Obstetrics & Gynecology:
Cervical Intraepithelial Neoplasia III: Long‐Term Outcome After Cold‐Knife Conization With Clear Margins
REICH, OLAF MD; PICKEL, HELLMUTH MD; LAHOUSEN, MANFRED MD; TAMUSSINO, KARL MD; WINTER, RAIMUND MD
Department of Obstetrics and Gynecology, University of Graz, Graz, Austria.
Olaf Reich, MD, Department of Obstetrics and Gynecology, University of Graz Auenbruggerplatz, 14 A-8036 Graz Austria; E-mail: firstname.lastname@example.org
Received May 16, 2000. Received in revised form October 2, 2000. Accepted October 19, 2000.
Objective: To evaluate the long-term outcome of patients with severe cervical intraepithelial neoplasia or squamous cell carcinoma in situ (CIN III) after cold-knife conization with clear margins.
Methods: A total of 4417 women (mean age 36, range 18–72 years) with histologically confirmed CIN III had cold-knife conization with clear margins at our institution between 1970 and 1994. All patients were followed up with colpos-copy, cytology, and pelvic examination for a mean of 18 years (range 5–30years).
Results: New high-grade squamous intraepithelial lesions (SILs) (CIN II and III) developed in 15 (0.35%) patients (mean age 35, range 25–65 years) after a median of 107 (range 40–201) months. A total of 4402 (99.65%) patients (mean age 36, range 18–72 years) were free of high-grade SILs after a mean follow-up of 18 (range 5–30) years. High-grade glandular intraepithelial lesions developed in two (0.05%) patients 14 and 17 years after conization. Twelve (0.3%) patients had metachronous vulvar intraepithelial neoplasia (VIN) grade III or vaginal intraepithelial neoplasia (VAIN) grade III, and one (0.02%) patient had invasive vaginal carcinoma 10 years after conization.
Conclusion: Cold-knife conization with clear margins was an adequate method to definitively treat CIN III.
Cold-knife conization is a standard technique to diagnose and treat cervical intraepithelial neoplasia (CIN). When the specimen is evaluated, important factors include the grade and extent of the lesion, the relation between the atypical epithelium and the stroma, the extent of invasion by epithelial strands, and the status of the surgical margins. Cold-knife conization is usually considered the definitive treatment of CIN if the cone has encompassed the entire extent of the epithelial change, ie, if the epithelium is clear of disease at the surgical margins. In a previous series from our institution the outcome of 1609 patients with squamous carcinoma in situ was reviewed, and among 634 patients treated with cold-knife conization with clear margins, there were no new CIN III lesions found during follow-up.1 Only two patients had CIN II, at 4 and 11 years after conization. The authors concluded that squamous cell carcinoma in situ is resectable by conization alone.
In the present study, we analyzed the recurrence rate of high-grade squamous intraepithelial lesions (SIL) (CIN II and III) in patients with severe cervical intra-epithelial neoplasia or squamous cell carcinoma in situ (CIN III) after cold-knife conization with clear histologic margins. We also analyzed the metachronous development of high-grade glandular intraepithelial lesions, vulvar intraepithelial neoplasia (VIN) grade III, and vaginal intraepithelial neoplasia (VAIN) grade III.
Materials and Methods
We reviewed the records of 4417 patients (mean age 36 years, range 18–72 years) with histologically verified CIN III who had cold-knife conization with clear margins at our institution between 1970 and 1994 and for whom long-term follow-up (mean follow-up 18 years, range 5–30 years) was available.
Our surgical technique was a modification of that described by Burghardt et al.2 The cervix is grasped and brought into view with two tenacula, placed at the 3 o'clock and 9 o'clock positions outside any lesion. According to the size of the cervix, 30–80 mL of diluted vasopressin is injected, enough to produce ballooning and blanching of the entire cervix. Then the cervix is stained with Lugol solution (2 g iodine and 4 g potassium iodide dissolved in 200 mL distilled water) to delineate the margins of nonstaining epithelium. The initial incision defines the base of the cone. Care is taken to keep a 5-mm margin outside iodine-negative fields. Flat cones are obtained for ectocervical lesions, taller cones for endocervical ones. The mean depth of the cones was 16 (range 9–22) mm. After removal of the specimen, the cut surface is electrocoagulated generously for hemostasis. After fixation, the cones were halved in the sagittal plane and each half was embedded in paraffin. The paraffin blocks were processed as 200 μm-thick sections and stained with hematoxylin and eosin. An average of 90 sections was obtained per cone.
All patients were white. Patients with incomplete follow-up or carcinoma precursors of the cervical glands, vulva, and vagina were excluded. None of the patients had clinical or laboratory evidence of immunosupression or human immunodeficiency virus (HIV) infection. Histologically, all CIN III lesions showed proliferation of atypical cells involving the upper third or the full thickness of the epithelium.3 Patients were followed up with colposcopy, cytology, and pelvic examination. Patients were seen at 3-month intervals during the first year, at 6-month intervals during years 2–4, and yearly thereafter. Recurrent CIN was diagnosed histologically according to the criteria of Richart.3 Cases of CIN I were not included. Cervical intraepithelial glandular neoplasia was diagnosed according to the criteria of Gloor and Hurlimann.4 The World Health Organization (WHO) criteria5 were used for diagnosis of VIN and VAIN. Twelve patients with recurrent high-grade SILs had vaginal hysterectomy and three had a repeat conization.
Statistical analysis was done with Student t test for age. P < .05 was considered statistically significant.
New high-grade SIL (CIN II and III) developed in 15 (0.35%) patients a median of 107 (range 40–201) months after initial therapy (Tables 1 and 2). A total of 4402 (99.65%) women were free of high-grade SIL. There was no incidence of invasive cervical carcinoma. No further recurrence was found in the three patients who had repeat conization. The mean age for patients with new high-grade SIL at the time of initial diagnosis was 35 years (range 25–65 years), which did not differ from the mean age of patients without new disease (36 years, range 18–72years). High-grade glandular intraepithelial lesions developed in two (0.05%) patients 14 and 17 years after conization. Twelve (0.3%) patients had metachronous VIN III or VAIN III and one (0.02%) patient had invasive vaginal carcinoma 10 years after conization (Table 2).
Our results show that the long-term efficacy of cold-knife conization of CIN III with clear margins is high, with no significant recurrence rate for high-grade SIL (CIN II and III). New high-grade SIL developed in only 0.35% of our patients a median of 107 months after initial therapy (Tables 1 and 2). The age of patients had no effect on long-term failure rate of cold-knife conization. On the basis of our data, cold-knife conization can be done before or in lieu of hysterectomy for patients with CIN III, even in older women. These results are in agreement with several studies showing that CIN III can be resected successfully with conization.1,6–8
The reappearance of high-grade SIL years after cold-knife conization with clear margins appeared to be new disease rather than recurrence. This finding is supported by the facts that the earliest new high-grade SIL in our series occurred 4 years after conization (Table 1). and that the high-grade glandular intraepithelial lesions were found in two patients 14 and 17 years after conization. However, it is difficult to estimate how long cervical carcionomas take to develop. In a study of 557 patients by Richart and Barron,9 the median transit time to carcinoma in situ was 86 months for a patient with very mild dysplasia, 58 months for mild dysplasia, 38 months for moderate dysplasia, and 12 months for severe dysplasia. That study was based on cytologic and colposcopic examinations. Our finding of a median of 107 months for development of new high-grade SIL is consistent with the results reported by Richart and Barron.9
Patients with a history of CIN III are at risk of developing multicentric lesions with synchronous or metachronous VIN or VAIN.10 Twelve patients (0.3%) in our series had metachronous VIN III or VAIN III, and one patient had invasive vaginal carcinoma 10 years after conization (Table 2).
Cervical intraepithelial neoplasia can be treated by different techniques, including ablative techniques (eg, cryosurgery, electrocautery, cold coagulation, or laser ablation) and excisional techniques (eg, cold-knife conization or loop diathermy conization). Optimal treatment should be based on detailed knowledge of development and spread of the lesion, reliable treatment methods, and any concomitant indications. Cervical intraepithelial neoplasia occurs both on the ectocervix and in the cervical canal and is seen most often in the cervical gland field. Complete replacement of the columnar epithelium by CIN results in pegs and bands that can reach more than 5 mm into the stroma11 and as far as 10 mm in conization specimens.2 When excisional techniques were compared, after laser cone biopsy with complete excision of abnormal epithelium, recurrent CIN ranged from 1.4% (mean follow-up 68 months)12 to 2.3% (mean follow-up 70 months).13 After large-loop excison of the transformation zone with clear margins, recurrent CIN ranged from 1.9% (follow-up 6 months)14 to 10.5% (mean follow-up 11 months).15 Confirming our results, no recurrent CIN III was found during follow-up of 6 months after complete removal of CIN III with large-loop excison of the transformation zone by Gardeil et al.14
In conclusion, cold-knife conization with clear margins is an adequate method to treat CIN III definitively. This result has led us to modify our posttreatment follow-up protocol for immunocompetent patients with CIN III after cold-knife conization and clear margins to yearly colposcopic and cytologic follow-up.
1. Burghardt E, Holzer E. Treatment of carcinoma in situ: Evaluation of 1609 cases. Obstet Gynecol 1980;55:539–45.
2. Burghardt E. Cold-knife conization. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G, eds. Surgical gynecologic oncology. Stuttgart: Thieme, 1993.
3. Richart RM. Natural history of cervical intraepithelial neoplasia. Clin Obstet Gynecol 1967;10:748–84.
4. Gloor E, Hurlimann J. Cervical intraepithelial glandular neoplasia (adenocarcinoma in situ and glandular dysplasia). Cancer 1986;58:1272–80.
5. Scully RE, Bonfiglio TA, Kurman RJ, Silverberg SG, Wilkinson EJ, eds. Histological typing of female genital tract tumours. Berlin: Thieme, 1994.
6. Ahlgren M, Ingemarsson I, Lindberg LG, Nordqvist SRB. Conization as treatment of carcinoma in situ of the uterine cervix. Obstet Gynecol 1975;46:135–40.
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8. Bjerre B, Eliasson G, Linell F, Söderberg H, Sjöberg NO. Conization as only treatment of carcinoma in situ of the uterine cervix. Am J Obstet Gynecol 1976;15:143–52.
9. Richart RM, Barron BA. A follow-up study of patients with cervical dysplasia. Am J Obstet Gynecol 1969;105:386–93.
10. Beckmann AM, Acker R, Christiansen AE, Sherman KJ. Human papillomavirus infection in women with multiple squamous cell neoplasia. Am J Obstet Gynecol 1991;165:1431–7.
11. Anderson MC, Hartley RB. Cervical crypt involvement by intra-epithelial neoplasia. Obstet Gynecol 1980;55:546–50.
12. Bandieramonte G, Lomo-Nico S, Quattrone P, Stefanono B, Merola M, Bucci A. Laser conization assisted by crypt visualization for cervical intraepithelial neoplasia. Obstet Gynecol 1998;91:263–9.
13. Andersen ES, Pedersen B, Nielsen K. Laser conization: The results of treatment of cervical intraepithelial neoplasia. Gynecol Oncol 1994;54:201–4.
14. Gardeil F, Barry-Walsh C, Prendiville W, Clinch J, Turner M. Persistent intraepithelial neoplasia after excision of cervical intra-epithelial neoplasia grade III. Obstet Gynecol 1997;89:419–22.
15. Duggan BD, Felix JC, Muderspach LI, Gebhardt MS, Groshen S, Morrow P, et al. Cold-knife conization versus conization by the loop electrosurgical excison procedure: A randomized, prospective study. Am J Obstet Gynecol 1999;180:276–82.
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