OBJECTIVE: To analyze the screening status, clinical characteristics, and risk of invasive cervical cancer in women with cytologic atypical squamous cells of undetermined significance (ASC-US) in general populations and to make recommendations for these women.
METHODS: The 95,309 women with initial cytologic ASC-US from the national cervical cancer screening database in Taiwan were divided into unscreened and screened groups based on their previous screening history. Newly diagnosed invasive cervical cancer cases in the follow-up period were retrieved for analysis.
RESULTS: There were 860 cases of invasive cervical cancer during the follow-up period of 556,758 person-years, with an overall incidence rate of 154.5 cases per 100,000 person-years. The incidence was 92.3 and 257.2 cases per 100,000 person-years in the screened and unscreened groups, respectively. Previous screening history was a strong risk predictor of invasive cervical cancer (hazard ratio 2.8, 95% confidence interval 2.4–3.1, P<.001) after adjustments for age, educational status, and hospital setting. Age was also a significant risk factor for developing invasive cervical cancer in the unscreened group but not in the screened group.
CONCLUSION: Women with cytologic ASC-US, especially those without a previous Pap test or older women, were more likely to develop invasive cervical cancer and should be followed up aggressively.
LEVEL OF EVIDENCE: II
Women with cytologic atypical squamous cells of undetermined significance who are older or who have not undergone a previous Pap test should be followed up aggressively.
From the 1Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University; the 2Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University; the 3Genomics Research Center, Academia Sinica; the 4School of Public Health, National Defense; and the 5Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.
Supported by a grant from the Bureau of Health Promotion of the Department of Health, Taiwan.
The authors thank the Taiwan Cancer Registration System and Taiwan Cervical Cancer Screening Task Force for providing the data.
Corresponding author: Dr. Chi-An Chen, Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100, Taiwan; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
Cervical cancer remains a major cause of mortality and morbidity among women in the world, including Taiwan.1,2 Cytologic evaluation of cells obtained from the cervix and vagina first was proposed by Dr. George Papanicolaou in the 1940s as a method for detecting cervical cancer and its precursors.3,4 With the development of the Bethesda system for reporting cervicovaginal cytologic diagnoses in 1988, cytologic atypia has become a dilemma for physicians.5 At the 2001 Bethesda meeting, the atypical squamous cells category was retained with subclassification into two categories: atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions (ASC-H).6
Most ASC-US investigations involve follow-up studies of high-risk populations.7,8 Only a few include general screening populations,9 even though ASC-US may be indicative of an increased risk of high-grade squamous intraepithelial lesions or carcinoma.10 Only a few nationwide follow-up studies about the outcome of ASC-US have been reported.11 In the present nationwide, population-based study, the database of cervical Pap test and histopathology results was retrieved from the Taiwan Cervical Cancer Screening Registration System. Women who had Pap test results of ASC-US for the first time were evaluated to estimate the risk of cervical cancer. Our objective was to analyze the screening status, clinical characteristics, and risk of invasive cervical cancer in women with ASC-US in general populations and to make recommendations for these women.
MATERIALS AND METHODS
In 1995, the annual cervical screening program using the Pap test was launched in Taiwan for women 30 years and older. The results of women diagnosed with ASC-US during the period from January 1, 1995, to December 31, 2004, were retrieved from the database of the Taiwan Cervical Cancer Screening Registration System. Registered data included personal identification information, date of birth, date of diagnosis, histological diagnosis, and treatment. The research protocol was approved by the Ethical Committee of the Bureau of the Health Promotion, Department of Health, Taiwan. The cervical Pap tests were performed nationwide by gynecologists, family physicians, or trained public health nurses. For cytologic examination, there were approximately 100 cytological laboratories with cytotechnicians or cytologists who classified the Pap tests. The results were further rechecked, revised, and confirmed by certificated cytopathologists. Only ASC-US was classified from 1995 to 1997. However, starting in 1998, ASC-US results were subclassified into ASC-US and ASC-H according to the 2001 Bethesda terminology in Taiwan.6 The laboratories then reported the test results to the respective hospitals/clinics and the central information system for registration. The central information system reported the abnormal Pap test results to the Health Promotion Bureau. The Health Promotion Bureau then asked the local public nurses to inform women of the abnormal Pap test results, to follow up with them, and to report back on the treatment of these women. Reported cytologic abnormalities included ASC-US, ASC-H, atypical glandular cells of undetermined significance, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and malignant diseases. The treatment of women with ASC-US included a repeated Pap test 3 to 6 months later, colposcopic examination, or the human papillomavirus (HPV) DNA test in Taiwan.
To investigate the newly diagnosed cases of ASC-US and to avoid misclassifying follow-up Pap tests after treatment, inclusion and exclusion criteria were set up. Only those women with the cytologic diagnosis of ASC-US for the first time were enrolled. The exclusion criteria were women with 1) any previous epithelial cell changes in Pap tests (including ASC-US), 2) previous cervical histology of low-grade squamous intraepithelial lesions/high-grade squamous intraepithelial lesions/invasive cancer, or 3) previous gynecologic cancer. Our aim was to investigate the ability of Pap tests (ASC-US) to predict invasive cervical cancer.
Women whose time from Pap test (ASC-US) to diagnosis of invasive cervical cancer was longer than 6 months were included. If the interval between Pap test (ASC-US) and the diagnosis of invasive cervical cancer was less than 6 months, it was regarded as an undetermined invasive cervical cancer and was excluded for analysis.
Women diagnosed with cytologic ASC-US for the first time then were divided into two groups. The unscreened group consisted of women who had no previous Pap screening, and the screened group consisted of women whose previous Pap tests reported no epithelial abnormalities. All cases of invasive cervical cancer among these women with cytologic ASC-US diagnosed between July 1995 and June 2005 were obtained from the computerized profiles of the National Cancer Registry System of the Department of Health.
The follow-up of each participant (in person-years) was calculated from the date of enrollment to the date of invasive cervical cancer diagnosis, date of death, or last date of linked data available from the Taiwan Cancer Registry or Death Certification Profile, whichever came first until December 31, 2004. Data for participants whose invasive cervical cancer was not diagnosed were censored on the date of death or the last date of follow-up until December 31, 2004. Incidence rates were calculated by dividing the number of invasive cervical cancer cases by the number of person-years of follow-up.
A Cox’s proportional-hazards model estimated the association between the history of Pap test and the risk of cervical cancer, with adjustments for other risk factors including age, participation year, previous screening status, educational status, and residence. The 95% confidence intervals for the hazard ratios also were calculated. Statistical significance levels were determined by two-tailed test, and a P<.05 was considered statistically significant. Statistical analysis was performed with SAS 8.12 (SAS Inc., Cary, NC).
A total of 95,309 women were diagnosed with cytologic ASC-US for the first time from January 1, 1995, to December 31, 2004, based on the inclusion and exclusion criteria. Their basic characteristics are shown in Table 1. Among them, 34.6% were older than 50 years and 66.5% received Pap tests in townships or counties. The mean age was 46.3 years. Of these women, 28,093 (29.5%) had never received any previous Pap tests and were defined as the unscreened group. The remaining 67,216 (70.5%) women, with previous Pap tests but without any abnormal epithelial changes, were defined as the screened group. In the screened group, 60.3% had had a Pap test within 3 years. The screened period, age, previous Pap test interval, education, and resident region are significantly different between the screened and unscreened groups (Table 1).
For women with cytologic ASC-US, there were 556,758 person-years of follow-up, with an average follow-up period of 5.84 years. A total of 860 invasive cervical cancer cases were identified during this period, for an overall incidence of 154.5 cases per 100,000 person-years. The incidence was 92.3 among those previously screened and 257.2 in the unscreened group (Table 2). The incidence of developing invasive cervical cancer in women with cytologic ASC-US, regardless of previous Pap tests, was significantly higher than the general screening population (18.59/100,000 person-years) in 2003 (Cancer Registration System, Taiwan, 2007). Previous screening status was a strong risk predictor of invasive cervical cancer (hazard ratio 2.8, 95% confidence interval 2.4–3.1, P<.001) after adjusting for participation year, age, educational status, and residential region. The risk of developing invasive cervical cancer also increased with age (Table 2). The incidence of invasive cervical cancer by age and screening history is shown in Table 3. Women who had ever undergone Pap tests had a similarly low risk of developing invasive cervical cancer in various age groups (except older than 60 years), and women who had never undergone Pap tests had a significantly higher risk of developing invasive cervical cancer in various age groups (except older than 60 years) as compared with the referent group (women who were between 30 and 39 years old and had ever undergone Pap tests).
When considering the interval between the previous and current Pap test, an interval of 3–5 years or longer showed significantly or marginally higher risks of developing invasive cervical cancer as compared with an interval of less than 1 year (Table 4). Educational level showed a negative risk of developing invasive cervical cancer. Women who lived in the metropolis had a decreased risk of developing invasive cervical cancer as compared with women who lived in other areas.
The 67,216 women in the screened group with cytological ASC-US then were analyzed. The risk of developing invasive cervical cancer did not correlate with age (Table 5). However, longer Pap-test intervals and lower educational levels showed a higher risk of developing invasive cervical cancer. The risk of developing invasive cervical cancer for the 28,093 women in the unscreened group with cytological ASC-US also increased with age (Table 5). In addition, lower educational level and living in the countryside were also two high risk factors for developing invasive cervical cancer (Table 5).
The clinical significance of an ASC result depends on a number of factors, including the patient’s age and clinical history and the subclassification of the result (eg, ASC-US or ASC-H).12–16 The current survey reveals that older women have higher risks of developing invasive cervical cancer as compared with younger women in the unscreened group but not in the screened group. These findings concur with the results of Cheung and colleagues that younger patients (younger than 30 years old) with ASC-US do not have invasive cervical carcinoma.17 It is believed that transient infections with HPV and associated cytologic and histologic changes may be more common in younger women. Most atypical squamous cells may be reactive changes to HPV infection, and colposcopy provides less value for younger women with cytologic ASC-US. Because age seems to be one risk factor for developing invasive cervical cancer in women with cytologic ASC-US, older women with ASC-US should be monitored closely.
Although the risk of invasive cancer in women with cytologic ASC-US is low, it still implies that some of women with invasive cervical cancer may present with equivocal results on cervical cytology. Although Raab reports that the risk of invasive cancer in women with cytologic ASC is not high,16 Wright et al still recommend that women with ASC-US should have some form of follow-up to search for more serious clinical conditions such as high-grade squamous intraepithelial lesions and invasive cancer.18 Parham et al have evaluated the significance of a first-time atypical Pap test in a high-risk population19 and report that 41% of 250 young, sexually active women had histologic cervical intraepithelial neoplasia (CIN) lesion by colposcopic biopsy, endocervical curettage, and repeat Pap test.
The current survey is a nationwide study of the general population to evaluate the clinical significance of a first-time cytologic ASC-US result, especially in terms of invasive cervical cancer prevention. Previous screening history is a significant indicator in women with first-time cytologic ASC-US. The incidence of developing invasive cervical cancer during the follow-up period in women in the unscreened group is higher than that in the screened group. When a woman presents with ASC-US as her first abnormal cytologic report, the previous screening history should be considered for cervical cancer risk assessment. Previous investigators also report that one third to one half of women with CIN 2/3 lesions are reported to have ASC as their initial abnormal cervical cytologic result.10,20 Older women having higher incidences of developing cervical cancer also was noted in the unscreened group in this survey. Taken together, the HPV DNA test or colposcopic examination is recommended for those previously unscreened woman with cytologic ASC-US.
The limitation of this study is the lack of HPV DNA testing for women with cytologic ASC-US; the HPV DNA test is not included in the national screening program in Taiwan. The HPV test has been recommended as a useful and economic triage test for women with cytologic ASC-US.21–23 Several studies also demonstrate the usefulness of HPV testing in the assessment of ASC-US Pap test results.24,25 Safaeian et al26 found that only 22 of 1,559 (1.4%) women with HPV-negative cytologic ASC-US had subsequent CIN 3 or worse in the subsequent 2 years, similar to women with a negative cytology in the absence of HPV testing. Women with HPV-negative cytologic ASC-US should have follow-up Pap testing in 1 year. The role of the HPV DNA test in women with cytologic ASC-US with or without previous screening history can be further analyzed in the future.
The current population-based, nationwide study allows for the comprehensive inclusion of all cases of ASC-US for analysis. The specimens for cytopathology evaluation were collected nationwide for cervical cancer screening in this study. Most of the patients were asymptomatic and at low risk for cervical cancer. Although there is no information on other risk factors, such as HPV infection, this study still provides important information about the effect of screening on the outcome of patients with first-time ASC-US results.
1. Chen CJ, You SL, Lin LH, Hsu WL, Yang YW. Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol 2002;32:S66–81.
2. Chen CJ, You SL. Epidemiology of cervical cancer in Taiwan. Gynecol Oncol 1997;67:115–6.
3. Wright TC Jr. Cervical cancer screening in the 21st century: is it time to retire the PAP smear? Clin Obstet Gynecol 2007;50:313–23.
4. Papanicolaou GN. A new procedure for staining vaginal smears. Science 1942;95:438–9.
5. Gatscha RM, Abadi M, Babore S, Chhieng D, Miller MJ, Saigo PE. Smears diagnosed as ASCUS: interobserver variation and follow-up. Diagn Cytopathol 2001;25:138–40.
6. 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.
7. 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;27:153–7.
8. Moodley JR, Hoffman M, Carrara H, Allan BR, Cooper DD, Rosenberg L, et al. HIV and pre-neoplastic and neoplastic lesions of the cervix in South Africa: a case-control study. BMC Cancer 2006;6:135–40.
9. 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;24:276–82.
10. 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;91:973–6.
11. Nygard JF, Sauer T, Skjeldestad FE, Skare GB, Thoresen SO. CIN 2/3 and cervical cancer after an ASCUS pap smear. A 7-year, prospective study of the Norwegian population-based, coordinated screening program. Acta Cytol 2003;47:991–1000.
12. Eltoum IA, Chhieng DC, Crowe DR, Roberson J, Jin G, Broker TR. Significance and possible causes of false-negative results of reflex human Papillomavirus infection testing. Cancer 2007;111:154–9.
13. Barcelos AC, Adad SJ, Michelin MA, Murta EF. Atypical squamous cells of undetermined significance: analysis of microbiology, cytological criteria and clinical conduct. Tumori 2006;92:213–8.
14. Sodhani P, Gupta S, Singh V, Sehgal A, Mitra AB. Eliminating the diagnosis atypical squamous cells of undetermined significance: impact on the accuracy of the Papanicolaou test. Acta Cytol 2004;48:783–7.
15. Arora CD, Schmidt DS, Rader AE, Abdul-Karim F, Lazebnik R. Adolescents with ASCUS: are they a high risk group? Clin Pediatr (Phila) 2001;40:133–8.
16. Raab SS, Bishop NS, Zaleski MS. Long-term outcome and relative risk in women with atypical squamous cells of undetermined significance. Am J Clin Pathol 1999;112:57–62.
17. Cheung AN, Szeto EF, Ng KM, Fong KW, Yeung AC, Tsun OK, et al. Atypical squamous cells of undetermined significance on cervical smears: follow-up study of an Asian screening population. Cancer 2004;102:74–80.
18. Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ; 2001 ASCCP-sponsored consensus conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120–9.
19. Parham GP, Shaver M, Brown P, Zumwalt T, Salem F, Savage EW. Significance of a first-time atypical Papanicolaou smear in a young, high-risk African-American and Latino-American population. J Natl Med Assoc 1994;86:273–7.
20. Lonky NM, Sadeghi M, Tsadik GW, Petitti D. The clinical significance of the poor correlation of cervical dysplasia and cervical malignancy with referral cytologic results. Am J Obstet Gynecol 1999;181:560–6.
21. Cox JT. Clinical role of HPV testing. Obstet Gynecol Clin North Am 1996;23:811–51.
22. Cox JT. American Society for Colposcopy and Cervical Pathology. The clinician’s view: role of human papillomavirus testing in the American Society for Colposcopy and Cervical Pathology Guidelines for the management of abnormal cervical cytology and cervical cancer precursors. Arch Pathol Lab Med 2003;127:950–8.
23. ASCUS-LSIL Traige Study (ALTS) Group. A randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:1383–92.
24. Wright JD, Herzog TJ, Mutch DG, Gibb RK, Rader JS, Davila RM, et al. Liquid-based cytology for the postirradiation surveillance of women with gynecologic malignancies. Gynecol Oncol 2003;91:134–8.
25. Manos MM, Kinney WK, Hurley LB, Sherman ME, Shieh-Ngai J, Kurman RJ, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999;281:1605–10.
© 2009 by The American College of Obstetricians and Gynecologists.
26. Safaeian M, Solomon D, Wacholder S, Schiffman M, Castle P. Risk of precancer and follow-up management strategies for women with human papillomavirus-negative atypical squamous cells of undetermined significance. Obstet Gynecol 2007;109:1325–31.