negative, low grade (ASC-US, LSIL, or CIN 1), and high grade (HSIL, CIN 2, CIN 3, and adenocarcinoma in situ [AIS]). As displayed in Table 2, 146 (34.6%) of the adolescents had negative follow-up. Low-grade abnormalities were seen in 199 (47.2%, 42.4–51.9%) of the adolescents, whereas high-grade lesions were documented in 77 (18.2%, 14.6–21.9%) adolescents.
At 12 months after the index Pap test, 27.5% of the LSIL cohort had regressed to normal, 14.9% had progressed to a moderate or severe lesion (HSIL, CIN 2, CIN 3 or AIS), and 57.6% had persistent low-grade abnormalities (ASC-US, LSIL, CIN 1). At 24 months, 54.7% had regressed, 26.1% had progressed, and 19.1% had persistent disease. After 36 months of follow-up, 61.7% had regressed, 31.3% had progressed, and 6.9% had persistent low-grade lesions (Table 3 and Fig. 1). The median time to the first negative specimen for the LSIL cohort was 7.8 months.
The mean age of the 55 adolescents in the HSIL cohort was 16.9 years and ranged from 12–18 years (Table 1). The median follow-up for the HSIL subjects was 16.0 months. Seventeen (30.9%) of the HSIL adolescents underwent an excisional procedure during the study interval. Follow-up cervical cytology alone was available for 5 (9.1%) of the adolescents, whereas a histologic specimen was obtained from 50 (90.9%) patients (Table 2). The histologic sample was reported as negative in 13 (26%), as CIN 1 in 10 (20%), CIN 2 in 13 (26%), and CIN 3 in 13 (26%). One 18-year-old was found with adenocarcinoma in situ on a cervical biopsy (Table 2). The cytologic and histologic follow-up of the adolescents with HSIL were then combined, and the most severe abnormality was recorded. A similar classification as was used for the adolescents with LSIL was then applied. Negative follow-up was documented in 12 (21.8%) adolescents, whereas 15 (27.3%, 15.5–39.0%) adolescents had low-grade abnormalities. Over one half of the adolescents (50.9%, 37.7–64.1%) with an initial Pap test reported as HSIL were subsequently found to have a high-grade abnormality. At 12 months after the index HSIL cytologic sample, 24% of the subjects had progressed to biopsy-confirmed CIN 3. After 36 months of follow-up, the rate of progression to CIN 3 had increased to 31%.
Our findings reveal that adolescents with squamous intraepithelial lesions of the cervix are at substantial risk for the development or persistence of high-grade cervical intraepithelial neoplasia. Recent population-based studies have indicated that the incidence of cervical cytologic abnormalities among adolescents is rising. In 1981 Sadeghi et al14 noted that the rate of dysplasia among more than 190,000 adolescents aged 15–19 years was 1.9%. Two decades later, Mount and coworkers6 reviewed 10,296 Pap tests in adolescents 10–19 years old and reported SIL in 3.7% and ASC-US in 9.8%. Among adolescents, the rate of ASC-US ranges from 7–16%, LSIL from 3–13%, and HSIL from 0.2–3%.5–7,10,15,16 The dramatic increase in the incidence of cervical abnormalities among adolescents is likely multifactorial, related primarily to increasing rates of sexual activity and HPV infection in this age group.8–11 The prevalence of HPV infection in sexually active adolescents is 20–43% and is highly dependent on the population studied.11,17 Our findings of LSIL in 5.7% and HSIL in 0.7% of the adolescents at our institution are in accord with previously published work.
Although the outcomes of adult women with cervical cytologic abnormalities have been well characterized, a paucity of data exists to describe the outcome of teenagers with cervical dysplasia.5,7,18 Economos et al18 reviewed 315 adolescents aged 14–19 with LSIL and HSIL cytology. Among the LSIL subjects, 47% had negative follow-up, 49% had mild abnormalities, and 3% had CIN 2 or 3. The corresponding rates for the HSIL cohort were 10%, 4%, and 86%, respectively. Overall, 35% of our subjects with LSIL cytology had negative follow-up, 47% had low-grade lesions, and 18% had high-grade abnormalities. For our HSIL cohort, follow-up was negative in 22%, revealed low-grade lesions in 27%, and high-grade abnormalities in 51%.
Perhaps the most important question addressed by the present study is whether a difference exists in the outcome of adolescents and adults with cervical dysplasia. In adult women with LSIL, 15–30% of those evaluated with cervical biopsy will be found to have CIN 2 or 3.4,19,20 In our cohort of LSIL patients who underwent biopsy, 23.6% had high-grade lesions, 13.6% with CIN 2 and 10% with CIN 3. Among adult women with HSIL cytology who undergo biopsy, 40–75% will have CIN 2 or 3 and 1–2% will have invasive neoplasms.3,4,19 Fifty-two percent of our HSIL subjects with histologic follow-up had CIN 2 or 3. To determine the natural history of cervical squamous intraepithelial lesions in adult women, Melnikow and colleagues21 performed a meta-analysis that included nearly 28,000 women. In their pooled analysis, after 24 months of follow-up 47% of women with LSIL had regressed to normal while 21% had progressed to a higher-grade lesion. The pooled analysis for women with HSIL revealed a regression rate of 35% and progression to CIN 3 in 23% of the women.21 In a cohort of women aged 13–22 years with LSIL, Moscicki et al22 noted that 61% of the women had regressed by 12 months, whereas 91% had regressed after 36 months of follow-up. In our cohort of LSIL subjects, 28% had regressed by 12 months, 55% had regressed by 24 months, and 62% had regressed after 3 years of follow-up. For our HSIL subjects 31% had progressed to biopsy-proven CIN 3 by 24 months of follow-up. Thus, our findings indicate that the natural history of cytologic abnormalities in adolescents is similar to adults.
The optimal timing and method of cytologic screening in adolescents remains to be determined. The American Cancer Society now recommends initiation of cervical cancer screening 3 years after vaginal intercourse, no later than 21 years of age.23 Given the presumed high rate of resolution of low-grade lesions in adolescents, the recommendation was implemented to avoid detection and treatment of clinically insignificant lesions. Similar recommendations have been put forth by other groups.24 The American Society for Colposcopy and Cervical Pathology guidelines for the management of women with cytologic abnormalities suggest that in adolescents with LSIL, follow-up cytology at 6 and 12 months may be appropriate in lieu of immediate colposcopy as proposed for adults. The panel suggests that colposcopic observation is appropriate in selected young, reproductive-age women when biopsy-confirmed CIN 2 or 3 is not identified.4 These guidelines are based on the knowledge that invasive cervical cancer is exceedingly rare in adolescents.25 Although our findings revealed a higher than expected rate of high-grade cervical abnormalities, no cases of invasive cancer were detected in our cohort.
The present study has the advantage of having evaluated nearly 650 consecutively collected cytologic specimens from adolescents. However, consistent with prior studies of cervical dysplasia and the retrospective nature of the report, follow-up was not available for the entire cohort. Additionally, diagnosis and management of the subjects was not standardized and was at the discretion of each participant’s physician. Finally, on a subset of the study population, only cytologic follow-up was available. Cytologic follow-up alone is commonly used for the follow-up of adolescents with cervical dysplasia. Thus, the lack of histologic correlation is not surprising and reflects the current practice patterns used for adolescents with dysplasia.
Our findings reveal that adolescents with LSIL and HSIL cytology are at significant risk for the development of high-grade cervical abnormalities. Overall, 18% of teenagers with LSIL and 51% with HSIL were eventually found with a high-grade lesion. These rates are similar to those previously reported in adult populations. Thus, adolescents with cytology reported as SIL carry a similar risk for underlying cervical intraepithelial neoplasia as adults. Although these findings help to define the underlying risk of CIN in adolescents with SIL, the natural history of biopsy-confirmed CIN 2 and 3 in adolescents remains poorly defined and is currently under investigation. Based on limited data, it has been suggested that CIN in adolescents is more likely to regress without treatment. Although less intensive intervention for adolescents with LSIL and HSIL certainly seems reasonable, these adolescents are still at considerable risk and warrant close follow-up. Contraceptive counseling at the time of follow-up would certainly seem prudent. Prospective studies to evaluate alternative management strategies for adolescents with LSIL and HSIL are clearly warranted.
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