DISCUSSION
The residual lesions in unresected tissue after cervical conization are the source of disease recurrence. For high-grade CIN after cervical conization, the overall risk of residual or recurrent CIN2+ was 6.6% (95% CI 4.9-8.4) and was increased with positive compared with negative resection margins (relative risk 4.8, 95% CI 3.2-7.2)6. Therefore, conization is considered to be safe and the preferred treatment for high-grade CIN. However, previous literature reports, the overall risk of residual after AIS conization was between 14.1-52.8%2, 7, which was significantly higher than that of CIN. Therefore, hysterectomy is preferred for AIS. Further studies found that positive conization margin was associated with a significant increase in the risk of residual disease. A meta-analysis of 1278 AIS patients indicates that achieving negative margins after a surgical excision is associated with a significantly lower rate of residual and recurrent disease (20.3% and 2.6%, respectively) compared with patients with positive margins (52.8% and 19.4%, respectively)2. Baalbergen8 reviewed 965 AIS patients in 35 studies, showed that the residual rate was 16.5% in negative margins versus 49.3% in positive margins. In this study, the overall rate of residual diseases was 16.13% in 310 specimens of hysterectomy and repeated conization. The rates of residual disease were 50.56% (45/89) for positive margin and 2.26% (5/221) for negative margin, respectively, with a significantly difference (p=0.000). On the other hand, residual invasive cancer is the greatest risk for the safety of conization. Retrospective studies reported that the rate of residual invasive cancer was less than 6%2, even lower in the negative margin patient. In our study the rates of residual invasive cancer were 5.26% (5/89) for positive margin and 0 % (0/221) for negative margin, respectively. Our and previously reported data suggest that the risk of residual lesion and residual invasive cancer was low after conical resection, provided the margin was negative.
Recurrence of the disease is the ”golden standard” for determining the safety of cervical conization for AIS. As the literature reported, the recurrent rate was about 0-5% in AIS patients underwent conization, and 0-3% in those with negative margins7-11. Baalbergen8 reviewed 36 studies involving 1277 AIS patients who were diagnosed by conization and underwent conservative treatment, 64 (5%) patients relapsed, of whom 3% had negative margins. Hanegem et al12 performed a retrospective study including 112 young(age ≤30 years) patients with AIS treated conservatively, but no recurrence was found. In this study, totally 5 patients recurred during mean 50.09 months follow-up period, and the recurrent rates were 1.33% in patients treated by hysterectomy and 0.65% in patients treated by cervical conization(s) alone, with no significant difference (p=0.431). Moreover, no invasive adenocarcinoma recurrence was identified in patients with negative conization margins. Both univariate and multivariate analysis did not demonstrate that surgery method was associated with recurrence. Our results suggested that the recurrent rate was extremely low for AIS patients with negative conization margin. Hysterectomy eliminates recurrence of CIN, but can not reduce the recurrence of vaginal lesions.
“Long-term follow-up with a combination of co-testing and colposcopy with endocervical sampling” is a recommended strategy for AIS patients treated with conization, according to the American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines13. The recommendation by ASCCP guidelines was supported by previous studies, in which cytology, HPV testing, and colposcopy evaluation was regarded as irreplaceable in monitoring recurrence of AIS with conservative treatment14, 15. In this study, we found that both cytology and HPV status were independent factors influencing recurrence of AIS. All recurrent patients were diagnosed by combined cytology and HPV testing followed by colposcopy at the precancerous stage, and no patient progressed to invasive cancer.
In summary, the rates of residual disease in specimens of hysterectomy and repeated conization were 50.56 % for positive margin and 2.26 % for negative margin, among 310 cervical AIS patients undergoing conization. During mean 50.09 months follow-up period, 1 patient recurred as CIN in those treated by conization alone and 4 recurred as VAIN in those treated by hysterectomy, and no invasive cancer recurrence was found. Surgery method was not an independent factor influencing residual and recurrence. Our results suggest that conization is an effective and safe option for patients with AIS of the cervix, provided the margin is negative.
Declarations section
Declaration of Conflict of Interest: None.
All authors of this research paper have directly participated in the planning, execution, or analysis of the study and have read and approved the final version submitted. This paper is new and has been seen and approved by all listed authors. These authors contributed equally: Jingjing Liu, Yu Wang.
The study was approved by the Human Research Ethics Committee of the Women’s Hospital Zhejiang University School of Medicine on June 28, 2021, and the reference number is PRO2020-656.
Acknowledgement: This research was supported by Natural Science Foundation of Zhejiang province China NO.LY19H160043.