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Negative loop electrosurgical cone biopsy finding following a biopsy diagnosis of high-grade squamous intraepithelial lesion: frequency and clinical significance.

At our institution, most high-grade squamous intraepithelial lesions (HSILs) corresponding to cervical intraepithelial neoplasia (CIN) II and III are treated by loop electrosurgical excision procedure (LEEP). The technique appears to be safe, and therapeutic results associated with LEEP appear to compare favorably with other therapeutic modalities. (1-9) High-grade squamous intraepithelial lesions are known to recur after LEEP treatment but at a relatively low frequency, as the reported success rate of the treatment is between 60% and 95%. (1-9) Reasons for failure of the LEEP procedure to eradicate HSIL are incompletely understood but may include margin status, extent of original HSIL, and endocervical gland involvement. (10)

In most LEEP specimens, foci of residual HSIL or invasive carcinoma are present, confirming the original biopsy diagnosis. However, in some cases, examination of LEEP specimens will fail to reveal residual disease. Few studies have investigated the frequency of negative LEEP findings following HSIL diagnosis but published data indicate that it occurs in 14% to 17% of cases. (10,11) Negative LEEP findings following a biopsy diagnosis of HSIL may result from a number of causes including diagnostic error in the biopsy, total removal of the dysplastic focus by the biopsy, or secondary destruction of the dysplasia by postbiopsy inflammation. While it is known that a significant number of women undergoing LEEPs will have recurrent HSIL or cervical carcinoma, the clinical significance of a negative LEEP result is poorly understood. Livasy et al (10) found no difference in recurrence rates for patients with positive and negative LEEP findings following a biopsy diagnosis of HSIL. We are unaware of other studies investigating the clinical significance of a negative LEEP result. Recurrence rates could conceivably be lower or higher for patients with negative LEEP findings than for those with positive LEEP findings. The recurrence rate could conceivably be lower with negative LEEP findings owing to the possibility that these women harbored smaller original lesions that were treated by 2 modalities, biopsy and then LEEP. Alternatively, the recurrence rate or persistence of the lesion might be more frequent for these patients, given the possibility that the LEEP failed to target and properly remove the lesion. We studied a series of 378 women undergoing LEEP excisions for a biopsy diagnosis of HSIL to determine the frequency of negative LEEP findings and the recurrence rates of HSIL following positive and negative LEEP findings.


The surgical pathology records at the University of Utah were searched for all patients with LEEP specimens obtained between July 1, 2003, and August 31, 2010. From this set of patients, the subset of patients with corresponding prior cervical biopsies performed at our institution was selected. The pathology laboratory information system was then queried through May 2011 for all post-LEEP surgical specimens and cervical cytology specimens to determine patient follow-up with regard to recurrence of dysplasia or development of invasive carcinoma. In the subset of patients with LEEP specimens, pre-LEEP cervical biopsies, and post-LEEP histologic or cytologic follow-up, the LEEP histologic slides and pre-LEEP biopsy slides were pulled and reviewed. For all cases, discrepancies or concordance was documented between the original biopsy and the subsequent LEEP specimen. Of the 612 LEEP specimens on file between July 1, 2003, and August 31, 2010, a total of 234 cases were excluded for reasons including disease other than cervical dysplasia/neoplasia (7), lack of retrievable patient charting (18), no previous cervical biopsy specimen on file (54), specimen other than LEEP (eg, trachelectomy) (6), "repeat" patients (9), lack of postprocedure follow-up (138), and noninterpretable original LEEP specimens (2). After excluding the above specimens from our study, 378 patients remained. These women ranged in age from 16 to 69 years at the time of the LEEP procedure, with a mean age of 33.2 years. The average clinical follow-up period was 25.8 months (range, 1-96 months).

The follow-up results were categorized as negative (negative for intraepithelial lesion or malignancy, atypical squamous cells of undetermined significance [ASCUS]/atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion [ASCH] with no follow-up biopsy, negative biopsy result, ASCUS/ASCH results followed by a negative biopsy result), low grade (low-grade squamous intraepithelial lesion/CIN I proven by follow-up biopsy or excision), high grade (HSIL, CIN II and CIN III proven by follow-up biopsy or excision), and carcinoma (including squamous cell carcinoma and adenocarcinoma).


Three hundred seventy-eight cases fulfilled the inclusion criteria for the study. Three hundred six of these had HSIL or worse on index biopsy and 72 were either negative or had low-grade squamous intraepithelial lesion on index biopsy (Table). For the 306 patients with HSIL or worse on index biopsy, subsequent LEEPs demonstrated no evidence of dysplasia or LSIL for 73 patients (24%); 223 LEEPs demonstrated HSIL (73%); and 10 LEEP biopsies demonstrated invasive adenocarcinoma (2), invasive squamous cell carcinoma (5), adenocarcinoma in situ (1), or dysplasia not otherwise specified (2) (Table). Thus, 24% of all biopsies with a diagnosis of HSIL or greater were followed by an LEEP showing either low-grade dysplasia or negative findings. Interestingly, 10 of 72 biopsies with negative results were associated with LEEPs demonstrating HSIL.

Patients with HSIL biopsies were followed up. Twenty-nine of 223 patients (13%) with HSIL biopsies and HSIL LEEPs had HSIL on subsequent biopsy or excisional follow-up. Seven of 73 patients (10%) with HSIL biopsies but negative or LSIL LEEP findings had HSIL on biopsy or excisional follow-up. The 8 patients showing either invasive carcinoma or adenocarcinoma in situ were not included in the follow-up cohort because more extensive procedures had been performed after the LEEP diagnosis. The 2 patients with dysplasia not otherwise specified were also omitted from the follow-up cohort.


Loop electrosurgical excision procedure has become a common, safe, and effective treatment for cervical dysplasia. (1-9) High-grade squamous intraepithelial lesion is known to recur after LEEP procedures, with margin status being the most important predictor of subsequent occurrence of HSIL. (12) In a minority of patients with HSIL diagnosis on biopsy, the subsequent LEEP will reveal no evidence of dysplasia or carcinoma. The precise frequency of negative LEEP findings with a prior history of a HSIL positive biopsy result appears to be between 10% and 20%. Diakomanolis et al (11) reported that approximately 16% of cone biopsies following a biopsy diagnosis of CIN II to III would show no evidence of dysplasia. Similarly, Livasy et al (10) reported a series of 674 patients with biopsy-confirmed high-grade cervical dysplasia treated by LEEP. In this series, 14% of LEEP specimens were negative for dysplasia. Our incidence of negative cone biopsy results following a biopsy diagnosis of HSIL is 24%. Potential explanations for negative LEEP findings following a biopsy diagnosis of HSIL include misdiagnosis of the original biopsy, total removal of the focus of HSIL by the biopsy, destruction of residual HSIL by the inflammatory response secondary to the biopsy, and a limited LEEP procedure that did not sample residual HSIL or invasive carcinoma. We reviewed both the LEEP procedures and HSIL to confirm the accuracy of the diagnosis in each case. We found no instances in which the original biopsy diagnosis of HSIL had been incorrect. In many cases, the LEEP demonstrated extensive destruction of the ectocervical and endocervical mucosa, related either to the biopsy procedure itself or the resultant inflammatory response. This seems a likely explanation for absence of HSIL in many LEEP specimens. The possibility of the LEEP procedure not sampling residual HSIL also remains a possible explanation for absence of HSIL in a subset of postbiopsy LEEP specimens.

The clinical implications of a negative LEEP finding following a biopsy diagnosis of HSIL have been rarely investigated. Diakomanolis et al (11) did not report clinical follow-up for the patients with negative LEEP results. Livasy et al (10) found little difference in recurrence rates for HSIL in patients with negative and positive LEEP results. Patients with negative LEEP findings had a recurrence rate similar to that of patients with positive LEEP findings, with a 24% recurrence in the negative category and 27% recurrence in the positive category. Our findings showed that 13% of patients with HSIL biopsies and LEEPs demonstrating HSIL had HSIL on clinical follow-up. Ten percent of patients with positive biopsy results but negative LEEP results had an HSIL on follow-up. Thus, no statistical difference was found for the incidence of HSIL on follow-up for the 2 groups of patients. Our percentage of recurrent HSIL in both groups was lower than that reported by Livasy et al. (10) On the basis of our data and that of Livasy et al, (10) patients with both positive and negative LEEP findings following a biopsy diagnosis of HSIL should be treated and followed up similarly. Interestingly, Livasy et al (10) found that LEEPs associated with negative margins but with residual HSIL demonstrated a lower recurrence rate on clinical follow-up than LEEPs with negative findings (15% versus 24%). (10) We found no such relationship. However, the data of Livasy et al (10) suggest that in some cases, negative LEEP findings may be associated with a failure to sample residual postbiopsy HSIL. (10) This would explain the higher recurrence rate with negative LEEP findings than with positive LEEP findings demonstrating negative margins.

Our findings indicate that a negative LEEP result following a positive initial cervical biopsy result should not be ascribed to a misdiagnosis of the original specimen. Additionally, LEEPs yielding both positive and negative findings are associated with large areas of biopsy-related tissue destruction with a potential obscuring of residual dysplasia. We did not detect a difference in frequency for such changes between positive and negative LEEP findings. In the report by Livasy et al, (10) the authors also were unable to demonstrate a statistical difference in histologic features, thus limiting pathologic interpretation between positive and negative LEEP findings. Our findings and those of Livasy et al (10) indicate that both LEEPs that are positive and those that are negative for residual HSIL should be followed up in a similar fashion, with the expectation that approximately 10% to 25% of LEEPs performed for HSIL biopsy diagnoses will demonstrate HSIL upon ensuing clinical follow-up.


(1.) Alvarez RD, Helm CW, Edwards RP, et al. Prospective randomized trial of LLETZ versus laser ablation in patients with cervical intraepithelial neoplasia. Gynecol Oncol. 1994;52(2):175-179.

(2.) Gold M, Dunton CJ, Murray J, Macones G, Hanau C, Carlson JA Jr. Loop electrocautery excisional procedure: therapeutic effectiveness as an ablation and a conization equivalent. Gynecol Oncol. 1996;61(2):241-244.

(3.) Linares AC, Storment J, Rhodes-Morris H, Malpica A, Mitchell MF. A comparison of three cone biopsy techniques for evaluation and treatment of squamous intraepithelial lesions. J Gynecol Tech. 1997;3:151-156.

(4.) Luesley DM, Cullimore J, Redman CW, et al. Loop diathermy excision of the cervical transformation zone in patients with abnormal cervical smears. BMJ. 1990;300(6741):1690-1693.

(5.) Naumann RW, Bell MC, Alvarez RD, et al. LLETZ is an acceptable alternative to diagnostic cold-knife conization. Gynecol Oncol. 1994;55(2):224-228.

(6.) Mathevet P, Dargent D, Roy M, Beau G. A randomized prospective study comparing three techniques of conization: cold knife, laser, and LEEP. Gynecol Oncol. 1994;54(2):175-179.

(7.) Oyesanya OA, Amerasinghe C, Manning EA. A comparison between loop diathermy conization and cold-knife conization for management of cervical dysplasia associated with unsatisfactory colposcopy. Gynecol Oncol. 1993;50(1): 84-88.

(8.) 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(9):1054-1060.

(9.) Wright TC Jr, Gagnon S, Richart RM, Ferenczy A. Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol. 1992;79(2):173-178.

(10.) Livasy CA, Moore DT, Van Le L. The clinical significance of a negative loop electrosurgical cone biopsy for high-grade dysplasia. Obstet Gynecol. 2004; 104(2):250-254.

(11.) Diakomanolis E, Haidopoulos D, Chatzipapas I, Rodolakis A, Stefanidis K, Markaki S. Negative cone biopsies: a reappraisal [erratum in J Reprod Med. 2003;48(10):833]. J Reprod Med. 2003;48(8):617-621.

(12.) Felix JC, Muderspach LI, Duggan BD, Roman LD. The significance of positive margins in loop electrosurgical cone biopsies. Obstet Gynecol. 1994; 84(6):996-1000.

Benjamin L. Witt, MD; Rachel E. Factor, MD; Elke A. Jarboe, MD; Lester J. Layfield, MD

Accepted for publication December 29, 2011.

From the Department of Pathology, University of Utah School of Medicine and ARUP Laboratories, Salt Lake City, Utah.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Lester J. Layfield, MD, Department of Pathology, 1950 Circle of Hope, Room 6755, Salt Lake City, UT 84112 (e-mail:
Correlation of Cervical Biopsy and Loop Electrosurgical
Excision Procedure (LEEP) Diagnosis


 Negative, HSIL, Total
 No. No.

LEEP Negative, No. 61 73 134
 HSIL, No. 10 223 233
 Carcinoma, dysplasia 1 10 11
 NOS, or ACIS, No.
 Total 72 306 378

Abbreviations: ACIS, adenocarcinoma in situ; HSIL, high-grade
intraepithelial lesion; NOS, not otherwise specified.
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Title Annotation:Original Articles
Author:Witt, Benjamin L.; Factor, Rachel E.; Jarboe, Elke A.; Layfield, Lester J.
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2012
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