Secondary Logo

Journal Logo

Original Research

Atypical Squamous Cells of Undetermined Significance in Girls and Women

Wright, Jason D. MD; Pinto, Anil B. MD; Powell, Matthew A. MD; Lu, Danielle W. MD; Gao, Feng PhD; Pinto, Karen R. MD

Author Information
doi: 10.1097/01.AOG.0000120145.85419.c4
  • Free

In the United States, 50 million women undergo cervical cancer screening by Papanicolaou (Pap) test annually.1 The appropriate evaluation and management of cytologic abnormalities, particularly atypical squamous cells, remains a challenge. In an attempt to clarify the reporting of abnormal cervical cytology, the 1988 Bethesda System introduced a classification for atypical squamous cells of undetermined significance.2 The category was used to designate “cellular abnormalities that were more marked than those attributable to reactive changes, but that quantitatively fell short of a definitive diagnosis of ‘squamous intraepithelial lesion’ (SIL).”2 The 2001 Bethesda System refined these guidelines by qualifying atypical squamous cells as either cells of undetermined significance (ASC-US) or as a test in which a high-grade intraepithelial lesion cannot be excluded (ASC-H).3

The identification of atypical squamous cells is associated with a significant risk for an underlying squamous intraepithelial lesion (SIL). It is estimated that 5–17% of women with ASC-US will be found to have cervical intraepithelial neoplasia (CIN) 2 or 3 upon further investigation.4 In an attempt to optimize the management of cytologic abnormalities, a recent consensus panel was convened and developed guidelines for the treatment and follow-up of atypical squamous cells.4

Although the prognostic importance of atypical squamous cells in adult populations has been recognized, relatively little data exist regarding the prevalence and natural history of ASC-US in adolescents. Several recent studies have suggested that the incidence of cytologic abnormalities in teenage populations is increasing.5,6,18 The etiology of the increasing prevalence of cytologic abnormalities in the teenage population is likely multifactorial and probably linked to rising rates of sexual activity and an increasing incidence of human papillomavirus (HPV) infections.7–11 We undertook this study to evaluate the prevalence and significance of ASC-US cytology in adolescents.


Study approval was obtained from the Washington University School of Medicine Human Studies Committee to evaluate the follow-up of atypical squamous cells among girls and women aged 10–19 years. Data on Pap tests evaluated at the Washington University-Barnes Jewish Hospital cytopathology laboratory between January 1995 and December 1999 were collected. The cytopathology database was searched for all cytology in girls and women aged 10–19 years that were interpreted as ASC-US, including ASC-US with and without a qualifying statement. The cytopathology and surgical pathology databases were then searched for follow-up cytology as well as cervical biopsies, endocervical curettings, and conization specimens. The follow-up outcome was recorded as the most significant (highest grade) subsequent cervical smear or biopsy.

Conventional cytologic specimens were collected with an Ayers spatula and an endocervical brush. All Pap tests were evaluated by a staff cytopathologist. Cytological abnormalities were classified according to the diagnostic criteria of the 1988 Bethesda System for the reporting of cervicovaginal tests.2 Pap tests with cellular abnormalities that were more marked than those attributable to reactive changes, but not consistent with SIL, were recorded as ASC-US. The ASC-US tests were then further subclassified as ASC-US favor reactive or ASC-US favor squamous intraepithelial lesion (ASC-US SIL). If it was not possible to further subclassify the test as ASC-US reactive or ASC-US SIL, the result was interpreted as ASC-US not otherwise specified. All biopsy specimens were paraffin embedded. After routine histologic processing, the slides were evaluated by a staff pathologist. Standard descriptions of CIN 1, 2, and 3 were used to grade the biopsy specimens. Means and standard deviations were used for the description of continuous variables. The cumulative incidence of CIN and SIL were estimated by the Kaplan–Meier method and compared by using the log-rank test. A P value of less than .05 was considered statistically significant.


During the study period, 7,897 cervical cytologic specimens were collected from girls and women aged 10–19 years. A total of 535 test results (6.8%) were reported as ASC-US. Cytologic or pathologic follow-up was available for 398 (74%) of the patients. These 398 patients comprise the study group.

The demographic characteristics of the population are displayed in Table 1. The mean age at the time of collection of the initial Pap test was 17.5 years, whereas the median age was 18 years. Follow-up ranged from 1 to 80 months, with a mean of 19.2 months and a median of 11 months. Follow-up consisted of repeat cytology in 251 (63%) patients and colposcopy with cervical biopsies or endocervical curettage in 147 (37%) of the adolescents.

Table 1
Table 1:
Demographic Characteristics

Follow-up of the ASC-US samples is shown in Table 2. During the study period, the incidence of cytologic abnormalities in our laboratory remained relatively constant. In 1999, 3% of tests were reported as ASC-US, 1% as low-grade squamous intraepithelial lesions (LSIL), 1% as high-grade squamous intraepithelial lesions (HSIL), and less than 1% as carcinoma. Among our adolescent subjects, repeat cytology was normal in 171 (68%). Follow-up cytology was reported as ASC-US in 62 (25%), LSIL in 15 (6%), and HSIL in 3 (1%) patients. In patients with biopsy specimens, 82 (56%) were normal, 3 (2%) were ASC-US, 29 (20%) were CIN 1, and 33 (23%) were CIN 2 or 3. No cases of invasive carcinoma were identified by either cytology or histology. Overall, SIL or CIN were identified in 20% of the adolescents, including 36 cases (9%) of HSIL or CIN 2 or 3. A Kaplan-Meier plot of follow-up of all cytologic and histologic abnormalities is displayed in Figure 1. Figure 2 displays the cumulative incidences of CIN and SIL. Women who underwent colposcopy and biopsy were more likely to have an abnormality than patients followed up with repeat cytology alone (P < .001).

Table 2
Table 2:
Follow-up of Girls and Women With ASC-US
Figure 1.
Figure 1.:
Cumulative incidences of all subsequent cytologic and histologic abnormalities (P < .001).Wright. ASC-US in Adolescents. Obstet Gynecol 2004.
Figure 2.
Figure 2.:
Cumulative incidences of cytologic and histologic cervical intraepithelial neoplasia (CIN) and squamous intraepithelial lesion (SIL) (P < .001).Wright. ASC-US in Adolescents. Obstet Gynecol 2004.

The diagnosis of ASC-US was subcategorized as follows: ASC-US reactive, 89 (22%); ASC-US SIL, 106 (27%); and ASCUS not otherwise specified, 203 (51%). The results of follow-up cytology and histology for each subgroup are displayed in Table 3 and Figure 3. Among adolescents with test results interpreted as ASC-US reactive, 23 (25.8%) were subsequently found with an abnormality. Follow-up was abnormal in 45 (42.4%) women with test results interpreted as ASC-US SIL and in 77 (37.9%) adolescents with ASC-US not otherwise specified. After adjusting for the duration of follow-up, CIN/SIL was less likely to develop in patients with test results interpreted as ASC-US reactive than in women with ASC-US SIL or ASC-US not otherwise specified (P < .01).

Table 3
Table 3:
ASC-US Subcategorization and Follow-up in Adolescents
Figure 3.
Figure 3.:
Cumulative incidences of cervical intraepithelial neoplasia (CIN) and squamous intraepithelial lesion (SIL) at 3 subcategories of diagnosis (P < .001). ASCUS-R = atypical squamous cells of undetermined significance–favor reactive; ASCUS-NOS = ASCUS–not otherwise specified; ASCUS-SIL = atypical squamous cells of undetermined significance–favor squamous intraepithelial lesion.Wright. ASC-US in Adolescents. Obstet Gynecol 2004.


Studies of screening cytology in adolescents have shown a rapid rise in the incidence of cervical abnormalities in the last 3 decades.12–18 In 1981, the rate of dysplasia was 1.9% among more than 190,000 adolescents and women aged 15–19 years.13 Two decades later, Mount et al6 reported rates of SIL as 3.7% and ASC-US as 9.8% in a study of more than 10,000 cytologic samples from patients aged 10–19 years. Our finding of a 6.8% incidence of ASC-US among screened adolescents is consistent with previous reports. Our cytopathology laboratory receives tests from a wide variety of practices, including specimens from inner city clinics and suburban private practices. Thus, our population is a heterogenous sample.

To date, this is one of the largest studies to describe the outcome of adolescents with ASC-US cytology. Rader et al19 evaluated 69 teenagers with ASC-US cytologic samples. Of patients in whom follow-up was available, 21.7% were found with SIL, including HSIL in 6.5%. Edelman et al18 reviewed cytology from a cohort of sexually active adolescents in New York. ASC-US was detected in 12.2% of their population. On follow-up, 30% of the patients with ASC-US had SIL. Finally, Simsir et al5 evaluated a large cohort of teenagers with Pap tests performed at the University of Maryland. Sixteen percent of their study population had a test result interpreted as ASC-US. On follow-up, 21.7% of their patients had SIL. In our series, we collected results of all adolescents with follow-up pathology, whether it was a repeat cytologic sample or a histologic specimen. We identified SIL or CIN on follow-up in 20% of patients with ASC-US, similar to the 22–30% incidence of SIL in previous, smaller reports. Of these patients, 36 (9% overall) had high-grade lesions, higher than previous reports in which the incidence of HSIL ranged from 2.7% to 6.5%. Of note, no cases of invasive carcinoma were identified in any of the studies, including our own. A comparative analysis of the studies of ASC-US among adolescents is shown in Table 4.

Table 4
Table 4:
Studies of ASC-US in Girls and Women

Several studies evaluating the incidence of HPV infections among adolescents have revealed that HPV now affects a significant number of teenagers.10,11 Although highly dependent on the population sampled, the prevalence of HPV in cervicovaginal samples taken from adolescents is 13–38%.10,11,20–23 Given the association between HPV and cytologic atypia, the rising rate of HPV among adolescents likely accounts, at least in part, for the increasing rates of cytologic abnormalities.24 Although common, most HPV infections are transient in young patients. Moscicki et al25 performed serial HPV testing on 618 girls and women aged 13–18 years of age. Seventy percent of the cohort had HPV regression by 24 months. Although the risk of HSIL appeared to dramatically increase if HPV persisted in 3 or more samples (relative risk of HSIL, 14.1), HSIL did not develop in most adolescents with persistent HPV. Given the high incidence and transient nature of HPV among adolescents, the value of HPV testing for the evaluation of ASC-US cytology in this age group may be limited.

A paucity of data exists regarding the optimal timing and method of cytologic screening for adolescents. Among adolescents, cervical cancer is exceedingly rare. The Surveillance, Epidemiology, and End Results database reported the incidence rate of cervical cancer as 0 per 100,000 per year among girls aged 10–14 years and as 1.7 per 100,000 per year for girls and women aged 15–19 years.26 Based on the low incidence of cervical cancer and the relatively long duration to the progression of cervical cancer, recent consensus guidelines have recommended that screening for cervical cancer should be delayed until 3 years after the onset of vaginal intercourse or 21 years of age, whichever occurs first.27 However, as noted in the American Cancer Society's guidelines, the risk of progression of high-grade cervical lesions among adolescents is unknown.27

Likewise, the preferred method to evaluate and follow up adolescents with cytologic abnormalities is uncertain. The National Cancer Institute's ASC-US/LSIL Triage Study compared 3 strategies for the management of women with ASC-US and LSIL cytology. However, the study included only patients aged 18 years or older.28,29 Guidelines developed by a consensus panel from the American Society for Colposcopy and Cervical Pathology suggested that repeat cytology, HPV testing, or colposcopy were all appropriate for women with ASC cytology. The panel recommended colposcopic evaluation for women with ASC-H. Although the group did not propose specific guidelines for adolescents with ASC or ASC-H cytology, they did suggest a more conservative approach for adolescents with LSIL and HSIL cytology.4 In addition, although the consensus conference recommended excision or ablation for adults with CIN 2 or 3, several experts on the panel expressed the opinion that adolescents with biopsy-confirmed CIN 2 who were reliable for follow-up could be observed.30 Our findings reveal that adolescents with ASC-US carry a risk of an underlying high-grade lesion that is similar to that of adults.

The present study has the advantage that all tests were evaluated in a single cytopathology laboratory. However, all data were collected between 1995 and 1999. During this period cervicovaginal cytology was interpreted by using the 1988 Bethesda System.2 In 2001, a revised Bethesda System was developed and is currently in use in our laboratory.3 Thus, some of the tests classified as ASC-US based on the 1988 Bethesda System, especially those interpreted as ASC-US reactive, may not have been classified as ASC under the new Bethesda System. The ASC-US subcategories are not retained in the 2001 Bethesda System.3 Data from the ASCUS-LSIL Triage Study in adult populations suggest that ASC-US favor SIL and may behave in a manner similar to ASC-H.31,32

Overall, 20% of the patients in the present series were found to have SIL or CIN, including 9% with high-grade lesions. This is in accordance with follow-up studies of adults with ASC, in which the chance of CIN 2 or 3 is 5–17%.4 Our findings therefore support managing adolescents with ASC-US cytology in a manner similar to adults. Currently accepted management strategies for ASC cytology include repeat cytology, colposcopy, or DNA testing for high-risk HPV types.4 The optimal management of ASC cytology and the utility of HPV testing in adolescents remain unknown and warrant study in a prospective trial.


1. Jones HW III. Impact of the Bethesda System. Cancer 1995;76(suppl):1914–8.
2. National Cancer Institute Workshop. The 1988 Bethesda System for reporting cervical/vaginal cytologic diagnoses. JAMA 1989;262:931–4.
3. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System terminology for reporting results of cervical cytology. JAMA 2002;287:2114–9.
4. Wright TC, 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.
5. Simsir A, Brooks S, Cochran L, Bourquin P, Ioffe OB. Cervicovaginal smear abnormalities in sexually active adolescents. Acta Cytol 2002;46:271–6.
6. Mount SL, Papillo JL. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics 1999;103:539–45.
7. Centers for Disease Control and Prevention. Youth Risk Behavior Surveillance System. MMWR CDC Surveill Summ 1996;45:1–83.
8. Schiffman MH, Brinton LA. The epidemiology of cervical carcinogenesis. Cancer 1995;76:1888–901.
9. Rosenfield WD, Vermund SH, Wentz SJ, Burk RD. High prevalence rate of human papillomavirus and association with abnormal Papanicolaou smears in sexually active adolescents. Am J Dis Child 1989;143:1443–7.
10. Moscicki A. Genital HPV infections in children and adolescents. Obstet Gynecol Clin North Am 1996;23:675–97.
11. Kahn JA. An update on human papillomavirus infection and Papanicolaou smears in adolescents. Curr Opin Pediatr 2001;13:303–9.
12. Kaufman RH, Burmeister RE, Spjut HJ. Cervical cytology in the teen-age patient. Am J Obstet Gynecol 1970;108:515–9.
13. Sadeghi SB, Hsieh EW, Gunn SW. Prevalence of cervical intraepithelial neoplasia in sexually active teenagers and young adults. Am J Obstet Gynecol 1984;148:726–9.
14. Diller C, Murphy G, Lauchlan SC. Cervicovaginal cytology in patients 16 years of age and younger. Acta Cytol 1983;27:426–8.
15. Schydlower M, Greenberg H, Patterson PH. Adolescents with abnormal cervical cytology. Clin Pediatr 1981;20:723–6.
16. Darnell Jones DE, Russo JF, Dombroski RA, Lentz SS. Cervical intraepithelial neoplasia in adolescents. J Adolesc Health Care 1984;5:243–7.
17. Economos K, Perez-Veridiano N, Mann M, Delke I, Tancer ML. Abnormal cervical cytology in adolescents: a 15-year experience. J Reprod Med 1994;39:973–6.
18. Edelman M, Fox AS, Alderman EM, Neal W, Shapiro A, Silver EJ, et al. Cervical Papanicolaou smear abnormalities in inner city Bronx adolescents. Cancer Cytopathol 1999;87:184–9.
19. Rader AE, Lazebnik R, Arora CD, Franklin J, Abdul-Karim FW. Atypical squamous cells of undetermined significance in the pediatric population: implications for management and comparison with the adult population. Acta Cytol 1997;41:1073–8.
20. Jamison JH, Kaplan DW, Hamman R, Eagar R, Beach R, Douglas JM. Spectrum of genital human papillomavirus infection in a female adolescent population. Sex Tranm Dis 1995;22:236–43.
21. Fisher M, Rosenfeld WD, Burk RD. Cervicovaginal human papillomavirus infection in suburban adolescents and young adults. J Pediatr 1991;119:821–5.
22. Moscicki A, Palefsky J, Gonzales J, Schoolnik GK. Human papillomavirus infection in sexually active adolescent females: prevalence and risk factors. Pediatr Res 1990;28:507–13.
23. Martinez J, Smith R, Farmer M, Resau J, Alger L, Daniel R, et al. High prevalence of genital tract papillomavirus infection in female adolescents. Pediatrics 1988;82:604–8.
24. Rader JS, Rosenzweig BA, Spirtas R, Padleckas R, Javaheri G, Gerardo L, et al. Atypical squamous cells a case-series study of the association between Papanicolaou smear results and human papillomavirus DNA genotype. J Reprod Med 1991;36:291–7.
25. Moscicki A, Shiboski S, Broering J, Powell K, Clayton L, Jay N, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent young women. J Pediatr 1998;132:277–84.
26. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, et al, editors. SEER cancer statistics review, 1973–1999. Bethesda (MD): National Cancer Institute; 2002.
27. Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, et al. American cancer society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342–62.
28. The 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;92:397–402.
29. The ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:1383–92.
30. Wright TC, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ, for the 2001 ASCCP-sponsored Consensus Workshop. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol 2003;189:295–304.
31. Sherman ME, Solomon D, Schiffman M for the ALTS Group. Qualification of ASCUS: a comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage Study. Am J Clin Pathol 2001;116:386–94.
32. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med 2003;127:946–9.

Cited By

This article has been cited 2 time(s).

Obstetrics & Gynecology
Human Papillomavirus Triage for Young Women With Atypical Squamous Cells of Undetermined Significance
Wright, JD; Rader, JS; Davila, R; Powell, MA; Mutch, DG; Gao, F; Gibb, RK
Obstetrics & Gynecology, 107(4): 822-829.
PDF (227) | CrossRef
Obstetrics & Gynecology
Cervical Dysplasia in Adolescents
Wright, JD; Davila, RM; Pinto, KR; Merritt, DF; Gibb, RK; Rader, JS; Mutch, DG; Gao, F; Powell, MA
Obstetrics & Gynecology, 106(1): 115-120.
PDF (221) | CrossRef
© 2004 The American College of Obstetricians and Gynecologists