How, when, and why to manage cervical dysplasia in adolescents

November 1, 2005

HPV infection is on the rise in teens and typically transient—yet it still raises the risk of dysplasia. The authors offer evidence-based yet practical guidelines for this management challenge.

Since cervical cancer screening with the Papanicolaou smear has become widespread, the incidence of invasive cervical cancer in developed countries has dramatically decreased. At the same time, the detection of cervical dysplasia has dramatically increased. Diagnosis, management, and follow-up of preinvasive cervical lesions are now a major public health challenge. With teens becoming sexually active earlier, the incidence of cervical dysplasia in adolescents has risen in the past decade. For these young women, the benefits of detecting and eradicating cervical dysplasia must be balanced against the long-term complications of treatment and the low incidence of cervical cancer.

The role of HPV

To date, more than 100 types of small, double-stranded DNA viruses known as human papillomaviruses (HPV) have been isolated. Approximately 40 of these HPV types are believed to infect the human genital tract.1 The papillomaviruses have been divided into low- and high-risk subgroups, based upon their oncogenic potential. Low-risk viruses-most commonly HPV 6 and 11-are associated with anogenital condyloma. The high-risk viruses-HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82-are associated with cervical dysplasia and cancer.2 More than 99% of invasive cervical neoplasms are associated with HPV.3

At any given time, the prevalence of HPV in the general population is 14% to 35%.4 The rate of HPV positivity is highly variable and depends on the demographics of the population being studied. HPV is even more prevalent among adolescents and young women, according to longitudinal sampling studies.5-8 In Woodman and colleagues' study of 1,075 women aged 15 to 19, the 3-year incidence of HPV infection was 44%. After 5 years of follow-up, 60% of the women had tested positive for HPV.5 Despite the high frequency of HPV infections, most infections are transient. The median duration of infection among college-aged women is 8 months.8 Spontaneous viral clearance is more common for low-risk viral infections and in younger women.9 The subset of patients who do have persistent viral infections are at substantial risk for developing cervical dysplasia.10 Despite the high incidence of HPV infection in young women, only a fraction of HPV-positive women develop cytologic abnormalities. In a series of 312 adolescents, nearly 52% of those who were HPV positive had normal cervical cytology.11

When to screen?

The goal of cervical cancer screening is to identify significant preinvasive lesions and prevent development of invasive cervical cancer. Age 18 has traditionally been accepted as the time to start cytologic screening, but recent consensus panels have recommended initiating screening later. The benchmark now is 3 years after the onset of sexual activity, but not later than age 21.12-14 This recommendation is based on the natural history of HPV infection and the rarity of cervical cancer in adolescents. The incidence of cervical cancer is 0 per 100,000 per year in girls aged 10 to 14 and 1.7 per 100,000 for those aged 15 to 19, according to the Surveillance, Epidemiology, and End Results database.15 Earlier screening is unlikely to add additional benefit and may lead to overtreatment of lesions that would spontaneously regress.

The American Cancer Society, American College of Obstetricians and Gynecologists, and the US Preventive Services Task Force all recommend screening at 1- to 3-year intervals (Table 1). Routine gynecologic care, counseling, and health maintenance should not be postponed until a teen is eligible for cervical cancer screening. While data in support of initiating screening at age 21 are limited, mathematical models support this strategy.12 Screening should be initiated earlier in adolescents who have HIV or who are immunocompromised. Women with HIV should undergo cytologic screening twice in the first year after their diagnosis and annually thereafter.

How to manage abnormalities?

Population-based studies indicate that the incidence of cervical cytologic abnormalities among adolescents is increasing. Of more than 190,000 women aged 15 to 19 evaluated in 1981, 1.9% had dysplasia.16 In 1999, Mount and colleagues examined Pap test results from 10,296 adolescents and found squamous intraepithelial lesions (SIL) in 4% and atypical squamous cells of undetermined significance (ASC-US) in 10%.17 Adolescents have an ASC-US rate of 7% to 16%, a 3% to 13% rate of low-grade (LSIL), and a 0.2% to 3% rate of high-grade squamous intraepithelial lesions (HSIL).17-19 Longitudinal studies of adolescents have shown that these women commonly develop cytologic abnormalities.5,7,20 In Woodman and colleagues' study, 28% of the adolescents developed cytologic abnormalities and 33% of those who were HPV positive developed cervical dysplasia.5

The ASC-US conundrum. In adult populations, ASC-US is associated with a significant risk of underlying pathology. Five to 17% of adults with ASC-US have CIN 2 or 3 upon further investigation.21 The largest series of adolescents and young women with ASC-US reported on follow-up of 398 patients aged 10 to 19. Overall, 67% of the women had normal follow-up, 16% had persistent ASC-US, 11% had low-grade lesions (LSIL or CIN 1), and 9% had high-grade abnormalities (HSIL, CIN 2 or 3).19 These findings suggest that adolescents have a risk of underlying cervical dysplasia similar to that of adults. Of note, no cases of invasive cancer were identified. While spontaneous regression would be expected in a high percentage of the women,19 the 9% incidence of high-grade abnormalities highlights the need for careful follow-up and evaluation.

Current guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP) do not specifically address management of ASC-US in adolescents. Strategies for management include reflex high-risk HPV testing, immediate colposcopy, and repeat cytology (Table 2). Reflex HPV testing is the management approach of choice in adults. Young women who are HPV positive should undergo colposcopy, whereas repeat cytology in 1 year is appropriate for those who are HPV negative.21

LSIL. Biopsy will confirm CIN 2 or 3 in 15% to 30% of adults with LSIL, whereas LSIL has a high rate of regression in adolescents and young women. Moscicki and colleagues' prospective evaluation of 187 women with LSIL found a 61% probability of regression by 12 months, and by 24 months, 91% of the subjects had regression.22 The median time to the first negative Pap test was 8.1 months. Of note, 55% of the women who underwent biopsy had normal histology. In a separate cohort of 477 adolescents age 18 or younger with LSIL, 18% ultimately were found to have high-grade cervical abnormalities (HSIL, CIN 2 or 3). By 36 months the cumulative rate of regression was 62%.18 No cases of cervical cancer were identified among any of the women.

These trials underscore the fact that in most young women, LSIL will regress without treatment. However, a portion-particularly those with persistent LSIL-will have underlying CIN 2 or 3. While conservative management is appropriate, these young women should be closely followed to ensure regression. Whether histologically verified high-grade CIN is biologically different in adolescents than in older women remains unknown.

The ASCCP consensus guidelines specifically address management of LSIL in adolescents. For adults with LSIL, colposcopy is recommended, whereas repeat cytology is appropriate for adolescents. Cytology should be repeated at 6 and 12 months, and colposcopy performed on any patient who is found to have ASC or higher-grade disease.21

HSIL. Data on the outcome of HSIL in adolescents is limited. Of 50 young women with HSIL who underwent biopsy at the time of follow-up, 13 were found to have CIN 2, 13 had CIN 3 identified and 1 patient had adenocar-cinoma in-situ.18 These findings highlight the fact that young women with HSIL are at substantial risk of harboring high-grade CIN. According to the ASCCP, young patients with HSIL should undergo colposcopy with directed biopsy of any suspicious lesions. Adolescents with biopsy-confirmed CIN 3 should undergo ablation or excision. Young women with CIN 2 who can be relied upon to return for follow-up can be counseled and observed with follow-up cytology. Adolescents with HSIL whose biopsies are negative for CIN 2 or 3 and have negative endocervical samples can be offered conservative follow-up with colposcopy and cytology every 4 to 6 months for 1 year (Figure 1).21,23

Conclusion

Rising rates of sexual activity among young women have led to an increased incidence of cervical dysplasia in adolescents. Because HPV infection tends to be transient and adolescents have an exceedingly low incidence of invasive cervical cancer, screening can be deferred in most young women until age 21 or 3 years after they become sexually active. When you do encounter a cytologic abnormality in a teen, be aware that most of them are from transient viral infections that will spontaneously regress without treatment. Follow young patients closely to ensure regression, however, as they still are at risk of underlying pathology. Use cervical ablation and excision sparingly in adolescents, as their long-term consequences in this group are not well understood. More data clearly are needed on the biology of biopsy-confirmed CIN in adolescents to further refine management guidelines.

DR. WRIGHT is Instructor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Mo. DR. MERRITT is Professor of Obstetrics and Gynecology and Director of Pediatric and Adolescent Gynecology, Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Mo. She is also a founding member of the North American Society of Pediatric and Adolescent Gynecology. DR. MUTCH is Ira C. and Judith Gall Professor of Obstetrics and Gynecology and Division Chief, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Mo.

REFERENCES

1. Wright JD, Herzog TJ. Human papillomavirus: emerging trends in detection and management. Curr Womens Health Rep. 2002;2:259-265.

2. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-527.

3. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995;87:796-802.

4. American College of Obstetricians and Gynecologists. Human Papillomavirus. ACOG Practice Bulletin No. 61, April 2005.

5. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet. 2001;357:1831-1836.

6. Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA. 2001;285:2995-3002.

7. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132:277-284.

8. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423-428.

9. Hildesheim A, Schiffman MH, Gravitt PE, et al. Persistence of type-specific human papillomavirus infection among cytologically normal women. J Infect Dis. 1994;169:235-240.

10. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, et al. Relation of human papillomavirus status to cervical lesions and consequences for cervical-cancer screening: a prospective study. Lancet. 1999;354:20-25.

11. Tarkowski TA, Koumans EH, Sawyer M, et al. Epidemiology of human papillomavirus infection and abnormal cytologic test results in an urban adolescent population. J Infect Dis. 2004;189:46-50.

12. Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52:342-362.

13. American College of Obstetricians and Gynecologists. Cervical cytology screening. ACOG Practice Bulletin No. 45, August 2003.

14. United States Preventive Services Task Force. Screening for cervical cancer. 2003.

15. Ries LA, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1975-2002. National Cancer Institute. Bethesda, MD: Available at: http://seer.cancer.gov/csr/1975_2002. Accessed August 3, 2005.

16. 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;148:726-729.

17. Mount SL, Papillo JL. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics. 1999;103:539-545.

18. Wright JD, Davila RM, Pinto KR, et al. Cervical dysplasia in adolescents. Obstet Gynecol. 2005;106:115-120.

19. Wright JD, Pinto AB, Powell MA, et al. Atypical squamous cells of undetermined significance in girls and women. Obstet Gynecol. 2004;103:632-638.

20. Brown DR, Shew ML, Qadadri B, et al. A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women. J Infect Dis. 2005;191:182-192.

21. Wright TC Jr, Cox JT, Massad LS, et al. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

22. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet. 2004;364:1678-1683.

23. Wright TC Jr, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.