The ethical committee of Radboud University Nijmegen Medical Centre stated that the current study did not fall within the purview of the Medical Research Involving Human Subjects Act. Therefore, it was possible to conduct the study without approval by an accredited research ethics committee.
Colposcopic examination is performed as an outpatient procedure at our department. Trained physicians, supervised by an experienced gynecologist, performed all examinations. After application of a 3% acetic acid solution, the transformation zone was examined.17 When the cervical smear result, the colposcopic impression of the lesion, or both was suggestive of a high-grade CIN (CIN 2 or worse), immediate treatment followed (see-and-treat approach). In the case of a low-grade cervical smear result and a low-grade colposcopic impression, no biopsy was taken and no further treatment was given. Follow-up with repeat cervical smears every 6 months was needed in all these patients. Specific circumstances made treatment preferable; eg, expected inadequate follow-up, a pregnancy wish for the near future, or complaints of a symptomatic ectropion.
When treatment was deemed necessary, local anesthesia was applied, and the whole transformation zone was removed using a low-voltage diathermy loop. This procedure is known as large loop excision of the transformation zone. After the procedure, hemostasis was obtained using diathermic coagulation. The CIN grade was determined by the pathologist using the international standard classification. In the case of an inadequate colposcopic examination, defined as an incomplete visualization of the transformation zone, no visualization of the entire lesion, if present, or no correlation between cytologic findings and the colposcopist's impression, diagnostic treatment was needed.
Some patients did not undergo a see-and-treat protocol for various reasons. Some patients preferred a biopsy first instead of treatment with the see-and-treat protocol. Other patients had lesions too large to remove in an outpatient setting or no lesion was seen during colposcopy in case of a high-grade smear result. Furthermore, some patients were too anxious to be treated in the outpatient clinic and therefore the colposcopist chose not to treat these patients in an outpatient setting.
In this study, overtreatment was defined as treatment for no CIN or low-grade CIN (CIN 1) found during final histopathology analysis. We investigated the rate of overtreatment for different subgroups. Subgroups were categorized by referral cervical smear result, colposcopic impression, histopathology results, age, and time of referral. These groups were analyzed separately and combined. For our combined analysis we excluded those patients with no referral cervical smear result, no registered colposcopic impression, or both (n=857).
For statistical analysis we used SPSS 18.0.1. Proportions were compared using χ2 tests. The effect of age on overtreatment was estimated using logistic regression adjusted for the combined effects of initial smear result and colposcopic impression. Two-sided P≤.05 was considered statistically significant.
From January 1, 1981, to December 31, 2010, a total of 4,808 women were initially referred to our clinic for colposcopic assessment. The mean age was 37 years (standard deviation 9.3 years, range 17–81 years). The referral cervical smear result showed a low-grade squamous intraepithelial lesion in 1,675 (34.8%) cases and HSIL in 3,090 (64.3%) cases. In 82 (2.7%) of HSIL cases, the smear result suggested a carcinoma (Pap 5). Histologic examination revealed 741 (15.4%) cases of no CIN or low-grade CIN and 2,985 (62.1%) cases of high-grade CIN, of which 200 (4.2%) cases of carcinoma (Table 1).
A see-and-treat protocol was used in a total of 3,192 (66%) of 4,808 patients. The mean age of the see-and-treat group was 36 years (standard deviation 8.7 years, range 17–81 years) (Table 1). A total of 78.4% of the women belonged to the age group of the population screening for cervical cancer (aged 30–60 years), 20% were younger than 30 years, and 1.6% exceeded the age-related eligibility for screening. The referral cervical smear result of 646 (20.2%, 95% confidence interval [CI] 18.8–21.7) cases showed low-grade squamous intraepithelial lesion and 2,532 (79.3%, 95% CI 77.8–80.7) cases of HSIL (Table 1). Histologic examination of the 3,192 excised samples revealed 579 cases (18.1%, 95% CI 16.7–19.5) with no CIN or low-grade CIN lesions and 2,613 cases (81.9%, 95% CI 80.6–83.2) with high-grade CIN lesions. We identified 177 cases (5.5%, 95% CI 4.8–6.4) with carcinoma. Based on the definition described in the “Methods” section, 579 (18.1%, 95% CI 16.7–19.5) women were overtreated (Table 2). Histopathology examination of cervical tissue from patients with a high-grade cervical smear result with any colposcopic impression and patients with a high-grade colposcopic impression with any smear result revealed 223 (8.8%, 95% CI 7.8–10.0) and 147 (8.1%, 95% CI 6.9–9.5) cases of no CIN or low-grade CIN, respectively. Women with a high-grade cervical smear result and a high-grade colposcopic impression were overtreated in 70 cases (4.5%, 95% CI 3.5–5.5) (Table 2).
Women aged younger than 40 years had the lowest rates of overtreatment (13.1%, 95% CI 11.7–14.5). With increasing age, the chance of unnecessary treatment rises: 24.2% (95% CI 21.2–27.4, adjusted odds ratio [OR] 1.77) for women aged 40–49 years and 42.2% (95% CI 36.5–47.7, adjusted OR 3.39) for women aged 50 years and older when compared with women aged younger than 40 years. This trend is seen for high-grade and low-grade cervical smear results, high-grade and low-grade colposcopic impression, and these groups combined (Table 3). The number needed to harm for women aged 40–49 and 50 years and older is nine and three, respectively.
In 1996, major changes were implemented in the Dutch cervical screening program. First, the CISOE-A classification for cytology was introduced and the use of this classification system increased the efficacy of screening.15 Second, the Dutch screening program changed from a 3-year program for women aged 35–55 years into a 5-year program for women aged 30–60 years. Third, more stringent criteria for cytologic diagnosis of atypical squamous cells of undetermined significance were introduced.18 Therefore, we compared overtreatment rates before and after 1996 as shown in Table 4. Except for a small but significant decrease in overtreatment rates, the group with a high-grade cervical smear result, and a high-grade colposcopic impression (P=.04), no significant differences were found between women referred before and after 1996.
Since the implementation of the see-and-treat approach in our hospital in 1980, a database has been constructed, which now results in a large, single-institution, case series. This database allowed the current study to describe age influences on the rate of overtreatment.
The overall 18.1% overtreatment rate in the group who underwent a see-and-treat protocol is quite low compared with overtreatment rates reported in other studies.19–21 In previous studies considering a see-and-treat management, a number of strategies was used to assess and treat a patient referred for colposcopy. This is the main reason why overtreatment rates in the literature range from 8.0% to as much as 83.3%.12,17,19,20,22–25 In 1990, Bigrigg and colleagues19 were the first to describe the outcome of a see-and-treat protocol and reported an overtreatment rate of 27.9%.
When a see-and-treat protocol is applied only to those women with a high-grade cervical smear result, the rate of overtreatment decreases dramatically. In the present study, we found 8.8% overtreatment for patients referred with a high-grade smear result, whereas in previous studies, the range of overtreatment varied from 3.0% to 39.4% for high-grade smear results at referral.26,27 Apart from the varying quality of laboratories and screening, a possible explanation for the variation in the rate of overtreatment in the literature is the design of the national screening program for cervical cancer in different countries. In The Netherlands, organized screening is offered to all women aged 30–60 years every 5 years, whereas other countries offer screening to a much wider group with a shorter interval.28 The percentage of abnormal cytologic smear results within these screening programs varies from 1.5% to 8% between countries.28 This may reflect differences in the prevalence of neoplastic lesions or differences in guidelines and cutoff points for referral. It is certainly clear that different rates of abnormal smear results and referral do influence the rate of overtreatment. It is also known that narrowing the screening interval increases the risk of unnecessary treatment.29
In the present study, the rate of overtreatment was lowest (2.8%) when a see-and-treat protocol was applied to women aged younger than 40 years who were referred with a high-grade cervical smear result and showed a high-grade colposcopic impression. This very low overtreatment rate must be considered “best practice” and is comparable to the lowest overtreatment rate reported in the literature. It is even lower than overtreatment rates after a two-step procedure in colposcopy clinics.30–32 The low overtreatment rate in this age group might be the result of a more conservative approach of the colposcopists to the treatment of fertile women, because of the increased risk of preterm birth, low birth weight, and premature rupture of membranes after large loop excision of the transformation zone.11,13
With increasing age, the chance of unnecessary treatment increases (adjusted OR 1.77, number needed to harm nine for women aged 40–49 years and adjusted OR 3.39, number needed to harm three for women aged 50 years and older) when compared with women aged younger than 40 years. Women aged older than 40 years, whether the lesion is high grade or low grade, might be treated more easily and at slighter pretenses than women aged younger than 40 years because fertility is no longer an issue.
Major changes implemented in the Dutch cervical screening program in 1996, as described in the “Results” section, had a great effect on the Dutch screening practice. Except for a small decrease in overtreatment rates in the group with a high-grade cervical smear result and a high-grade colposcopic impression, no significant differences were found between women referred before and after 1996. Only since 2008, high-risk HPV testing for women with a persistent borderline or mildly dyskaryotic cytology has been recommended in the Dutch guidelines. Therefore, we do not expect an effect of this recent change on the data of the current study.
Considerable research has been conducted on patient convenience and clinical and economic aspects of follow-up after an abnormal cervical smear result. A see-and-treat protocol seems to be an efficient policy, because diagnosis and treatment are combined, which results in cost savings for both the clinic and patient.8,33,34 Using a see-and-treat protocol improves patient convenience with only one disruption of the daily schedule and this increases compliance.9
One of the main criticisms of a see-and-treat procedure is the risk of overtreatment. Our study showed that the rate of overtreatment is very low when applied to a specific group of women for whom see-and-treat might be the preferred procedure. Punch biopsies and selective recall may be better for patients more likely to be overtreated, although in some cases, a see-and-treat approach is still justifiable. The results of the current study permit us to counsel patients effectively with regard to overtreatment, allowing patients to be actively involved in the decision-making so they receive care that meets their needs and wishes.
A disadvantage of this study is the lack of colposcopic impressions in 847 cases (26.5%). The largest part of these missing data (668 cases [78.9%]) was not registered in the first 10 years of data collection. These data could not be retrieved. However, the long period of study in a single institution, with prospective registration of all data, makes the outcomes a very reliable reflection of day-to-day practice at the outpatient clinic of the department.
The see-and-treat approach was also used in cases of inadequate colposcopic examination in our clinic. In these cases, we used the see-and-treat approach as a diagnostic treatment, eg, in case of high-grade endocervical cells in the cervical smear result and a normal colposcopic impression. Exact numbers of diagnostic treatment in these cases could not be established but are expected to be low and supposedly have no influence on the overall overtreatment rate.
In conclusion, this study shows that the overtreatment rate is low for patients in all age groups who were referred with a high-grade smear result and subsequently were found to have a high-grade colposcopic impression. We strongly recommend a see-and-treat approach as the preferred management strategy to be adopted for these patients. For patients in all age groups referred with a low-grade smear result and with a low-grade colposcopic impression, conservative management and surveillance with repeated cytology and colposcopy to exclude progression to (micro)invasive cervical cancer should be adopted. In women with either a high-grade smear result or high-grade colposcopic impression, a see-and-treat approach may still be preferred but has higher overtreatment rates. Given the side effects of cervical surgery on pregnancy outcome, young women may benefit from a two-step approach. Older women may prefer a see-and-treat policy.
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917.
2. Baron RC, Melillo S, Rimer BK, Coates RJ, Kerner J, Habarta N, et al.. Intervention to increase recommendation and delivery of screening for breast, cervical, and colorectal cancers by healthcare providers: a systematic review of provider reminders. Am J Prev Med 2010;38:110–7.
3. Rebolj M, van Ballegooijen M, Berkers LM, Habbema D. Monitoring a national cancer prevention program: successful changes in cervical cancer screening in the Netherlands. Int J Cancer 2007;120:806–12.
4. Council NHI. Starting points for the restructuring of the organised cervical cancer screening programme—final decision [in Dutch]. Amstelveen (The Netherlands): ZiekenfondsRaad; 1993.
5. Gustafsson L, Ponten J, Zack M, Adami HO. International incidence rates of invasive cervical cancer after introduction of cytological screening. Cancer Causes Control 1997;8:755–63.
6. de Kok IM, van der Aa MA, van Ballegooijen M, Siesling S, Karim-Kos HE, van Kemenade FJ, et al.. Trends in cervical cancer in the Netherlands until 2007: has the bottom been reached? Int J Cancer 2011;128:2174–81.
8. Holschneider CH, Ghosh K, Montz FJ. See-and-treat in the management of high-grade squamous intraepithelial lesions of the cervix: a resource utilization analysis. Obstet Gynecol 1999;94:377–85.
9. Balasubramani L, Orbell S, Hagger M, Brown V, Tidy J. Do women with high-grade cervical intraepithelial neoplasia prefer a see and treat option in colposcopy? BJOG 2007;114:39–45.
10. Mitchell MF, Tortolero-Luna G, Cook E, Whittaker L, Rhodes-Morris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstet Gynecol 1998;92:737–44.
11. Crane JM. Pregnancy outcome after loop electrosurgical excision procedure: a systematic review. Obstet Gynecol 2003;102:1058–62.
12. Cardenas-Turanzas M, Follen M, Benedet JL, Cantor SB. See-and-treat strategy for diagnosis and management of cervical squamous intraepithelial lesions. Lancet Oncol 2005;6:43–50.
13. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489–98.
14. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, et al.. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008;337:a1284.
15. Bulk S, Van Kemenade FJ, Rozendaal L, Meijer CJ. The Dutch CISOE-A framework for cytology reporting increases efficacy of screening upon standardisation since 1996. J Clin Pathol 2004;57:388–93.
16. 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.
17. Keijser KG, Kenemans P, van der Zanden PH, Schijf CP, Vooijs GP, Rolland R. Diathermy loop excision in the management of cervical intraepithelial neoplasia: diagnosis and treatment in one procedure. Am J Obstet Gynecol 1992;166:1281–7.
18. Briet MC, Berger TH, van Ballegooijen M, Boon ME, Rebolj M. Effects of streamlining cervical cancer screening the Dutch way: consequences of changes in the Dutch KOPAC-based follow-up protocol and consensus-based limitation of equivocal cytology. Acta Cytol 2010;54:1095–100.
19. Bigrigg MA, Codling BW, Pearson P, Read MD, Swingler GR. Colposcopic diagnosis and treatment of cervical dysplasia at a single clinic visit. Experience of low-voltage diathermy loop in 1000 patients. Lancet 1990;336:229–31.
20. Hallam NF, West J, Harper C, Edwards A, Hope S, Merriman H, et al.. Large loop excision of the transformation zone (LLETZ) as an alternative to both local ablative and cone biopsy treatment: a series of 1000 patients. J Gynecol Surg 1993;9:77–82.
21. Kjellberg L, Tavelin B. ‘See and treat’ regime by LEEP conisation is a safe and time saving procedure among women with cytological high-grade squamous intraepithelial lesion. Acta Obstet Gynecol Scand 2007;86:1140–4.
22. Darwish A, Gadallah H. One-step management of cervical lesions. Int J Gynaecol Obstet 1998;61:261–7.
23. TOMBOLA Group. Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy: multicentre randomised controlled trial. BMJ 2009;339:b2548.
24. Das SS, Elias AH. Diagnosis and treatment of cervical intraepithelial neoplasia in a single visit. Aust N Z J Obstet Gynaecol 1998;38:246–50.
25. Numnum TM, Kirby TO, Leath CA 3rd, Huh WK, Alvarez RD, Straughn JM Jr. A prospective evaluation of ‘see and treat’ in women with HSIL Pap smear results: is this an appropriate strategy? J Low Genit Tract Dis 2005;9:2–6.
26. Dunn TS, Burke M, Shwayder J. A ‘see and treat’ management for high-grade squamous intraepithelial lesion Pap smears. J Lower Genit Tract Dis 2003;7:104–6.
27. Szurkus DC, Harrison TA. Loop excision for high-grade squamous intraepithelial lesion on cytology: correlation with colposcopic and histologic findings. Am J Obstet Gynecol 2003;188:1180–2.
28. van Ballegooijen M, van den Akker-van Marle E, Patnick J, Lynge E, Arbyn M, Anttila A, et al.. Overview of important cervical cancer screening process values in European Union (EU) countries, and tentative predictions of the corresponding effectiveness and cost-effectiveness. Eur J Cancer 2000;36:2177–88.
29. van Ballegooijen M, Koopmanschap MA, van Oortmarssen GJ, Habbema JD, Lubbe KT, van Agt HM. Diagnostic and treatment procedures induced by cervical cancer screening. Eur J Cancer 1990;26:941–5.
30. Sadan O, Yarden H, Schejter E, Bilavski E, Bachar R, Lurie S. Treatment of high-grade squamous intraepithelial lesions: a ‘see and treat’ versus a three-step approach. Eur J Obstet Gynecol Reprod Biol 2007;131:73–5.
31. Denny LA, Soeters R, Dehaeck K, Bloch B. Does colposcopically directed punch biopsy reduce the incidence of negative LLETZ? Br J Obstet Gynaecol 1995;102:545–8.
32. Li ZG, Qian de Y, Cen JM, Chen GD, Shu YH. Three-step versus ‘see-and-treat’ approach in women with high-grade squamous intraepithelial lesions in a low-resource country. Int J Gynaecol Obstet 2009;106:202–5.
33. Fung HY, Cheung LP, Rogers MS, To KF. The treatment of cervical intra-epithelial neoplasia: when could we ‘see and loop.' Eur J Obstet Gynecol Reprod Biol 1997;72:199–204.
© 2013 The American College of Obstetricians and Gynecologists
34. Cantor SB, Mitchell MF, Tortolero-Luna G, Bratka CS, Bodurka DC, Richards-Kortum R. Cost-effectiveness analysis of diagnosis and management of cervical squamous intraepithelial lesions. Obstet Gynecol 1998;91:270–7.