Group members are listed at the end of the report.
The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial
Article first published online: 18 MAR 2010
© 2010 The Authors Journal compilation © RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
BJOG: An International Journal of Obstetrics & Gynaecology
Volume 117, Issue 6, pages 645–659, May 2010
How to Cite
Cotton, S., Sharp, L., Little, J., Cruickshank, M., Seth, R., Smart, L., Duncan, I., Harrild, K., Neal, K., Waugh, N. and 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 & Gynaecology, 117: 645–659. doi: 10.1111/j.1471-0528.2010.02519.x
Name of trial, registration: TOMBOLA (Trial of Management of Borderline and Other Low-grade Abnormal smears), ISRCTN 34841617.
- Issue published online: 8 APR 2010
- Article first published online: 18 MAR 2010
- Accepted 20 December 2009. Published Online 18 March 2010.
- Borderline nuclear abnormality;
- cervical intraepithelial neoplasia;
- cervical screening;
- cytological surveillance;
- human papillomavirus;
- low-grade abnormalities;
- mass screening;
- mild dyskaryosis;
- randomised controlled trial
Please cite this paper as: 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. BJOG 2010; DOI: 10.1111/j.1471-0528.2010.02519.x.
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.