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ORIGINAL RESEARCH |
From the 1Department of Obstetrics and Gynecology, Division of Gynecologic Oncology; and the 2Department of Medicine, Medical Statistics Section, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
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ABSTRACT |
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 ABSTRACT PARTICIPANTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Adolescent women (ages 14–21 years) referred to colposcopy clinic for abnormal cytology from 1992 to 2004 were identified by computerized database. Only adolescents with biopsy-proven CIN were evaluated. Demographic and risk factor data were obtained from medical records. Referral cytology, histology on biopsy and loop electrosurgical excisional procedure (LEEP), and follow-up cytology were analyzed and compared. Statistical analysis was performed by 
2 or Fisher exact test, Student t tests, and logistic regression.
RESULTS: Of 1,678 adolescents, 517 had biopsy-proven CIN and follow-up. Seventy-seven patients were referred with atypical squamous cells of undetermined significance (ASCUS) cytology; 174 patients were referred with low-grade squamous intraepithelial lesions (LSIL), 258 with high-grade squamous intraepithelial lesions (HSIL) and eight with atypical glandular cells (AGC). The rate of CIN 2/3 in patients with ASCUS, LSIL, and HSIL was 35% (95% confidence interval 24–46%), 36% (29–43%), and 50% (44–56%), respectively. A total of 192 patients with biopsy-proven CIN 2/3 underwent a LEEP. No patients were diagnosed with cervical carcinoma. Fifty-five percent (95% confidence interval 48–62%) of patients had abnormal cytology on follow-up, suggesting recurrence or reinfection.
CONCLUSION: Adolescents with abnormal cytology have a high incidence of CIN2/3 and high rates of abnormal cytology after LEEP. Cervical intraepithelial neoplasia 2/3 is common in adolescents with abnormal cytology, yet no cases of cancer were identified. Importantly, LEEP fails to meet its therapeutic goals given a high incidence of abnormal follow-up cytology and may represent overly aggressive therapy because the majority of human papillomavirus infections are transient with high regression rates.
LEVEL OF EVIDENCE: III
Human papilloma virus (HPV) infections, which are linked to the development of CIN and cervical neoplasia, are common in adolescent women. Up to 70% of sexually active adolescents are HPV-positive, and recent reports suggest this subgroup of women may be more susceptible to the HPV virus secondary to biologic immunity or cervical factors.3,4 With the increasing numbers of sexually active adolescents as well as increasing rates of HPV infection in this subgroup, the prevalence of abnormal Pap test results and incidence of CIN in this population has dramatically increased. The overall incidence of abnormal cytology in large adolescent cohort studies has been reported to be 21–29%.5,6 Biopsy-proven CIN in these adolescents has been demonstrated to be as high as 13.3 per 1,000 adolescents.7
Guidelines for the management of women with cervical cytological abnormalities were revised and amended in 2001 at a consensus conference sponsored by the American Society for Colposcopy and Cervical Pathology (ASCCP).8 Adolescents were identified as a special population with less clear management guidelines and more acceptable treatment options. Optimal management of this cohort is unknown, and adolescents with CIN create a management quandary even for experienced physicians. Some physicians are more conservative with excisional procedures in this cohort given the potential for future obstetric problems with cervical incompetence, premature rupture of membranes, and preterm labor. Our goal was to estimate the incidence of CIN and treatment outcomes in adolescent women with abnormal cytology who were referred to a university-based colposcopy clinic.
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PARTICIPANTS AND METHODS |
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ABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A chart review was conducted; demographic data, referral cytology, and subsequent histologic biopsy for each patient were recorded. Additionally, data about risk factors for CIN such as number of sexual partners, smoking history, parity, race, contraceptive choice, and prior treatments for CIN were collected. Follow-up cytology and number of days since biopsy to most recent cytologic data were obtained from the pathology database. For those patients with multiple follow-up visits, all cytology and histology reports since initial biopsy were recorded.
Patients were classified according to their initial biopsy results of negative, CIN 1, CIN 2, or CIN 3. Management of each adolescent followed ASCCP guidelines, with individualization by the staff gynecologist. With the publication of the 2001 revised guidelines, adolescents were given special consideration in regard to treatment per guideline recommendations. The number of adolescents who underwent a loop electrosurgical excisional procedure (LEEP) was noted, and LEEP histology was recorded. Follow-up consisted of repeat cytology.
During the study period, all Pap smears and cervical biopsies were routinely processed and evaluated by university cytopathologists. Both conventional and liquid-based cytologic samples were obtained. All cytologic preparations were classified according to the 1988 or 2001 Bethesda System terminology. The same cytopathologists interpreted cervical biopsies using standard histologic descriptions of CIN 1, 2, and 3.
Referral cytology was compared with histology on biopsy and LEEP. In addition, the most significant cytology on follow-up after LEEP procedure was determined and compared with initial cytology. Statistical analysis was performed with 2 or Fisher exact tests, Student t tests, and logistic regression (multivariable analysis) using SPSS 11 (SPSS Inc, Chicago, IL) and SAS 9.1 (SAS Institute Inc, Cary, NC).
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RESULTS |
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ABSTRACTPARTICIPANTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study group characteristics and demographics are depicted in Table 1. Adolescents ranged from age 14 to 21 years, with a median of age of 19. Median age of initiation of sexual activity was 15 years. Sixty percent of all patients denied any smoking history, and of those who were smokers, the majority smoked 0.5–1 pack per day. Seventy-two (14%) adolescents reported no contraception usage, and 45 women (9%) were pregnant at the time of colposcopy. The most frequent method of contraception was the oral contraceptive pill (36%), followed by medroxyprogesterone acetate (31%). Three consecutive ASCUS, an ASC-H, or ASCUS with high risk HPV accounted for 15% of all referral cytology; 34% of referrals were LSIL cytology and 50% were HSIL cytology. Atypical glandular cells were found in only 1% of referral patients.
Colposcopic-directed biopsy demonstrated 42 (8%) adolescents with a negative biopsy. Cervical intraepithelial neoplasia 1 was diagnosed in 252 patients (49%), CIN 2 in 119 patients (23%), and CIN 3 in 104 patients (20%). No cases of invasive cancer were discovered. Forty-three percent of all patients were found to have CIN 2/3. Of those patients with ASCUS referral cytology, 35% (95% confidence interval [CI] 24–46%) were found to have CIN 2/3. Thirty-six percent (95% CI 29–43%) of patients with LSIL referral cytology and 50% (95% CI 44–56%) of those with HSIL cytology also demonstrated CIN 2/3 on biopsy. Referral cytology is compared with biopsy results in Table 2 (P=.005).
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A total of 241 patients underwent LEEP. The majority of these adolescents (80%) had CIN 2/3 on biopsy and underwent LEEP for treatment. Forty-nine patients (20%) with CIN 1 or negative biopsies had a diagnostic LEEP for a discrepancy between cytology and histology or for an inadequate colposcopy. Of these patients with negative or CIN 1 biopsies, CIN 2/3 was found in 61% (95% CI 47–75%) of patients.
Mean follow-up was 465 days. The most abnormal cytology was used in follow-up data analysis. A median of two follow-up Pap smears were obtained. Follow-up cytology was obtained at the university colposcopy clinic utilizing the same cytopathologist who had interpreted previous cytology and histology. Follow up data are depicted in Figure 1. In women who underwent a therapeutic LEEP procedure for CIN 2/3, 86 patients (45% with 95% CI 37–51%) had normal cytology on follow-up; 106 patients (55% with 95% CI 48–62%) had abnormal cytology during follow-up. Fifty-eight adolescents at follow-up had ASCUS cytology, 26 had LSIL cytology, and 22 had a HSIL after LEEP. Of the 31 patients with CIN 2/3 who did not undergo LEEP, HSIL persisted in only 13% on follow-up cytology.
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Univariable and multivariable (logistic regression) statistical analysis did not reveal any significant demographic factors associated with increased risk of persistence or recurrence of abnormal cytology after LEEP, including age, race, parity, smoking history, contraception, and age at first intercourse (Tables 3 and 4).
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DISCUSSION |
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Human papillomavirus infection has been shown to have a clear association with both CIN and cervical cancer. The prevalence of HPV infections in sexually active adolescents has been reported to be as high as 70–80%.10 However, the majority of these infections are transient and clear in an average duration of 6 months.10 For those adolescents who have persistent viral infections, cytologic and histologic abnormalities do ensue, but cervical cancer in adolescents is exceedingly rare. The incidence of cervical cancer in girls aged 10–14 years is 0 per 100,000 per year and is 1.7 per 100,000 for those aged 15–19 years.2
In one of the largest data analyses of Pap tests among 796,000 adolescent women, the rates of abnormal cytology were 24%. The rates of biopsy-proven CIN was reported to be 2.8 per 1,000 among these women.7 Another study of 110,283 adolescents reported CIN in 1.73% of patients.11 A study of 10,296 adolescents found a 9.75% ASCUS prevalence and 3.77% prevalence of squamous intraepithelial lesions.12 These studies demonstrate the high rates of abnormal cytology in adolescent females. The appropriate diagnostic workup of abnormal cytology as well as treatment strategies represents a growing public health challenge. The 2001 Consensus Guidelines for the management of women with cervical cytologic abnormalities did concede that adolescents were a special group, and management of LSIL and HSIL cytology included several potential treatment strategies.8 For example, repeat cytology at 6 and 12 months or HPV test at 12 months for LSIL was described as an acceptable treatment option in adolescents compared with immediate colposcopy for adults. Also close follow-up for adolescents with CIN 2 on biopsy is acceptable, whereas treatment is generally recommended in adults.
The majority of previous studies of CIN in adolescents are based on cytologic data alone. Wright et al2 used both cytologic and histologic follow-up in an adolescent cohort. They reported high-grade abnormalities in 18% of patients with LSIL cytology and in 51% of those with HSIL cytology. This progression was noted to be similar to that seen in the adult population. Our study demonstrated high rates of biopsy-proven CIN in the adolescent population. Patients with an ASCUS or LSIL referral cytology had a 35–36% chance of having CIN 2/3 on biopsy or LEEP. Adolescents with HSIL referral were found to have CIN 2/3 50% of the time. We believe that our colposcopy clinic likely represents a high-risk adolescent population, thereby contributing to the high rates of CIN 2/3.
The majority of adolescents in this study with CIN 2/3 underwent a LEEP procedure for treatment. Despite an excisional procedure at a 12-month follow-up, the majority (55%) of adolescents had abnormal cytology depicting persistent disease or reinfection with HPV. Although the majority of these lesions were ASCUS or LSIL, 11% did demonstrate HSIL cytology. For those patients with CIN 2/3 who did not undergo a LEEP procedure, a similar percentage, 13%, had persistence of HSIL on follow-up cytology. In the adolescents with negative or CIN 1 biopsies, the majority did not undergo LEEP and were followed with cytologic smears.
Weaknesses of this study include the retrospective nature of the study, lack of follow-up, and short mean duration of follow-up. Many patients are eventually released back to their primary physician or health department for cytologic follow-up, thereby limiting the numbers in our pathology database.
This large adolescent retrospective study, based on biopsy-proven CIN as opposed to abnormal cytology alone, provides some important conclusions. The rates of CIN 2/3 are higher than those previously published, demonstrating that adolescents are at significant risk for acquiring high-grade CIN lesions. Adolescents with ASCUS or LSIL have a significant risk of CIN 2/3 histology. Importantly no cases of cancer were detected in this large cohort.
Excisional or destructive procedures in nulliparous young women may cause future obstetric problems. Sampson et al,13 in a recent study of 571 women who underwent a LEEP procedure and then had a subsequent singleton pregnancy of greater than 20 weeks of gestation, found an increased risk of overall preterm delivery, preterm delivery after premature rupture of membranes, and low birth weight. In this cohort of adolescents, abnormal cytology persisted or recurred in the majority of adolescents after LEEP, suggesting that LEEP failed to meet a therapeutic role. The detection of CIN and prevention of cancer must be weighed against potential treatment complications, high rates of HPV regression, and the extremely low incidence of cervical cancer in adolescent women. Expectant management in this population of patients with CIN may be warranted.
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Footnotes |
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Corresponding author: Ashley S. Case, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, 3rd Floor Maternity, St. Louis, MO 63110; e-mail: casea{at}wudosis.wustl.edu.
doi:10.1097/01.AOG.0000245448.19446.81
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REFERENCES |
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2. Wright JD, Davila RM, Pinto KR, Merritt DF, Gibb RK, Rader JS, et al. Cervical dysplasia in adolescents. Obstet Gynecol 2005;106:115–20.
3. Moscicki A, Shiboski S, Hills NK, Powell KJ, Jay N, Hanson EN, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet 2004;364:1678–83.[Medline]
4. Moscicki AB, Hills N, Shiboski S, Powell K, Jay N, Hanson E, et al. Risks for incident human papillomavirus infection and low-grade intraepithelial lesion development in young females. JAMA 2001;285:2995–3002.
5. Simsir A, Brooks S, Cochran L, Bourquin P, Ioffe OB. Cervicovaginal smear abnormalities in sexually active adolescents: implications for management. Acta Cytol 2002;46:271–6.[Medline]
6. Edelman M, Fox AS, Alderman EM, Neal W, Shapiro A, Silver EJ, et al. Cervical Papanicolaou smear abnormalities in inner city Bronx adolescents: prevalence, progression, and immune modifiers. Cancer 1999;87:184–9.[Medline]
7. Sadeghi SB, Hsieh EW, Gunn SW. Prevalence of cervical intraepithelial neoplasia in sexually active teenagers and young adults: results of data analysis of mass Papanicolaou screening of 796,337 women in the United States in 1981. Am J Obstet Gynecol 1984;148:726–9.[Medline]
8. Wright, TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120–9.
9. Grunbaum JA, Kann L, Kinchen S, Ross J, Hawkins J, Lowry R, et al. Youth risk behavior surveillance-United States, 2003 [published errata appear in MMWR Morb Mortal Wkly Rep 2004;53:536; and in MMWR Morb Mortal Wkly Rep 2005;54:608]. MMWR Surveill Summ 2004;53:1–96.[Medline]
10. Wright JD, Merritt DF, Mutch DG. How, when and why to manage cervical dysplasia in adolescents. Contemporary OB/Gyn 2005;Nov:40–45.
11. Silva CS, Souza MA, Angelo AG, Pavani R, Adad SJ, Murta EF. Increased frequency of abnormal Papanicolaou smears in adolescents. Arch Gynecol Obstet 2002;266:154–6.[Medline]
12. Mount SL, Papillo JL. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics 1999;103:539–45.
13. Sampson SL, Bentley JR, Fahey TJ, McKay DJ, Gill GH. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol 2005;105:325–32.
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