Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: a population-based cohort study

Yi-Jou Tai; Yun-Yuan Chen; Huang-Cheng Hsu; Chun-Ju Chiang; San-Lin You; Chi-An Chen; Wen-Fang Cheng

doi:10.3802/jgo.2018.29.e55

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Tai, Chen, Hsu, Chiang, You, Chen, and Cheng: Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: a population-based cohort study

Original Article

J Gynecol Oncol 2018;29(4):e55.

Published online: 4 July 2018

DOI: https://doi.org/10.3802/jgo.2018.29.e55

Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: a population-based cohort study

Yi-Jou Tai^1,², Yun-Yuan Chen^1,³, Huang-Cheng Hsu¹, Chun-Ju Chiang^4,⁵, San-Lin You⁶, Chi-An Chen^1,, Wen-Fang Cheng^1,^2,⁷

¹Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan

²Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

³Taiwan Blood Services Foundation, Taipei, Taiwan

⁴Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan

⁵Taiwan Cancer Registry, Taipei, Taiwan

⁶Department of Public Health, College of Medicine and Big Data Research Centre, Fu-Jen Catholic University, New Taipei City, Taiwan

⁷Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

Correspondence to Chi-An Chen Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan. E-mail: chianchen@ntu.edu.tw

Received 18 December 2017 Revised 21 February 2018 Accepted 6 036 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

To investigate the progression risk of atypical squamous cells of undetermined significance (ASCUS) with different clinical managements.

Methods

Women with their first diagnosis of ASCUS cytology were retrieved from the national cervical cancer screening database and linked to the national health insurance research database to identify the management of these women. The incidences of developing cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+) were calculated, and the hazard ratios (HRs) were estimated using a Cox proportional hazards model. This study was approved by the Research Ethics Committee of the National Taiwan University Hospital and is registered at ClinicalTrials.gov (Identifier: NCT02063152).

Results

There were total 69,741 women included. Various management strategies including colposcopy, cervical biopsies and/or endocervical curettage, and cryotherapy, failed to reduce the risk of subsequent CIN3+ compared with repeat cervical smears. Loop electrosurgical excision procedure/conization significantly decreased risk of subsequent CIN3+ lesions (HR=0.22; 95% confidence interval [CI]=0.07–0.68; p=0.010). Women in their 40s–50s had an approximately 30% risk reduction compared to other age groups. Women with a previous screening history >5 years from the present ASCUS diagnosis were at increased risk for CIN3+ (HR=1.24; 95% CI=1.03–1.49; p=0.020).

Conclusion

In women of first-time ASCUS cytology, a program of repeat cytology can be an acceptable clinical option in low-resource settings. Caution should be taken especially in women with remote cervical screening history more than 5 years.

Keywords: Atypical Squamous Cells of Undetermined Significance, Cervical Intraepithelial Neoplasia Grade III, Uterine Cervical Neoplasms, Colposcopy, Cervical Biopsy, Cryotherapy

References

1. Papanicolaou GN, Traut HF. Diagnosis of uterine cancer by the vaginal smear. New York, NY: Commonwealth Fund;1943.

2. Ayre JE. Selective cytologic smear for the diagnosis of cancer. Am J Obstet Gynecol. 1947; 53:609–17.

3. Gagnon F. Contribution to the study of the etiology and prevention of cancer of the cervix of the uterus. Am J Obstet Gynecol. 1950; 60:516–22.

4. Chen YY, You SL, Chen CA, Shih LY, Koong SL, Chao KY, et al. Effectiveness of national cervical cancer screening programme in Taiwan: 12-year experiences. Br J Cancer. 2009; 101:174–7.

5. Davey DD, Neal MH, Wilbur DC, Colgan TJ, Styer PE, Mody DR. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2004; 128:1224–9.

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. Bulten J, de Wilde PC, Boonstra H, Gemmink JH, Hanselaar AG. Proliferation in “atypical” atrophic Pap smears. Gynecol Oncol. 2000; 79:225–9.

8. Saminathan T, Lahoti C, Kannan V, Kline TS. Postmenopausal squamous-cell atypias: a diagnostic challenge. Diagn Cytopathol. 1994; 11:226–30.

9. Solomon D, Schiffman M. Tarone RALTS Study group. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst. 2001; 93:293–9.

10. 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.

11. Siebers AG, Arbyn M, Melchers WJ, van Kemenade FJ, Vedder JE, van der Linden H, et al. Effectiveness of two strategies to follow-up ASC-US and LSIL screening results in the Netherlands using repeat cytology with or without additional hrHPV testing: a retrospective cohort study. Cancer Causes Control. 2014; 25:1141–9.

12. Wen CP, Tsai SP, Chung WS. A 10-year experience with universal health insurance in Taiwan: measuring changes in health and health disparity. Ann Intern Med. 2008; 148:258–67.

13. Lu TH, Lee MC, Chou MC. Accuracy of cause-of-death coding in Taiwan: types of miscoding and effects on mortality statistics. Int J Epidemiol. 2000; 29:336–43.

14. Cheng WF, Huang CY, You SL, Chen CJ, Hu CH, Chen CA. Clinical significance of cytologic atypical squamous cells of undetermined significance. Obstet Gynecol. 2009; 113:888–94.

15. Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993; 12:186–92.

16. Winer RL, Hughes JP, Feng Q, Xi LF, Cherne S, O'Reilly S, et al. Early natural history of incident, type-specific human papillomavirus infections in newly sexually active young women. Cancer Epidemiol Biomarkers Prev. 2011; 20:699–707.

17. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998; 338:423–8.

18. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999; 91:252–8.

19. Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the effectiveness of cryotherapy in the treatment of cervical intraepithelial neoplasia. Int J Gynaecol Obstet. 2013; 120:218–23.

20. Chumworathayi B, Thinkhamrop J, Blumenthal PD, Thinkhamrop B, Pientong C, Ekalaksananan T. Cryotherapy for HPV clearance in women with biopsy-confirmed cervical low-grade squamous intraepithelial lesions. Int J Gynaecol Obstet. 2010; 108:119–22.

21. Poomtavorn Y, Suwannarurk K, Thaweekul Y, Maireang K. Diagnostic value of endocervical curettage for detecting dysplastic lesions in women with atypical squamous cells of undetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL) Papanicolaou smears. Asian Pac J Cancer Prev. 2014; 15:3461–4.

22. Jakobsson M, Gissler M, Paavonen J, Tapper AM. Loop electrosurgical excision procedure and the risk for preterm birth. Obstet Gynecol. 2009; 114:504–10.

23. Bevis KS, Biggio JR. Cervical conization and the risk of preterm delivery. Am J Obstet Gynecol. 2011; 205:19–27.

24. de Sanjosé S, Diaz M, Castellsagué X, Clifford G, Bruni L, Muñoz N, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007; 7:453–9.

25. Chiang YC, Cheng WF, Chen YL, Chang MC, Hsieh CY, Lin MC, et al. High-risk human papillomavirus, other than type 16/18, in predominantly older Taiwanese women with high-grade cervical preinvasive lesions. Taiwan J Obstet Gynecol. 2013; 52:222–6.

26. Hammer A, Mejlgaard E, Gravitt P, Høgdall E, Christiansen P, Steiniche T, et al. HPV genotype distribution in older Danish women undergoing surgery due to cervical cancer. Acta Obstet Gynecol Scand. 2015; 94:1262–8.

27. Chen CA, Liu CY, Chou HH, Chou CY, Ho CM, Twu NF, et al. The distribution and differential risks of human papillomavirus genotypes in cervical preinvasive lesions: a Taiwan Cooperative Oncologic Group Study. Int J Gynecol Cancer. 2006; 16:1801–8.

28. Bentley JSociety of Canadian Colposcopists. Colposcopic management of abnormal cervical cytology and histology. J Obstet Gynaecol Can. 2012; 34:1188–202.

29. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013; 17:S1–27.

30. 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 Papnicolaou results. JAMA. 1999; 281:1605–10.

Fig. 1.

Flow of the study population among all women who attended cervical cancer screening with ASCUS cytology during 2004–2007. ASCUS, atypical squamous cells of undetermined significance; CIN3+, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer; ECC, endocervical curettage; LEEP, loop electrosurgical excision procedure.

Fig. 2.

Survival analysis of subsequent risk for CIN3+ diagnosis in 69,741 women with ASCUS cytology according to management. X-axis refers to follow-up time in months since 1 year after the ASCUS cytology. Y-axis refers to cumulative incidence of subsequent CIN3+. ASCUS, atypical squamous cells of undetermined significance; CIN3+, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer; ECC, endocervical curettage; LEEP, loop electrosurgical excision procedure.

Table 1.

Baseline characteristics of 69,741 women with ASCUS cytology according to age distribution, screening interval, educational status, management, and incidence of subsequent CIN3+

Characteristics	No. of ASCUS patients	Person-years of follow-up	No. of CIN3	No. of invasive cancer	No. of p CIN3+	Incidence of CIN3+ per 100,000 person-years^*
Total	69,741	266,011	669	103	772	290.2
Age (yr)
20–29	6,136	24,263	71	3	74	305.0
30–39	19,193	73,320	227	29	256	349.2
40–49	22,448	85,621	179	42	221	258.1
50–59	13,999	52,798	100	19	119	225.4
60–69	5,423	20,580	68	5	73	354.7
>70	2,542	9,429	24	5	29	307.6
Previous screening interval (yr)
<1	15,368	60,333	105	22	127	210.5
1–3	31,505	118,413	307	23	330	278.7
3–5	7,927	29,703	84	23	107	360.2
>5 or never	14,941	57,562	173	35	208	361.3
Educational status
<6 years of schooling	15,210	58,696	146	28	174	296.4
Junior high school	11,923	45,686	115	19	134	293.3
Senior high school	24,541	93,593	242	45	287	306.6
College or graduate school	17,412	65,567	165	11	176	268.4
Management
No management	18,028	68,557	198	59	257	374.9
Non-interventional procedures
Repeated Pap smear	26,000	99,659	232	27	259	259.9
Colposcopy	3,841	14,208	28	4	32	225.2
Cervical biopsy and/or ECC	15,535	58,765	172	6	178	302.9
Interventional procedures
Cryotherapy	5,210	20,267	36	7	43	212.2
LEEP/conization	1,127	4,555	3	0	3	65.9

Data are number (%) unless otherwise specified.

ASCUS, atypical squamous cells of undetermined significance; CIN3, cervical intraepithelial neoplasia grade 3; CIN3+, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer; ECC, endocervical curettage; LEEP, loop electrosurgical excision procedure.

^* Age-adjusted incidence rate of CIN3+ per 100,000 person-years.

Table 2.

Multivariate analysis of the risk of subsequent CIN3+ lesion in 69,741 women with ASCUS cytology

Variables	HR	95% CI of HR	p
Age (yr)
20–29	0.77	0.59–1.00	0.060
30–39	1.00
40–49	0.73	0.60–0.88	<0.001
50–59	0.61	0.48–0.78	<0.001
60–69	0.90	0.66–1.23	0.500
>70	0.72	0.47–1.11	0.140
Previous screening interval (yr)
<1	0.77	0.62–0.94	0.010
1–3	1.00
3–5	1.25	1.00–1.55	0.050
>5 or never	1.24	1.03–1.49	0.020
Educational status
<6 years of schooling	1.00
Junior high school	0.98	0.76–1.26	0.860
Senior high school	0.96	0.75–1.22	0.720
College or graduate school	0.80	0.61–1.04	0.100
Management
No management	1.39	1.17–1.66	<0.001
Non-interventional procedures
Repeated Pap smear	1.00
Colposcopy	0.80	0.55–1.16	0.240
Cervical biopsy and/or ECC	1.05	0.87–1.28	0.590
Interventional procedures
Cryotherapy	0.76	0.55–1.05	0.100
LEEP/conization	0.22	0.07–0.68	0.010

ASCUS, atypical squamous cells of undetermined significance; CI, confidence interval; CIN3+, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer; ECC, endocervical curettage; HR, hazard ratio; LEEP, loop electrosurgical excision procedure.

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