Adolescent Health Care: A Practical Guide
Pap Smears and Abnormal Cervical Cytology
Prevalence of Abnormal Cytology
Several large studies have shown that approximately 3% to 14% of females younger than 19 years have abnormal cervical cytology (Bjorge et al., 1995; Mount and Papillo, 1999;Sadeghi et al., 1984). Fortunately, most of these abnormal cytologies are primarily low-grade squamous intraepithelial lesions (LSILs), which are considered as benign changes due to human papillomavirus (HPV) infection. These rates are consistent with the high rates of HPV infection reported in this age-group, which range from 20% to 57% (Moscicki et al., 1990,1999; Rosenfeld et al., 1989, Winer et al., 2003) with approximately 50% of adolescents acquiring an HPV infection within 5 years of starting sexual activity. Although rates of high-grade squamous intraepithelial lesions (HSILs), considered true pre-cancer lesions, are substantially lower than those of LSILs in adolescents, recent studies suggest that these rates are higher than previously reported. In 1981, Sadeghi et al. (1984) performed an analysis of more than 194,000 Papanicolaou (Pap) smears in adolescents aged 15 to 19 years. Using the World Health Organization's cytological classification, they found a combined rate for cervical intraepithelial neoplasia (CIN) grades 1 and 2 of 18/1,000 smears, and for carcinoma in situ, 1/1,000. In comparison, Mount et al. (1999) examined more than 10,000 Pap smears from young women and found that 14% of the smear results from females aged 15 to 19 years were considered abnormal, with 7% having LSIL and 0.7% having HSIL. Interestingly, the rate of HSIL in the 15- to 19-year-old group was similar to that reported in comparable smear tests from women aged 20 to 29 years (0.8%) and higher than that for women aged 30 to 39 years (0.5%). These rates reported for adolescents are likely underestimates because they only reflect women who enter the health care system. In a nationwide organized cervical screening program, Bjorge et al. (1995) reported a 0.2% incidence rate for HSIL among 20,000 smears of adolescents aged 15 to 19 years. However, the LSIL rate was highest for this age-group. Because of this disproportionate rate between LSIL and HSIL in adolescents, most adolescents with abnormal cytology are unnecessarily referred for colposcopy.
Vulnerability of the Cervix to Human Papillomavirus
The characteristic histological changes of the cervix associated with HPV infections generally occur within the transformation zone (T-zone). It is useful to review the formation of this zone and the natural history of HPV in understanding abnormal cervical changes.
During embryological development, the müllerian ducts give rise to the fallopian tubes, uterus, and vagina. These structures in the fetus are lined by immature cuboidal epithelium (which becomes columnar epithelium) from the uterus to the hymenal ring. The urogenital sinus epithelium grows up the vaginal vault and replaces the native epithelium up to the ectocervix with squamous epithelium. This replacement is usually incomplete, creating an abrupt squamocolumnar junction (SCJ) on the ectocervix. Squamous metaplasia is a process during which undifferentiated columnar cells transform themselves into squamous epithelium. However, the process is relatively quiescent until puberty, resulting in little changes to the SCJ during childhood. The area of columnar epithelium seen on the ectocervix is referred to as ectopy.
With puberty the pH level of the vagina drops. This is associated with glycogen production by squamous cells induced by rising levels of estrogen. The glycogen provides a source of carbohydrate for the vaginal flora. Vaginal bacteria proliferate, and the lactobacilli convert glycogen to lactic acids, resulting in a lowered pH level. This new acidic environment most likely contributes to the augmentation of the squamous metaplastic process, resulting in relatively rapid replacement of columnar epithelium by squamous epithelium.
Transformation Zone (T-zone)
With conversion of the columnar epithelium to squamous epithelium, a T-zone is created. The T-zone is a relatively fluid area of definition, because it represents the area between the original SCJ and the current SCJ. By a woman's late 20 s and early 30 s, most have had substantial replacement of their columnar epithelium, resulting in
little to no visible ectopy. Although squamous metaplasia continues, it is now found well inside the endocervical canal.
Native squamous epithelium appears as smooth, pink, and featureless epithelium. In general, it covers the vagina and a portion of ectocervix. Native columnar epithelium is a single-layer, mucus-producing, tall epithelium extending between the endometrium and into the T-zone. This area has an irregular surface with long papillae and deep clefts, often referred to as having a “grape-like” appearance. The physiological T-zone has a combination of columnar and squamous epithelium features, as well as several unique features, which are dependent on the stage of development. In early stages, the zone is predominantly covered with columnar epithelium and discrete patches where the fusion of the villi causes a loss of translucency and the villi assume a ground glass appearance. Later, successive villi are fused and the intervening spaces are filled. Eventually the papillary structures are lost, and the new surface takes on a less translucent, vascular, pearly tongue appearance. Because the conversion of columnar epithelium to squamous epithelium occurs in often disjointed or fragmented segments, the examiner can often see small glands that are predominantly lined with columnar or metaplastic epithelium. When these gland openings become completely closed by squamous epithelium, the mucus-secreting epithelium may continue to produce mucus. If that mucus becomes inspissated, the gland dilates and a nabothian cyst results. Nabothian cysts eventually self-destruct from the pressure of the inspissated mucus.
Vulnerability of the T-Zone
The T-zone is the area of the cervix most prone to the development of squamous intraepithelial lesions (SILs) and invasive squamous cell cancers. The vulnerability of the T-zone is most likely related to the process of squamous metaplasia and its vulnerability to HPV and SIL development (Moscicki et al., 1999). This association reflects the natural life cycle of HPV and its dependence on host cell proliferation and differentiation, both characteristics of squamous metaplasia. Initial HPV infections are thought to occur by invasion of cells of the basal epithelium. Disruption of the epithelium by inflammation or trauma may cause an increased risk for infection with HPV. Differentiation of these basal cells to well-differentiated squamous epithelial cells supports HPV replication by allowing expression of certain viral proteins at different layers of differentiation. The expression of the oncogenic proteins E6 and E7 in turn causes histological changes, which include abnormal cell proliferation, and the appearance of abnormal mitotic figures, both features of SIL. Features that are mild in nature and restricted to the basal and parabasal areas are referred to as LSIL. When these features become more extensive and extend into the upper half of the epithelium, the changes are referred to as HSIL. These changes coincide with increased expression of the oncogenes E6 and E7. Consequently, both LSIL and HSIL are pathological changes due to HPV infection.
Impact of Cofactors
HPV infection is clearly the causative factor for cervical SIL. However, because rates of HPV are 4 to 10 times more common than SIL, and 100 to 700 times more common than invasive cancers, it is assumed that HPV is necessary but not sufficient for the development of these lesions. In the case of cancer, numerous molecular events are most likely needed. Although HPV infection is clearly one of the first steps, most HPV infections are quickly eliminated by the host's immune response. Lack of an adequate immune response results in persistence of HPV infection, and in turn, HPV persistence is a strong risk for the development of HSIL (Ho et al., 1995; Moscicki et al., 1998, Ylitalo et al., 2000). HPV persistence is a common problem among persons with immunodeficiencies including human immunodeficiency virus (HIV) infection (Moscicki et al., 2004a; Sun et al., 1997). Other factors associated with HSIL and cancer development include tobacco exposure. Even when adjusted for numbers of sex partners, women who smoke have a higher risk of developing cervical SIL and invasive cancers than nonsmokers (Haverkos et al., 2003). This relationship appears to be dose related, because women who are heavier smokers for a longer time have the highest risk for developing SIL and cancers. Other risk factors implicated include herpes simplex virus (HSV) and Chlamydia Trachomatis infections, multiparity, and history of prolonged oral contraceptive use (Smith et al., 2003, 2004).
Cervical Screening Tests
Three U.S. organizations have established guidelines for the initiation and frequency of cervical cancer screening (Table 54.1). Current recommendations for Pap smear testing are that women should start having Pap smears within 3 years of becoming sexually active or at age 21 years (American College of Obstetricians and Gynecologists, 2004; Saslow et al., 2002). After a patient has had three consecutive annual tests whose results are read as normal, she may be screened at 1- to 3-year intervals, depending on risk behavior (i.e., multiple partners), older partners, and a high rate of sexually transmitted diseases (STDs) (ACOG, 2006; American Medical Association, 1997) . STD screening is generally performed at least annually for sexually active adolescents. The pelvic examination is generally included in this screening at least every 1 to 2 years starting 3 years after the initiation of sexual intercourse, and following the first three consecutive annual Pap smears. The recommendation to wait for Pap smears is recent because many groups recommended screening once sexual activity ensued. Waiting has raised anxiety among health care providers because the first Pap smear was considered an opportune time to discuss anatomy, birth control, and risk behaviors. The new guidelines continue to support this, but do not recommend starting a chain of events with triage and referral for abnormal cytology when most (93%) lesions in this age-group will regress (Moscicki et al., 2004).
Most cytologists in the United States have adopted the Bethesda reporting system and now provide more descriptive reports of their findings after screening of the specimen for adequacy and correct preparation. Smear tests that are considered inadequate or with missing endocervical cells should be repeated. A summary of the Bethesda system findings is found in Figure 54.1.
Sample preparation may contribute to the poor sensitivity of the Pap smears; that is, most Pap smears are difficult to read because of obscuring cells, drying artifact, and cell distortion. Liquid cytology has been devised, whereby exfoliated cells are placed immediately into a liquid fixative rather than smeared onto a slide. The fixative solution is transported to the laboratory, where monolayers are prepared using a company's processor. The cells are transferred from the filter onto a glass slide for routine Pap staining. An advantage is clearer images of the cells because the samples are depleted of blood and inflammatory cells that can obscure the readings. Because the agreement rate between conventional smears and liquid cytology is more than 90%, and the cost of liquid cytology smears is sometimes substantially more than that of conventional smears, the cost-effectiveness of using liquid cytology is in question. One advantage may be that the cells preserved in the liquid fixative can be used for ancillary studies such as reflex HPV testing (see subsequent text). Another advantage is that liquid cytology appears to pick up more abnormalities; hence screening intervals may be increased to every 2 years if liquid cytology is used (Saslow et al., 2002). The American Cancer Society has recommended biennial testing using this method (Table 54.1).
The follow-up evaluation required for benign Pap smear findings not associated with neoplastic changes is shown in Table 54.2. Current triage practices for abnormal Pap smear changes in adults followed by recommendations for adolescents are outlined in the following sections.
Recommendations for Adult Women
- Atypical squamous cells of undetermined significance (ASCUS)
- Alternative one: One option is to repeat the Pap smear within 4 to 6 months. If the Pap smear results remain positive for ASCUS or worsen, the patients should be referred for colposcopy. If the second Pap smear result is normal, another Pap smear should be obtained within 6 months. After two consecutive smears, the patient may return to routine screening. A diagnosis of ASCUS that cannot rule out HSIL should be treated as HSIL.
- Alternative two: An alternative to repeat cytology is HPV DNA testing. HPV testing is best performed in the situation of reflex testing. This currently refers to using a liquid cytological method in which the sample obtained for cytology is also adequate to test for the presence of high-risk HPV DNA at a later date. In these situations, the reference laboratory would automatically run an HPV DNA test for high-risk types if an ASCUS result was present on cytology. Studies show that HPV testing is more sensitive for
the detection of HSIL than repeat cytology (Manos et al., 1999). This triage works best in women aged 21 years and older. HPV testing in adolescents (see subsequent text) is not recommended. Currently, Hybrid Capture II HPV Test (Digene Diagnostics, Gaithersburg, MD) is the only U.S. Food and Drug Administration-approved commercially available test kit for clinical high-risk DNA detection in the United States. ASCUS with a positive result for high-risk HPV DNA test should be referred for colposcopy in the nonadolescent age-group.
- LSIL: This category includes evidence of HPV infection referred to as koilocytosisand CIN 1 lesions merged together to reflect the technical difficulties in artificially distinguishing between them and to reflect the fact that very few of these lesions have any progressive or oncogenic potential.
The original intent of the developers of the Bethesda system was to permit more conservative management of patients with low-grade lesions. However, as many as 25% to 30% of patients with LSIL on Pap smears actually harbor more advanced disease, including HSIL and rarely invasive cancer. Currently, it is recommended that all LSIL in adult women be referred for colposcopy. HPV testing for triage in patients with LSIL is not recommended (Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study [ALTS] Group, 2000).
- HSIL: This category includes moderate and severe dysplasia and carcinoma in situ. HSIL requires colposcopic evaluation with directed biopsies and endocervical evaluation
- HPV testing as primary screening in women 30 years or older (Fig. 54.2). Natural history studies have shown that HPV DNA detection in older women commonly reflects a persistent HPV infection, which is in contrast to HPV DNA detection in adolescents and young women where it is predominantly transient. This distinction has been modeled into screening strategies for older women. It is now recommended that women 30 years and older have both high-risk HPV DNA testing and cytology for primary cervical cancer screening. The high negative predictive value of HPV DNA testing allows a greater interval for repeat testing in women who are HPV DNA negative and have normal cytology. Recommended options for the use of the FDA-approved HPV DNA test for colposcopy triage in patients with abnormal cytology are as follows (Fig. 54.2):
- Cytology normal, HPV test negative: Repeat cytology and HPV test in 3 years.
- Cytology normal, HPV test positive: Repeat cytology and HPV test 6 to 12 months later.
Triage on the basis of cytology results using this dual screening method in women older than 30 with ASCUS, LSIL, and HSIL is the same as the preceding recommendations 1 to 3. The major purpose of this dual screening is to allow a longer screening interval in those at low risk (negative cytology and HPV screening) and a more intense follow-up for those with HPV positive test despite negative cytology.
FIGURE 54.1 Summary of Bethesda system findings. (From Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda system: terminology for reporting results of cervical cytology. JAMA 2002;287;(16):2114, with permission.)
Special Considerations for Triage of Cytology in Adolescents
The rate of invasive cancers among adolescents is extremely low, whereas a LSIL diagnosis is at its highest. The common nature of LSIL in adolescents is not surprising given the high rate of HPV infections in this group. Fortunately, LSIL and HPV are mostly transient in this age-group, with more than 90% of HPV infections and LSIL showing regression in adolescents and young women within 3 years (Moscicki et al., 2004a). For this reason, triage for ASCUS and LSIL differ for adolescents (defined as <21 years of age) than adult women. The following are recommendations by the author and other experts in adolescent health care, but are always subject to the latest consensus recommendations available at the American Society for Colposcopy and Cervical Pathology Web site: http://www.asccp.org/consensus.shtml. The major consensus recommendations have been based on consensus reports from 2001, ACOG committee opinion and expert opinion.
FIGURE 54.2 Algorithm for human papilloma virus (HPV) DNA testing and cytology as primary screening in women aged 30 years and older. ASCUS, atypical squamous cells of undetermined significance.
- HPV testing in triage or follow-up for ASCUS or LSIL is not recommended in this age-group. Detection of HPV in adolescents is reflective of a transient infection, whereas in adult women, HPV detection most likely reflects a persistent infection which is a strong risk for HSIL development. These data support the use of HPV in triage for ASCUS in adult women and its use in primary screening in women 30 years or older, but not in adolescents.
- ASCUS and LSIL are both treated with identical follow-up strategies that include follow-up with cytology alone for up to 2 years. It is recommended that patients with ASCUS/LSIL can be followed up with repeat cytology at 12-month intervals for 2 years, without immediate referral for colposcopy. During the 2 years of follow-up, a threshold of HSIL or greater is recommended before referral for colposcopy. After 2 years, a threshold of ASCUS or greater is recommended before referral for colposcopy. These guidelines do not include HIV infected adolescents because progression to HSIL is common (Moscicki et al., 2004b).
Therapy for Cervical Dysplasia
The colposcopically directed biopsy and the endocervical test results determine the extent of the lesion and direct the therapy. The principle in developing a treatment plan is that cervical dysplasia, specifically HSIL, is treated to prevent progression to cancer. If the lesions are confined to the ectocervix, a wide range of treatment options is available (Table54.3).
One practice to be avoided, particularly in adolescents, is to combine the diagnostic and treatment steps by performing colposcopic examination to rule out invasion and excising the T-zone by a loop electrocautery excision procedure (LEEP) without biopsy confirmation. This practice is inappropriate and expensive. Approximately 90% of such referred adolescents have no HSIL found on the specimen on undergoing an LEEP, and the cost exceeds the benefit for patients without dysplasia with regard to side effects (Sadler et al., 2004). As can be seen in Table 54.3, each of the major treatment modalities has minimal adverse impacts when used once. However, because recurrent lesions may develop and require further treatment, the cumulative effects of multiple treatments (particularly LEEP) must be considered. A recent meta-analysis showed that excisional therapy has a higher rate of premature labor and low birth weight (Kyrgiou et al., 2006). Hillard et al. (1991) reported another complication of treatment of cervical dysplasia related to cryotherapy in a group of 67 adolescents. Nine percent developed pelvic inflammatory disease (PID) within 1 month of treatment, and 2 teens developed cervical stenosis and hematometra. In general, screening for STDs before cryotherapy or LEEP is recommended to avoid the complications of PID. Because of the benign nature of histological CIN 1 in all ages, it is recommended that CIN 1 be observed and not treated. Observation of CIN 2 in compliant adolescents is also allowed. (www.asccp.org and American College of Obstetricians-Gynecologists ACOG Committee Opinion, 2006).
All women with dysplasia who smoke should be encouraged to stop smoking. Advise them that continued tobacco use increases susceptibility to cancer. Condom use has been shown to enhance LSIL regression, so condom use should be encouraged (Hogewoning et al., 2003).
After treatment, patients require repeat cytology or colposcopy and cytology at 4 to 6 months until three consecutive normal Pap smears are reported. The patient then can return to normal screening, including annual Pap smears for 3 years, then if all results remain normal, every 3 years. Follow-up with HPV testing at 6 months is also considered optional. The patient can return to normal screening after a single HPV negative test (www.asccp.org).
Conflicting information exists for associations between cervical cancer and HSV and C. Trachomatis infections, prolonged oral contraceptive use (>5–8 years), and multiparity (>6 children) (Smith et al., 2003, 2004, Lehtinen et al., 2002). It is currently not recommended to screen male partners of women with abnormal Pap smears for HPV infections
because few studies have demonstrated HPV disease in this group.
Recommendations for treatment of cervical lesions change over time and differ based on the patient's age and other risk factors. Clinicians involved in the treatment of cervical lesions should refer to the American Society for Colposcopy and Cervical Pathology Web site where consensus recommendations are updated as they become available: http://www.asccp.org/consensus.html.
The latest intervention for prevention of HPV infection is the HPV vaccine. One vaccine was approved in 2006 for types 6/11/16/18 and another vaccine is under approval process for types 16/18. These vaccines have the potential to significantly alter the prevalence of HPV infections in women (see Chapter 66).
For Teenagers and Parents
http://www.ashastd.org. American Social Health Association: Learn about STDs/HPV.
http://www.youngwomenshealth.org/abpap.html. Center for Young Women's Health information sheet for teens on abnormal Pap smears.
http://www.familydoctor.org/handouts/223.html. American Academy of Family Physicians handout.
http://www.nccc-online.org/. National Cervical Cancer Coalition site.
http://www.4woman.gov/faq/pap.htm. National Women's Health information center frequently asked questions sheet.
http://www.asccp.org. American Society for Colposcopy and Cervical Pathology: Patient Education.
For Health Professionals
http://www.asccp.org. American Society for Colposcopy and Cervical Pathology: Practice Recommendations.
http://www.asct.com/. American Society for Cytotechnologists.
http://www.ascp.org/general/pub_resources/papsmear/questions.asp. American Society of Clinical Pathologists.
http://www.bethesda2001.cancer.gov/terminology.html. Bethesda 2001 classifications.
References And Additional Readings
Adimora AA, Quinlivan EG. Papillomavirus infection: recent findings on progression to cervical cancer. Postgrad Med 1995;98:109.
American College of Obstetricians-Gynecologists ACOG Committee Opinion. Evaluation and management of abnormal cervical cytology and histology in the adolescent. Obstet Gynecol 2006;107:963.
American College of Obstetricians and Gynecologists. ACOG guidelines for women's health care. Washington: American College of Obstetricians and Gynecologists; 1996.
American Family Physician. NIH releases consensus statement on cervical cancer. Am Fam Physician 1996;54:2310.
American Medical Association. Guidelines for adolescent preventive services. Chicago, IL: American Medical Association; 1997.
Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. J Natl Cancer Inst 2000;92:397.
Becker TM. Genital warts—a Sexually Transmitted Disease (STD) epidemic. Colposc Gynecol Laser Surg 1984;1:193.
Beckmann A, Daling JR, Sherman KJ, et al. Human papillomavirus infection and anal cancer. Int J Cancer 1989;43:1042.
Bjorge T, Gunbjorud AB, Langmark F, et al. Cervical mass screening in Norway—510,000 smears a year. Cancer Detect Prev 1994;18:463.
Campion MJ, McCance DJ, Cuzick J, et al. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, and virological study. Lancet 1986;2:237.
Campion MJ, Singer A, McCance DJ, et al. Subclinical penile human papillomavirus infection in consorts of women with cervical neoplasia: a due to the high-risk male. Colposc Gynecol Laser Surg 1987;3:11.
Centers for Disease Control and Prevention, Department of Health and Human Services. Guidelines for treatment of sexually transmitted diseases, cervical cancer screening for women who attend STD clinics or have a history of STDs. MMWR Morb Mortal Wkly Rep 1998;47:95.
Chuang T, Perry HO, Kurland LT, et al. Condylomata acuminatum in Rochester, Minn., 1950–1979. Arch Dermatol 1984; 120:476.
Davis AL, Emans SJ. Human papillomavirus infection in the pediatric and adolescent patient. J Pediatr 1989;115:1.
Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata acuminata. N Engl J Med 1986;315:1059.
Evander M, Edlund K, Gustafsson A, et al. Human papillomavirus infection is transient in young women: a population-based cohort study. J Infect Dis 1995;171:1026.
Ferenczy A, Mitae M, Nagai N, et al. Latent papillomavirus and recurring genital warts. N Engl J Med 1986;313:1059.
Ferenczy A. Epidemiology and clinical pathophysiology of condylomata acuminata. Am J Obstet Gynecol 1995;172:1331.
Ferenczy A, Choukroun D, Falcone T, et al. The effect of cervical loop electrosurgical excision on subsequent pregnancy outcome: North American experience. Am J Obstet Gynecol 1995;172(4):1246.
Haverkos HW, Soon G, Steckley SL, et al. Cigarette smoking and cervical cancer: Part I: a meta-analysis. Biomed Pharmacother 2003;57:67–77.
Hillard PA, Biro FM, Wildey L. Complications of cervical cryotherapy in adolescents. J Reprod Med 1991;36:711.
Ho GYF, Birman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423.
Ho GY, Burk KD, Klein S, et al. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst 1995;87:1365.
Hogewoning CJ, Bleeker MC, van den Brule AJ, et al. Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. Int J Cancer 2003;107:811.
Johnstone JD, McGoogan E, Smart GE, et al. A population-based, controlled study of the relation between HIV infection and cervical neoplasia. Br J Obstet Gynaecol1994;101:986.
Kiviat NB, Koutsky LA, Critchlow CW, et al. Prevalence and cytologic manifestations of human papilloma virus HPV types 6, 11, 16, 18, 31, 33, 35, 42, 44, 45, 51, 52 and 56 among 500 consecutive women. Int J Gynecol Pathol 1992;11:197.
Korkolopoulou P, Kolokythas C, Kittas C, et al. Correlation of colposcopy and histology in cervical biopsies positive for CIN and/or HPV infection. Eur J Gynaecol Oncol1992;13:502.
Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489.
Lehtinen M, Koskela P, Jellum E, et al. Herpes simplex virus and risk of cervical cancer: a longitudinal, nested case-control in the Nordic countries. Am J Epidemiol 2002;156:687.
Lonky NM, Navarre GL, Saunders S, et al. Low-grade Papanicolaou smears and the Bethesda system: a prospective cytohistopathologic analysis. Obstet Gynecol 1995;85:716.
Lynch PD. Condylomata acuminata. Clin Obstet Gynecol 1985;28:142.
Manos MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA1999;281:1605.
Maymon R, Bekerman A, Werchow M, et al. Clinical and subclinical condyloma: rates among male sexual partners of women with genital human papillomavirus infection. J Reprod Med 1995;40:31.
McLachlin CM. Pathology of human papillomavirus in the female genital tract. Curr Opin Obstet Gynecol 1995;7:24.
Moscicki AB. Cervical cytology testing in teens. Curr Opin Obstet Gynecol 2005;17:471.
Moscicki AB, Ellenberg JH, Farhat S, et al. HPV persistence in HIV infected and uninfected adolescent girls: risk factors and differences by phylogenetic types. J Infect Dis2004a;190:37.
Moscicki AB, Ellenberg JH, Crowley-Nowick P, et al. Risk of high-grade squamous intraepithelial lesion in HIV-infected adolescents. J Infect Dis 2004b;190:1413.
Moscicki AB, Grubbs-Burt V, Kanowitz S, et al. The significance of squamous metaplasia in the development of low grade squamous intra-epithelial lesions in young women.Cancer 1999;85:1139.
Moscicki AB, Palefsky J, Gonzales J, et al. Human papillomavirus infection in sexually active adolescent females: prevalence and risk factors. Pediatr Res 1990;28:507.
Moscicki AB, Palefsky JM, Gonzales J, et al. The association between human papillomavirus deoxyribonucleic acid status and the results of cytologic rescreening tests in young, sexually active women. Am J Obstet Gynecol 1991;165:67.
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 Pediatr1998; 132:277.
Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet 2004;364:1678.
Mount SL, Papillo JL. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics 1999;103:539.
Quek SC, Mould T, Canfell K, et al. The Polarprobe—emerging technology for cervical cancer screening. Ann Acad Med Singapore 1998;5:717.
Reid R, Greenberg M, Jenson AB, et al. Sexually transmitted papilloma viral infections: the anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types. Am J Obstet Gynecol 1987;156:212.
Reid R, Herschman BR, Crum CP, et al. Genital warts and cervical cancer: the tissue basis of colposcopic change. Am J Obstet Gynecol 1984;149:293.
Rosenfeld WD, Vermund SH, Wentz SJ, et al. High prevalence rate of human papillomavirus infection and association with abnormal Papanicolaou smears in sexually active adolescents. Am J Dis Child 1989;143:1443–1447.
Sadeghi SB, Hsieh EW, Gunn SW. Prevalence of cervical intraepithelial neoplasia in sexually active teenagers and young adults. Am J Obstet Gynecol 1984;148:726.
Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA 2004;291:2100.
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(6):342.
Sawaya GF. A 21-year-old woman with atypical squamous cells of undetermined significance. JAMA 2005;294:2210.
Sherman ME, Kurman RJ. The role of exfoliative cytology and histopathology in screening and triage. Obstet Gynecol Clin North Am 1996;23:641.
Shew ML, Fortenberry JD, Miles P. Interval between menarche and first sexual intercourse, related to risk of human papillomavirus infection. J Pediatr 1994;125:661.
Sidawy MK, Tabbara SO. Reactive change and atypical squamous cells of undetermined significance in Papanicolaou smears: a cytohistologic correlation. Diagn Cytopathol1993;9:423.
Singer A. The cervical epithelium during puberty and adolescents. In: Gordon JA, Singer A, eds. The cervix. Philadelphia: WB Saunders; 1978:88.
Smith JS, Bosetti C, Munoz N, et al. Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int J Cancer2004;111(3):431.
Smith JS, Green J, Berrington de Gonzalez A, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003;361(9364):1159.
Sun XW, Kuhn L, Ellerbrock TV, et al. Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 1997;337:1343.
Vermund SH, Kelley KF, Klein RS, et al. High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection. Am J Obstet Gynecol 1991;165:392.
Widra EA, Dookhan D, Jordan A, et al. Evaluation of the atypical cytologic smear: validity of the 1991 Bethesda system. J Reprod Med 1994;39(9):682.
Winer RL, Lee SK, Hughes JP, et al. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218.
Wright TC Jr, Cox JT, Massad LS, et al. 2001 Consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287(16):2120.
Wright JD, Davila RM, Pinto KR, et al. Cervical dysplasia in adolescents. Obstet Gynecol 2005;106(1):115.
Wright TC Jr, Gagnon S, Richart RM, et al. Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol 1992;79:173.
Ylitalo N, Josefsson A, Melbye M, et al. A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ.Cancer Res 2000;60:6027.