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YGYNO-975819; No.

of pages: 6; 4C:
Gynecologic Oncology xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

1Q2 Comparison of cold knife cone biopsy and loop electrosurgical excision
2 procedure in the management of cervical adenocarcinoma in situ:

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3 What is the gold standard?

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4Q3 A. Munro a,, Y. Leung b, K. Spilsbury c, C.J.R. Stewart b, J. Semmens c, J. Codde c, V. Williams d, P. O'Leary e,
5 N. Steel a, P. Cohen b

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6 a
WA Cervical Cancer Prevention Program, Perth, WA, Australia
7 b
School of Women's and Infants' Health, University of Western Australia, Crawley, WA, Australia
8 c
Centre for Population Health Research, Curtin University, Bentley, WA, Australia

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9Q4 d
School of Biomedical Sciences, Curtin University, Bentley, WA, Australia
10 e
Faculty of Health Science, Curtin University, Bentley, WA, Australia
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1 2 H I G H L I G H T S
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14 Women treated for ACIS by cold knife cone biopsy or LEEP were monitored for disease persistence.
15 There was no difference in ACIS disease persistence between CKC and LEEP after 3.6 years of follow-up.
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1 9 a r t i c l e i n f o a b s t r a c t
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20 Article history: Objective. To compare the outcomes of patients with cervical adenocarcinoma in situ (ACIS) treated with 30
21 Received 14 January 2015 cold knife cone (CKC) biopsy or loop electrosurgical excision procedure (LEEP) for the treatment of cervical 31
22 Accepted 26 February 2015 adenocarcinoma in situ (ACIS). 32
23
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Available online xxxx Study design. This is a retrospective, population-based cohort study of Western Australian patients with 33
ACIS diagnosed between 2001 and 2012. Outcomes included pathological margin status and the incidence of 34
24 Keywords:
persistent or recurrent endocervical neoplasia (ACIS and adenocarcinoma) during follow-up (b 12 months) 35
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25 Adenocarcinoma in situ
26 Cervical
and surveillance (12 months) periods. 36
27 CKC Results. The study group comprised 338 patients including 107 (32%) treated initially by LEEP and 231 (68%) 37
38
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28 LEEP treated by CKC biopsy. The mean age was 33.2 years (range 18 to 76 years) and median follow-up interval was
29 Management 3.6 years (range b1 year to 11.8 years). Overall, 27 (8.0%) patients had ACIS persistence/recurrence while 9 (2.7%) 39
were diagnosed with adenocarcinoma during the follow-up and surveillance periods. No patient died of cervical 40
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cancer within the study period. There were no signicant differences in the incidence of persistent and/or 41
recurrent endocervical neoplasia according to the type of excisional procedure. Patients with positive biopsy 42
margins were 3.4 times more likely to have disease persistence or recurrence. 43
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Conclusion(s). LEEP and CKC biopsy appear equally effective in the treatment of ACIS for women wishing 44
to preserve fertility. Patients undergoing conservative management for ACIS should be closely monitored, 45
particularly if biopsy margins are positive in initial excision specimens. Patients and their clinicians should be 46
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aware of the potential risks of residual and recurrent disease. 47


48 2015 Elsevier Inc. All rights reserved.
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52
50
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53 1. Introduction adoption of public health screening programmes, but this mainly 56
reects a decrease in squamous cell carcinoma [13]. By contrast, 57
54 The incidence of cervical cancer in developed countries has the incidence of cervical adenocarcinoma has increased in both rela- 58
55 decreased signicantly in the past few decades largely due to the tive and absolute terms, and now represents 2025% of all cervical 59
cancer cases [13]. The recognised precursor to cervical adenocarcino- 60
ma is adenocarcinoma in situ (ACIS), and this frequently coexists with 61
Corresponding author at: WA Cervical Cancer Prevention Program Level 2, Eastpoint
high-grade squamous intraepithelial neoplasia (CIN) and/or squa- 62
Plaza, 233 Adelaide Terrace, Perth, WA 6000, Australia. Tel.: + 61 89323 6781(W),
Tel.: +61 8 404 990 169(M). mous cell carcinoma [46]. Cervical cytology is generally less sensitive 63
E-mail address: aime.munro@health.wa.gov.au (A. Munro). in the detection of cervical glandular abnormalities compared to CIN, 64

http://dx.doi.org/10.1016/j.ygyno.2015.02.024
0090-8258/ 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Munro A, et al, Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of
cervical adenocarcinoma in situ: What is the gold standard? Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.024
2 A. Munro et al. / Gynecologic Oncology xxx (2015) xxxxxx

65 and it is reported that ACIS may also evade detection at colposcopy the study. Patients were excluded if they had prior histological docu- 126
66 [710]. mentation of CIN or cervical cancer. Cervical cytology was classied 127
67 Conservative management of women with ACIS is controversial according to the Australian Modied Bethesda System 2004 [12]. 128
68 since these lesions can persist/recur and may co-exist with, or progress Patient age at the time of treatment was classied as 30 years or 129
69 to, cervical adenocarcinoma [5,6,11]. Consequently hysterectomy is N30 years. Postcode of residence was used to assign a socioeconomic 130
70 regarded as the denitive treatment [12,13]. However, ACIS commonly level using the Australian Bureau of Statistics 2006 Socio Economic 131
71 affects young women who may wish to preserve fertility and therefore Indexes for Areas (SEIFA) [27]. Patients underwent CKC or LEEP proce- 132
72 local excisional procedures such as cold knife cone (CKC) biopsy or dures according to the surgeon's standard practice. 133
73 loop electrosurgical excision procedure (LEEP) have been utilized as
74 alternatives to hysterectomy [6,7,1114]. 2.3. Histopathology ndings 134
75 In Australia, CKC is regarded as the gold standard treatment for ACIS
76 [12]. There is a perception that there is a greater likelihood of incom- The following biopsy ndings were determined from review of the 135
77 plete excision with LEEP because the depth of excised tissue and the histopathology reports: the type of biopsy (CKC or LEEP), depth of the 136
78 overall dimensions of the specimen tend to be smaller in comparison specimen (measured macroscopic extent along the cervical canal), 137

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79 to CKC. It is also argued that the tissue margins in a LEEP biopsy may presence of concurrent CIN and resection margin status. The latter was 138
80 show signicant thermal artefact, which can interfere with the patho- considered positive if any margin (ectocervical, endocervical or deep/ 139

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81 logical assessment of biopsy margins [15,16]. Some studies have circumferential) was involved by ACIS, negative if all margins were 140
82 shown a greater risk of positive endocervical margin with LEEP but histologically clear, and indeterminate if margins could not be assessed 141
83 these have included cases in which ACIS was not suspected prior to or were not documented. 142

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84 the excisional procedure [1719]. Conventional management has also
85 been challenged by recent data which suggest that the risk of positive 2.4. Follow-up 143
86 margins and disease recurrence are equivalent following LEEP or CKC

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87 biopsy [6,11]. Such ndings could potentially alter treatment guidelines Management following the initial CKC biopsy or LEEP was deter- 144
88 since accepted advantages of LEEP include the avoidance of general mined. Subsequent management potentially included cytological review, 145

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89 anaesthesia, provision of treatment in an outpatient setting, lower repeat CKC biopsy or LEEP, or hysterectomy. The follow-up period was 146
90 morbidity, and reduced rates of obstetric complications, all of which dened as the date of the initial ACIS treatment to the date of the last 147
91 have signicant cost benets [6,11,1923]. follow-up procedure (e.g., cervical cytology, biopsy or hysterectomy).
D 148
92 Nevertheless, the efcacy of conservative treatment of ACIS remains
93 uncertain since most studies to date have been limited by small sample 2.5. Principal outcomes 149
94 size and short follow-up [6,7,1719]. In the present study we have
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95 determined the rates of residual and recurrent endocervical neoplasia The principal outcomes investigated were i) persistence of ACIS 150
96 in a large, population-based cohort of women in Western Australia or diagnosis of adenocarcinoma during the follow-up period (dened 151
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97 (WA) who had conservative management of ACIS. Outcomes were as disease detection b 12 months after the initial diagnosis), and ii) re- 152
98 correlated with patient age and socioeconomic background, type of currence of ACIS or diagnosis of adenocarcinoma within the surveillance 153
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99 excisional procedure, margin status, and the presence of concurrent period (dened as disease detection 12 months after the initial 154
100 high grade CIN. diagnosis). Cancer mortality was a secondary outcome measure. 155
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101 2. Methods 2.6. Statistics 156


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102 2.1. Data sources and linkage procedure STATA/IC 13.0 (STATA Corporation, College Station, USA) was used 157
for data manipulation and statistical analysis. Fisher's exact test was 158
103 The Cervical Screening Register (CSR) of WA is required by legisla- used to evaluate similarities between the CKC and LEEP groups. Time- 159
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104 tion to compile all cervical test results (human papillomavirus (HPV) to-event (survival) analysis was performed using Cox models to inves- 160
105 detection, cytology and histology) for women who reside in WA. The tigate patient and clinical factors associated with disease persistence 161
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106 CSR is an opt out register and less than 0.05% of women request remov- and/or recurrence. Variables included in the modelling process were 162
107 al of their demographic information and results. The WA Data Linkage age at diagnosis, SEIFA indices, type of treatment (CKC or LEEP), margin 163
108 System (WADLS) provided a de-identied extraction of linked cancer status, and depth of excised tissue. Statistical signicance was deter- 164
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109 registrations and death records for all women with ACIS identied by mined as a p-value b 0.05 and the 95% condence intervals (CI) for haz- 165
110 the CSR of WA from 2001 to 2012. The WADLS is an internationally ard rate ratios were calculated. Plausible interaction terms were tested 166
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111 renowned, population-based, validated and ongoing data linkage sys- using likelihood ratio tests. Violation of the Cox model proportional haz- 167
112 tem that creates links among a number of state health administrative ard assumption was tested using Schoenfeld residuals. Due to small 168
113 data sets [2426]. numbers, time to event analysis was not performed for cervical cancers. 169
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114
Q5 Follow-up data were available up to May 2013. Death records were
115 used to verify the number of cervical cancer related deaths and to censor 3. Results 170
116 women who died during follow-up. Study data were obtained following
117 approval from the Curtin University Human Research Ethics Committee 3.1. Study cohort 171
118 (ethics research project number: HR 86/2012) and the Western
119 Australian Department of Health Human Research Ethics Committee There were 338 patients with ACIS eligible for the study following 172
120 (ethics research project number: 2012/49). exclusion of 8 patients who had a hysterectomy as initial treatment 173
and 16 patients for whom follow-up data were not available. An 174
121 2.2. Participants overview of the study cohort is presented in Fig. 1. The mean age was 175
33.2 years (range 18 to 76 years) and the median follow-up interval 176
122 The CSR was used to identify women aged 18 years or older was 3.6 years (range b 1 year to 11.8 years). Two hundred and thirty 177
123 who were reported to have ACIS on either routine cervical cytology one patients (68.3%) had a CKC while the remainder (n = 107, 31.7%) 178
124 screening or on cervical punch biopsy. Only women who had histologi- had a LEEP procedure. The clinicopathological ndings are summarised 179
125 cal conrmation of ACIS following CKC or LEEP biopsy were included in in Table 1. 180

Please cite this article as: Munro A, et al, Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of
cervical adenocarcinoma in situ: What is the gold standard? Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.024
A. Munro et al. / Gynecologic Oncology xxx (2015) xxxxxx 3

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Q1 Fig 1.

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181 3.2. Margin status
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(29%) cases including 34 LEEP biopsies (31.8%) and 59 CKC specimens 184
(25.5%) (p = 0.432, Fig. 1 and Table 1). 185
182 The biopsy margins were indeterminate in 17 cases (Fig. 1). In the
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183 remaining 321 specimens, positive margins were documented in 93
3.3. Number of surgical specimens excised 186
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t1:1 Table 1 LEEP was associated with a greater likelihood of more than one 187
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t1:2 Clinicopathological summary according to initial treatment (n = 338). surgical specimen being excised during the procedure compared to 188
t1:3 CKC biopsy LEEP p-Value CKC (see Table 1). 189
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t1:4 n = 231 % n = 107 %

t1:5 Age (years) 3.4. Follow-up period (b12 months post treatment) 190
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t1:6 30 92 39.8 47 43.9 0.476


t1:7 N30 139 60.2 60 56.1
t1:8 In the 12 months following the initial CKC or LEEP biopsies, 105 191
t1:9 Socio-economic index (31%) patients underwent further histological evaluation due to an 192
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t1:10 Least disadvantaged 76 32.9 29 27.1 0.159


abnormal Pap smear and/or abnormality at colposcopy. Of these, 70 193
t1:11 Less disadvantaged 48 20.8 17 15.9
t1:12 Middle 36 15.6 30 28.1 had negative ndings, 5 had CIN 1, 24 had persistent disease (ACIS) 194
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t1:13 More disadvantaged 49 21.2 21 19.6 and eight patients were diagnosed with endocervical adenocarcinoma. 195
t1:14 Most disadvantaged 22 9.5 10 9.3 Of the 24 cases with persistent ACIS, 10 (41.7%) had negative patho- 196
t1:15 logical margins in the original treatment specimen. The remaining 197
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t1:16 Initial diagnosis


t1:17 Cervical cytology 156 67.5 77 72.0 0.413 233 patients underwent cytological surveillance which was either neg- 198
t1:18 Punch biopsy 75 32.5 30 28.0 ative or showed only low-grade abnormalities within the immediate 199
t1:19
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t1:20 Number of specimens post treatment 12 month period. 200


t1:21 1 209 90.5 72 67.3 0.000
t1:22 N1 22 9.5 35 32.7
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t1:23 3.5. Surveillance period (12 months post treatment) 201


t1:24 Specimen depth (mm)
t1:25 Mean (range) 16.1 (240) 10.7 (227) 0.000
t1:26 After excluding the 86 patients who had disease persistence, adeno- 202
t1:27 Specimen depth group (mm)
t1:28 10 58 25.1 63 58.9 0.000 carcinoma, or who underwent hysterectomy in the follow-up period, 203
t1:29 N1015 58 25.1 27 25.2 252 women entered the surveillance period. Of these, 57 (22.6%) 204
t1:30 N15 40 115 49.8 17 15.9 women underwent further treatment (CKC biopsy or LEEP) and histo- 205
t1:31 logical evaluation. Forty-four had negative ndings, 7 had CIN 1, 2 had 206
t1:32 Concurrent CIN
t1:33 Absent 92 39.8 50 46.7 0.232 CIN 2/3, 3 had recurrent ACIS, and 1 patient had adenocarcinoma. The 207
t1:34 Present 139 60.2 57 53.3 remaining 195 (77.4%) women had cytological surveillance showing 208
t1:35 either negative ndings or low-grade abnormalities. No patient died of 209
t1:36 Margin status
t1:37 Negative 161 69.7 67 62.6 0.432 cervical cancer during the study period. Overall, 27 (8.0%) patients 210
t1:38 Positive 59 25.5 34 31.8 had ACIS persistence/recurrence and a further 9 (2.7%) patients were di- 211
t1:39 Indeterminate 11 4.8 6 5.6 agnosed with adenocarcinoma during the follow-up and surveillance 212
t1:40 CKC cold knife cone, LEEP loop electrosurgical excision procedure. periods. 213

Please cite this article as: Munro A, et al, Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of
cervical adenocarcinoma in situ: What is the gold standard? Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.024
4 A. Munro et al. / Gynecologic Oncology xxx (2015) xxxxxx

214 3.6. Signicance of positive margins Table 3 t3:1


Hazard ratios of persistent or recurrent endocervical neoplasia according to age, socio- t3:2
economic index, concurrent CIN and margin status. t3:3
215 The initial treatment specimen in 93 patients showed positive path-
216 ological margins. Of these patients, 54 (58%) underwent a subsequent Variable Hazard rate ratio 95% condence interval p-Value t3:4
217 excisional procedure and the ndings are presented in Table 2. The Age (years) t3:5
218 remaining 39 (42%) patients had surveillance only; none of these 30 0.7 0.31.8 0.477 t3:6
219 patients had recurrent ACIS or developed cervical adenocarcinoma. N30 (base) 1.0 t3:7
t3:8
Socio-economic index t3:9
220 3.7. Factors associated with disease persistence and recurrence Least disadvantaged (base) 1.0 t3:10
Less disadvantaged 1.6 0.45.9 0.469 t3:11
Middle 1.7 0.56.1 0.433 t3:12
221 The results of the Cox regression analysis for disease persistence and
More disadvantaged 3.0 0.99.6 0.068 t3:13
222 recurrence are summarised in Table 3. Positive margin status was Most disadvantaged 0.6 0.15.8 0.689 t3:14
223 associated with a 3.4 (95% CI 1.57.8) times increased rate of ACIS t3:15
Initial treatment t3:16
224 persistence and/or recurrence. After adjusting for margin status there
t3:17

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LEEP 0.8 0.32.0 0.578
225 was no statistically signicant association between patient age, socio- CKC biopsy (base) 1.0 t3:18
226 economic status, coexistence of CIN 2/3, specimen depth or treatment t3:19

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Number of specimens t3:20
227 type (CKC biopsy or LEEP) and ACIS persistence and/or recurrence.
1 (base) 1.0 t3:21
N1 0.9 0.32.5 0.847 t3:22
228 4. Comment t3:23

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Concurrent CIN t3:24
Absent (base) 1.0 t3:25
229 This large population-based study found no difference in ACIS dis- Present 0.9 0.42.2 0.870 t3:26
230 ease persistence/recurrence between CKC and LEEP and no signicant

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t3:27
Margin status t3:28
231 difference in the rate of positive margins between the two treatment
Negative (base) 1.0 t3:29
232 modalities. Positive 3.4 1.47.8 0.004 t3:30

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233 To date there have been only a small number of studies which have Indeterminate 1.2 0.19.5 0.885 t3:31
234 compared the efcacy of CKC biopsy to LEEP for the treatment of ACIS. t3:32
Specimen depth (mm) t3:33
235 Many are single institution reviews and are limited due to age restric- 10D 1.6 0.64.0 0.337 t3:34
236 tion (excluding either older or younger women) and/or small sample N1015 0.4 0.11.5 0.183 t3:35
237 size [5,6,11,1719,28]. Women wishing to preserve their fertility may N15 40 (base) 1.0 t3:36
238 opt for conservative treatment following the diagnosis of ACIS, but to CKC cold knife cone, LEEP loop electrosurgical excision procedure. t3:37
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239 date there are conicting data regarding rates of recurrence and residual
240 disease in these patients [2932].
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241 To our knowledge this is the largest study of women with biopsy signicantly greater in the CKC group compared to the LEEP group but 252
242 conrmed ACIS to have analysed outcomes according to patient age, there were no differences in outcomes. However, our study was not 253
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243 socio-economic status, coexistence of CIN 2/3 and margin status follow- designed to assess this as the differences in depth of excision between 254
244 ing treatment with either LEEP or CKC biopsy. We also investigated ACIS the two groups may have reected clinical decisions, which we were 255
245 persistence and recurrence by specimen depth because a possible unable to verify. For example, clinicians may have opted to use LEEP 256
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246 explanation for our results is that LEEP may have been used to treat for smaller ACIS lesions and CKC for larger lesions so we cannot 257
247 smaller ACIS lesions. However, there were no signicant differences be- conclude that deeper excisions are over-treatment of ACIS. A carefully 258
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248 tween LEEP and CKC in the proportion of persistent or recurrent ACIS selected procedure will likely be the appropriate procedure for a partic- 259
249 when stratifying outcomes according to specimen depth (Table 3). ular patient. 260
250 It is interesting to speculate whether deep excisions (N 15 mm) are LEEP was associated with a greater likelihood of more than one 261
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251 required to adequately treat ACIS given that the depth of excision was surgical specimen being excised compared to CKC but many of these 262
are likely to have included intentional two-stage procedures (LEEP 263
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followed by top hat endocervical sampling) as well as technically 264


t2:1 Table 2 difcult procedures which resulted in multiple, fragmented or incom- 265
t2:2 Histology ndings in patients with positive margins who underwent a second excisional
plete specimens. Many of the latter would, however, likely result in 266
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t2:3 procedure (n = 54).


indeterminate margins histologically. It is noteworthy that there was 267
t2:4 Second procedure Initial procedure no signicant difference in margin status between CKC and LEEP. A sin- 268
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t2:5 CKC biopsy LEEP gle intact specimen is, of course, ideal for comprehensive histological 269
t2:6 n = 35 n = 19 assessment. 270
t2:7 CKC biopsy The management of women diagnosed with ACIS following LEEP or 271
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t2:8 Negative 3 4 CKC biopsy is often dependent on the patient's age and fertility require- 272
t2:9 Low-grade changes 1 0 ments and the status of the excision margins. Hysterectomy is recom- 273
t2:10 ACIS 6 2
mended for women who have completed child bearing [6,1113,33] 274
t2:11 Adenocarcinoma 1 2
t2:12 because cytological follow-up is less reliable and rates of recurrence 275
t2:13 LEEP may be high [5,12,17,19,32]. It is also noteworthy that 10/24 patients 276
t2:14 Negative 1 0
in this series who had ACIS on a second excisional procedure had nega- 277
t2:15 Low-grade changes 0 0
t2:16 ACIS 1 1 tive initial biopsy margins. This may reect the multifocal distribution of 278
t2:17 Adenocarcinoma 0 0 ACIS in some cases and emphasizes the requirement for follow-up even 279
t2:18 after apparently complete local excision. 280
t2:19 Hysterectomy
t2:20 Negative 14 8 The main limitation of this study is its retrospective design so it is 281
t2:21 Low-grade changes 0 0 conceivable that selection bias or exposure to confounding variables 282
t2:22 ACIS 4 1 may have inuenced outcomes between the two treatment groups. 283
t2:23 Adenocarcinoma 4 1 Although this is the largest population-based study ever reported, it 284
t2:24 CKC cold knife cone, LEEP loop electrosurgical excision procedure. was only sufciently powered to detect a relatively large difference in 285

Please cite this article as: Munro A, et al, Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of
cervical adenocarcinoma in situ: What is the gold standard? Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.024
A. Munro et al. / Gynecologic Oncology xxx (2015) xxxxxx 5

286 the treatment effects due to the small number of recurrent ACIS cases. [5] Bull-Phelps SL, Garner EI, Walsh CS, Gehrig PA, Miller DS, Schorge JO. Fertility- 345
sparing surgery in 101 women with adenocarcinoma in situ of the cervix. Obstet 346
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Oncol 2012;124(1):727. http://dx.doi.org/10.1016/j.ygyno.2011.09.006. 350
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[11] Latif NA, Neubauer NL, Helenowski IB, Lurain JR. Management of adenocarcinoma in
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307 appear to compromise oncologic outcomes when compared to CKC. s1.html). 373
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311 Two authors (A Munro and N Steel) are employed at the WA Cervical Cancer Prevention
1993;169(2):28995. http://dx.doi.org/10.1016/0002-9378(93)90078-W. 380
312
313
Program that is responsible for maintaining and operating the Cervical Screening Register
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315 Study data were obtained in June 2013 following approval from the [18] Denehy TR, Gregori CA, Breen JL, Thad R. Endocervical curettage, cone margins, and 387
316 Curtin University Human Research Ethics Committee (ethics research residual adenocarcinoma in situ of the cervix. Obstet Gynecol 1997;90(1):16. 388
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2009;201(1):e133. http://dx.doi.org/10.1016/j.ajog.2009.02.004. 403


324 Acknowledgements [23] Noehr B, Jensen A, Frederiksen K, Tabor A, Kjaer S. Depth of cervical cone removed 404
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325 The authors would like to thank the staff of the Health Information preterm delivery. Obstet Gynecol 2009;114(6):12328. http://dx.doi.org/10.1097/
AOG.0b013e3181bf1ef2. 407
326 Linkage Branch for access to the WADLS and for their assistance in
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327 obtaining the data, the WA Health Data Custodians for access to the istrative data on end-stage renal failure: application of record linkage to a clinical 409
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328 core health datasets and the Western Australian Department of Health. base population. Aust N Z J Public Health 1999;23(5):4647. http://dx.doi.org/10. 410
329 A thank you must also be extended to Mrs. Christine Fletcher (WA 1111/j.1467-842X.1999.tb01299.x. 411
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Please cite this article as: Munro A, et al, Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of
cervical adenocarcinoma in situ: What is the gold standard? Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.02.024

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