Cold-knife conization is definitive treatment of severe cervical intraepithelial neoplasia (CIN) III or squamous carcinoma in situ, if the margins are clear. Fewer than 1% of patients develop new high-grade intraepithelial lesions during long-term follow-up.1 However, 18% of patients undergoing conization for CIN III at our institution have disease at the margins of the conization specimen. These patients are at risk for persistent, recurrent, or progressive disease, and many such patients have undergone hysterectomy.2 However, the rate of persistent or recurrent disease after incomplete excision of CIN III seems to be low.3 Preservation of the uterus is an obvious issue in young women who wish to preserve fertility. In the present study, we analyzed the long-term results of patients with CIN III after cold-knife conization with involved margins who underwent no further treatment.
MATERIALS AND METHODS
Between 1970 and 1994, a total of 5386 patients underwent conization for CIN III at our institution. Clear margins were obtained in 4417 patients (82%), who have been reported previously.1 Of the 969 patients with positive margins, 390 (median age 39 years, range 20–69) were followed expectantly for a mean of 19 (range 6–30) years and form the basis of the present study.
All conizations were performed with a cold-knife technique and general anesthesia. The cervix was 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 was injected to produce ballooning and blanching of the entire cervix. Then, the cervix was stained with Lugol solution to delineate the margins of nonstaining epithelium. The initial incision defined the base of the cone. Flat cones were obtained for ectocervical lesions, taller cones for endocervical ones.4 The mean depth of the cones was 16 (range 9–22) mm. After removal of the specimen, the cut surface was 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 were obtained per cone. Histologically, all CIN III lesions showed proliferation of atypical cells involving the upper third or the full thickness of the epithelium.5 Involved margins were diagnosed if CIN III was present at the ectocervical or endocervical margin or both. The endocervical margin of the cone was affected by disease in 207 (53%), the ectocervical margin in 152 (39%), and both the ectocervical and endocervical margins were affected in 31 (8%) cones (Table 1).
Patients were followed-up with colposcopy, cytology, histology, and pelvic examination. If the endocervical margin of the cone was involved, endocervical curettage was performed at 6-month intervals approximately for 4 years. If the ectocervical margin was involved, the ectocervix was inspected by colposcopy, and biopsy was performed if indicated. Patients were seen at 3-month intervals during the first year, at 6-month intervals during years 2–4, and yearly thereafter. Persisting CIN III was diagnosed if CIN III was detected in the first year after conization and recurrent CIN III in patients if CIN III was detected thereafter. All patients were white. None had clinical or laboratory evidence of immunosuppression or human immunodeficiency virus infection. Data were analyzed with χ2 test (StatXact 4.0 software, Cytel, Cambridge, MA). P values < .05 were considered statistically significant.
Overall, 306 (78%) patients with positive margins at conization were free of CIN III during a mean follow-up of 19 (range 6–30) years, and 84 (22%) developed persisting or recurrent CIN III or carcinoma (Figure 1). Seventy-eight patients showed persisting or developed recurrent CIN III. Fifty-three (68%) of these 78 patients had persisting disease in the first year after conization, and 25 (32%) had recurrent disease after a median of 3 (range 2–28) years. Seventy-five (96%) of the 78 patients with persisting or recurrent CIN III underwent hysterectomy, and three (4%) had repeat conization. Five patients developed microinvasive carcinomas 3, 6, 7, 12, and 23 years after conization, and one developed a stage IB cancer with purely intracervical growth at 8 years. Persisting or recurrent disease was more common in patients in whom both the endocervical and the ectocervical cone margins were involved than in those in whom only the ectocervical or the endocervical margin was positive (52% versus 17% and 21%, respectively, P < .001) (Table 1). Of the six patients with invasive findings, three had a positive endocervical margin, one had a positive ectocervical margin, and one had both. Two patients with invasive findings were treated by radical abdominal hysterectomy with pelvic lymphadenectomy, two had simple hysterectomy with pelvic lymphadenectomy, and two had simple hysterectomy.
In our study, one-fifth of patients with CIN III followed expectantly after cold-knife conization with involved margins had persistent or recurrent disease. The rate of microinvasive recurrence was 1.3%, and one patient developed invasive disease at 8 years with purely intracervical growth. Two-thirds of the new intraepithelial lesions were detected during the first year after treatment, whereas one-third of patients developed disease after a median of 3 years, with one case 28 years after initial therapy (Figure 1).
Rates of residual or recurrent disease after incomplete removal of CIN III with different excisional techniques have been reported to be 5–16%.3,6–9 The median follow-up in these studies was between 3 and 70 months. Our finding of a 20% residual and recurrence rate for CIN III is probably a result of the long follow-up in our series. Persistent or new lesions were most common in patients who had both positive ectocervical and endocervical margins (Table 1). This suggests that these patients should be considered for further treatment rather than expectant follow-up.
However, most patients after incomplete excision of CIN III do not develop persistent or recurrent disease. This is probably because of the effect of diathermy on the cut surface of the cervix after removal of the cone and the inflammatory response associated with wound healing. Dysplastic or malignant epithelium within the inner zone of necrosis and an outer zone of white cell infiltration appears to be eradicated after cold-knife conization. Only lesions outside these zones can persist, regress, or progress.10 A previous series from our institution reviewed 183 patients with CIN III treated with hysterectomy after cold-knife conization with involved margins. Forty-nine (27%) contained residual CIN III, and one (0.5%) contained a microinvasive carcinoma.2 On the other hand, persisting CIN III lesions have a potential to regress during follow-up, and a proportion of these high-grade lesions develop to a normal or lower-degree abnormality with no therapy.11,12
The most worrying risk after incomplete treatment of CIN is invasive cancer.2,13 In our series, 1.3% of patients developed microinvasive findings, and one patient had a stage IB lesion with purely intracervical growth. This is consistent with the 0.9% rate of invasive lesions after conization with and without involved margins in the series of 1121 patients with CIN III followed for 5–25 years by Kolstad and Klem3 and with the 1.6% rate of invasive lesions after treatment of CIN using different methods in a multicenter study of 2116 women followed for 8 years.13 These cases with invasive findings after treatment of CIN III result from inadequate diagnosis, probably failure to identify invasive lesions by biopsies. However, not all invasive lesions of the cervix are amenable to early diagnosis. Colposcopic and cytologic signs of early invasion can be missed when early invasive foci develop deep in cervical glands or within the endocervical canal without connection to the surface epithelium.14 Furthermore, it is difficult to estimate the transit time and progression rate from CIN III to microinvasive cancer.15 In our series, invasive findings were observed after the second year of incomplete conization of CIN III. In conclusion, our findings suggest that expectant management is reasonable for patients with CIN III and positive margins after cold-knife conization, provided that careful follow-up is available, particularly during the first year.
1. Reich O, Pickel H, Lahousen M, Tamussino K, Winter R. Cervical intraepithelial neoplasia III: Long-term outcome after cold-knife conization with clear margins. Obstet Gynecol 2001;97:428–30.
2. Burghardt E, Holzer E. Treatment of carcinoma in situ: Evaluation of 1609 cases. Obstet Gynecol 1980;55:539–45.
3. Kolstad P, Klem V. Long-term follow up of 1121 cases of carcinoma in situ. Obstet Gynecol 1976;48:125–9.
4. Burghardt E. Cold-knife conization. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G, eds. Surgical gynecologic oncology. Stuttgart: Thieme, 1993:269–73.
5. Richart RM. Natural history of cervical intraepithelial neoplasia. Clin Obstet Gynecol 1967;10:748–84.
6. Andersen ES, Pedersen B, Nielsen K. Laser conization: The results of treatment of cervical intraepithelial neoplasia. Gynecol Oncol 1994;54:201–4.
7. Gardeil F, Barry-Walsh C, Prendiville W, Clinch J, Turner M. Persistent intraepithelial neoplasia after excision of cervical intraepithelial neoplasia grade III. Obstet Gynecol 1997;89:419–22.
8. Mohamed-Noor K, Quinn MA, Tan J. Outcomes after cervical cold knife conization with complete and incomplete excision of abnormal epithelium: A review of 699 cases. Gynecol Oncol 1997;67:34–8.
9. Murdoch JB, Morgan PR, Lopes A, Monaghan JM. Histological incomplete excision of CIN after large loop excision of the transformation zone (LLETZ) merits careful follow up, not treatment. Br J Obstet Gynaecol 1992;99:990–3.
10. Reich O, Lahousen M, Pickel H, Winter R. Morphologic changes at the uterine cervix after cold-knife conization. Geburtsh Frauenheilk 2000;60:273–5.
11. Östör AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol 1993;12:186–92.
12. Coppleson LW, Brown B. Observations on a model of the biology of carcinoma of the cervix: A poor fit between observation and theory. Am J Obstet Gynecol 1975;122:127–36.
13. Soutter WP, Lopes AB, Fletscher A, Monaghan JM, Paraskevaidis E, Kitschener HC. Invasive cervical cancer after conservative therapy of cervical intraepithelial neoplasia. Lancet 1997;349:978–80.
14. Reich O, Pickel H, Tamussino K, Winter R. Microcarcinoma of the cervix: Site of first focus of invasion. Obstet Gynecol 2001;97:890–2.
15. Noda K. Cervical intraepithelial neoplasia and microinvasive carcinoma of the cervix. In: Sasano N, ed. Gynecological tumors. Recent progress in diagnostic pathology. Berlin: Springer, 1992:35–56.