Abstract
Objective
To evaluate the ability of various factors to predict persistent/recurrent disease after excisional biopsy of the transformation zone (cold knife conization or loop electrosurgical excision procedure) with special attention to the endocervical curettage (ECC).
Study Design
We reviewed the charts and histopathology findings of 152 women who underwent endocervical curettage at the time of conization (cold knife conization) or loop electrosurgical excision procedure (LEEP). Age, histopathologic findings on the cervical conization specimen, ectocervical margin, endocervical margin, and ECC specimens were assessed. These findings were analyzed for a relationship with the presence of cervical disease on subsequent follow-up (to include hysterectomy, repeat conization, colposcopically directed biopsies, endocervical curettage, and/or cytology).
Results
Positive endocervical margin (odds ratio [OR], 9.168; 95% confidence interval [95% CI], 3.939, 23.488), positive ectocervical margin (OR, 3.561; 95% CI, 1.626, 7.799), positive specimens (OR, 17.683; 95% CI, 5.308, 58.912), and severity of disease (OR, 2.730; 95% CI 1.507, 4.947) on the conization were all individually significantly associated with the presence of persistent/recurrent disease. Age of the patient at the time of cervical conization was not statistically associated with the ability to predict persistent/recurrent disease. In the multivariate analysis, the endocervical curettage (OR, 8.710; 95% CI, 2.302, 32.958) and the endocervical margin status (OR, 9.170; 95% CI, 2.887, 29.125) together were significant predictors of persistent/recurrent disease after adjusting for the other variable. However, when the degree of dysplasia and ectocervical margin status was included in the multivariate analysis, endocervical margin status (OR, 6.761; 95% CI, 2.657, 17.202) and severity of cervical disease (OR, 1.930; 95% CI, 1.038, 3.59) were the only statistically significant predictors of persistent/recurrent cervical neoplasia.
Conclusion
In this retrospective analysis, positive endocervical or ectocervical margin, positive ECC specimens, and severity of cervical disease were all predictors of persistent/recurrent disease. However, on the multivariate stepwise logistic regression analysis, only endocervical margin status and severity of neoplasia significantly predicted the occurrence of persistent/recurrent disease. The results of the ECC, after adjustment for the degree of dysplasia and the endocervical margin status, do not add incremental value to the prediction of persistent/recurrent disease. At this time, ECC does not need to be routinely performed at the time of excisional biopsy of the cervical transformation zone.
Introduction
There is controversy as to which factors are most predictive of persistent or recurrent disease after cervical cold knife conization or loop electrosurgical excision procedure (LEEP).[1–11] There is a lack of agreement on the usefulness of performing an endocervical curettage (ECC) at the time of excisional biopsy of the cervix and the ability of the ECC to help predict persistent disease above the site of excision.[12–16] Recommendations for the clinical management of patients after conization are based on the histopathologic findings, the status of the surgical margin, patient's age and parity, patient's desire for future fertility, and concomitant upper genital tract pathology.
This retrospective observational study explored the ability of various factors to predict persistent/recurrent disease after a conization, with special attention to the ECC.
Material and Methods
This retrospective study was registered with the Institutional Review Board. We reviewed 152 cases of cervical conization (cold knife conization or LEEP) performed at Temple University Hospital between January 1, 1992 and July 31, 2001 for which an ECC was obtained and follow-up information was available. During the interval studied, we retrieved 281 cases that had an ECC at the time of cervical conization, but follow-up information was not available in 129 (46%). Indications for cold knife conization or LEEP included evaluation and management of abnormal cervical cytology in patients with unsatisfactory colposcopic evaluation (defined as inability to visualize entire lesion or entire transformation zone on colposcopy, poor correlation between cytology and colposcopically directed biopsies, abnormality involving more than 2 quadrants of the surface of the cervix), dysplasia or cancer present in the ECC specimens at the time of colposcopy, microinvasive carcinoma on colposcopically directed biopsy, or for the treatment of cervical intraepithelial neoplasia (CIN) 2 or 3. Approximately one half of the 152 patients underwent LEEP and the other half underwent cold knife conization. With rare exceptions, gynecology residents under direct supervision of the same gynecologic oncologist performed the procedures. Colposcopy was not routinely performed at the time of the cold knife conization or LEEP. The surgical bed was routinely electrocauterized after LEEP or cold knife conization and Monsel solution was also applied. There were no changes in clinical practice during the years included in the study. All conization specimens were processed in a standard fashion. At least 12 sections from each cone or LEEP specimen were submitted for microscopic study. All slides were reviewed by a staff pathologist of the Department of Pathology, Temple University Hospital. Data were obtained by manual review of patient charts. Pathology reports were obtained from the Temple University Hospital medical information computer system. Data abstracted included age, race, gravidity, parity, type of procedure (cold knife conization or LEEP), ECC specimen findings, and histopathologic diagnoses to include status of the ectocervical and endocervical margins. The highest degree of abnormality on the conization specimen was recorded. Severity of disease on the conization specimens was classified as CIN 1, CIN 2/3, microinvasive carcinoma, and invasive cancer. The ectocervical and endocervical margins were classified as either positive (margins involved with dysplasia or cancer) or negative (margins uninvolved with dysplasia or cancer). ECC was classified as either positive (if it contained dysplastic squamous epithelium or cancer), negative or tissue insufficient for histopathologic diagnosis.
Follow-up information up to 12 months after the procedure (to include hysterectomy, repeat conization, colposcopically directed biopsies, ECC, and/or cytology) was abstracted. Patients who did not undergo a hysterectomy or repeat excisional biopsy were asked to return for colposcopy and cervical cytology every 4 months until 3 normal consecutive examinations or an abnormality was documented. Patients were considered to have persistent/recurrent disease if after the cervical conization there was any evidence of CIN or carcinoma on a subsequent hysterectomy specimen, repeat conization, cervical biopsy after conization, endocervical curettage after conization, or cervical cytology after conization. For patients with persistent/recurrent cervical neoplasia, the most severe degree of neoplasia was recorded.
Univariate logistic regression was used to estimate the relationship of findings from ECC specimens, endocervical margin status, ectocervical margin status, degree of dysplasia on conization, and age with the occurrence of persistent/recurrent disease. The odds ratio (an estimate of the relative risk of persistent/recurrent disease) and the 95% confidence interval were calculated for each variable. The variables (ECC specimen findings, endocervical margin status, ectocervical margin status and degree of dysplasia on conization) were then combined in a multivariate stepwise logistic regression to estimate the incremental risk of persistent/recurrent disease for each factor independent of (adjusted for) the other factors. The relative risk of persistent/recurrent disease was also estimated using these variables. A P value less than or equal to .05 was the significance level used for all analyses.
Results
The median age of the 152 patients was 35 years, with a mean of 34 and a range of 17 to 71 years. The median gravidity was 3 and the median parity was 2. The majority (83%) of the patients were parous. Race distribution was: 67% black, 16% white, 11% Hispanic, and 6% other or unknown.
The conization specimen had no pathology in 26 (17%) cases. It had CIN 1 in 21 (14%). CIN 2 or 3 was present in 94 (62%), and microinvasive or invasive carcinoma was identified in 11 (7%). The endocervical margin was positive in 30 (20%) of the 152 cases and the ectocervical margin was positive in 38 (25%). Twenty (13%) of the 152 ECC specimens obtained at the time of conization were positive for dysplasia or carcinoma. In 29 (19%) of the 152 ECC specimens there was not enough tissue for histopathologic diagnosis.
Thirty-three of the 152 patients underwent a hysterectomy within 12 months of the conization. Ten had a repeat conization and 17 had a cervical biopsy with or without ECC. In addition to follow-up colposcopy and cervical cytology, 4 had an ECC. The follow-up of the other 88 patients consisted of cervical cytology and colposcopy only (ie, no biopsies were obtained). Persistent/recurrent dysplasia or cancer was seen in 41 (27%) of the 152 cases (15 CIN 1, 22 CIN 2/3, 4 carcinoma). Persistent/recurrent disease was detected by hysterectomy in 18 cases (3 CIN 1, 11 CIN 2/3, 4 carcinoma), repeat conization in 7 (3 CIN 1, 4 CIN 2/3), cervical biopsy in 2 (both with CIN 1), and cervical cytology in 14 (7 CIN 1, 7 CIN 2/3).
Table 1 presents a summary of the presence or absence of persistent/recurrent disease in patients with positive, negative or “tissue insufficient for diagnosis” on ECC. Persistent/recurrent dysplasia or cancer was present in 16 of 20 patients (80%) with a positive ECC. Nineteen of 103 patients (18.5%) with a negative ECC and 6 of 29 patients (20.7%) with insufficient tissue for histopathologic diagnosis had persistent/recurrent disease.
Table 1.
Presence or Absence of Persistent/Recurrent Disease in Patients With Positive/Negative/TID Endocervical Curettage (ECC) and Ability of ECC to Predict Persistent/Recurrent Cervical Neoplasia
| Endocervical Curettage | ||||
|---|---|---|---|---|
| Follow-Up Findings | Positive No. (%) (95% CI) | Negative No. (%) (95% CI) | TID No. (%) (95% CI) | Total No. (%) (95% CI) |
| SIL/Cancer | 16 (80) (56, 93) | 19 (18.5) (72, 88) | 6 (20.7) (9, 40) | 41 (27) (20, 35) |
| Normal | 4 (20) (66, 44) | 84 (81.5) (72, 88) | 23 (79.3) (60, 91) | 111 (73) (65, 80) |
| Total | 20 (100) | 103 (100) | 29 (100) | 152 (100) |
CI = confidence interval; TID = tissue insufficient for diagnosis; SIL = squamous intraepithelial lesion; sensitivity = 16/35 = 0.46 (95% CI: 0.29, 0.63); specificity = 84/86 = 0.96 (95% CI: 0.88, 0.99); positive predictive value = 16/20 = 0.80 (95% CI: 0.56, 0.94); negative predictive value = 84/103 = 0.82 (95% CI: 0.72, 0.88)
Persistent/recurrent dysplasia or cancer was detected in 20 of 30 patients (66.7%) with positive endocervical margins in the cervical conization specimen. Twenty-one of 122 patients (17.2%) with negative endocervical margins had persistent/recurrent disease. Eighteen of 38 patients (47.4%) with positive ectocervical margins had persistent/recurrent dysplasia or cancer. Twenty-three of 114 patients (20.2%) with negative ectocervical margins had persistent/recurrent disease. Persistent/recurrent disease was present in 26 of 52 patients (50%) with positive endocervical and/or ectocervical margins. Persistent/recurrent disease was found in 15 of 100 patients with negative endocervical and ectocervical margins.
Table 2 presents a summary of the presence or absence of persistent/recurrent cervical neoplasia as it relates to the status of the ECC specimens and the endocervical margin. Thirteen of 13 patients (100%) with both a positive ECC and positive endocervical margins had persistent/recurrent disease. Persistent/recurrent disease was detected in 13 of 91 patients (14.3%) with a negative ECC and a negative endocervical margin. Three of 7 patients (42.9%) with positive ECC and negative endocervical margins had persistent/recurrent cervical neoplasia. Six of 12 patients (50%) with negative ECC and positive endocervical margin had persistent/recurrent disease. Persistent/recurrent cervical neoplasia was detected in 1 of 5 patients (20%) with insufficient tissue for diagnosis on ECC and positive endocervical margin. Five of 24 patients (20.8%) with insufficient tissue for diagnosis on endocervical curettage and negative endocervical margins had persistent/recurrent disease.
Table 2.
Presence or Absence of Persistent/Recurrent Disease in Patients With Positive/Negative/TID Endocervical Curetting Specimens and Positive/Negative Endocervical Margin
| +ECC +Endo | −ECC −Endo | +ECC −Endo | −ECC +Endo | TID ECC +Endo | TID ECC −Endo | Total | |
|---|---|---|---|---|---|---|---|
| Follow-Up Findings | No. (%) (95% CI) | No. (%) (95% CI) | No. (%) (95% CI) | No. (%) (95% CI) | No. (%) (95% CI) | No. (%) (95% CI) | No. (%) (95% CI) |
| SIL/Cancer | 13 (100) (77, 100) | 13 (14.3) (8, 24) | 3 (42.9) (12, 80) | 6 (50) (22, 78) | 1 (20) (11, 70) | 5 (20.8) (8, 43) | 41 (27) (20, 35) |
| Normal | 0 (–) | 78 (85.7) (77, 92) | 4 (57.1) (20, 88) | 6 (50) (22, 78) | 4 (80) (30, 99) | 19 (79.2) (57, 92) | 111 (73) (65, 80) |
| Total | 13 (100) | 91 (100) | 7 (100) | 12 (100) | 5 (100) | 24 (100) | 152 (100) |
Cox multivariate analysis, endocervical curetting specimens (OR, 8.710; 95% CI, 2.302, 32.958) and endocervical margin (OR, 9.170; 95% CI: 2.887, 29.125) together were significant predictors of persistent/recurrent disease having adjusted for the other variable. Cox multivariate analysis, endocervical curetting specimens (OR, 8.710; 95% CI: 2.302, 32.958) and endocervical margin (OR, 9.170; 95% CI: 2.887, 29.125) together were significant predictors of persistent/recurrent disease having adjusted for the other variable. CI = confidence interval; TID = tissue insufficient for histopathologic diagnosis; SIL = squamous intraepithelial lesion; Endo = endocervical margin; ECC = endocervical curetting specimens
The sensitivity of the ECC at time of conization to detect persistent/recurrent disease is 0.46 (95% confidence interval [CI]: 0.29, 0.63). The specificity is 0.96 (95% CI: 0.88, 0.99). The positive predictive value is 0.80 (95% CI: 0.56, 0.93), and the negative predictive value is 0.82 (95% CI: 0.72, 0.88). The sensitivity of the endocervical and/or ectocervical margin status to predict persistent/recurrent disease is 0.63 (95% CI: 0.47, 0.77). The specificity is 0.77 (95% CI: 0.67, 0.84). The positive predictive value is 0.50 (95% CI: 0.36, 0.64), and the negative predictive value is 0.85 (95% CI: 0.36. 0.64).
In patients with normal or CIN 1 findings on the conization specimen, 7.7% and 9.5%, respectively, had persistent/recurrent disease (3 CIN 1, 1 CIN2/3). In patients with CIN 2/3 or cancer diagnosis on the conization, 33% and 54.5%, respectively, had persistent/recurrent disease. More than 90% of patients with normal or CIN 1 on the conization did not have persistent/recurrent disease. As the severity of cervical neoplasia in the conization specimen increases, there is an increase in the percentage of patients who have persistent/recurrent disease.
Using univariate logistic regression, a positive endocervical margin (odds ratio [OR], 9.618; 95% CI: 3.939, 23.488), positive ectocervical margin (OR, 3.561; 95% CI: 1.626, 7.799), positive ECC specimens (OR, 17.683; 95% CI: 5.308, 58.912), and histopathologic diagnosis (OR, 2.730 per grade; 95% CI: 1.507, 4.947) were all individually significantly associated with the presence of persistent/recurrent disease. Age of the patient at the time of cervical conization was not significantly associated with the presence of persistent/recurrent disease (OR, 1.008; 95% CI: 0.975, 1.042).
In the multivariate stepwise logistic regression analysis, the endocervical margin status and the ECC specimen findings together, ECC specimens (OR, 8.710; 95% CI: 2.302, 32.958) and endocervical margin (OR, 9.170; 95% CI: 2.887, 29.125) were significant predictors of persistent/recurrent disease having adjusted for the other variable.
Four variables (endocervical margin status, ectocervical margin status, ECC specimen findings, and histopathologic diagnosis in the conization specimen) were combined in a multivariate stepwise logistic regression to estimate the incremental risk of persistent/recurrent disease for each factor independent of (adjusted for) the other factors. Based on this analysis, endocervical margin (OR, 6.761; 95% CI: 2.657, 17.202) and histopathologic diagnosis in the conization specimen (OR, 1.930, 95% CI: 1.038, 3.59) significantly predicted the occurrence of persistent/recurrent disease. Adding the results of the ECC specimens to the histopathologic diagnosis and the endocervical margin status did not add incremental value to the ability of predicting persistent/recurrent cervical neoplasia.
Comment
Like other retrospective studies, ours has its limitations. This study is limited by the lack of follow-up in almost one half of the patients who underwent an ECC at the time of excisional biopsy of the cervical transformation zone during the interval studied. Because a repeat excisional biopsy or hysterectomy was not done on every patient, it is possible that the number of patients with persistent/recurrent disease is higher than what we identified. Some will argue that the rate of persistent disease after a LEEP should be less than that after a conization due to the thermal damage of the surgical bed. However, all of our patients had cauterization of the surgical bed regardless of whether they underwent a LEEP or a cold knife conization. Despite these findings, our findings are consistent with those reported by others.
We found that 100 (66%) of our cases had negative endocervical and/or ectocervical margins. In a retrospective study of 95 patients who had either a diagnostic LEEP (n = 45) or cold knife conization (n = 50), both margins were negative in 46% of those who underwent LEEP and in 48% of those who underwent cold knife conization.[17] Murdoch and colleagues[18] reported negative margins in 56% of 721 patients who underwent LEEP. Dietrich and colleagues[19] reported negative margins in 77% of their LEEP specimens. The specimen margins are reported as clear in 59% to 92% of women undergoing a cold knife conization.[1,7,8, 20–25]
The endocervical margin was positive in 20% of our patients. Johnson and colleagues[26] reviewed 702 consecutive medical records of patients who underwent either a LEEP or cold knife conization. The endocervical margin was positive in 18% of the patients for which follow-up information was available. In a prospective randomized study comparing LEEP to cold knife conization, the endocervical margin was involved in 18% of those who underwent a LEEP and in 27% of those undergoing a cold knife conization.[27]
Our study showed that 27% of the patients had persistent/recurrent disease, which is similar to that reported by others. Giacalone and colleagues[28] randomized 66 women to undergo a LEEP (n = 28) or cold knife conization (n = 38). They followed their patients with colposcopy and cervical cytology. They reported histologically confirmed persistent dysplasia in 6 (21%) of the patients who had previously undergone a LEEP and in 4 (10.5%) patients in the cold knife conization group. Duggan and colleagues[27] randomized 180 patients to undergo a LEEP (n = 89) or cold knife conization (n = 91) and observed no difference in the rate of lesion clearance or disease recurrence between the 2 groups. Johnson and colleagues,[26] in a large retrospective study, found no difference in the rate of persistent or recurrent dysplasia following LEEP or cold knife conization. Dietrich and colleagues[19] reported 29% persistent cervical cytologic abnormality within 3 months after a LEEP. Abnormal cytology at a 3-month cervical smear was reported by Paterson-Brown and colleagues[8] among 27% of patients following a cold knife conization with a positive margin and in 9% of cases with a negative margin. The rate of persistent disease is much higher when defined as disease in a hysterectomy specimen obtained within 6 weeks of the conization.[4,12,29] In our study, only 3 of 33 patients who underwent a hysterectomy within 12 months of the excisional biopsy had no pathologic findings in the hysterectomy specimen. Fifteen (45%) had CIN 2/3 or cancer. This high rate of persistent/recurrent disease is expected because patients are selected to undergo hysterectomy after the conization based on factors that will predispose them to have persistent/recurrent disease (eg, high-grade dysplasia, cancer, positive margins). We opted to be inclusive and use all types of follow-up data in an effort to avoid that bias, but were aware that it could result in a falsely low rate of persistent/recurrent disease (eg, false-negative colposcopy and cytology findings).
As in other studies, by univariate analysis we found a statistically significant association between persistent/recurrent disease after excisional biopsy of the cervix and the histopathologic diagnosis in the excisional biopsy specimen, positive endocervical or ectocervical margin, and positive ECC.
We did not find an association between persistent/recurrent disease after cervical conization and age. However, Lu and colleagues[30] in a retrospective study of 120 women with CIN 3 who underwent a hysterectomy within 6 months of an excisional biopsy, found that residual disease was present in 56.5% of patients 50 years of age or older and in 29% of those younger than 50. Age greater than 50 years was also found to be associated with persistent/residual disease among 449 women who underwent conization for CIN 3 and who had at least 1 cytologic/histologic follow-up within 1 year of conization.[31]
The retrospective nature of our study did not allow us to look at the size of the cervical lesion or endocervical gland involvement as possible predictors of persistent/recurrent disease. Demopoulos and colleagues[32] found that both positive margins and endocervical gland involvement were highly significant predictors of persistent or recurrent disease in 245 women who had undergone a cold knife conization for CIN 3. Lu and colleagues[30] found that the rate of persistent disease in a hysterectomy done within 6 months of a cervical conization was 48% in women whose excisional biopsy specimen showed more than 2 quadrants of involvement and 26% with 1- or 2-quadrant disease. Others have also shown a higher risk of persistent disease within 6 months of treatment for CIN among women with large lesions.[33]
We did not exclude any of the excisional biopsy specimens (based on grade of CIN) in order to be able to evaluate the impact that the histopathologic diagnosis had on predicting persistent/recurrent disease. We found that as the severity of the disease in the cervical conization specimen increases so does the percentage of patients who have persistent/recurrent disease. Persistent/recurrent disease was found in 33% of patients who had CIN 2/3 in the excisional biopsy specimen and in 54.5% of those who had carcinoma. By univariate analysis, Chang and colleagues[29] found an association between the severity of cervical neoplasia and residual disease in a postcone hysterectomy and between the severity of the cervical neoplasia and the rate of positive cone margins. The rate of residual disease was 0, 23%, 23.8%, and 43.8% in patients with CIN 1, CIN 2/3, stage IA1 cancer, or stage IA2 cancer, respectively.
Persistent/recurrent disease was found in 50% of patients with positive endocervical and/or ectocervical margins, but only in 15% of those whose margins were negative. Many have shown a significantly higher rate of residual disease after a positive cone margin compared to a negative margin.[12,26,29] The rate of persistent or recurrent cervical neoplasia is highest when both the endocervical and ectocervical conization margins are positive, followed by a positive endocervical margin only, and lowest when only the ectocervical margin is positive.[22,24] In our multivariate stepwise regression analysis that included endocervical and ectocervical margins, severity of the neoplasia, and the ECC results, endocervical margin, and severity of the neoplasia best predicted persistent/recurrent disease.
Persistent/recurrent cervical neoplasia was found in 80% of patients with a positive ECC, but only in 18.5% with a negative ECC, and 20% with an ECC with insufficient tissue for diagnosis. There was not enough tissue for a histopathologic diagnosis in 19% of the ECC specimen, a finding reported by others.[14,33]
Persistent/recurrent disease was found in all 13 patients who had both a positive ECC and endocervical margin. This is consistent with the findings reported by Husseinzadeh and colleagues.[12] However, on the multivariate stepwise logistic regression analysis, endocervical margin status coupled to severity of neoplasia significantly predicted the occurrence of persistent/recurrent disease. Adding the results of the ECC did not add incremental value to their ability to predict persistent/recurrent cervical neoplasia.
Aware of the limitations of our retrospective study, the data suggest that the rate of persistent/recurrent cervical neoplasia is low in patients whose conization specimen shows CIN 1. As others have shown, the rate of persistent/recurrent disease is high when the conization specimen has CIN2/3 or cancer and the endocervical margin is involved. On multivariate stepwise regression analysis the ECC at the time of the conization offered no incremental value for predicting persistent/recurrent disease. ECC at the time of excisional biopsy of the cervical transformation zone does not need to be routinely performed.
Figure 1.
Footnotes
Readers are encouraged to respond to Paul Blumenthal, MD, Deputy Editor of MedGenMed, for the editor's eyes only or for possible publication via email: pblumen@stanford.edu
Contributor Information
Sanjay M. Ramchandani, Department of Obstetrics, Gynecology and Reproductive Sciences, Temple University Hospital; currently in private practice in Corpus Christi, Texas..
Karen L. Houck, Gynecology and Reproductive Sciences, Temple University School of Medicine; currently is Physician at Morristown Memorial Hospital in Morristown, New Jersey.
Enrique Hernandez, Biostatistics Consulting Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
John P. Gaughan, Department of Obstetrics, Gynecology and Reproductive Sciences, Temple University School of Medicine Philadelphia, Pennsylvania.
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