The role of human papillomavirus testing in the management of women with low-grade abnormalities

multicentre randomised controlled trial

S Cotton, L Sharp, J Little, M Cruickshank, R Seth, L Smart, I Duncan, K Harrild, K Neal, N Waugh, The TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) Group

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objective To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ).

Design Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ.

Setting Grampian, Tayside and Nottingham.

Population Women (n = 4439), aged 20–59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002.

Methods High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined.

Main outcome measures Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy.

Results There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8–81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7–77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5–74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2–51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9–96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years.

Conclusions We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.
Original languageEnglish
Pages (from-to)645-659
Number of pages15
JournalBJOG-An International Journal of Obstetrics and Gynaecology
Volume117
Issue number6
Early online date18 Mar 2010
DOIs
Publication statusPublished - May 2010

Fingerprint

Randomized Controlled Trials
Colposcopy
Cervical Intraepithelial Neoplasia
Referral and Consultation
Short-Term Memory
Biopsy
Cell Biology
Random Allocation
Primary Health Care
Decision Making
Appointments and Schedules
Outcome Assessment (Health Care)
Sensitivity and Specificity
Polymerase Chain Reaction

Keywords

  • HPV cervical cancer colposcopy
  • borderline nuclear abnormality
  • cervical intraepithelial neoplasia
  • cervical screening
  • cytological surveillance
  • colposcopy
  • follow-up
  • human papillomavirus
  • low-grade abnormalities
  • management
  • mass screening
  • mild dyskaryosis
  • randomised controlled trial

Cite this

The role of human papillomavirus testing in the management of women with low-grade abnormalities : multicentre randomised controlled trial. / Cotton, S; Sharp, L; Little, J; Cruickshank, M; Seth, R; Smart, L; Duncan, I; Harrild, K; Neal, K; Waugh, N; The TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) Group.

In: BJOG-An International Journal of Obstetrics and Gynaecology, Vol. 117, No. 6, 05.2010, p. 645-659.

Research output: Contribution to journalArticle

Cotton, S, Sharp, L, Little, J, Cruickshank, M, Seth, R, Smart, L, Duncan, I, Harrild, K, Neal, K, Waugh, N & The TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) Group 2010, 'The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial', BJOG-An International Journal of Obstetrics and Gynaecology, vol. 117, no. 6, pp. 645-659. https://doi.org/10.1111/j.1471-0528.2010.02519.x
Cotton, S ; Sharp, L ; Little, J ; Cruickshank, M ; Seth, R ; Smart, L ; Duncan, I ; Harrild, K ; Neal, K ; Waugh, N ; The TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) Group. / The role of human papillomavirus testing in the management of women with low-grade abnormalities : multicentre randomised controlled trial. In: BJOG-An International Journal of Obstetrics and Gynaecology. 2010 ; Vol. 117, No. 6. pp. 645-659.
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abstract = "Objective To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ).Design Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ.Setting Grampian, Tayside and Nottingham.Population Women (n = 4439), aged 20–59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002.Methods High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined.Main outcome measures Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy.Results There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2{\%} (95{\%} CI 68.8–81.0{\%}) among women with mild dyskaryosis and 69.9{\%} (95{\%} CI 61.7–77.3{\%}) among those with BNA. Specificity was higher in those with BNA (71.3{\%}; 95{\%} CI 68.5–74.1{\%}) than in those with mild dyskaryosis (46.9{\%}; 95{\%} CI 42.2–51.6{\%}). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5{\%}; 95{\%} CI 92.9–96.0{\%}). Across all ages, 22{\%} of women who had CIN2 or worse were HPV negative. Conversely, 40{\%} of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years.Conclusions We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.",
keywords = "HPV cervical cancer colposcopy, borderline nuclear abnormality, cervical intraepithelial neoplasia, cervical screening, cytological surveillance, colposcopy, follow-up, human papillomavirus, low-grade abnormalities, management, mass screening, mild dyskaryosis, randomised controlled trial",
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TY - JOUR

T1 - The role of human papillomavirus testing in the management of women with low-grade abnormalities

T2 - multicentre randomised controlled trial

AU - Cotton, S

AU - Sharp, L

AU - Little, J

AU - Cruickshank, M

AU - Seth, R

AU - Smart, L

AU - Duncan, I

AU - Harrild, K

AU - Neal, K

AU - Waugh, N

AU - The TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) Group

PY - 2010/5

Y1 - 2010/5

N2 - Objective To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ).Design Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ.Setting Grampian, Tayside and Nottingham.Population Women (n = 4439), aged 20–59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002.Methods High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined.Main outcome measures Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy.Results There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8–81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7–77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5–74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2–51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9–96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years.Conclusions We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.

AB - Objective To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ).Design Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ.Setting Grampian, Tayside and Nottingham.Population Women (n = 4439), aged 20–59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002.Methods High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined.Main outcome measures Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy.Results There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8–81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7–77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5–74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2–51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9–96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years.Conclusions We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.

KW - HPV cervical cancer colposcopy

KW - borderline nuclear abnormality

KW - cervical intraepithelial neoplasia

KW - cervical screening

KW - cytological surveillance

KW - colposcopy

KW - follow-up

KW - human papillomavirus

KW - low-grade abnormalities

KW - management

KW - mass screening

KW - mild dyskaryosis

KW - randomised controlled trial

U2 - 10.1111/j.1471-0528.2010.02519.x

DO - 10.1111/j.1471-0528.2010.02519.x

M3 - Article

VL - 117

SP - 645

EP - 659

JO - BJOG-An International Journal of Obstetrics and Gynaecology

JF - BJOG-An International Journal of Obstetrics and Gynaecology

SN - 1470-0328

IS - 6

ER -