# Long-Term Reassurance with Negative High-Risk Human Papillomavirus (HR-HPV) and Clear Margins After Large Loop Excision of the Transformation Zone (LLETZ)

## TL;DR

This study shows that negative HPV and clear surgical margins after LLETZ treatment for cervical cancer precursors strongly reduce long-term recurrence risk.

## Contribution

The study identifies HR-HPV negativity and clear margins as the strongest predictors of long-term reassurance after LLETZ, surpassing traditional surgical metrics.

## Key findings

- Negative HR-HPV and clear surgical margins post-LLETZ are strongly associated with reduced persistent/recurrent CIN2-3 risk.
- Over 90% of CIN2-3 recurrences occurred within 5 years post-LLETZ.
- LLETZ characteristics like cone length and excision type correlate with clear margins but not long-term outcomes.

## Abstract

Cervical intraepithelial neoplasia grade 2-3 (CIN2-3) is often treated by large loop excision of the transformation zone (LLETZ) to prevent invasive cervical cancer. However, there is a high risk of persistent/recurrent CIN2-3 and cervical cancer for up to 20 years post-treatment. Factors such as high-risk human papillomavirus (HR-HPV) and surgical margins influence this risk. Clinicians using LLETZ aim to achieve clear surgical margins while minimizing the volume of tissue removal and side effects. This retrospective study assessed the roles of HR-HPV status post-LLETZ, surgical margins, and LLETZ characteristics (excision type, cone volume, and dimensions [length, thickness, and circumference]) for long-term reassurance against persistent/recurrent CIN2-3 in a large population spanning 25 years. We showed greater reassurance associated with negative HR-HPV post-LLETZ and clear surgical margins, but not with LLETZ characteristics, although cone length and type 3 excision correlated with clear margins. These findings provide valuable insights into long-term outcomes that may help optimize LLETZ.

Background/Objective: Women treated with large loop excision of the transformation zone (LLETZ) for cervical intraepithelial neoplasia grade 2-3 (CIN2-3) remain at risk of CIN2-3 and cervical cancer for many years. We assessed the roles of high-risk human papillomavirus (HR-HPV) post-LLETZ, surgical margins, and LLETZ characteristics on the long-term risk of CIN2-3. Methods: A retrospective observational study was performed using data for 432 women with a histological diagnosis of CIN2-3 treated by LLETZ between 1996 and 2020 and followed-up until October 2021 at Hospital Bellvitge in Barcelona, Spain. Age, surgical margins, 6-month HR-HPV status, excision type, and cone volume/dimensions were analyzed in association with the risk of persistent/recurrent CIN2-3. The cumulative probability of persistent/recurrent CIN2-3 was calculated using the Kaplan–Meier and Cox models. Results: Persistent/recurrent CIN2-3 was detected in 7.4%, with over 90% found within 5 years post-LLETZ. Predictors of persistent/recurrent CIN2-3 were HR-HPV (HR = 7.36, 95% CI = 3.55–15.26), involved margins (HR = 3.94, 95% CI = 1.68–9.25), uncertain margins (HR = 4.42, 95% CI = 1.55–12.55), and age ≥ 35 years (HR = 2.92, 95% CI = 1.19–7.13). Type 3 excision (p = 0.035) and cone length (p = 0.010) correlated with clear margins. The negative predictive value (NPV) of both negative HR-HPV and clear margins post-LLETZ was 98.7%. Conclusions: The combination of negative HR-HPV and clear margins post-LLETZ provides stronger reassurance against the risk of persistent/recurrent CIN2-3 than do LLETZ characteristics. However, larger excisions in older women likely reduce the risk of involved margins. Close surveillance, including repeat HR-HPV testing in the first 5 years post-LLETZ, is crucial.