Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test

Maria Kyrgiou, Ilkka E. J. Kalliala, Anita Mitra , Christina Fotopoulou, Sadaf Ghaem-Maghami, Pierre P. L. Martin-Hirsch, Margaret Cruickshank, Marc Arbyn, Evangelos Paraskevaidis

Research output: Contribution to journalArticle

3 Citations (Scopus)
5 Downloads (Pure)

Abstract

Background

A significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease.
Objectives

To assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV (human papillomavirus) DNA test.
Search methods

We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2016), MEDLINE (1946 to April week 2 2016) and Embase (1980 to 2016 week 16).
Selection criteria

We included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis).
Data collection and analysis

The primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measures studied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.

We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model with inverse variance weighting. Inter-study heterogeneity was assessed with I2 statistics.
Main results

We identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I2 greater than 90%). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality.

When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I2 greater than 60%) and we considered the evidence to be of moderate quality).

The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence).

Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 95% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moderate-quality evidence).
Authors' conclusions

Based on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.
Original languageEnglish
Article numberCD009836
Number of pages65
JournalCochrane Database of Systematic Reviews
Issue number1
Early online date26 Jan 2017
DOIs
Publication statusPublished - 2017

Fingerprint

Colposcopy
Referral and Consultation
Odds Ratio
Confidence Intervals
Cell Biology
Human Papillomavirus DNA Tests
Randomized Controlled Trials
Outcome Assessment (Health Care)
Neoplasms
Triage
Incidence

Cite this

Kyrgiou, M., Kalliala, I. E. J., Mitra , A., Fotopoulou, C., Ghaem-Maghami, S., Martin-Hirsch, P. P. L., ... Paraskevaidis, E. (2017). Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test. Cochrane Database of Systematic Reviews, (1), [CD009836]. https://doi.org/10.1002/14651858.CD009836.pub2

Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test. / Kyrgiou, Maria; Kalliala, Ilkka E. J.; Mitra , Anita; Fotopoulou, Christina; Ghaem-Maghami, Sadaf; Martin-Hirsch, Pierre P. L.; Cruickshank, Margaret; Arbyn, Marc; Paraskevaidis, Evangelos.

In: Cochrane Database of Systematic Reviews, No. 1, CD009836, 2017.

Research output: Contribution to journalArticle

Kyrgiou, Maria ; Kalliala, Ilkka E. J. ; Mitra , Anita ; Fotopoulou, Christina ; Ghaem-Maghami, Sadaf ; Martin-Hirsch, Pierre P. L. ; Cruickshank, Margaret ; Arbyn, Marc ; Paraskevaidis, Evangelos. / Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test. In: Cochrane Database of Systematic Reviews. 2017 ; No. 1.
@article{bf6fbdfe0fef45e8bebf6b174ab6c0ed,
title = "Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test",
abstract = "BackgroundA significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease.ObjectivesTo assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV (human papillomavirus) DNA test.Search methodsWe searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2016), MEDLINE (1946 to April week 2 2016) and Embase (1980 to 2016 week 16).Selection criteriaWe included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis).Data collection and analysisThe primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measures studied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95{\%} confidence intervals (CI) using a random-effects model with inverse variance weighting. Inter-study heterogeneity was assessed with I2 statistics.Main resultsWe identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9{\%} versus 18.3{\%}, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3{\%} versus 11.9{\%}, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I2 greater than 90{\%}). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality.When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3{\%} versus 10.1{\%}, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8{\%} versus 6.9{\%}, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I2 greater than 60{\%}) and we considered the evidence to be of moderate quality).The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32{\%} versus 21{\%}, RR 1.49, 95{\%} CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64{\%} versus 32{\%}, RR 2.02, 95{\%} CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21{\%} versus 8{\%}, RR 2.58, 95{\%} CI 1.69 to 3.94, moderate-quality evidence).Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3{\%} versus 13.3{\%}, RR 3.85, 95{\%} CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3{\%} versus 14.8{\%}, RR 6.39, 95{\%} CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9{\%} versus 16.1{\%}, RR 19.1, 95{\%} CI 9.02 to 40.43, moderate-quality evidence).Authors' conclusionsBased on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.",
author = "Maria Kyrgiou and Kalliala, {Ilkka E. J.} and Anita Mitra and Christina Fotopoulou and Sadaf Ghaem-Maghami and Martin-Hirsch, {Pierre P. L.} and Margaret Cruickshank and Marc Arbyn and Evangelos Paraskevaidis",
note = "A C K N O W L E D G E M E N T S The authors wish to acknowledge Jo Morrison for her clinical and editorial advice, Jane Hayes f or designing the search strategy and Gail Quinn, Clare Jess and Tracey Bishop for their contribution to the editorial process.This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors andd o not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.",
year = "2017",
doi = "10.1002/14651858.CD009836.pub2",
language = "English",
journal = "Cochrane Database of Systematic Reviews",
issn = "1469-493X",
publisher = "Wiley",
number = "1",

}

TY - JOUR

T1 - Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test

AU - Kyrgiou, Maria

AU - Kalliala, Ilkka E. J.

AU - Mitra , Anita

AU - Fotopoulou, Christina

AU - Ghaem-Maghami, Sadaf

AU - Martin-Hirsch, Pierre P. L.

AU - Cruickshank, Margaret

AU - Arbyn, Marc

AU - Paraskevaidis, Evangelos

N1 - A C K N O W L E D G E M E N T S The authors wish to acknowledge Jo Morrison for her clinical and editorial advice, Jane Hayes f or designing the search strategy and Gail Quinn, Clare Jess and Tracey Bishop for their contribution to the editorial process.This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors andd o not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

PY - 2017

Y1 - 2017

N2 - BackgroundA significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease.ObjectivesTo assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV (human papillomavirus) DNA test.Search methodsWe searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2016), MEDLINE (1946 to April week 2 2016) and Embase (1980 to 2016 week 16).Selection criteriaWe included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis).Data collection and analysisThe primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measures studied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model with inverse variance weighting. Inter-study heterogeneity was assessed with I2 statistics.Main resultsWe identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I2 greater than 90%). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality.When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I2 greater than 60%) and we considered the evidence to be of moderate quality).The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence).Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 95% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moderate-quality evidence).Authors' conclusionsBased on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.

AB - BackgroundA significant number of women are diagnosed with minor cytological abnormalities on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease.ObjectivesTo assess the optimum management strategy for women with minor cervical cytological abnormalities (atypical squamous cells of undetermined significance - ASCUS or low-grade squamous intra-epithelial lesions - LSIL) at primary screening in the absence of HPV (human papillomavirus) DNA test.Search methodsWe searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2016), MEDLINE (1946 to April week 2 2016) and Embase (1980 to 2016 week 16).Selection criteriaWe included randomised controlled trials (RCTs) comparing immediate colposcopy to cytological surveillance in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis).Data collection and analysisThe primary outcome measure studied was the occurrence of cervical intra-epithelial neoplasia (CIN). The secondary outcome measures studied included default rate, clinically significant anxiety and depression, and other self-reported adverse effects.We classified studies according to period of surveillance, at 6, 12, 24 or 36 months, as well as at 18 months, excluding a possible exit-examination. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using a random-effects model with inverse variance weighting. Inter-study heterogeneity was assessed with I2 statistics.Main resultsWe identified five RCTs with 11,466 participants that fulfilled the inclusion criteria. There were 18 cases of invasive cervical cancer, seven in the immediate colposcopy and 11 in the cytological surveillance groups, respectively. Although immediate colposcopy detects CIN2+ and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN2+: 3 studies, 4331 women; 17.9% versus 18.3%, RR 1.14, CI 0.66 to 1.97; CIN3+: 3 studies, 4331 women; 10.3% versus 11.9%, RR 1.02, CI 0.53 to 1.97). The inter-study heterogeneity was considerable (I2 greater than 90%). Furthermore, the inclusion of the results of the exit examinations at 24 months, which could inflate the CIN detection rate of cytological surveillance, may have led to study design-derived bias; we therefore considered the evidence to be of low quality.When we excluded the exit examination, the detection rate of high-grade lesions at the 18-month follow-up was higher after immediate colposcopy (CIN2+: 2 studies, 4028 women; 14.3% versus 10.1%, RR 1.50, CI 1.12 to 2.01; CIN3+: 2 studies, 4028 women, 7.8% versus 6.9%, RR 1.24, CI 0.77 to 1.98) both had substantial inter-study heterogeneity (I2 greater than 60%) and we considered the evidence to be of moderate quality).The meta-analysis revealed that immediate referral to colposcopy significantly increased the detection of clinically insignificant cervical abnormalities, as opposed to repeat cytology after 24 months of surveillance (occurrence of koilocytosis: 2 studies, 656 women; 32% versus 21%, RR 1.49, 95% CI 1.17 to 1.90; moderate-quality evidence) incidence of any CIN: 2 studies, 656 women; 64% versus 32%, RR 2.02, 95% CI 1.33 to 3.08, low-quality evidence; incidence of CIN1: 2 studies, 656 women; 21% versus 8%, RR 2.58, 95% CI 1.69 to 3.94, moderate-quality evidence).Due to differences in trial designs and settings, there was large variation in default rates between the included studies. The risk for default was higher for the repeat cytology group, with a four-fold increase at 6 months, a six-fold at 12 and a 19-fold at 24 months (6 months: 3 studies, 5117 women; 6.3% versus 13.3%, RR 3.85, 95% CI 1.27 to 11.63, moderate-quality evidence; 12 months: 3 studies, 5115 women; 6.3% versus 14.8%, RR 6.39, 95% CI 1.49 to 29.29, moderate-quality evidence; 24 months: 3 studies, 4331 women; 0.9% versus 16.1%, RR 19.1, 95% CI 9.02 to 40.43, moderate-quality evidence).Authors' conclusionsBased on low- or moderate-quality evidence using the GRADE approach and generally low risk of bias, the detection rate of CIN2+ or CIN3+ after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing, although women may default from follow-up. Immediate colposcopy probably leads to earlier detection of high-grade lesions, but also detects more clinically insignificant low-grade lesions. Colposcopy may therefore be the first choice when good compliance is not assured. These results emphasize the need for an accurate reflex HPV triage test to distinguish women who need diagnostic follow-up from those who can return safely to routine recall.

U2 - 10.1002/14651858.CD009836.pub2

DO - 10.1002/14651858.CD009836.pub2

M3 - Article

JO - Cochrane Database of Systematic Reviews

JF - Cochrane Database of Systematic Reviews

SN - 1469-493X

IS - 1

M1 - CD009836

ER -