In 1988, the National Cancer Institute developed the Bethesda System. Atypical Squamous Cells of Undetermined Significance on Cervical Smears CANCER

Transcription

1 74 CANCER CYTOPATHOLOGY Atypical Squamous Cells of Undetermined Significance on Cervical Smears Follow-Up Study of an Asian Screening Population Annie N. Y. Cheung, M.D. Elaine F. Szeto, B.Sc. Kin-Man Ng, B.Sc. Ka-Wah Fong, B.Sc. Ang Chan Elvinia Yeung, B.Sc. Obe K. L. Tsun, B.Sc.. Ui-soon Khoo, M.D. Kelvin Y. K. Chan, Ph.D. Anita W. Y. Ng, B.Sc. Department of Pathology, The University of Hong Kong, Hong Kong, China. BACKGROUND. The current study reports on the significance of cervical smears identified as atypical squamous cells of undetermined significance (ASCUS) in the largest Asian screening population to date. METHODS. From January 1998 to December 1999, 190,000 cervical smears were evaluated by the cervical cytology laboratory at the University of Hong Kong (Hong Kong, China). From these smears, 5579 ASCUS were identified. Follow-up cytology and histology findings were analyzed. RESULTS. Follow-up cytology or biopsy results were retrieved for 3601 women (64.5%). Of these, 544 (9.8%) and 96 women (1.7%) were found to have low-grade (LSIL) and high-grade (HSIL) squamous intraepithelial lesions, respectively. Biopsy results were obtained for 198 (36.4%) of the 544 women with LSIL. One hundred seventy-nine (32.9%) and 19 women (3.5%) were confirmed to have cervical intraepithelial neoplasia (CIN)-1 and CIN-2 CIN-3, respectively. Biopsy results were retrieved for 53 (55.2%) women with HSIL. Forty patients (41.7%) were confirmed to have CIN-2 CIN-3, whereas CIN-1 was found in the remaining patients. One woman with squamous cell carcinoma was diagnosed by colposcopic biopsy after immediate referral following a diagnosis of ASCUS. There was a significantly larger proportion of LSIL or HSIL (P ) or higher-grade findings in women with ASCUS compared with the general screening population. Infective organisms were identified in 412 women (7.4%) with ASCUS. These women had a decreased risk of subsequent development of LSIL (P ) or HSIL (P 0.027). CONCLUSIONS: ASCUS smears indicated an increased risk of HSIL or carcinoma. The authors suggested careful patient follow-up in such cases. Cancer (Cancer Cytopathol) 2004;102: American Cancer Society. KEYWORDS: cervix, cytology, atypical squamous cells of undetermined significance, Asian screening population. The authors thank Dr. Susan Fan, Dr. Robert J. Collins, Professor Ho Keung Ng, Dr. John Chan, Dr. Andrew Choy, Dr. Elaine Gwi, Dr. Kam Cheong Lee, Dr. Wing-Fung Ng, Dr. Siu Wah Pang, Dr. Michael Suen, and Dr. Man Ching Tang for providing follow-up data. Address for reprints: Annie N.Y. Cheung, M.D., Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China; Fax: (011) ; anycheun@hkucc.hku.hk Received August 12, 2003; revision received November 28, 2003; accepted December 9, In 1988, the National Cancer Institute developed the Bethesda System (TBS) for reporting cervicovaginal cytologic diagnoses. The TBS is an attempt to establish uniform standards for cervical carcinoma screening programs. 1,2 Borderline cytologic abnormalities, especially atypical squamous cells of undetermined significance (ASCUS), are the most common abnormalities observed in smears obtained for cervical carcinoma screening. According to the 1988 Bethesda System Conference, ASCUS was established as a diagnostic category to allow the reporting of cervicovaginal smears that could not be definitively assigned to the normal, benign cellular changes, orsquamous intraepithelial lesion (SIL) categories. ASCUS refers to cellular abnormalities that are more marked than those resulting from reactive alterations but are quan American Cancer Society DOI /cncr.20045

2 ASCUS in an Asian Screening Population/Cheung et al. 75 titatively and/or qualitatively insufficient for a definitive diagnosis of SIL. 3 The cytopathologic criteria that define ASCUS include an enlarged nucleus (2.5 3 times the size of a normal intermediate cell nucleus), mild nuclear hyperchromasia, regular nuclear borders with a slightly modified shape, or the presence of 2 of the 3 cytologic criteria that define human papillomavirus infection. Despite efforts to establish specific criteria to define ASCUS, interobserver variability exists. Most follow-up studies of ASCUS have been provided by laboratories serving high-risk populations, including the hospital laboratories. 4 Few studies report data on screening populations 5 or the Asian population. To our knowledge, the current investigation is the largest single-institution study of an Asian screening group to determine whether findings of ASCUS do define a population that has a significant risk of developing neoplasia. Associated risk factors also will be explored. MATERIALS AND METHODS From January 1998 to December 1999, 190,000 conventional cervical smears were performed at the clinics of the Family Planning Association and sent for analysis to the cervical cytology laboratory at the University of Hong Kong (Hong Kong, China). Women attending these clinics were considered to be representative of the screening population in Hong Kong, because the prevalence of low-grade or more severe SIL was 5%. 6 8 The adequacy and the cytologic features for each specimen were then evaluated by cytotechnologists using TBS. 2 Slides that contained abnormal cells or clinical information, such as abnormal vaginal bleeding, were referred to pathologists. Cytologic abnormalities reported by pathologists included ASCUS, atypical glandular cells of undetermined significance (AGUS), low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and malignant disease. According to computer records, 5579 of these women were diagnosed as having ASCUS. There was no further subcategorization into ASCUS, favor SIL or ASCUS, favor reactive categories. During the next 2 years, the cytology and histology laboratory databases of major public hospitals in Hong Kong were searched for follow-up data on these patients with findings of ASCUS. The cytology and histology slides were not reviewed. Among the 190,000 specimens contributed by women in the general screening population within this 2-year period, follow-up cytologic and histologic information was available for 76.2%. Follow-up information for patients diagnosed TABLE 1 Follow-Up Cytology Findings in Repeat Smears after Findings of Atypical Squamous Cells of Undetermined Significance Characteristic No. of cases a Percentage (of 3601 cases with available follow-up data) Unsatisfactory Negative Reactive changes AGUS ASCUS Low-grade squamous intraepithelial lesion High-grade squamous intraepithelial lesion Total 3601 Percentage (of a total of 5579 cases of ASCUS) ASCUS: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance. with ASCUS was retrieved, and the outcome was reported as the most significant (highest-grade) cervical smear or biopsy observed during the 2-year period. Patients with ASCUS who had previous abnormal smears were included in the study. Analysis was performed with the Fisher exact test. The chi-square method was used, and two-tailed P values were calculated. RESULTS Of the 190,000 women with cytology smears, 5579 (2.9%) were diagnosed with ASCUS. The women with ASCUS ranged in age from 16 to 90 years, but the majority were ages years. There were no follow-up cytology or biopsy results for 1978 (35.5%) of the 5579 women. Results were available for the remaining 3601 women (64.5%; Table 1). Three women had unsatisfactory repeat smears. Negative repeat smear and reactive changes were found in 1986 (35.6%) and 274 women (4.9%), respectively. A second diagnosis of ASCUS was noted in 690 women (12.4%). AGUS was found in 8 women (0.14%). Five hundred forty-four (9.8%) and 96 women (1.7%) had LSIL and HSIL, respectively, in their repeat smears. HSIL was diagnosed in women in all age groups but was most common among women ages years. Biopsy findings were retrieved for 36.4% of women with LSIL and 55.2% of women with HSIL (Table 2). Among patients with histologic follow-up, 179 women with LSIL (32.9%) were confirmed to have cervical intraepithelial neoplasia (CIN)-1, and 19

3 76 CANCER (CANCER CYTOPATHOLOGY) April 25, 2004 / Volume 102 / Number 2 TABLE 2 Follow-Up Biopsy Findings Cytologic diagnosis Histologic diagnosis (%) CIN-1 CIN-2 CIN-3 Not available LSIL (n 544) 179 (32.9) 19 (3.5) 347 (63.8) HSIL (n 96) 13 (13.5) 40 (41.7) 43 (44.8) CIN: cervical intraepithelial neoplasia; LSIL: low-grade squamous intraepithelial lesion; HSIL: highgrade squamous intraepithelial lesion. FIGURE 1. A conventional smear showing atypical squamous cells of undetermined significance with a moderate number of dyskeratotic cells and atypical squamous cells. Squamous cell carcinoma was found on colposcopic biopsy. (3.5%) were found to have CIN-2 CIN-3. Forty women (41.7%) with a cytologically confirmed diagnosis of HSIL were found to have CIN-2 CIN-3, whereas CIN-1 was found in the remaining patients with cytologically confirmed HSIL; no diagnoses of invasive carcinoma were made in this group. ASCUS was diagnosed in a 44-year-old patient who had a moderate number of dyskeratotic cells (Fig. 1). The pathologist considered these findings to be troublesome, although the features were not diagnostic of HSIL or carcinoma. Immediate referral was recommended, and subsequent colposcopic biopsy diagnosed squamous cell carcinoma (SCC). No intervening smears were performed for this patient. Regarding the time needed for discovery of subsequent HSIL and carcinoma after ASCUS was diagnosed, the final cytologic diagnosis was made 3 6 months after the first ASCUS diagnosis in 56% of patients. For 26% of patients, the diagnosis was made 1 year after the initial diagnosis. Table 3 compares the incidence of LSIL or highergrade findings in patients diagnosed with ASCUS compared with the general screening population. Significantly larger proportions of LSIL and HSIL or highergrade findings were diagnosed in the group of patients with ASCUS compared with the general screening population. Table 4 summarizes follow-up cytologic findings by patient age in repeat smears following findings of ASCUS. Table 5 reports on correlations between age at diagnosis of ASCUS and subsequent detection of LSIL or detection of HSIL or higer-grade findings. Women with ASCUS who are younger than age 35 years are less likely to exhibit LSIL or higher-grade findings than are women older than age 35 years (P 0.05). However, women ages years are more likely to exhibit LSIL or higher-grade findings compared with older women. There was no statistically significant difference between women age 50 years and women age 50 years regarding subsequent detection of LSIL or higher-grade findings. No correlation was demonstrated between age at detection of ASCUS and subsequent detection of HSIL in any age group (P 0.05). Of the 690 women with ASCUS found again on the second smear, 413 (59.86%) had no record of a follow-up smear in the next 2 years, whereas 140 (20.29%) had negative smears. On the repeat smears, 70 women (10.14%) exhibited ASCUS again, 1 woman (0.14%) exhibited AGUS, and 9 women (1.3%) exhibited reactive atypia. Forty-six (6.67%) and 11 women (1.59%) exhibited LSIL and HSIL, respectively. All cases of HSIL were confirmed by histologic methods. Infectious organisms were found in 412 patients (7.4%) with ASCUS, including Actinomyces (n 53), herpesvirus (n 15), Trichomonas (n 53), and Monilia (n 291). An additional 25 patients (0.45%) had features suggestive of follicular cervicitis. There was an inverse statistical correlation between the presence of infectious organisms and the subsequent detection of a significant lesion (Table 6). Women with identifiable infectious organisms had a decreased risk of subsequent detection of significant epithelial lesions. DISCUSSION In the current study, we attempted to evaluate outcomes in the largest group of women diagnosed with ASCUS on cervical smears reported in a single laboratory serving an Asian screening population. Since the 1991 TBS meeting, ASCUS has been subdivided into favor reactive and favor SIL subcategories. Some authors have found this practice to have clinical utility These investigators found that a diagnosis of ASCUS, favor reactive, was similar to a diagnosis of ASCUS not otherwise specified (NOS) and that a diagnosis of ASCUS, favor SIL, approximated a

4 ASCUS in an Asian Screening Population/Cheung et al. 77 TABLE 3 Incidence of LSIL or Higher-Grade Findings in Patients Diagnosed with Atypical Squamous Cells of Undetermined Significance Compared with the General Screening Population Follow-up cytology Found in follow-up cytology (%) Confirmed by histology (%) Incidence in same screening population (%) P value (chi-square test) Relative risk compared with screening population Subsequent detection of LSIL 544/3601 (15.1) 179/3601 (5.0) 1876/190,000 (0.99) Subsequent detection of HSIL 96/3601 (2.7) 40 a /3601 (1.1) 494/190,000 (0.26) ASCUS: atypical squamous cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion. a There was an additional case of atypical squamous cells of undetermined significance that was recommended for immediate referral due to the presence of suspicious cytologic features. Colposcopic biopsy diagnosed squamous cell carcinoma. There were no intervening smears. TABLE 4 Follow-Up Cytologic Findings on Repeat Smears after Findings of Atypical Squamous Cells of Undetermined Significance, ( ) by Patient Age Age (yrs) no follow-up (%) Unsatisfactory (%) Negative (%) Reactive changes (%) ASCUS (%) AGUS (%) LSIL (%) HSIL (%) CA (%) Total (%) 15 2 (0.10) 0 (0.00) 1 (0.05) 0 (0.00) 1 (0.14) 0 (0.00) 2 (0.37) 0 (0.00) 0 (0.00) 6 (0.11) (5.06) 1 (33.33) 35 (1.76) 12 (4.38) 19 (2.75) 0 (0.00) 30 (5.51) 1 (1.04) 0 (0.00) 198 (3.55) (8.90) 0 (0.00) 148 (7.45) 7 (2.55) 41 (5.94) 1 (12.50) 39 (7.17) 6 (6.25) 0 (0.00) 418 (7.49) (16.13) 0 (0.00) 218 (10.98) 20 (7.30) 81 (11.74) 1 (12.50) 73 (13.42) 13 (13.54) 0 (0.00) 725 (13.00) (18.66) 1 (33.33) 300 (15.11) 37 (13.50) 102 (14.78) 0 (0.00) 77 (14.15) 22 (22.92) 0 (0.00) 908 (16.28) (21.99) 0 (0.00) 454 (22.86) 61 (22.26) 170 (24.64) 3 (37.50) 137 (25.18) 23 (23.96) 0 (0.00) 1283 (23.00) (13.14) 0 (0.00) 426 (21.45) 67 (24.45) 140 (20.29) 0 (0.00) 103 (18.93) 19 (19.79) 0 (0.00) 1015 (18.19) (8.19) 1 (33.33) 268 (13.49) 53 (19.34) 77 (11.16) 2 (25.00) 50 (9.19) 6 (6.25) 0 (0.00) 619 (11.10) (5.16) 0 (0.00) 96 (4.83) 11 (4.01) 39 (5.65) 0 (0.00) 22 (4.04) 3 (3.13) 0 (0.00) 273 (4.89) (1.16) 0 (0.00) 23 (1.16) 6 (2.19) 11 (1.59) 0 (0.00) 8 (1.47) 0 (0.00) 0 (0.00) 71 (1.27) (1.16) 0 (0.00) 17 (0.86) 0 (0.00) 9 (1.30) 1 (12.50) 3 (0.55) 1 (1.04) 0 (0.00) 54 (0.97) Unknown a 7(0.35) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 2 (2.08) 0 (0.00) 9 (0.16) Total 1978 (100) 3 (100) 1986 (100) 274 (100) 690 (100) 8 (100) 544 (100) 96 (100) 0 (0) 5579 (100) ASCUS: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion; CA: carcinoma. a Age not provided by patients. diagnosis of LSIL in terms of the rate of histologically proven dysplasia. It has been argued that equivocal diagnoses should be avoided and that ASCUS should be assigned definitively to a reactive category or to SIL. 16 Others have disagreed, as they have observed dysplasia on follow-up in a large percentage of patients with ASCUS, favor reactive. 17 At the 2001 TBS meeting, the ASCUS category was retained with subclassification into only two categories: atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot exclude HSIL (ASC-H). 18 In the current study, we have not attempted to further subcategorize ASCUS into diagnoses favoring reactive changes or diagnoses suspicious of malignancy to have a broader view of the general implications of these categories. The prevalence of ASCUS varies from 1.8% to 10% in different studies Such a wide variation may be TABLE 5 Relation between Age and Subsequent Diagnosis of Squamous Intraepithelial Lesions Age (yrs) Subsequent diagnosis > LSIL (%) P value (chi-square test) Subsequent diagnosis > HSIL (%) (5.2) (1) (12.2) (7.3) (25.6) (20.8) (41.1) (43.8) (66.1) (67.7) (85.2) (87.5) (93.9) (93.8) P value (chi-square test) LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion.

5 78 CANCER (CANCER CYTOPATHOLOGY) April 25, 2004 / Volume 102 / Number 2 TABLE 6 Presence of Infection and Subsequent Cytologic Diagnosis > ASCUS or AGUS (%) > LSIL (%) >HSIL (%) Infection 88/1338 (6.6) 34/640 (5.3) 4/96 (4.2) No. infection 1250/1338 (93.4) 606/640 (94.7) 92/96 (95.8) P value (Fisher exact test) ASCUS: atypical squamous cells of undetermined significance; AGUS: atypical glandular cells of undetermined significance; LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion. due to differences in population characteristics and differences in the characteristics of the samples studied. In the current study, the specimens for cytopathologic evaluation were collected at clinics for the purpose of cervical carcinoma screening. Most patients were asymptomatic and were representative of a population at low risk for cervical carcinoma. Therefore, it should be expected that the current results would be different from those obtained at tertiary care institutions (e.g., clinics specializing in cervical pathologies or sexually transmitted diseases). Other studies that did not involve high-risk populations reported prevalence rates similar to the one found in the current study. 5,20,22 In general, TBS recommends that the frequency of ASCUS diagnoses should not exceed two or three times the rate of SIL in any given laboratory. 3 In the current series, we found those values to be 2.9% for ASCUS and 1.25% for SIL, which are in accordance with TBS guidelines. The management of patients with ASCUS has been a controversial problem for some time. Conservative follow-up with repeat cytologic evaluations at shortened intervals has been regarded as the standard practice However, several investigators have found substantial rates of SIL, including HSIL, with histologic and repeat cytologic evaluation of patients with ASCUS. They recommend immediate colposcopy and biopsy for patients with ASCUS diagnoses In Hong Kong, patients with ASCUS are generally followed up with repeat smears in 3 6 months. Referral for colposcopy may be recommended for patients with troublesome cytologic features. In the current study, we reported on a patient with ASCUS who was referred for colposocopy and was found to have SCC. No macroscopic abnormalities were observed during a vaginal examination during smear taking. Diagnosis of ASCUS does identify populations at risk for SIL, including HSIL. 20,22,36 In some studies, follow-up of patients with ASCUS has resulted in a 39% rate of histologically documented HSIL. 22 Manos et al. 36 have proposed that the rate of progression from ASCUS to HSIL is significant but substantially less than the rate of progression from LSIL to HSIL. These same authors suggested that the risk of progression (within 2 years) from ASCUS to HSIL is greater than the risk of progression from normal or reactive findings to HSIL but less than the risk of progression from LSIL to HSIL. 36 ASCUS, therefore, truly is an intermediate cytologic category. Our findings concur with the results of other studies in that most patients with ASCUS did not have cervical carcinoma. Nevertheless, cases of HSIL and malignant disease were observed among women diagnosed with ASCUS in the current study. Among patients with ASCUS who were followed for 2 years, approximately 15% developed LSIL and 2.7% developed HSIL, corresponding to incidence rates times greater than those observed in the general population. Nearly one-half of these diagnoses were confirmed histologically. Patients with ASCUS have a statistically significantly higher risk of harboring SIL or even carcinoma compared with the general screening population. The risk of cervical carcinoma increases with age, and the median age at diagnosis is approximately 54 years. 37 In contrast, it is believed that transient infections with HPV and the associated cytologic and histologic changes may be more common among younger women We sought to evaluate the effect of age on subsequent identification of significant neoplasia in patients with ASCUS. In the current study, LSIL or higher-grade findings were more common among older women. Among women age 20 years, approximately 5% of patients with ASCUS had LSIL or higher-grade findings. In other words, most atypical squamous cells are reactive by nature in this age group. Therefore, colposcopy in younger women is less strongly indicated. In contrast, we did not find that older women with ASCUS were more likely to harbor HSIL. This interpretation, however, is limited by the small number of women detected with HSIL in this segment of the study population. We also found that among women diagnosed with ASCUS, those with infection by identifiable organisms had a reduced risk of subsequent development of serious lesions, possibly because the atypical cytologic changes observed in these women were produced by the reactive changes of these organisms. In conclusion, women with ASCUS have a fold greater risk of harboring SIL or even malignant disease compared with the general population. The probability of detecting abnormalities is lower in younger patients and in patients with identifiable in-

6 ASCUS in an Asian Screening Population/Cheung et al. 79 fectious organisms. ASCUS should be retained as a diagnostic category, because it defines a group of patients who are at an increased risk for the development of HSIL. Careful follow-up and referral are necessary for patients who exhibit ASCUS. REFERENCES 1. National Cancer Institute Workshop. The 1988 Bethesda system for reporting cervical/vaginal cytologic diagnoses. JAMA. 1988;262: National Cancer Institute Workshop. The revised Bethesda System for reporting cervical/vaginal cytological diagnoses. Report of 1991 Workshop. Anal Quant Cytol Histol. 1992;14: Kurman JK, Solomon D. Atypical squamous cells of undetermined significance. In: Kurman JK, Solomon D, editors. The Bethesda system for reporting cervical/vaginal cytologic diagnoses: definitions, criteria and explanatory notes for terminology and specimen adequacy. New York: Springer, 1994: Emerson RE, Puzanov A, Brunnemer C, Younger C, Cramer H. Long-term follow-up of women with atypical squamous cells of undetermined significance (ASCUS). Diagn Cytopathol. 2002;27: Becker E Jr., Edelweiss MI, Nonnenmacher B, Bozzetti MC. Prevalence and epidemiologic correlates of atypical squamous cells of undetermined significance in women at low risk for cervical cancer. Diagn Cytopathol. 2001;24: Jones W. Impact of the Bethesda System. Cancer. 1995;76: Lee KR, Ashfaq R, Birdsong GG, Corkill ME, McIntosh KM, Inhorn SL. Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer screening. Obstet Gynecol. 1997;90: Cheung AN, Szeto EF, Leung BS, Khoo US, Ng AW. Liquid based cytology and conventional cervical smears: a comparison study in an Asian screening population. Cancer (Cancer Cytopathol). 2003;99: Sidawy MK, Tabbara SO. Reactive change and atypical squamous cells of undetermined significance in Papanicolaou smears: a cytohistologic correlation. Diagn Cytopathol. 1993;9: Collins LC, Wang HH, Abu-Jawdeh GM. Qualifiers of atypical squamous cells of undetermined significance help in patient management. Mod Pathol. 1996;9: Gonzalez D, Hernandez E, Anderson L, Heller P, Atkinson BF. Clinical significance of a cervical cytologic diagnosis of atypical squamous cells of undetermined significance. Favoring a reactive process or low grade squamous intraepithelial lesion. J Reprod Med. 1996;41: Kline MJ, Davey DD. Atypical squamous cells of undetermined significance qualified: a follow-up study. Diagn Cytopathol. 1996;14: Sheils LA, Wilbur DC. Atypical cells of undetermined significance: stratification of the risk of association with, or progression to, squamous intraepithelial lesions based on morphologic subcategorization. Acta Cytol. 1997;41: Crum CP, Genest DR, Krane JF, et al. Subclassifying atypical squamous cells in Thin-Prep cervical cytology correlates with detection of high-risk human papillomavirus DNA. Am J Clin Pathol. 1999;112: Sherman ME, Tabbara SO, Scott DR, et al. ASCUS, rule out HSIL : cytologic features, histologic correlates, and human papilloma virus detection. Mod Pathol. 1999;12: Solomon D, Frable WJ, Vooijs GP, et al. ASCUS and AGUS criteria. International Academy of Cytology Towards the 21st Century: an international expert conference and tutorial. Acta Cytol. 1998;42: Malik SN, Wilkinson EJ, Drew PA, Bennett BB, Hardt NS. Do qualifiers of ASCUS distinguish between low- and high-risk patients? Acta Cytol. 1999;43: Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System. Terminology and reporting results of cervical cytology. JAMA. 2002;287: Titus K. HPV test: antidote to ASCUS headache? CAP Today. 1996;10: Williams ML, Rimm DL, Pedigo MA, Frable WJ. Atypical squamous cells of undetermined significance: correlative histologic and follow-up studies from an academic medical center. Diagn Cytopathol. 1997;16: Rader AE, Rose PG, Rodriguez M, Mansbacher S, Pitlik D, Abdul Karim FW. Atypical squamous cells of undetermined significance in women over 55. Comparison with the general population and implications for management. Acta Cytol. 1999;43: Kinney WK, Manos MM, Hurley LB, Ransley JE. Where s the high grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses. Obstet Gynecol. 1998;91: Brown MS, Phillips GL. Management of the mildly abnormal Pap smear: a conservative approach. Gynecol Oncol. 1985; 22: Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology. JAMA. 1994;271: Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical lesions: a metaanalysis. Obstet Gynecol. 1998;92: Kohan S, Noumoff J, Beckman EM, Morris M, Weiner E, Douglas GW. Colposcopic screening of women with atypical Papanicolaou smears. J Reprod Med. 1985;30: Maier RC, Schultenover SJ. Evaluation of the atypical squamous cell Papanicolau smear. Int J Gynecol Pathol. 1986;5: Davis GL, Hernandez E, Davis JL, Miyazawa K. Atypical squamous cells in Papanicolaou smears. Obstet Gynecol. 1987;69: Jones DE, Creasman WT, Dombroski RA, Lentz SS, Waeltz JL. Evaluation of the atypical Pap smear. Am J Obstet Gynecol. 1987;157: Noumoff JS. Atypia in cervical cytology as a risk factor for intraepithelial neoplasia. Am J Obstet Gynecol. 1987;156: Soutter WP, Wisdom S, Brough AK, Monaghan JM. Should patients with mild atypia in a cervical smear be referred for colposcopy? Br J Obstet Gynecol. 1986;93: Andrews S, Hernandez E, Miyazawa K. Paired Papanicolaou smears in the evaluation of atypical squamous cells. Obstet Gynecol. 1989;5: Lindheim SR, Smith-Nguyen G. Aggressive evaluation for atypical squamous cells in Papanicolaou smears. J Reprod Med. 1990;35: Slawson DC, Bennett JH, Herman JM. Follow-up Papanicolaou smear for cervical atypia: are we missing significant disease? J Fam Pract. 1993;36:

7 80 CANCER (CANCER CYTOPATHOLOGY) April 25, 2004 / Volume 102 / Number Paavonen J, Kiviat NB, Wolner-Hanssen P, et al. Significance of mild cervical cytologic atypia in a sexually transmitted disease clinic population. Acta Cytol. 1989;33: Manos MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA. 1999;281: Cannistra SA, Niloff JM. Cancer of the uterine cervix. N Engl J Med. 1996;334: Burk RD, Kelly P, Feldman J, et al. Declining prevalence of cervicovaginal human papillomavirus infection with age is independent of other factors. Sex Transm Dis. 1996;23: Carson HJ, DeMay RM. The mode ages of women with cervical dysplasia. Obstet Gynecol. 1993;82: Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol. 2000;151: