A comparative study of two methods of large loop excision of the transformation zone

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1 BJOG: an International Journal of Obstetrics and Gynaecology April 2005, Vol. 112, pp DOI: /j x A comparative study of two methods of large loop excision of the transformation zone Mohamed A. Mossa, a,1 Paul G. Carter, a Salah Abdu, a Martin P.A. Young, b Valerie A. Thomas, b Desmond P.J. Barton a,1 Objective To determine whether the conventional large loop excision of the transformation zone (CLLETZ) and the top-hat technique (THLLETZ) differ in (a) completeness of excision of the cervical lesion, (b) depth of cervical tissue excised and (c) adequacy of follow up by cytology and colposcopy. Design Retrospective case review. Setting University Teaching Hospital, London. Sample Five hundred and thirteen consecutive patients matched for age, parity, smoking history and referral cytology who had either CLLETZ (286 5%) or THLLETZ (227 44%) for cervical intraepithelial neoplasia (CIN). Methods All procedures were performed or supervised by BSCCP-accredited colposcopists. All cytology and histology were reviewed by two specialist cytohistopathologists. Cervical stenosis was defined as difficulty in or inability in obtaining an endocervical brush smear. Main outcome measures Depth of cervical tissue excised, histology of endocervical margins, post-lletz cytologic and colposcopic findings. Results The mean depth of excision in the CLLETZ group was 12.1 mm (SD ¼ 4.4 mm) and 20.8 mm (SD ¼ 6.4 mm) in the THLLETZ group. The incidence of involved endocervical margins was 2.8% in the CLLETZ group and 5.2% in the THLLETZ group (P ¼ 0.1). There was CIN in the top-hat specimen of 10 THLLETZ cases (4.4%, CI ¼ 95%). The first post-treatment cervical smear was inadequate in 5 (4.1%) cases in the CLLETZ group and 20 (11.7%) in the THLLETZ group (P ¼ 0.022). Cervical stenosis was found in 21 (7.7%) cases in the CLLETZ group and in 64 (30.9%) cases in the THLLETZ group (P < ). Eleven (4%) patients in the CLLETZ group had cytological and/or colposcopic evidence of residual CIN compared with 12(5.8%) patients in THLLETZ group (P ¼ 0.4). In the first follow up assessment, 21.7% of the CLLETZ group had incomplete colposcopy compared with 48.7% in the THLLETZ group (P < ). Conclusions Compared with the CLLETZ, the THLLETZ (1) removed more cervical tissue but did not have a lower incidence of involved endocervical margins, and (2) resulted in significantly higher incidence of inadequate post-treatment colposcopic and cytological follow up. These data indicate that there is no justification to performing a top-hat LLETZ routinely. INTRODUCTION Since Prendiville et al. 1 introduced the procedure of large loop excision of the transformation zone (LLETZ), it has gained an increasing popularity. LLETZ combines the advantages of simplicity and a limited and relatively nonmutilating treatment which provides tissue for histological examination of the entire lesion. When compared with a Department of Obstetrics and Gynaecology, St George Hospital and Medical School, London, UK b Department of Pathology, St George Hospital and Medical School, London, UK Correspondence: Mr M. Mossa, Department of Obstetrics and Gynaecology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK. 1 Both authors made an equal contribution to this work. D RCOG 2005 BJOG: an International Journal of Obstetrics and Gynaecology colposcopically directed biopsy, LLETZ is more reported to reveal high grade cervical intraepithelial neoplasia (CIN) and microinvasive disease. 2,3 LLETZ appears to offer a therapeutic advantage to local destructive techniques when compared with carbon dioxide laser vaporisation, LLETZ-treated patients had fewer side effects, there was a cost advantage and, more importantly, further histological material was provided for confirmation of the diagnosis. 4 Although many studies have compared LLETZ with other modalities of treatment, we are not aware of any published study comparing different methods of LLETZ. In this report, we have compared two methods of LLETZ: the conventional method as described by Prendiville et al. and the so-called top-hat LLETZ. 1 The latter entails excising the transformation zone by one loop followed by an additional apical excision of the endocervical canal using a smaller loop.

2 COMPARISON OF LLETZ PROCEDURES 491 Table 1. Indications for colposcopy. Values are presented as n (%). Indications CLLETZ a THLLETZ b Total BNC c 8 (2.8) 2 10 Mild dyskaryosis 135 (47.2) 86 (37.8) 221 Moderate dyskaryosis 57 (19.9) 63 (27.1) 120 Severe dyskaryosis 37 (7.7) 49 (21.5) 86 Glandular neoplasia Miscellaneous d 49 (17.1) 26 (11.4) 75 a CLLETZ ¼ conventional LLETZ. b THLLETZ ¼ tophat LLETZ procedure in which a second deeper excision is performed [the same acronyms are used in other tables]. c BNC ¼ borderline nuclear change. d Miscellaneous indications included: recurrent inadequate smears, abnormal looking cervix and persistent cervicitis. METHODS We retrospectively reviewed the medical records of 513 patients treated consecutively by LLETZ for CIN at St George s Hospital in 1998 and Patients with cervical glandular neoplasia were excluded. Four accredited colposcopists performed or supervised the procedures. Two operators performed THLLETZ almost routinely and the other two used CLLETZ as their method of choice. Patients were followed up by colposcopy and cytology four to six months after LLETZ. The adequacy of the cytology was studied. The follow up colposcopic assessment included: (a) whether or not the transformation zone was seen in its entirety, (b) the presence or absence of residual CIN and (c) the presence or absence of excessive scarring and/or cervical stenosis. Cervical stenosis was defined as difficulty or inability in obtaining an endocervical brush smear. For all LLETZ procedures, the same electrosurgical unit was used (ERBOTOM ICC 200; ERBE Medical UK). The unit was set to deliver W of power at blend (interrupted 350 khz sinusoid waves, 80% duty cycle). The loops used ranged from to cm for excision of the transformation zone, and from to for apical excision of the endocervical canal, with a 0.02-mm diameter stainless steel wire. Most of the procedures were performed under local anaesthesia using prilocaine hydrochloride 3% with octapressin (Citanest, Astra) or lignocaine 1% with adrenaline 1 in 200,000 Table 3. Histological diagnosis of the LLETZ specimens. Values are presented as n or n (%). (Lignostab A, Astra) in dental cartridges. General anaesthesia was used in cases when an additional procedure (e.g. laparoscopy) was contemplated or if the patient was too anxious, or declined to be awake during the procedure. All cytology and histology were reviewed by two specialist cytohistopathologists (MPAY and VT). All specimens were fixed in 10% formalin, serially sliced, entirely embedded, processed with the standard overnight technique, and stained with haematoxylin and eosin. STATISTICAL ANALYSIS All statistical relationships were assessed by m 2 test except for the post-operative complication rates where Fisher s exact test was used. RESULTS No CIN CIN1 High grade lesions Total Normal HPV Cervicitis CIN2 CIN3 MI CLLETZ (49) 37 (13) 88 (31) 2 (1) 286 THLLETZ (39) 34 (15) 93 (41) 4 (2) 227 MI ¼ microinvasion. Of the 513 women treated, 286 (56%) underwent CLLETZ and 227 (44%) underwent THLLETZ. The two groups were matched for age, parity, smoking history and referral cytology (Table 1). Eighty-eight women (30.7%) in the CLLLETZ group, and 80 women (35%) in the THLLETZ group admitted to regular cigarette smoking (P ¼ 0.3). The initial colposcopic assessment revealed features of high grade CIN (CIN2 and CIN3) in 139 (49%) cases in the CLLETZ group and 154 (67%) in the THLLETZ Table 2. Colposcopic diagnosis. Values are presented as n or n (%). Normal Cervicitis HPV CIN1 CIN2 CIN3 Total CLLETZ (2) 137 (48) 69 (24) 70 (24) 286 THLLETZ (1) 67 (30) 70 (31) 84 (37) 227 Total HPV ¼ features Human Papilloma Virus infection. In cases where there was more than one lesion, the higher grade was taken as the colposcopic diagnosis. Fig. 1. Histogram of histological diagnoses for all patients who underwent CLLETZ or THLLETZ.

3 492 M.A. MOSSA ET AL. Table 4. Histological involvement of surgical margins. CLLETZ (n ¼ 281) THLLETZ (n ¼ 217)* P Endocervical 8 (2.8) 12 (5.5) 0.1 Ectocervical 23 (8.1) 28 (12.9) 0.1 Both 5 (1.8) 2 (0.9) 0.7 * Histology on first-pass only. Table 6. Depth of excision. N Min (mm) Max (mm) Mean Mode SD CLLETZ THLLETZ N ¼ number of specimens where the measurements were available; SD ¼ standard deviation. group (P ¼ 0.026). The details of colposcopic diagnosis are illustrated in Table 2. The histological diagnosis of the LLETZ specimens is illustrated in Table 3 and Fig. 1. There was no CIN in 16 (6%) cases in the CLLETZ group and in 7 (3%) in the THLLETZ group. The histological diagnosis of CIN1 was made in 143 (49%) of cases in the CLLETZ group and in 89 (39%) of cases in the THLLETZ group. There were high grade lesions (CIN2, CIN3 and microinvasion) in 127 (44%) cases in the CLLETZ group and in 131 (57%) cases in the THLLETZ (P ¼0.001). In 281(98%) CLLETZ cases and in 217(95.6%) THLLETZ cases, the histopathologist was able to comment on the presence or absence of disease on the margins. In the remaining cases, it was difficult to decide on margin involvement due to fragmentation, artefact and/or lack of orientation. The endocervical margins were involved in 8 (2.8%) of the CLLETZ specimens and in 12 (5.5%) of the main firstpass THLLETZ specimens (P ¼ 0.1). In addition, both ectocervical and endocervical margins were involved in 5 (1.8%) CLLETZ cases and in 2 (0.9%) THLLETZ cases (Table 4). Overall, in 23 patients, the histology of the LLETZ was negative for CIN (Table 5). The depth of excision in the CLLETZ group ranged from 3 to 25 mm (mean ¼ 12.1 [SD 4.4]). In the THLLETZ group, the range in depth of tissue excised [sum of first pass and second pass ( tophat )] was 5 to 35 mm (mean ¼ 20.8 [SD 6.4], P < ) (Table 6 and Fig. 2). There was CIN in the apical endocervical specimen (second pass) of 10 out of the 227 THLLETZ cases (4.4%, 95% CI %). The grades of CIN in the apical endocervical specimens were CIN2 in three cases and CIN3 in the remaining seven cases. The endocervical margins of the firstpass LLETZ specimens were positive for CIN in 4 (the ectocervical margins were involved as well in two of those four cases) of these 10 cases where the deep cones contained CIN. As shown in Table 4, there was CIN in the endocervical margin in 14 THLLETZ cases of which 4 (28%) had CIN in their deep cones. There was no statistically significant difference between the two groups in terms of morbidity (haemorrhage and hospital admissions). Haemorrhage was defined as cervical bleeding that needed more than coagulation diathermy to be controlled (e.g. sutures or packs). Three CLLETZ patients (1.04%) had haemorrhage, two of whom needed hospital admission, and seven THLLETZ patients (3.08%) had haemorrhage, four of whom were admitted to hospital (P ¼ 0.18 haemorrhage and 0.48 admission ). At the first follow up appointment, 271 (94%) women of the CLLETZ group and 207 (91%) of the THLLETZ returned for colposcopy and cytology. The colposcopic assessments were reported as incomplete (transformation zone not seen in its entirety) in 73 (26.9%) CLLETZ cases, of whom 14 had incomplete pretreatment colposcopies, and in 128 (60%) THLLETZ cases, of whom 27 had incomplete pretreatment colposcopies. After excluding those who had incomplete pretreatment colposcopy, the incidence of incomplete post-treatment colposcopic assessment in the THLLETZ group (48.7%) was significantly higher than that in the CLLETZ group (21.7%) [P < ] (Table 7). Post-treatment cervical stenosis was reported in 21 (7.7%) of 271 CLLETZ patients in the first Table 5. Referral smears where the histology of LLETZ was negative for CIN. Referral smear Histology of CLLETZ Histology of THLLETZ Normal HPV Cervicitis Normal HPV Cervicitis Normal* Mild dyskaryosis Moderate dyskaryosis Severe dyskaryosis Glandular atypia * Cases which did not have abnormal smears but referred for a variety of reasons (e.g. symptomatic). Fig. 2. Histogram of the depth of excision of LLETZ procedures (mm). For the THLLETZ, the depth of excision was defined as the sum of the depth of excision of the first-pass and top-hat (second-pass) excision.

4 COMPARISON OF LLETZ PROCEDURES 493 Table 7. First follow up colposcopy assessment of entire transformation zone. Values are presented as n or n (%). Complete colposcopy Incomplete colposcopy Total X Y Z Table 9. Inadequatefollowupcervicalsmears.Valuesarepresentedasn(%). CLLETZ (121 cases) THLLETZ (170 cases) m 2 df P 5 (4.1) 20 (11.7) CLLETZ 198 (73) (21.7) 271 THLLETZ 79 (38) (48.7) 207 X ¼ total number of incomplete follow up colposcopies; Y ¼ number of women who had incomplete pretreatment colposcopies as well; Z ¼ X Y. follow up colposcopy and in 64 (30.9%) out of the 207 THLLETZ patients (P < ) (Table 8). At the time of collecting the data for this study, the follow up cytology results of 121 CLLETZ patients and 170 THLLETZ patients were available. These smears were reported as inadequate in 5 (4.1%) cases in the CLLETZ group and 20 (11.7%) cases in the THLLETZ group [P ¼ 0.022] (Table 9). The two groups were similar with respect to the presence of residual CIN at the first follow up colposcopy and/or cytology. Residual CIN was reported in 11 (4%) CLLETZ cases and in 12 (5.8%) THLLETZ cases (P ¼ 0.4). DISCUSSION AND CONCLUSION The National Health Service Cervical Screening Programme (NHSCSP) is based on the fact that detection and treatment of CIN reduces the incidence of, and mortality from cervical carcinoma. There is substantial evidence that the mortality from cervical carcinoma is now falling faster as the formalisation of the programme. 5 There are many methods to treat CIN, and these are broadly defined as ablative or excisional. The ease of LLETZ has contributed to its popularity, but with this is the potential of over-treatment. It has been shown to be the most commonly used method of treatment accounting for 44% of all treatments performed, 6 and 59% of treatments at first visits. 6 There has been concern about the proportion of LLETZ biopsies that contain no CIN, with reports of negative biopsy rates of between 4.7% and 41% The NHSCSP has stipulated that at least 85% of all biopsies should contain CIN. 9 However, a survey by Semple et al. 6 showed that most colposcopy clinics failed this standard. In our study, there was histological evidence of CIN in 94% and 97% in the CLLETZ and first-pass THLLETZ Table 8. Cervical stenosis on first follow up subsequent colposcopy. Values are presented as n (%). CLLETZ THLLETZ m 2 df P 21 (7.7) 64 (30.9) < specimens, respectively. However, only 4.4% of the apical endocervical specimens ( top hats ) contained CIN. As far as we know, this is the first study to compare two methods of LLETZ for CIN, the originally described CLLETZ 1 and the so-called THLLETZ. This latter technique has come into practice and the rationale was to remove disease deep in the endocervix while at the same time not excising excess adjacent normal cervical tissue. Our study reveals the following important findings: 1. THLLETZ removed more cervical tissue compared with the CLLETZ. This is an expected finding. 2. In the THLLETZ procedure, only 4.4% of the deep cones ( top hats, deep biopsies or second pass ) contained disease. Arguably, as more patients in the THLLETZ group had high grade cervical dysplasia and high grade CIN compared with the CLLETZ group, the second-pass or deep LLETZ should have shown a large number of cases with CIN. 3. The incidence of involved endocervical margins was similar in the CLLETZ and THLLETZ groups. 4. Follow up by cytology and colposcopy in the THLLETZ group is much less reliable than in the CLLETZ group. As more patients in this group had high grade cervical dysplasia and high grade CIN, one might argue that it is this subset of patients in whom reliable follow up is even more important. Although not all patients had attended for follow up and the follow up is relatively short, the results are of both statistical and clinical significance. We have shown that excising deeper tissue in the THLLETZ is excessive treatment, scarring the cervix sufficiently to compromise follow up by cytology and colposcopy. The effects of LLETZ on the subsequent colposcopy have been described in a number of studies The transformation zone was reported to be visible in its entirety in 73 90% of patients after LLETZ. 10,11 In our study, 73% of CLLETZ patients had satisfactory colposcopy compared with 38% in the THLLETZ group (P < ). In a study comparing cold knife conisation and LLETZ conisation, the depth of excision was greater in the cold knife conisation group, and adequate post-treatment colposcopy, defined by visualisation of the squamo-columnar junction, was significantly higher in the LLETZ group (71%). 13 A surprising finding, and further evidence against the THLLETZ procedure, was that it was not associated with a lower incidence of incomplete excision. The management of incompletely excised CIN remains controversial.

5 494 M.A. MOSSA ET AL. In fact, some experienced operators rely on ablative methods. 17 The NHSCSP-published guidelines on the minimum data set for the histological reporting of cervical biopsies (punch biopsies, cervical conisations and LLETZ) stipulated that involvement of margins must be stated. 18 Our study was confined to patients with CIN only. There has been a vogue in the USA for performing endocervical curretage at the time of LLETZ. 19 This approach followed a report by Townsend et al., 20 who evaluated patients who developed invasive cancer after cryotherapy and concluded that the most common pretreatment colposcopic errors were failure to perform endocervical curretage and to take adequate numbers of biopsies. Subsequent reports have not established that routine use of endocervical curretage decreases the risk of missing occult invasive or pre-invasive disease. 20 Endocervical curretage is not a common procedure in the UK, even in patients with glandular cervical neoplasias. While similar in concept to the apical excision of the endocervical canal in the top-hat LLETZ procedure, the data on endocervical curretage are unclear. The results of our study, and in particular, the low incidence of CIN in the second-pass LLETZ, provide evidence against the routine use of endocervical curretage. A possible argument for routine THLLETZ is to diagnose skip lesions that could be missed without an endocervical histological specimen. However, neoplastic lesions cephalad but not adjacent to the squamo-columnar junction (skip lesions) in previously untreated women are rare. 21 We have not studied other potential sequelae of treatment such as dysmenorrhoea and subfertility. Anecdotal evidence and personal experience would suggest these problems are uncommon although widely reported. Long term side effects of LLETZ are still incompletely documented. Bigrigg et al. 12 described the long term complications for up to 22 months after treatment. Another study described 44 pregnancies from a group of 1000 women who underwent LLETZ and no possible LLETZ-related problems were reported. 22 In conclusion, THLLETZ excised more cervical tissue, did not reduce the incidence of involved endocervical margins, rarely revealed disease in the deeper excision and significantly compromised cytologic and colposcopic follow up. These data indicate that the THLLETZ technique is not justified for CIN. References 1. Prendiville W, Cullimore J, Norman S. Large Loop Excision of the Transformation Zone (LLETZ). A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynaecol 1989;96: Prendiville W, Davies R, Berry PJ. A low voltage diathermy loop for taking cervical biopsies: a qualitative comparison with punch biopsy forceps. Br J Obstet Gynaecol 1986;93: Howe DT, Vincenti AC. Is large loop excision of the transformation zone (LLETZ) more accurate than colposcopically directed punch biopsy in the diagnosis of cervical intraepithelial neoplasia. Br J Obstet Gynaecol 1991;98: Gunasekera PC, Phipps JH, Lewis BV. Large loop excision of the transformation zone compared to carbon dioxide laser in the treatment of CIN: a superior mode of treatment. Br J Obstet Gynaecol 1990; 97: Sasieni P, Cuzick J, Farmery E. Accelerated decline in cervical cancer mortality in England and Wales [letter]. Lancet 1995;346: Semple D, Saha A, Maresh M. Colposcopy and treatment of cervical intraepithelial neoplasia: are national standards achievable? Br J Obstet Gynaecol 1999;106: Howells REJ, O Mahony F, Tucker H, Millinship J, Jones PW, Redman CWE. How can the incidence of negative specimens resulting from large loop excision of the transformation zone be reduced? An analysis of negative LLETZ specimens and development of a predictive model. Br J Obstet Gynaecol 2000;107: Bigrigg A, Codling B, Pearson P, Read M, Swingler G. Colposcopic diagnosis and treatment of cervical dysplasia at single clinic visit. Lancet 1990;336: Standards and quality in colposcopy: NHS Cervical Screening Programme. NHSCSP Publication No 2, Luseley DM, Cullimore J, Redman CW, et al. Loop diathermy excision of the cervical transformation zone in patients with abnormal smears. BMJ 1990;300: Murdoch JB, Grimshaw RN, Monaghan JM. Loop diathermy excision of the abnormal cervical transformation zone. Int J Gynaecol Cancer 1991;1: Bigrigg A, Haffenden DK, Sheehan AL, Codling BW, Read MD. Efficacy and safety of large-loop excision of the transformation. Lancet 1994;343: Gicalone P-G, Laffargue F, Aligier N, et al. Randomized study comparing two techniques of conisation: cold knife versus loop excision. Gynecol Oncol 1999;75: Monk A, Pushkin SF, Nelson AL, Gunning JE. Conservative management of options for patients with dysplasia involving endocervical margins of cervical cone specimens. Am J Obstet Gynecol 1996; 174: Dobbs S, Asmussen T, Nunns D, et al. Does histological incomplete excision of cervical intraepithelial neoplasia following large loop excision of transformation increase recurrence rates? A six year cytological follow up. Br J Obstet Gynaecol 2000;107: Flannelly G, Bolger B, Fawzi H, De Lopes AB, Monaghan JM. Follow up after LLETZ: could schedules be modified according to risk of recurrence. Br J Obstet Gynaecol 2001;108: Duncan ID. Treatment of CIN by destruction cold coagulator. In: Jordan JA, Sharp F, Singer A, editors. Pre-clinical Neoplasia of the Cervix (Proceedings of the IX RCOG Study Group). London: RCOG, 1981: Histopathology Reporting in Cervical Screening. Working Party of the Royal College of Pathologists and the NHS Cervical Screening Programme. NHSCSP Publication 10, Spirtos NM, Schlaerth JB, d Ablaing III G, Morrow CP. A critical evaluation of the endocervical curettage. Obstet Gynecol 1987;70: Townsend DE, Richart RM, Marks E, Nielsen J. Invasive cancer following outpatient evaluation and therapy for cervical disease. Obstet Gynaecol 1981;57: Moseley KR, Dinh TV, Hannigan EV, Dillard Jr EA, Yandell RB. Necessity of endocervical curettage in colposcopy. Am J Obstet Gynecol 1986;154: Bigrigg A, Codling B, Pearson P, Read M, Swingler G. Pregnancy after cervical loop diathermy. Lancet 1991;337:149. Accepted 12 July 2004