This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Objective. When pathologic discrepancy arises between high-grade cytology on Papanicolaou [Pap] smear and low-grade histology on cervical biopsy, Loop Electrosurgical Excisional Procedure [LEEP] is one management alternative. Our objective was to determine whether the time from initial HGSIL Pap to LEEP affects the pathologic grade of the LEEP specimen. Study Design. We performed a retrospective case-control study identifying LEEPs performed for discrepancy over a 10-year period [1997–2007]. 121 subjects were separated into two groups based on LEEP pathology [≤CIN 1 and CIN 2,3] and compared using χ 2. Results. Of the 121 LEEP specimens, 67 [55.4%] had CIN 2,3. CIN 2,3 was more often discovered when LEEP was performed within 3 months of the HGSIL Pap smear versus after 5 months [55.2% versus 16.4%, P = .096]. Conclusion. Women undergoing LEEP for discrepancy >5 months from their HGSIL Pap demonstrated a trend toward less CIN 2,3 on LEEP pathology.
1. Introduction
Women with high-grade Papanicolaou [Pap] smears have a 43%–66% risk of having moderate- to high-grade intraepithelial neoplasia [CIN 2 or CIN 3] on subsequent biopsy and a 2% risk of having invasive cancer [1]. However, when discrepancies occur between Pap smear cytology and cervical biopsy histology, this can cause a clinical dilemma. We define discrepancy as patients with High-Grade Squamous Intraepithelial Lesion [HGSIL] Pap smear followed by cervical biopsies with Cervical Intraepithelial Neoplasia [CIN] 1 histology or less. In cases of discrepancy, the American Society for Colposcopy and Cervical Pathology [ASCCP] previously favored an excisional procedure for diagnosis in nonpregnant patients when no lesion or CIN1 is identified with satisfactory colposcopy [2]. As we develop a better understanding of HPV infection, its clinical course, and prognosis, more people are considering conservative management. The most recent ASCCP guidelines in 2006 included the option of repeating Pap smear and colposcopy every 6 months for 1 year in women over 20 with discrepancy and recommended this conservative monitoring pathway in the adolescent population [3].
In nonadolescent patients, a loop electrosurgical excisional procedure [LEEP] is a reasonable management option for discrepancy, as there is a concern that the high-grade lesion found on Pap smear was missed on the colposcopically directed biopsy. However, we know that as many as 35% of women with HGSIL will regress spontaneously, making the excisional procedure unnecessary [4]. Data evaluating the time from the initial HGSIL cytology to the LEEP, as it impacts likelihood of finding significant pathology in the LEEP specimen, has not been well characterized. Our objective was to determine whether the time from initial HGSIL Pap to LEEP, when done for discrepancy, affects the pathologic grade of CIN in the LEEP specimen. We hypothesized that, as the time interval between the initial HGSIL Pap and subsequent LEEP for discrepancy increased, the likelihood of finding CIN 2-3 in the LEEP specimen would decrease.
2. Materials and Methods
This was a retrospective case-control study of all LEEP procedures done for discrepancy at the University of Washington Medical Center and Harborview Medical Center in Seattle, Washington. We identified potential cases by performing a search in the pathology database to identify all LEEP specimens between January 1, 1997 and August 31, 2007. Of note, the Dysplasia Clinics at these two medical centers serve as referral centers for women diagnosed with abnormal cytology at local clinics. Thus, not all initial Pap smears originated from these two medical centers. In the two Dysplasia Clinics, a standardized colposcopy form is used to record impression and results of colposcopy, but the Pap smear is not routinely repeated, nor do we have a complete history of prior Pap smears. Based on colposcopic findings, biopsies were performed at the discretion of the attending physician.
To determine which LEEPs were done for discrepancy, we linked all LEEPs with their respective preceding Pap smear, colposcopy report, and cervical biopsy result. We included all women, 18–49 years old, who had pathologic discrepancy as defined by HGSIL Pap smear and a subsequent colposcopy with cervical biopsies of CIN 1 or less. We excluded those who had an unsatisfactory colposcopy exam, previous excisional procedure, and positive endocervical curettage and those who were pregnant or HIV positive.
Once discrepant cases were identified, we performed a chart review and used a standardized data collection instrument to gather general demographic information and risk factors associated with progression of cervical neoplasia [smoking, number of partners, age of coitarche, history of sexually transmitted infections, and birth control method]. On this form we also documented cytologic and histologic results of the Pap smear, cervical biopsy, and LEEP procedure, and recorded the length of time between the Pap smear and the LEEP.
A power calculation was based on the assumption that, in LEEPs done for discrepancy, the prevalence of CIN 2 or 3 found in the LEEP specimen will be higher when the LEEP was performed closer to the time of the HGSIL Pap. We divided the time intervals from Pap smear to LEEP into three intervals: less than three months, between three and five months, and greater than five months. As this was a retrospective study, we used our data of 55% prevalence of CIN 2,3 in LEEP specimens when the time interval from the Pap smear to the LEEP is less then 3 months and 16% when the interval is greater than five months. From this, the calculated sample size was 23 women to give 80% power and α = 0.05 to detect this difference in pathologic result, demonstrating that the study was appropriately powered to test our hypothesis.
Based on their LEEP histology, subjects were separated into two groups: CIN 1 or less and CIN 2,3. The “CIN 1 or less” group included normal, cervicitis, and CIN 1. The “CIN 2,3” group included CIN 2 and CIN 3. We chose these two groups based on clinical application, as this is the general division that determines treatment management. Statistical analysis was executed with SPSS v.16. Differences between the two groups were examined using Student's t-test and χ ². Univariate and multivariate logistic regressions were used to calculate odds ratios and 95% confidence intervals for the association between time since HGSIL and histologic grade of LEEP.
This study was approved by the International Review Board at the University of Washington, IRB Application Number 07-8885-E/A 01.
3. Results
Of the 1,356 patients who underwent a LEEP during this time period, 157 were performed for discrepancy. Of these, 36 women were excluded: 24 had unsatisfactory colposcopy, six had endocervical curettings positive for neoplasia, four were HIV positive, and two were older than 49. The 121 remaining patients were divided into two groups based on the pathologic grade of CIN in their LEEP specimen [CIN 1 or CIN 2,3]. As demonstrated by Table 1, the two groups were similar with regard to age, ethnicity, parity, tobacco use, coitarche, number of partners, and history of sexually transmitted infections. There was a difference noted in the use of birth control method, likely due to the number of Depo-Provera users in the CIN 2,3 group.
Table 1
Demographic characteristics comparing women with CIN 1 or CIN 2,3 on LEEP.
CharacteristicCIN 1 or lessCIN 2-3Pn = 54 [%]n = 67 [%]Age: [years] ± SD28.2 ± 8.727.2 ± 5.7.46ªEthnicityCaucasian35 [66]37 [55].48bAfrican American5 [9]5 [8]Hispanic4 [8]9 [13]Asian6 [11]7 [10]Other/Unknown4 [6]9 [13]Parity036 [67]38/65 [59].06b113 [24]8/65 [12]22 [4]13/65 [20]>23 [6]6/65 [9]TobaccoNone41 [76]46 [69].10b