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Cervical cancer is the fourth most common malignancy in females worldwide, affecting 5.7 per 100,000 women in New Zealand, with higher rates in Māori compared to non-Māori (8.1 vs 4.4, per 100,000 women, respectively).[[1-3]] Despite Australia and New Zealand both having some of the lowest rates of cervical cancer in the world,[[4]] cervical cancer remains an important and preventable cause of morbidity and mortality.[[5,6]] Squamous cervical intraepithelial (CIN) lesions are the precursor lesions to the majority of cervical cancers. These lesions are clinically detectable for many years prior to the development of cancer, through cervical cytology screening.[[7]] Due to the long latency period of cervical cancer, the identification and removal of precancerous cervical lesions is highly effective in preventing the development of invasive disease.[[3,6]] In New Zealand, the National Cervical Screening Programme and the human papillomavirus vaccine have both significantly reduced the incidence of abnormal cervical cytology and cervical cancer over the past 40 years.[[8,9]]

The majority of CIN lesions occur in the cervical transformation zone (TZ), due to the ability of simple columnar epithelium within this site to transform into stratified squamous epithelium via metaplasia.[[10]] TZ location varies between patients, with younger patients typically having a distal TZ along the cervical canal, which is more exposed and thus more susceptible to infection.[[11]] HPV infection of these specialised TZ cells is associated with a high risk of cancer progression.[[10]] Correct identification of TZ type is therefore critical when determining the appropriate depth of excision within the cervical canal.[[10–12]]

Large loop excision of the transformation zone (LLETZ) procedure remain the preferred method for removal of squamous cervical intraepithelial neoplasia (CIN) lesions worldwide.[[13]] Excisional techniques enable histological analysis of CIN lesions and identification of resection margins; two important prognostic indicators of residual disease or recurrence.[[12,13]] The recommended depth of LLETZ excision is dependent on TZ type, alongside other patient and obstetric variables.[[14,15]] Inadequate excision depth and positive excisional margins increase the risk of residual precancerous cells, and hence are both associated with a significant risk of treatment failure.[[16]] In contrast, multiple excisions and increasing excision depths are both associated with an increased risk of cervical incompetence and preterm birth, which is of particular importance in patients of reproductive age.[[14,17,18]]

In 2020, Public Health England (PHE) updated their colposcopy management guidelines, on which New Zealand’s standards of care for LLETZ procedures are based.[[15]] The PHE standards are derived from large clinical studies and meta-analyses that guide the minimum depth to avoid treatment failure and the depth at which preterm birth rates significantly increase.[[19,20]] Given the risks associated with under- and over-sampling of LLETZ excisions, this study aimed to audit the depth of cervical tissue excised in LLETZ procedures performed at Counties Manukau District Health Board (CMDHB), relative to PHE’s standards of care.

Methods

Ethics statement

Ethics approval was obtained for this study from the University of Auckland Human Participants Ethics Committee on 19 November 2018 (Ethics number: 021825).

Study procedures

NHIs of patients undergoing LLETZ procedures at CMDHB between 1 June 2020 to 30 May 2021 were obtained by the healthAlliance health analysts. Hospital records were reviewed to determine eligibility. Patients who did not undergo LLETZ procedures, or had inadequate or missing surgical or histological data, were excluded. Demographic, clinical, and laboratory variables were collected following a review of clinic letters, surgical or examination notes, and laboratory records using the Regional Clinical Portal and the CMDHB Colposcopy Database. Demographic variables included age at the time of procedure, ethnicity, and menopausal status (where menopausal status was not clearly documented, patients ≤45 years old were assumed to be pre-menopausal). Treatment variables included excision depth as reported by the pathologist (where multiple passes were taken, the depth of all passes and the location of each pass i.e., central or peripheral were recorded), reported transformation zone classification as per operating surgeon (types 1–3), primary operator (Registered Medical Officer (RMO) or Consultant Senior Medical Officer (SMO)), type of anaesthesia (local vs general anaesthesia), indication for treatment, and the number of passes performed. Outcome data included completeness of TZ excision (as recorded “complete” by the pathologist on the histopathology report) and margin status of the excised tissue (as recorded “clear” by the pathologist on the histopathology report). Where the histopathology report described the completeness of excision margins or TZ as being unclear, the excision/TZ was considered incomplete.

Audit standards

All standards used were based on the PHE guidelines which is in line with current practice in New Zealand.[[15]]

• Depth of excision:

o Type 1 TZ—excision should remove a depth of more than 7mm; target ≥95% of cases.

        In individuals of reproductive age, the excision should be no greater than 10mm.

o Type 2 TZ—excisions should remove a depth of 10–15mm; target ≥95% of cases.

o Type 3 TZ—excisions should remove a depth of 15–25mm; target ≥95% of cases.

• Number of passes: at least 80% of cases should have the specimen removed as a single sample.

• Local anaesthesia: the proportion of individuals managed as outpatients with local anaesthesia should be at least 85%.

When considering whether cases met the standard of care, pre-menopausal patients with a type 1 TZ were only deemed to meet the standard if the excised depth was between 7–10 mm. For procedures where more than one pass was performed, passes that were central (i.e., an anterior lip pass and a posterior lip pass) both had to meet the required depth in order to meet PHE’s standard. However, additional peripheral passes that did not meet the required depth did not influence whether a procedure met the standard or not.

Chi-squared test, or Fisher’s exact test (for comparisons where there were low frequency cells) were used to determine if there were statistically significant differences in meeting PHE’s standards. Where data were missing or unknown, this is reported but not included in the analysis. Comparisons were made by TZ type, primary operator, type of anaesthetic, menopausal status or ethnicity. Comparisons were also made between groups, based on adequacy of excision depth, to determine if adequate versus a depth that was too shallow or too deep was associated with positive margins on histopathology report. A p-value <0.05 was regarded as statistically significant. All statistical analyses were performed using GraphPad Prism software (version 9.0).

Results

A total of 214 patients were identified using the outlined sampling strategy, eight of which were excluded due to having inaccessible data (Figure 1). Of the remaining 206 auditable records, 22 patients were excluded with a recorded reason. The main indications for exclusion included no recorded excision depth or no LLETZ procedure taking place. Subsequently, 184 LLETZ procedures were analysed.

View Figures & Tables.

Demographic characteristics

The majority of patients were between 31–40 years of age, were pre-menopausal (Table 1) and had type 1 TZs (Table 2). The majority of patients were of NZ European ethnicity (40%), followed by Asian (19%), Māori (16%) and Pasifika peoples (13%). The demographic characteristics of the audit population are summarised in Table 1.

Audit standards

Of the 184 LLETZ procedures performed during the study period, the majority of patients had a type 1 TZ (72%), followed by type 2 TZ (24%) and type 3 (4%). Only 48% of all LLETZ procedures performed during this study were of appropriate excision depth, relative to PHE’s ≥95% threshold. Rates of successful LLETZ excision depths were similar for patients with type 1 and type 2 TZs; however, 86% of type 3 TZ excisions did not meet the standard of care. The main reason for procedures not meeting the standard of care was a suboptimal excision depth, particularly in patients with type 2 and type 3 TZs (43% and 86%, respectively) (Table 2).

Treatment characteristics

The majority of procedures were performed by an SMO (87%) and under local anaesthesia (67%). The majority of LLETZ excisions were performed using a single pass (69%), followed by two passes (25%) and three passes (5%). Only 36% of all LLETZ excisions had clear margins, with the lowest proportion of clear margins in patients with type 1 TZ (35% in type 1, 39% in type 2 and 43% in type 3). Overall, 18% of TZs were determined to be completely excised, with low rates seen across all TZ types (18.0% in type 1; 18% in type 2; and 14% in type 3). The treatment characteristics of the audit population are summarised in Table 3.

There were no significant differences in the proportion of patients meeting the standard of care by anaesthetic type (local vs other), primary operator (SMO vs RMO), TZ type (1, 2 or 3), menopausal status (pre or post) or ethnicity (Appendix 1). Finally, we observed that when the PHE standard was met, margins were most likely to be clear (47% clear margins), compared with excisions that were either too shallow (30% clear margins) and too deep (20% clear margins) (p=0.03).

Discussion

Cervical cancer remains a significant cause of morbidity and mortality in New Zealand. LLETZ excisions of precancerous CIN lesions can be highly effective in preventing the development of invasive cervical disease. However, under- and over-sampling of LLETZ procedures are both associated with complications, including an increased risk of disease progression,[[13]] and preterm birth in women of child-bearing age,[[11,14,15,19]] respectively. Equitable access to LLETZ procedures nationwide is crucial, especially in light of the high rates of cervical cancer in Māori and Pasifika in New Zealand.[[20]]

Herein we report the findings of our audit of LLETZ procedures at CMDHB, which shows that only 48% of LLETZ procedures were of an appropriate excision depth, relative to PHE’s recommended threshold of ≥95%.[[12]] Inadequate excision depth was the primary reason for not meeting the standard of care for all three TZ types, particularly in patients with type 2 or type 3 TZs (43% and 86%, respectively).[[15]] Despite the depth of excision at LLETZ being a well-defined, internationally recognised standard, there is a deficit of published audited data worldwide. Only two conference poster abstracts were available from the United Kingdom and identified an adequate depth of excision in 95.5% (n=83),[[21]] and 69% (n=224)[[22]] of patients undergoing LLETZ procedures. The only comparable report from Australasia was a locally presented audit of 104 patients undergoing LLETZ procedures in Auckland District Health Board (ADHB) between 1 June to 31 December 2020 (online via The University of Auckland intranet, available on request). This report identified an insufficient depth of excision in 15% of type 1 TZ, 38% of type 2 TZ and 73% of type 3 TZ excisions.[[15]] The variation in meeting the standard between these three reports highlights the importance of regular audits within centres.

We observed that LLETZ excisions that were too shallow and too deep were both associated with positive margins. Unfortunately, data were not collected on which margins were reported positive, as endocervical margins that are positive are the most strongly associated with disease persistence.[[16]] Therefore, collecting data on location of positive margins is an important consideration of future audits. Under-sampling in all three TZ classification groups may reflect a lack of knowledge of excision depths specific to TZ type, or fears over the consequences of excessive depth in an overall young population in CMDHB.[[14,17]] National guidelines outline that individuals who have had a previous LLETZ of ≥10mm are at high risk of spontaneous preterm birth and second-trimester loss, and should receive cervical length screening during pregnancy.[[23]] Knowledge of these guidelines likely contributes to colposcopists’ tendency to remain conservative with their LLETZ excision depths. It may also reflect technical difficulties or lack of access to appropriate loops in achieving the required depths, as highlighted in the Ishikawa cause and effect diagram (Figure 2).

This study also identified an excessive depth of excision in 22% of patients with type 1 TZs. No published reports on the rates of deep LLETZ excisions relative to PHE’s recommendations were available in the literature. However, similar findings were reported in the ADHB audit (33% of type 1 TZs excisions were of excessive depth), suggesting our centre is not unique. This finding is clinically significant, given that 94% of type 1 TZ patients in this study (and 92% in the ADHB cohort) were pre-menopausal, thus increasing these patients’ risks of preterm labour in future pregnancies.[[14,17]] However, the PHE colposcopy guidelines only allow for a small margin of error for LLETZ excisions (3mm in type 1 TZ patients), adding to the difficulty of achieving the correct depth in this group of patients.[[15]] Greater training in how to achieve the desired depth of excision across all TZ types may be beneficial in increasing the accuracy of excision. One study reported that auditing of consecutive LLETZ excisions resulted in significant improvement in the accuracy of colposcopists' presumed and actual depth of excision.[[2]][[4]] Increased guideline exposure in theatre and clinic, in addition to increased auditing of colposcopists’ excision depths, may increase the efficacy of LLETZ procedures.

Only 69% of LLETZ procedures were performed using a single pass and 67% under local anaesthesia, relative to PHE’s standard of ≤80% and ≤85%, respectively.[[15]] It is known that multiple tissue fragments can impact the accuracy of the histopathologic assessment. However, given the elevated rates of obesity in CMDHB (16% of adults in CMDHB are obese, and 19% morbidly obese), performing a LLETZ procedure using a single pass or under local anaesthesia may compromise the surgeon’s ability to obtain an adequate sample.[[2]][[5]] Thus, the use of multiple passes or general anaesthetic are likely prioritised in patients with difficult access, in order to optimise the adequacy of excision. Theoretically, analysis of multiple passes may underestimate the average depth of excision, as the minimum recorded depth for each segment was used for analysis. However, when two passes are performed, this is more likely to represent a separate anterior and posterior pass, rather than superimposed passes of the same area, and thus, should not impact the results. Inclusion of cases with three or more passes are more likely to underestimate depth; however, these only represented a small proportion (6%) of the sample and are therefore also unlikely to have influenced the overall result.

Although not the primary outcome of this study, we observed that non-Māori and non-Pasifika patients were more likely to have LLETZ procedures than Māori and Pasifika patients. This is despite the over-representation of Māori and Pasifika peoples in cervical cancer rates in New Zealand.[[3,20]] These findings are consistent with the reduced rates of cervical screening in Māori and Pasifika peoples seen nationwide, and the subsequent disparities in disease burden and stage at diagnosis.[[8,20,2]][[6]][[,27]] These findings highlight the urgent need for future work focused on ensuring that the health service is able to provide equitable cervical screening throughout Aotearoa New Zealand.

There were several limitations to this study. Firstly, patients undergoing cone biopsies were not included in this analysis, due to only a small proportion of patients undergoing this procedure. This may limit interpretations of the management of type 3 TZ patients, given that only one surgical management option was included in this analysis. Secondly, formalin fixation is known to result in minor cervical tissue specimen shrinkage of around 2.7% in the longitudinal dimensions.[[2]][[8]] Consistent with other studies, this shrinkage was deemed clinically insignificant and thus no changes were made to the excision depth measurements in our analysis.[[24,28]] Diathermy ball fulguration to the base of the LLETZ excision is also routinely used to help achieve haemostasis following resection and may have additional benefits in terms of treating residual CIN, the impact of which was not investigated in this audit.[[29]] Finally, although this study was sufficiently powered overall, subgroup analysis had smaller patient populations, and thus was not always sufficiently powered. This may have implications on the study’s ability to identify robust differences between audit standard outcomes according to clinical subgroups. Future studies would benefit from including a larger patient cohort in order to mitigate this effect.

Ultimately, these findings highlight the need for additional quality improvement processes to address barriers to meeting standard excision depth. Suggestions include having picture descriptions of the different transformation zone types alongside PHE’s colposcopy management guidelines in colposcopy rooms, in order to increase intraoperative awareness of the recommended excision depths. Secondly, increased access to a wider range of LLETZ loops may help facilitate excision of the correct cervical depth with only one pass. Finally, increased access to training opportunities, such as simulation-based teaching, may foster greater skill in excising the correct tissue depths.

Conclusion

This is the first study to audit and analyse the outcomes of patients undergoing LLETZ procedures at CMDHB, relative to established colposcopy guidelines and standards of care. Differences in the excision depths were identified relative to PHE’s established thresholds, with a large proportion of excisions being too shallow, particularly in patients with type 2 and type 3 TZs. These findings highlight the importance of considering the associated risks of LLETZ procedures in individual patients and the need to adapt the surgical approach and equipment used accordingly. Importantly, this study has also identified reduced rates of LLETZ procedures in Māori and Pasifika patients, emphasising the need for improved screening in these high-risk communities going forward. Finally, this study has highlighted the need to audit LLETZ procedures in other DHBs in New Zealand to identify issues and optimise the quality of care for CIN provided nationwide.

View Appendices.

Summary

Abstract

Aim

Cervical cancer is the fourth most common malignancy in females worldwide. Large loop excision of the transformation zone (LLETZ) procedures remain the preferred surgical technique to remove squamous cervical intraepithelial neoplasia (CIN) lesions globally. This study aimed to assess whether the depth of LLETZ procedures at Counties Manukau District Health Board (CMDHB) met established standards of care.

Method

Hospital records were reviewed for all LLETZ procedures performed at CMDHB between 1 June 2020 to 3 May 2021, and these were compared to Public Health England’s (PHE) 2020 Colposcopy Guidelines.

Results

One hundred and eighty-four cases were identified. Forty-eight percent of all LLETZ procedures were the correct excision depth relative to PHE’s ≥95% threshold, primarily due to excisions being too shallow, particularly in patients with type 2 and 3 transformation zones (TZ), 48% and 86%, respectively. Māori and Pasifika patients represented only 16% and 13% of all LLETZ procedures in this study, respectively.

Conclusion

This study identified significant oversampling of LLETZ excisions in patients with type 1 TZs, and significant under-sampling in patients with types 2 and 3 TZs. Ultimately, these findings highlight the need for additional quality improvement processes and emphasise the importance of auditing LLETZ procedures nationwide.

Author Information

Dr Sita T Clark: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: sitaclark12@gmail.com Dr Hilary R Barker: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: hilaryrbarker@gmail.com Dr Luke R Bradshaw: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: luke.bradshaw14@gmail.com Dr Jyoti Kathuria: Consultant Gynaecologist, Department of Obstetrics and Gynaecology, Counties Manukau District Health Board, Auckland, New Zealand. E: jyoti.kathuria@middlemore.co.nz Dr Charlotte Oyston: Consultant Obstetrician, Senior Lecturer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Department of Obstetrics and Gynaecology, Counties Manukau District Health Board, Auckland, New Zealand. E: c.oyston@auckland.ac.nz

Acknowledgements

We would like to thank the Counties Manukau District Health Board Research Offices and Clinical Records departments for their assistance with collating the data required to write this manuscript. We would also like to thank Dr Carina Miles for her advice and input in this study, and Sharon Arrol and Andrea O’Brien for their assistance with data extraction.

Correspondence

Sita Tarini Clark: Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland 1023, New Zealand.

Correspondence Email

sitaclark12@gmail.com

Competing Interests

Nil.

1) Zhang X, Zeng Q, Cai W, Ruan W. Trends of cervical cancer at global, regional, and national level: data from the Global Burden of Disease study 2019. BMC Public Health. 2021;21(1):894.

2) Torre LA, Islami F, Siegel RL, et al. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev. 2017;26(4):444-57.

3) Sykes P, Williman J, Innes C, Hider P. Review of cervical cancer occurrences in relation to screening history in New Zealand for the years 2013-2017 [Internet]. Christchurch (NZ): The University of Otago; 2019 [cited 2021 Nov 30]. Report No.: 2. [Available from: https://www.nsu.govt.nz/system/files/resources/cancer-case-review-2013-2017-final-report-29-august-2019.pdf].

4) Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010;127(12):2893-917.

5) Garland SM, Brotherton JML, Skinner SR, et al. Human papillomavirus and cervical cancer in Australasia and Oceania: risk-factors, epidemiology and prevention. Vaccine. 2008;26: M80-8.

6) Sykes P, Gopala K, Tan AL, et al. Type distribution of human papillomavirus among adult women diagnosed with invasive cervical cancer (stage 1b or higher) in New Zealand. BMC Infect Dis. 2014;14(1):374.

7) Brisson M, Kim JJ, Canfell K, et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet. 2020;395(10224):575-90.

8) Smith MA, Edwards S, Canfell K. Impact of the National Cervical Screening Programme in New Zealand by age: analysis of cervical cancer trends 1985-2013 in all women and in Māori women. Cancer Causes Control. 2017;28(12):1393-404.

9) Innes CR, Williman JA, Simcock BJ, et al. Impact of human papillomavirus vaccination on rates of abnormal cervical cytology and histology in young New Zealand women. N Z Med J. 2020;133(1508):72-84.

10)  Doorbar J, Griffin H. Refining our understanding of cervical neoplasia and its cellular origins. Papillomavirus Res. 2019;7:176-9.

11) Luyten A, Buttmann-Schweiger N, Hagemann I, et al. Utility and reproducibility of the international federation for cervical pathology and colposcopy classification of transformation zones in daily practice: a multicenter study of the german colposcopy network. J Low Genit Tract Dis. 2015;19(3):185-8.

12) Martin-Hirsch PP, Paraskevaidis E, Bryant A, Dickinson HO. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2013;(12):CD001318.

13) Yap S-J, Nathan E, Farrell L. LLETZ make it simple: anxiety, pain and treatment outcomes with outpatient large loop excision of the transformation zone under local anaesthesia. Aust N Z J Obstet Gynaecol. 2020;60(3):438-43.

14) Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ. 2016;354:i3633.

15) Public Health England. Cervical Screening Programme and Colposcopy Management [Internet]. 2020 [cited 2021 Jul 5]. [Available from: https://www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management/3-colposcopic-diagnosis-treatment-and-follow-up].

16)  Ghaem-Maghami S, De-Silva D, Tipples M, et al. Determinants of success in treating cervical intraepithelial neoplasia. BJOG. 2011;118(6):679-84.

17) Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008;337:a1284.

18) Arbyn M, Redman CW, Verdoodt F, et al. Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis. Lancet Oncol. 2017;18(12):1665-79.

19) Khalid S, Dimitriou E, Conroy R, et al. The thickness and volume of LLETZ specimens can predict the relative risk of pregnancy-related morbidity. BJOG. 2012;119(6):685-91.

20) Meredith I, Sarfati D, Ikeda T, Blakely T. Cancer in Pacific people in New Zealand. Cancer Causes Control. 2012;23(7):1173-84.

21) Polymeros K, Chakrabarti J, Hickey S. Colposcopy practice in Calderdale Royal Hospital and compliance with national guidelines [Internet]. The British Society for Colposcopy and Cervical Pathology 2013 Annual Scientific Meeting; 2013 April 24; Glasgow. [Available from: https://www.bsccp.org.uk/assets/file/uploads/resources/BSCCP_Abstracts_2013.pdf].

22) Razvi K, Rothnie K, Speed T, Clark S. EPO1085 Surgical margins of large loop excision of the transformation zone: histological comparison with patient characteristics and colposcopists’ experience. Int J Gynaecol Cancer. 2019;29:A568-A569.

23) Ministry of Health [Internet]. Wellington (NZ): Ministry of Health. Cervical length screening; 2019 [cited 2021 Nov 28]. [Available from: https://www.health.govt.nz/our-work/life-stages/maternity-services/new-zealand-obstetric-ultrasound-guidelines/cervical-length-screening].

24)  Papoutsis D, Kandanearachchi P, Antonakou A, et al. A method to improve the accuracy between the presumed depth of excision and the actual depth of excision in women receiving LLETZ cervical treatment; a single-center, two-operator experience. Hippokratia. 2018;22(3):113-21.

25)  Middlemore Clinical Trials [Internet]. Auckland (NZ): Counties Manukau District Health Board. Counties Manukau Health: Diabetes Snapshot. 2021 [cited 2021 Nov 30]. [Available from: https://www.middlemoretrials.nz/files/dmfile/cmh-diabetes-snapshot-aug-2021.pdf].

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Cervical cancer is the fourth most common malignancy in females worldwide, affecting 5.7 per 100,000 women in New Zealand, with higher rates in Māori compared to non-Māori (8.1 vs 4.4, per 100,000 women, respectively).[[1-3]] Despite Australia and New Zealand both having some of the lowest rates of cervical cancer in the world,[[4]] cervical cancer remains an important and preventable cause of morbidity and mortality.[[5,6]] Squamous cervical intraepithelial (CIN) lesions are the precursor lesions to the majority of cervical cancers. These lesions are clinically detectable for many years prior to the development of cancer, through cervical cytology screening.[[7]] Due to the long latency period of cervical cancer, the identification and removal of precancerous cervical lesions is highly effective in preventing the development of invasive disease.[[3,6]] In New Zealand, the National Cervical Screening Programme and the human papillomavirus vaccine have both significantly reduced the incidence of abnormal cervical cytology and cervical cancer over the past 40 years.[[8,9]]

The majority of CIN lesions occur in the cervical transformation zone (TZ), due to the ability of simple columnar epithelium within this site to transform into stratified squamous epithelium via metaplasia.[[10]] TZ location varies between patients, with younger patients typically having a distal TZ along the cervical canal, which is more exposed and thus more susceptible to infection.[[11]] HPV infection of these specialised TZ cells is associated with a high risk of cancer progression.[[10]] Correct identification of TZ type is therefore critical when determining the appropriate depth of excision within the cervical canal.[[10–12]]

Large loop excision of the transformation zone (LLETZ) procedure remain the preferred method for removal of squamous cervical intraepithelial neoplasia (CIN) lesions worldwide.[[13]] Excisional techniques enable histological analysis of CIN lesions and identification of resection margins; two important prognostic indicators of residual disease or recurrence.[[12,13]] The recommended depth of LLETZ excision is dependent on TZ type, alongside other patient and obstetric variables.[[14,15]] Inadequate excision depth and positive excisional margins increase the risk of residual precancerous cells, and hence are both associated with a significant risk of treatment failure.[[16]] In contrast, multiple excisions and increasing excision depths are both associated with an increased risk of cervical incompetence and preterm birth, which is of particular importance in patients of reproductive age.[[14,17,18]]

In 2020, Public Health England (PHE) updated their colposcopy management guidelines, on which New Zealand’s standards of care for LLETZ procedures are based.[[15]] The PHE standards are derived from large clinical studies and meta-analyses that guide the minimum depth to avoid treatment failure and the depth at which preterm birth rates significantly increase.[[19,20]] Given the risks associated with under- and over-sampling of LLETZ excisions, this study aimed to audit the depth of cervical tissue excised in LLETZ procedures performed at Counties Manukau District Health Board (CMDHB), relative to PHE’s standards of care.

Methods

Ethics statement

Ethics approval was obtained for this study from the University of Auckland Human Participants Ethics Committee on 19 November 2018 (Ethics number: 021825).

Study procedures

NHIs of patients undergoing LLETZ procedures at CMDHB between 1 June 2020 to 30 May 2021 were obtained by the healthAlliance health analysts. Hospital records were reviewed to determine eligibility. Patients who did not undergo LLETZ procedures, or had inadequate or missing surgical or histological data, were excluded. Demographic, clinical, and laboratory variables were collected following a review of clinic letters, surgical or examination notes, and laboratory records using the Regional Clinical Portal and the CMDHB Colposcopy Database. Demographic variables included age at the time of procedure, ethnicity, and menopausal status (where menopausal status was not clearly documented, patients ≤45 years old were assumed to be pre-menopausal). Treatment variables included excision depth as reported by the pathologist (where multiple passes were taken, the depth of all passes and the location of each pass i.e., central or peripheral were recorded), reported transformation zone classification as per operating surgeon (types 1–3), primary operator (Registered Medical Officer (RMO) or Consultant Senior Medical Officer (SMO)), type of anaesthesia (local vs general anaesthesia), indication for treatment, and the number of passes performed. Outcome data included completeness of TZ excision (as recorded “complete” by the pathologist on the histopathology report) and margin status of the excised tissue (as recorded “clear” by the pathologist on the histopathology report). Where the histopathology report described the completeness of excision margins or TZ as being unclear, the excision/TZ was considered incomplete.

Audit standards

All standards used were based on the PHE guidelines which is in line with current practice in New Zealand.[[15]]

• Depth of excision:

o Type 1 TZ—excision should remove a depth of more than 7mm; target ≥95% of cases.

        In individuals of reproductive age, the excision should be no greater than 10mm.

o Type 2 TZ—excisions should remove a depth of 10–15mm; target ≥95% of cases.

o Type 3 TZ—excisions should remove a depth of 15–25mm; target ≥95% of cases.

• Number of passes: at least 80% of cases should have the specimen removed as a single sample.

• Local anaesthesia: the proportion of individuals managed as outpatients with local anaesthesia should be at least 85%.

When considering whether cases met the standard of care, pre-menopausal patients with a type 1 TZ were only deemed to meet the standard if the excised depth was between 7–10 mm. For procedures where more than one pass was performed, passes that were central (i.e., an anterior lip pass and a posterior lip pass) both had to meet the required depth in order to meet PHE’s standard. However, additional peripheral passes that did not meet the required depth did not influence whether a procedure met the standard or not.

Chi-squared test, or Fisher’s exact test (for comparisons where there were low frequency cells) were used to determine if there were statistically significant differences in meeting PHE’s standards. Where data were missing or unknown, this is reported but not included in the analysis. Comparisons were made by TZ type, primary operator, type of anaesthetic, menopausal status or ethnicity. Comparisons were also made between groups, based on adequacy of excision depth, to determine if adequate versus a depth that was too shallow or too deep was associated with positive margins on histopathology report. A p-value <0.05 was regarded as statistically significant. All statistical analyses were performed using GraphPad Prism software (version 9.0).

Results

A total of 214 patients were identified using the outlined sampling strategy, eight of which were excluded due to having inaccessible data (Figure 1). Of the remaining 206 auditable records, 22 patients were excluded with a recorded reason. The main indications for exclusion included no recorded excision depth or no LLETZ procedure taking place. Subsequently, 184 LLETZ procedures were analysed.

View Figures & Tables.

Demographic characteristics

The majority of patients were between 31–40 years of age, were pre-menopausal (Table 1) and had type 1 TZs (Table 2). The majority of patients were of NZ European ethnicity (40%), followed by Asian (19%), Māori (16%) and Pasifika peoples (13%). The demographic characteristics of the audit population are summarised in Table 1.

Audit standards

Of the 184 LLETZ procedures performed during the study period, the majority of patients had a type 1 TZ (72%), followed by type 2 TZ (24%) and type 3 (4%). Only 48% of all LLETZ procedures performed during this study were of appropriate excision depth, relative to PHE’s ≥95% threshold. Rates of successful LLETZ excision depths were similar for patients with type 1 and type 2 TZs; however, 86% of type 3 TZ excisions did not meet the standard of care. The main reason for procedures not meeting the standard of care was a suboptimal excision depth, particularly in patients with type 2 and type 3 TZs (43% and 86%, respectively) (Table 2).

Treatment characteristics

The majority of procedures were performed by an SMO (87%) and under local anaesthesia (67%). The majority of LLETZ excisions were performed using a single pass (69%), followed by two passes (25%) and three passes (5%). Only 36% of all LLETZ excisions had clear margins, with the lowest proportion of clear margins in patients with type 1 TZ (35% in type 1, 39% in type 2 and 43% in type 3). Overall, 18% of TZs were determined to be completely excised, with low rates seen across all TZ types (18.0% in type 1; 18% in type 2; and 14% in type 3). The treatment characteristics of the audit population are summarised in Table 3.

There were no significant differences in the proportion of patients meeting the standard of care by anaesthetic type (local vs other), primary operator (SMO vs RMO), TZ type (1, 2 or 3), menopausal status (pre or post) or ethnicity (Appendix 1). Finally, we observed that when the PHE standard was met, margins were most likely to be clear (47% clear margins), compared with excisions that were either too shallow (30% clear margins) and too deep (20% clear margins) (p=0.03).

Discussion

Cervical cancer remains a significant cause of morbidity and mortality in New Zealand. LLETZ excisions of precancerous CIN lesions can be highly effective in preventing the development of invasive cervical disease. However, under- and over-sampling of LLETZ procedures are both associated with complications, including an increased risk of disease progression,[[13]] and preterm birth in women of child-bearing age,[[11,14,15,19]] respectively. Equitable access to LLETZ procedures nationwide is crucial, especially in light of the high rates of cervical cancer in Māori and Pasifika in New Zealand.[[20]]

Herein we report the findings of our audit of LLETZ procedures at CMDHB, which shows that only 48% of LLETZ procedures were of an appropriate excision depth, relative to PHE’s recommended threshold of ≥95%.[[12]] Inadequate excision depth was the primary reason for not meeting the standard of care for all three TZ types, particularly in patients with type 2 or type 3 TZs (43% and 86%, respectively).[[15]] Despite the depth of excision at LLETZ being a well-defined, internationally recognised standard, there is a deficit of published audited data worldwide. Only two conference poster abstracts were available from the United Kingdom and identified an adequate depth of excision in 95.5% (n=83),[[21]] and 69% (n=224)[[22]] of patients undergoing LLETZ procedures. The only comparable report from Australasia was a locally presented audit of 104 patients undergoing LLETZ procedures in Auckland District Health Board (ADHB) between 1 June to 31 December 2020 (online via The University of Auckland intranet, available on request). This report identified an insufficient depth of excision in 15% of type 1 TZ, 38% of type 2 TZ and 73% of type 3 TZ excisions.[[15]] The variation in meeting the standard between these three reports highlights the importance of regular audits within centres.

We observed that LLETZ excisions that were too shallow and too deep were both associated with positive margins. Unfortunately, data were not collected on which margins were reported positive, as endocervical margins that are positive are the most strongly associated with disease persistence.[[16]] Therefore, collecting data on location of positive margins is an important consideration of future audits. Under-sampling in all three TZ classification groups may reflect a lack of knowledge of excision depths specific to TZ type, or fears over the consequences of excessive depth in an overall young population in CMDHB.[[14,17]] National guidelines outline that individuals who have had a previous LLETZ of ≥10mm are at high risk of spontaneous preterm birth and second-trimester loss, and should receive cervical length screening during pregnancy.[[23]] Knowledge of these guidelines likely contributes to colposcopists’ tendency to remain conservative with their LLETZ excision depths. It may also reflect technical difficulties or lack of access to appropriate loops in achieving the required depths, as highlighted in the Ishikawa cause and effect diagram (Figure 2).

This study also identified an excessive depth of excision in 22% of patients with type 1 TZs. No published reports on the rates of deep LLETZ excisions relative to PHE’s recommendations were available in the literature. However, similar findings were reported in the ADHB audit (33% of type 1 TZs excisions were of excessive depth), suggesting our centre is not unique. This finding is clinically significant, given that 94% of type 1 TZ patients in this study (and 92% in the ADHB cohort) were pre-menopausal, thus increasing these patients’ risks of preterm labour in future pregnancies.[[14,17]] However, the PHE colposcopy guidelines only allow for a small margin of error for LLETZ excisions (3mm in type 1 TZ patients), adding to the difficulty of achieving the correct depth in this group of patients.[[15]] Greater training in how to achieve the desired depth of excision across all TZ types may be beneficial in increasing the accuracy of excision. One study reported that auditing of consecutive LLETZ excisions resulted in significant improvement in the accuracy of colposcopists' presumed and actual depth of excision.[[2]][[4]] Increased guideline exposure in theatre and clinic, in addition to increased auditing of colposcopists’ excision depths, may increase the efficacy of LLETZ procedures.

Only 69% of LLETZ procedures were performed using a single pass and 67% under local anaesthesia, relative to PHE’s standard of ≤80% and ≤85%, respectively.[[15]] It is known that multiple tissue fragments can impact the accuracy of the histopathologic assessment. However, given the elevated rates of obesity in CMDHB (16% of adults in CMDHB are obese, and 19% morbidly obese), performing a LLETZ procedure using a single pass or under local anaesthesia may compromise the surgeon’s ability to obtain an adequate sample.[[2]][[5]] Thus, the use of multiple passes or general anaesthetic are likely prioritised in patients with difficult access, in order to optimise the adequacy of excision. Theoretically, analysis of multiple passes may underestimate the average depth of excision, as the minimum recorded depth for each segment was used for analysis. However, when two passes are performed, this is more likely to represent a separate anterior and posterior pass, rather than superimposed passes of the same area, and thus, should not impact the results. Inclusion of cases with three or more passes are more likely to underestimate depth; however, these only represented a small proportion (6%) of the sample and are therefore also unlikely to have influenced the overall result.

Although not the primary outcome of this study, we observed that non-Māori and non-Pasifika patients were more likely to have LLETZ procedures than Māori and Pasifika patients. This is despite the over-representation of Māori and Pasifika peoples in cervical cancer rates in New Zealand.[[3,20]] These findings are consistent with the reduced rates of cervical screening in Māori and Pasifika peoples seen nationwide, and the subsequent disparities in disease burden and stage at diagnosis.[[8,20,2]][[6]][[,27]] These findings highlight the urgent need for future work focused on ensuring that the health service is able to provide equitable cervical screening throughout Aotearoa New Zealand.

There were several limitations to this study. Firstly, patients undergoing cone biopsies were not included in this analysis, due to only a small proportion of patients undergoing this procedure. This may limit interpretations of the management of type 3 TZ patients, given that only one surgical management option was included in this analysis. Secondly, formalin fixation is known to result in minor cervical tissue specimen shrinkage of around 2.7% in the longitudinal dimensions.[[2]][[8]] Consistent with other studies, this shrinkage was deemed clinically insignificant and thus no changes were made to the excision depth measurements in our analysis.[[24,28]] Diathermy ball fulguration to the base of the LLETZ excision is also routinely used to help achieve haemostasis following resection and may have additional benefits in terms of treating residual CIN, the impact of which was not investigated in this audit.[[29]] Finally, although this study was sufficiently powered overall, subgroup analysis had smaller patient populations, and thus was not always sufficiently powered. This may have implications on the study’s ability to identify robust differences between audit standard outcomes according to clinical subgroups. Future studies would benefit from including a larger patient cohort in order to mitigate this effect.

Ultimately, these findings highlight the need for additional quality improvement processes to address barriers to meeting standard excision depth. Suggestions include having picture descriptions of the different transformation zone types alongside PHE’s colposcopy management guidelines in colposcopy rooms, in order to increase intraoperative awareness of the recommended excision depths. Secondly, increased access to a wider range of LLETZ loops may help facilitate excision of the correct cervical depth with only one pass. Finally, increased access to training opportunities, such as simulation-based teaching, may foster greater skill in excising the correct tissue depths.

Conclusion

This is the first study to audit and analyse the outcomes of patients undergoing LLETZ procedures at CMDHB, relative to established colposcopy guidelines and standards of care. Differences in the excision depths were identified relative to PHE’s established thresholds, with a large proportion of excisions being too shallow, particularly in patients with type 2 and type 3 TZs. These findings highlight the importance of considering the associated risks of LLETZ procedures in individual patients and the need to adapt the surgical approach and equipment used accordingly. Importantly, this study has also identified reduced rates of LLETZ procedures in Māori and Pasifika patients, emphasising the need for improved screening in these high-risk communities going forward. Finally, this study has highlighted the need to audit LLETZ procedures in other DHBs in New Zealand to identify issues and optimise the quality of care for CIN provided nationwide.

View Appendices.

Summary

Abstract

Aim

Cervical cancer is the fourth most common malignancy in females worldwide. Large loop excision of the transformation zone (LLETZ) procedures remain the preferred surgical technique to remove squamous cervical intraepithelial neoplasia (CIN) lesions globally. This study aimed to assess whether the depth of LLETZ procedures at Counties Manukau District Health Board (CMDHB) met established standards of care.

Method

Hospital records were reviewed for all LLETZ procedures performed at CMDHB between 1 June 2020 to 3 May 2021, and these were compared to Public Health England’s (PHE) 2020 Colposcopy Guidelines.

Results

One hundred and eighty-four cases were identified. Forty-eight percent of all LLETZ procedures were the correct excision depth relative to PHE’s ≥95% threshold, primarily due to excisions being too shallow, particularly in patients with type 2 and 3 transformation zones (TZ), 48% and 86%, respectively. Māori and Pasifika patients represented only 16% and 13% of all LLETZ procedures in this study, respectively.

Conclusion

This study identified significant oversampling of LLETZ excisions in patients with type 1 TZs, and significant under-sampling in patients with types 2 and 3 TZs. Ultimately, these findings highlight the need for additional quality improvement processes and emphasise the importance of auditing LLETZ procedures nationwide.

Author Information

Dr Sita T Clark: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: sitaclark12@gmail.com Dr Hilary R Barker: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: hilaryrbarker@gmail.com Dr Luke R Bradshaw: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: luke.bradshaw14@gmail.com Dr Jyoti Kathuria: Consultant Gynaecologist, Department of Obstetrics and Gynaecology, Counties Manukau District Health Board, Auckland, New Zealand. E: jyoti.kathuria@middlemore.co.nz Dr Charlotte Oyston: Consultant Obstetrician, Senior Lecturer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Department of Obstetrics and Gynaecology, Counties Manukau District Health Board, Auckland, New Zealand. E: c.oyston@auckland.ac.nz

Acknowledgements

We would like to thank the Counties Manukau District Health Board Research Offices and Clinical Records departments for their assistance with collating the data required to write this manuscript. We would also like to thank Dr Carina Miles for her advice and input in this study, and Sharon Arrol and Andrea O’Brien for their assistance with data extraction.

Correspondence

Sita Tarini Clark: Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland 1023, New Zealand.

Correspondence Email

sitaclark12@gmail.com

Competing Interests

Nil.

1) Zhang X, Zeng Q, Cai W, Ruan W. Trends of cervical cancer at global, regional, and national level: data from the Global Burden of Disease study 2019. BMC Public Health. 2021;21(1):894.

2) Torre LA, Islami F, Siegel RL, et al. Global cancer in women: burden and trends. Cancer Epidemiol Biomarkers Prev. 2017;26(4):444-57.

3) Sykes P, Williman J, Innes C, Hider P. Review of cervical cancer occurrences in relation to screening history in New Zealand for the years 2013-2017 [Internet]. Christchurch (NZ): The University of Otago; 2019 [cited 2021 Nov 30]. Report No.: 2. [Available from: https://www.nsu.govt.nz/system/files/resources/cancer-case-review-2013-2017-final-report-29-august-2019.pdf].

4) Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010;127(12):2893-917.

5) Garland SM, Brotherton JML, Skinner SR, et al. Human papillomavirus and cervical cancer in Australasia and Oceania: risk-factors, epidemiology and prevention. Vaccine. 2008;26: M80-8.

6) Sykes P, Gopala K, Tan AL, et al. Type distribution of human papillomavirus among adult women diagnosed with invasive cervical cancer (stage 1b or higher) in New Zealand. BMC Infect Dis. 2014;14(1):374.

7) Brisson M, Kim JJ, Canfell K, et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet. 2020;395(10224):575-90.

8) Smith MA, Edwards S, Canfell K. Impact of the National Cervical Screening Programme in New Zealand by age: analysis of cervical cancer trends 1985-2013 in all women and in Māori women. Cancer Causes Control. 2017;28(12):1393-404.

9) Innes CR, Williman JA, Simcock BJ, et al. Impact of human papillomavirus vaccination on rates of abnormal cervical cytology and histology in young New Zealand women. N Z Med J. 2020;133(1508):72-84.

10)  Doorbar J, Griffin H. Refining our understanding of cervical neoplasia and its cellular origins. Papillomavirus Res. 2019;7:176-9.

11) Luyten A, Buttmann-Schweiger N, Hagemann I, et al. Utility and reproducibility of the international federation for cervical pathology and colposcopy classification of transformation zones in daily practice: a multicenter study of the german colposcopy network. J Low Genit Tract Dis. 2015;19(3):185-8.

12) Martin-Hirsch PP, Paraskevaidis E, Bryant A, Dickinson HO. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2013;(12):CD001318.

13) Yap S-J, Nathan E, Farrell L. LLETZ make it simple: anxiety, pain and treatment outcomes with outpatient large loop excision of the transformation zone under local anaesthesia. Aust N Z J Obstet Gynaecol. 2020;60(3):438-43.

14) Kyrgiou M, Athanasiou A, Paraskevaidi M, et al. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ. 2016;354:i3633.

15) Public Health England. Cervical Screening Programme and Colposcopy Management [Internet]. 2020 [cited 2021 Jul 5]. [Available from: https://www.gov.uk/government/publications/cervical-screening-programme-and-colposcopy-management/3-colposcopic-diagnosis-treatment-and-follow-up].

16)  Ghaem-Maghami S, De-Silva D, Tipples M, et al. Determinants of success in treating cervical intraepithelial neoplasia. BJOG. 2011;118(6):679-84.

17) Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008;337:a1284.

18) Arbyn M, Redman CW, Verdoodt F, et al. Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis. Lancet Oncol. 2017;18(12):1665-79.

19) Khalid S, Dimitriou E, Conroy R, et al. The thickness and volume of LLETZ specimens can predict the relative risk of pregnancy-related morbidity. BJOG. 2012;119(6):685-91.

20) Meredith I, Sarfati D, Ikeda T, Blakely T. Cancer in Pacific people in New Zealand. Cancer Causes Control. 2012;23(7):1173-84.

21) Polymeros K, Chakrabarti J, Hickey S. Colposcopy practice in Calderdale Royal Hospital and compliance with national guidelines [Internet]. The British Society for Colposcopy and Cervical Pathology 2013 Annual Scientific Meeting; 2013 April 24; Glasgow. [Available from: https://www.bsccp.org.uk/assets/file/uploads/resources/BSCCP_Abstracts_2013.pdf].

22) Razvi K, Rothnie K, Speed T, Clark S. EPO1085 Surgical margins of large loop excision of the transformation zone: histological comparison with patient characteristics and colposcopists’ experience. Int J Gynaecol Cancer. 2019;29:A568-A569.

23) Ministry of Health [Internet]. Wellington (NZ): Ministry of Health. Cervical length screening; 2019 [cited 2021 Nov 28]. [Available from: https://www.health.govt.nz/our-work/life-stages/maternity-services/new-zealand-obstetric-ultrasound-guidelines/cervical-length-screening].

24)  Papoutsis D, Kandanearachchi P, Antonakou A, et al. A method to improve the accuracy between the presumed depth of excision and the actual depth of excision in women receiving LLETZ cervical treatment; a single-center, two-operator experience. Hippokratia. 2018;22(3):113-21.

25)  Middlemore Clinical Trials [Internet]. Auckland (NZ): Counties Manukau District Health Board. Counties Manukau Health: Diabetes Snapshot. 2021 [cited 2021 Nov 30]. [Available from: https://www.middlemoretrials.nz/files/dmfile/cmh-diabetes-snapshot-aug-2021.pdf].

26)  Smith M, Rumlee L, Sherrah M, Canfell K. National cervical screening programme [Internet]. Wellington (NZ): National Screening Unit; 2018 [cited 2021 Nov 30]. Report No.: 49. [Available from: https://www.nsu.govt.nz/system/files/page/monitoringreport49_v2.4_to_moh_clean_0.docx].

27) Ministry of Health [Internet]. Wellington (NZ): Ministry of Health. Population of Counties Manukau DHB; 2021 [cited 2021 Sep 19]. [Available from: https://www.health.govt.nz/new-zealand-health-system/my-dhb/counties-manukau-dhb/population-counties-manukau-dhb].

28) Boonstra H, Oosterhuis JW, Oosterhuis AM, Fleuren GJ. Cervical tissue shrinkage by formaldehyde fixation, paraffin wax embedding, section cutting and mounting. Virchows Arch A Pathol Anat Histopathol. 1983;402(2):195-201.

29)   Prendiville W, Sankaranarayanan R. Treatment of cervical intraepithelial neoplasia (CIN). Lyon (FR): International Agency for Research on Cancer; 2017. Report No.: 45.

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Cervical cancer is the fourth most common malignancy in females worldwide, affecting 5.7 per 100,000 women in New Zealand, with higher rates in Māori compared to non-Māori (8.1 vs 4.4, per 100,000 women, respectively).[[1-3]] Despite Australia and New Zealand both having some of the lowest rates of cervical cancer in the world,[[4]] cervical cancer remains an important and preventable cause of morbidity and mortality.[[5,6]] Squamous cervical intraepithelial (CIN) lesions are the precursor lesions to the majority of cervical cancers. These lesions are clinically detectable for many years prior to the development of cancer, through cervical cytology screening.[[7]] Due to the long latency period of cervical cancer, the identification and removal of precancerous cervical lesions is highly effective in preventing the development of invasive disease.[[3,6]] In New Zealand, the National Cervical Screening Programme and the human papillomavirus vaccine have both significantly reduced the incidence of abnormal cervical cytology and cervical cancer over the past 40 years.[[8,9]]

The majority of CIN lesions occur in the cervical transformation zone (TZ), due to the ability of simple columnar epithelium within this site to transform into stratified squamous epithelium via metaplasia.[[10]] TZ location varies between patients, with younger patients typically having a distal TZ along the cervical canal, which is more exposed and thus more susceptible to infection.[[11]] HPV infection of these specialised TZ cells is associated with a high risk of cancer progression.[[10]] Correct identification of TZ type is therefore critical when determining the appropriate depth of excision within the cervical canal.[[10–12]]

Large loop excision of the transformation zone (LLETZ) procedure remain the preferred method for removal of squamous cervical intraepithelial neoplasia (CIN) lesions worldwide.[[13]] Excisional techniques enable histological analysis of CIN lesions and identification of resection margins; two important prognostic indicators of residual disease or recurrence.[[12,13]] The recommended depth of LLETZ excision is dependent on TZ type, alongside other patient and obstetric variables.[[14,15]] Inadequate excision depth and positive excisional margins increase the risk of residual precancerous cells, and hence are both associated with a significant risk of treatment failure.[[16]] In contrast, multiple excisions and increasing excision depths are both associated with an increased risk of cervical incompetence and preterm birth, which is of particular importance in patients of reproductive age.[[14,17,18]]

In 2020, Public Health England (PHE) updated their colposcopy management guidelines, on which New Zealand’s standards of care for LLETZ procedures are based.[[15]] The PHE standards are derived from large clinical studies and meta-analyses that guide the minimum depth to avoid treatment failure and the depth at which preterm birth rates significantly increase.[[19,20]] Given the risks associated with under- and over-sampling of LLETZ excisions, this study aimed to audit the depth of cervical tissue excised in LLETZ procedures performed at Counties Manukau District Health Board (CMDHB), relative to PHE’s standards of care.

Methods

Ethics statement

Ethics approval was obtained for this study from the University of Auckland Human Participants Ethics Committee on 19 November 2018 (Ethics number: 021825).

Study procedures

NHIs of patients undergoing LLETZ procedures at CMDHB between 1 June 2020 to 30 May 2021 were obtained by the healthAlliance health analysts. Hospital records were reviewed to determine eligibility. Patients who did not undergo LLETZ procedures, or had inadequate or missing surgical or histological data, were excluded. Demographic, clinical, and laboratory variables were collected following a review of clinic letters, surgical or examination notes, and laboratory records using the Regional Clinical Portal and the CMDHB Colposcopy Database. Demographic variables included age at the time of procedure, ethnicity, and menopausal status (where menopausal status was not clearly documented, patients ≤45 years old were assumed to be pre-menopausal). Treatment variables included excision depth as reported by the pathologist (where multiple passes were taken, the depth of all passes and the location of each pass i.e., central or peripheral were recorded), reported transformation zone classification as per operating surgeon (types 1–3), primary operator (Registered Medical Officer (RMO) or Consultant Senior Medical Officer (SMO)), type of anaesthesia (local vs general anaesthesia), indication for treatment, and the number of passes performed. Outcome data included completeness of TZ excision (as recorded “complete” by the pathologist on the histopathology report) and margin status of the excised tissue (as recorded “clear” by the pathologist on the histopathology report). Where the histopathology report described the completeness of excision margins or TZ as being unclear, the excision/TZ was considered incomplete.

Audit standards

All standards used were based on the PHE guidelines which is in line with current practice in New Zealand.[[15]]

• Depth of excision:

o Type 1 TZ—excision should remove a depth of more than 7mm; target ≥95% of cases.

        In individuals of reproductive age, the excision should be no greater than 10mm.

o Type 2 TZ—excisions should remove a depth of 10–15mm; target ≥95% of cases.

o Type 3 TZ—excisions should remove a depth of 15–25mm; target ≥95% of cases.

• Number of passes: at least 80% of cases should have the specimen removed as a single sample.

• Local anaesthesia: the proportion of individuals managed as outpatients with local anaesthesia should be at least 85%.

When considering whether cases met the standard of care, pre-menopausal patients with a type 1 TZ were only deemed to meet the standard if the excised depth was between 7–10 mm. For procedures where more than one pass was performed, passes that were central (i.e., an anterior lip pass and a posterior lip pass) both had to meet the required depth in order to meet PHE’s standard. However, additional peripheral passes that did not meet the required depth did not influence whether a procedure met the standard or not.

Chi-squared test, or Fisher’s exact test (for comparisons where there were low frequency cells) were used to determine if there were statistically significant differences in meeting PHE’s standards. Where data were missing or unknown, this is reported but not included in the analysis. Comparisons were made by TZ type, primary operator, type of anaesthetic, menopausal status or ethnicity. Comparisons were also made between groups, based on adequacy of excision depth, to determine if adequate versus a depth that was too shallow or too deep was associated with positive margins on histopathology report. A p-value <0.05 was regarded as statistically significant. All statistical analyses were performed using GraphPad Prism software (version 9.0).

Results

A total of 214 patients were identified using the outlined sampling strategy, eight of which were excluded due to having inaccessible data (Figure 1). Of the remaining 206 auditable records, 22 patients were excluded with a recorded reason. The main indications for exclusion included no recorded excision depth or no LLETZ procedure taking place. Subsequently, 184 LLETZ procedures were analysed.

View Figures & Tables.

Demographic characteristics

The majority of patients were between 31–40 years of age, were pre-menopausal (Table 1) and had type 1 TZs (Table 2). The majority of patients were of NZ European ethnicity (40%), followed by Asian (19%), Māori (16%) and Pasifika peoples (13%). The demographic characteristics of the audit population are summarised in Table 1.

Audit standards

Of the 184 LLETZ procedures performed during the study period, the majority of patients had a type 1 TZ (72%), followed by type 2 TZ (24%) and type 3 (4%). Only 48% of all LLETZ procedures performed during this study were of appropriate excision depth, relative to PHE’s ≥95% threshold. Rates of successful LLETZ excision depths were similar for patients with type 1 and type 2 TZs; however, 86% of type 3 TZ excisions did not meet the standard of care. The main reason for procedures not meeting the standard of care was a suboptimal excision depth, particularly in patients with type 2 and type 3 TZs (43% and 86%, respectively) (Table 2).

Treatment characteristics

The majority of procedures were performed by an SMO (87%) and under local anaesthesia (67%). The majority of LLETZ excisions were performed using a single pass (69%), followed by two passes (25%) and three passes (5%). Only 36% of all LLETZ excisions had clear margins, with the lowest proportion of clear margins in patients with type 1 TZ (35% in type 1, 39% in type 2 and 43% in type 3). Overall, 18% of TZs were determined to be completely excised, with low rates seen across all TZ types (18.0% in type 1; 18% in type 2; and 14% in type 3). The treatment characteristics of the audit population are summarised in Table 3.

There were no significant differences in the proportion of patients meeting the standard of care by anaesthetic type (local vs other), primary operator (SMO vs RMO), TZ type (1, 2 or 3), menopausal status (pre or post) or ethnicity (Appendix 1). Finally, we observed that when the PHE standard was met, margins were most likely to be clear (47% clear margins), compared with excisions that were either too shallow (30% clear margins) and too deep (20% clear margins) (p=0.03).

Discussion

Cervical cancer remains a significant cause of morbidity and mortality in New Zealand. LLETZ excisions of precancerous CIN lesions can be highly effective in preventing the development of invasive cervical disease. However, under- and over-sampling of LLETZ procedures are both associated with complications, including an increased risk of disease progression,[[13]] and preterm birth in women of child-bearing age,[[11,14,15,19]] respectively. Equitable access to LLETZ procedures nationwide is crucial, especially in light of the high rates of cervical cancer in Māori and Pasifika in New Zealand.[[20]]

Herein we report the findings of our audit of LLETZ procedures at CMDHB, which shows that only 48% of LLETZ procedures were of an appropriate excision depth, relative to PHE’s recommended threshold of ≥95%.[[12]] Inadequate excision depth was the primary reason for not meeting the standard of care for all three TZ types, particularly in patients with type 2 or type 3 TZs (43% and 86%, respectively).[[15]] Despite the depth of excision at LLETZ being a well-defined, internationally recognised standard, there is a deficit of published audited data worldwide. Only two conference poster abstracts were available from the United Kingdom and identified an adequate depth of excision in 95.5% (n=83),[[21]] and 69% (n=224)[[22]] of patients undergoing LLETZ procedures. The only comparable report from Australasia was a locally presented audit of 104 patients undergoing LLETZ procedures in Auckland District Health Board (ADHB) between 1 June to 31 December 2020 (online via The University of Auckland intranet, available on request). This report identified an insufficient depth of excision in 15% of type 1 TZ, 38% of type 2 TZ and 73% of type 3 TZ excisions.[[15]] The variation in meeting the standard between these three reports highlights the importance of regular audits within centres.

We observed that LLETZ excisions that were too shallow and too deep were both associated with positive margins. Unfortunately, data were not collected on which margins were reported positive, as endocervical margins that are positive are the most strongly associated with disease persistence.[[16]] Therefore, collecting data on location of positive margins is an important consideration of future audits. Under-sampling in all three TZ classification groups may reflect a lack of knowledge of excision depths specific to TZ type, or fears over the consequences of excessive depth in an overall young population in CMDHB.[[14,17]] National guidelines outline that individuals who have had a previous LLETZ of ≥10mm are at high risk of spontaneous preterm birth and second-trimester loss, and should receive cervical length screening during pregnancy.[[23]] Knowledge of these guidelines likely contributes to colposcopists’ tendency to remain conservative with their LLETZ excision depths. It may also reflect technical difficulties or lack of access to appropriate loops in achieving the required depths, as highlighted in the Ishikawa cause and effect diagram (Figure 2).

This study also identified an excessive depth of excision in 22% of patients with type 1 TZs. No published reports on the rates of deep LLETZ excisions relative to PHE’s recommendations were available in the literature. However, similar findings were reported in the ADHB audit (33% of type 1 TZs excisions were of excessive depth), suggesting our centre is not unique. This finding is clinically significant, given that 94% of type 1 TZ patients in this study (and 92% in the ADHB cohort) were pre-menopausal, thus increasing these patients’ risks of preterm labour in future pregnancies.[[14,17]] However, the PHE colposcopy guidelines only allow for a small margin of error for LLETZ excisions (3mm in type 1 TZ patients), adding to the difficulty of achieving the correct depth in this group of patients.[[15]] Greater training in how to achieve the desired depth of excision across all TZ types may be beneficial in increasing the accuracy of excision. One study reported that auditing of consecutive LLETZ excisions resulted in significant improvement in the accuracy of colposcopists' presumed and actual depth of excision.[[2]][[4]] Increased guideline exposure in theatre and clinic, in addition to increased auditing of colposcopists’ excision depths, may increase the efficacy of LLETZ procedures.

Only 69% of LLETZ procedures were performed using a single pass and 67% under local anaesthesia, relative to PHE’s standard of ≤80% and ≤85%, respectively.[[15]] It is known that multiple tissue fragments can impact the accuracy of the histopathologic assessment. However, given the elevated rates of obesity in CMDHB (16% of adults in CMDHB are obese, and 19% morbidly obese), performing a LLETZ procedure using a single pass or under local anaesthesia may compromise the surgeon’s ability to obtain an adequate sample.[[2]][[5]] Thus, the use of multiple passes or general anaesthetic are likely prioritised in patients with difficult access, in order to optimise the adequacy of excision. Theoretically, analysis of multiple passes may underestimate the average depth of excision, as the minimum recorded depth for each segment was used for analysis. However, when two passes are performed, this is more likely to represent a separate anterior and posterior pass, rather than superimposed passes of the same area, and thus, should not impact the results. Inclusion of cases with three or more passes are more likely to underestimate depth; however, these only represented a small proportion (6%) of the sample and are therefore also unlikely to have influenced the overall result.

Although not the primary outcome of this study, we observed that non-Māori and non-Pasifika patients were more likely to have LLETZ procedures than Māori and Pasifika patients. This is despite the over-representation of Māori and Pasifika peoples in cervical cancer rates in New Zealand.[[3,20]] These findings are consistent with the reduced rates of cervical screening in Māori and Pasifika peoples seen nationwide, and the subsequent disparities in disease burden and stage at diagnosis.[[8,20,2]][[6]][[,27]] These findings highlight the urgent need for future work focused on ensuring that the health service is able to provide equitable cervical screening throughout Aotearoa New Zealand.

There were several limitations to this study. Firstly, patients undergoing cone biopsies were not included in this analysis, due to only a small proportion of patients undergoing this procedure. This may limit interpretations of the management of type 3 TZ patients, given that only one surgical management option was included in this analysis. Secondly, formalin fixation is known to result in minor cervical tissue specimen shrinkage of around 2.7% in the longitudinal dimensions.[[2]][[8]] Consistent with other studies, this shrinkage was deemed clinically insignificant and thus no changes were made to the excision depth measurements in our analysis.[[24,28]] Diathermy ball fulguration to the base of the LLETZ excision is also routinely used to help achieve haemostasis following resection and may have additional benefits in terms of treating residual CIN, the impact of which was not investigated in this audit.[[29]] Finally, although this study was sufficiently powered overall, subgroup analysis had smaller patient populations, and thus was not always sufficiently powered. This may have implications on the study’s ability to identify robust differences between audit standard outcomes according to clinical subgroups. Future studies would benefit from including a larger patient cohort in order to mitigate this effect.

Ultimately, these findings highlight the need for additional quality improvement processes to address barriers to meeting standard excision depth. Suggestions include having picture descriptions of the different transformation zone types alongside PHE’s colposcopy management guidelines in colposcopy rooms, in order to increase intraoperative awareness of the recommended excision depths. Secondly, increased access to a wider range of LLETZ loops may help facilitate excision of the correct cervical depth with only one pass. Finally, increased access to training opportunities, such as simulation-based teaching, may foster greater skill in excising the correct tissue depths.

Conclusion

This is the first study to audit and analyse the outcomes of patients undergoing LLETZ procedures at CMDHB, relative to established colposcopy guidelines and standards of care. Differences in the excision depths were identified relative to PHE’s established thresholds, with a large proportion of excisions being too shallow, particularly in patients with type 2 and type 3 TZs. These findings highlight the importance of considering the associated risks of LLETZ procedures in individual patients and the need to adapt the surgical approach and equipment used accordingly. Importantly, this study has also identified reduced rates of LLETZ procedures in Māori and Pasifika patients, emphasising the need for improved screening in these high-risk communities going forward. Finally, this study has highlighted the need to audit LLETZ procedures in other DHBs in New Zealand to identify issues and optimise the quality of care for CIN provided nationwide.

View Appendices.

Summary

Abstract

Aim

Cervical cancer is the fourth most common malignancy in females worldwide. Large loop excision of the transformation zone (LLETZ) procedures remain the preferred surgical technique to remove squamous cervical intraepithelial neoplasia (CIN) lesions globally. This study aimed to assess whether the depth of LLETZ procedures at Counties Manukau District Health Board (CMDHB) met established standards of care.

Method

Hospital records were reviewed for all LLETZ procedures performed at CMDHB between 1 June 2020 to 3 May 2021, and these were compared to Public Health England’s (PHE) 2020 Colposcopy Guidelines.

Results

One hundred and eighty-four cases were identified. Forty-eight percent of all LLETZ procedures were the correct excision depth relative to PHE’s ≥95% threshold, primarily due to excisions being too shallow, particularly in patients with type 2 and 3 transformation zones (TZ), 48% and 86%, respectively. Māori and Pasifika patients represented only 16% and 13% of all LLETZ procedures in this study, respectively.

Conclusion

This study identified significant oversampling of LLETZ excisions in patients with type 1 TZs, and significant under-sampling in patients with types 2 and 3 TZs. Ultimately, these findings highlight the need for additional quality improvement processes and emphasise the importance of auditing LLETZ procedures nationwide.

Author Information

Dr Sita T Clark: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: sitaclark12@gmail.com Dr Hilary R Barker: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: hilaryrbarker@gmail.com Dr Luke R Bradshaw: PGY1 House Officer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. E: luke.bradshaw14@gmail.com Dr Jyoti Kathuria: Consultant Gynaecologist, Department of Obstetrics and Gynaecology, Counties Manukau District Health Board, Auckland, New Zealand. E: jyoti.kathuria@middlemore.co.nz Dr Charlotte Oyston: Consultant Obstetrician, Senior Lecturer, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Department of Obstetrics and Gynaecology, Counties Manukau District Health Board, Auckland, New Zealand. E: c.oyston@auckland.ac.nz

Acknowledgements

We would like to thank the Counties Manukau District Health Board Research Offices and Clinical Records departments for their assistance with collating the data required to write this manuscript. We would also like to thank Dr Carina Miles for her advice and input in this study, and Sharon Arrol and Andrea O’Brien for their assistance with data extraction.

Correspondence

Sita Tarini Clark: Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland 1023, New Zealand.

Correspondence Email

sitaclark12@gmail.com

Competing Interests

Nil.

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