Our results demonstrate a retreatment rate of 3.2% due to high grade cervical dysplasia after undergoing a primary LEEP and having no evidence of disease at first follow-up colposcopy. One tenth of patients underwent a third colposcopy assessment and did not require further treatment or colposcopy follow up. This data is a reflection of the local practice in Calgary, Alberta, Canada, where laser is used in combination with LEEP in approximately one-third (34%) of cases.
Of all patients who underwent a primary LEEP for high grade cervical dysplasia (CIN 2-3), the vast majority (86%) were discharged from colposcopic with cytologic follow-up, having two ‘negative’ post-LEEP colposcopic and cytologic assessments. Of the remaining patients, most (10.4%) were discharged from colposcopic follow up to annual cytology after the third, post-LEEP assessment. The remaining 3.2% were re-treated with a second LEEP to excise CIN 2 or 3. If all patients were discharged from colposcopy follow-up after a single negative post-LEEP assessment, necessary re-treatment would not have been achieved in a timely manner.
The rationale for use of laser ablation at the time of LEEP concerns itself with mitigating obstetrical adverse outcomes, such as pre-term labour and cervical insufficiency. By potentially limiting the volume of cervix excised, use of a smaller LEEP specimen followed by laser ablation may adequately treat superficial dysplasia while sparing cervical parenchyma. Kyrgiou et al. demonstrated a dose related response to increasing depth of tissue excision although patients with untreated CIN and pregnancies prior to excision demonstrated an increased rate of preterm birth, above the baseline population.[7] A depth of 10mm or less should be targeted for women of reproductive age but does increase the rate of recurrence in women > 35. [8, 9]
The majority of published literature on rates of treatment success and recurrence rates of CIN 2-3 indicate variable numbers to what has been documented in the Calgary Zone [10-15]. Methodology within each study was variable with regard to type of treatment, number of visits, follow-up intervals, colposcopic assessment versus cytology only, use of laser in addition to LEEP, as well as patient demographics, including HPV immunization protocols. Rates have been documented from 1.4% to 26.3% [16, 17]. This large discrepancy can be attributed to the heterogeneous methodology in the literature.
Santesso et al, in a meta-analysis of RCTs assessing outcomes between different modalities, documented a recurrence rate of CIN 2/3 of 5.3% on review of over 8 000 patients [18]. These included cold-knife conization, LEEP, and cryotherapy but none of the literature assessed LEEP with the addition of laser ablation. An elevated rate of pre-term labor was associated with all modalities, but most notably with cold knife conization suggesting that a smaller tissue specimen may be advantageous for patients who may conceive a pregnancy.
The rate of CIN 2-3 at 12-months (3.2%) may be lower than other studies due to the combination of LEEP and laser use if a wider treatment field is targeted, the lack of HPV testing in follow up (false negative cytology, ECC, or biopsy), as HPV testing has been shown to have higher sensitivity and specificity compared to cytology alone [19]. Our study also excluded patients who had CIN2-3 documented on biopsy within six months of primary LEEP. Had these cases been included, the re-treatment rate would have been higher, similar to Wu, Ju, and Cecchini’s publications [20-22].
The rate of dysplasia that we detected may be elevated relative to Prendville’s study due to their smaller sample size (102 vs. 221 in our study), consistent with a skewed population sample [23]. Papoutsis followed patients with cytology only which also may have been responsible for producing an artificially low rate of high-grade dysplasia [9].
There are several notable strengths and limitations of our study. The health information system, ARIA, and the use of REDCap data collection software allowed for thorough record keeping and referencing. Although there were limited patient numbers, the collected and complete data facilitated accurate analysis. Another strength of our study is the minimal operator variation between colposcopists. The LEEPs included in this Calgary based study were performed by five Gynecologic Oncologists and follow-up was completed by all five members of the group. This enhances the internal validity and, in turn, may hinder the external validity as protocols vary by center.
The use of laser in combination with the LEEP may affect disease rates for multiple reasons. First, tissue destruction with a laser may treat lesions not excised, or where margins are positive. This may result in a higher treatment success than if laser was not used in combination with the LEEP. Second, the availability and use of laser may result in a smaller specimen, and in turn, positive margin status. This was mitigated by excluding patients who had evidence of disease present at the first, six-month follow-up, but may still affect the results of our study. Disease recurrence beyond 12 months with LEEP and laser ablation remains to be documented.
A power calculation resulted in a target of 292 patients. After exclusions, our sample size reached 221 data points. A larger data set would have increased the reliability and precision of our estimate of the retreatment rate. This concern was balanced with the option of including LEEPs performed in the Women's Health Clinic in Calgary[1]; however, variations in providers, charting, and data access made this option less feasible and would have subjected our data set to more variability.
A final limiting factor for this study is the lack of documentation of HPV vaccination status or HPV genotyping, which is not currently part of the standard of care in Canada. HPV vaccinations were first offered to girls in grade 5 (aged 10/11) in Alberta in 2008. Correlating HPV vaccination status and genotyping with disease and recurrence rates may provide useful prognostic information and will be an informative relationship to investigate.
Patients should be made aware of the importance of follow up after undergoing a LEEP and counselled appropriately. Until a protocol with better outcomes is established, this standard of care can be used to predict HSIL/CIN2-3 disease rates at one year after treatment, and more accurately, in a setting which utilizes laser ablation with approximately one third of LEEPs. Future research may assess the cost effectiveness of a second visit, knowing approximately 10% of patients have a third assessment which does not result in additional dysplasia detection. Future research may also seek to assess the long-term rates of disease recurrence when LEEP is combined with user of laser vaporization.
[1] Laser is not used in the out-patient setting in the Women’s Health Clinic. The exclusion of patients from this setting may result in data skewness.
There are several notable strengths and limitations of our study. The health information system, ARIA, and the use of REDCap data collection software allowed for thorough record keeping and referencing. Although there were limited patient numbers, the collected and complete data facilitated accurate analysis. Another strength of our study is the minimal operator variation between colposcopists. The LEEPs included in this Calgary based study were performed by five Gynecologic Oncologists and follow-up was completed by all five members of the group. This enhances the internal validity and, in turn, may hinder the external validity as protocols vary by center.
The use of laser in combination with the LEEP may affect disease rates for multiple reasons. First, tissue destruction with a laser may treat lesions not excised, or where margins are positive. This may result in a higher treatment success than if laser was not used in combination with the LEEP. Second, the availability and use of laser may result in a smaller specimen, and in turn, positive margin status. This was mitigated by excluding patients who had evidence of disease present at the first, six-month follow-up, but may still affect the results of our study. Disease recurrence beyond 12 months with LEEP and laser ablation remains to be documented.
A power calculation resulted in a target of 292 patients. After exclusions, our sample size reached 221 data points. A larger data set would have increased the reliability and precision of our estimate of the retreatment rate. This concern was balanced with the option of including LEEPs performed in the Women’s Health Clinic in Calgary; however, variations in providers, charting, and data access made this option less feasible and would have subjected our data set to more variability.
A final limiting factor for this study is the lack of information on HPV vaccination status or HPV genotyping, which is not currently part of the standard of care in Canada. Correlating HPV vaccination status and genotyping with disease and recurrence rates may provide useful prognostic information and will be an informative relationship to investigate.