Mirte Schaafsma

Nationwide cohort study on the risk of high‐grade cervical dysplasia and carcinoma after conservative treatment or hysterectomy for adenocarcinoma in situ

AbstractInternationally, little consensus exists about the best treatment for cervical adenocarcinoma in situ (AIS). This study aimed to determine the incidence of recurrent high‐grade cervical dysplasia and development of local cervical cancer after treatment for AIS. This nationwide, retrospective cohort study included patients with AIS, who were treated by a large loop excision of the transformation zone (LLETZ), cold‐knife conization (CKC), or hysterectomy between January 1, 1990 and December 31, 2021 in the Netherlands. Pathology reports were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were the cumulative incidences of high‐grade cervical dysplasia (cervical intraepithelial neoplasia grade 2 or 3, and AIS) and local cervical cancer up to 20 years after primary treatment. In total, 4243 patients with AIS were included. The primary treatment was a LLETZ, CKC, or hysterectomy in 1593, 2118, and 532 patients, respectively. The incidence of recurrent high‐grade cervical dysplasia after LLETZ (10.5%; 95%CI: 8.6–12.3) was higher than after CKC (5.5%; 95%CI: 4.4–6.6, p <.0001). When a radical excision, that is, surgical margins free of dysplasia at end of treatment, was achieved, the incidence of recurrent high‐grade dysplasia and local cervical cancer did not differ between LLETZ (5.6% [95%CI: 3.3–7.9] and 1.9% [95%CI: 0–4.4]) and CKC (4.7% [95%CI: 3.5–5.8], p = .631 and 1.5% [95%CI: 0.7–2.3], p = .918). After hysterectomy, none of the patients developed cervical dysplasia or local cervical cancer. Conservative treatment for AIS can be considered a safe and final treatment modality when a radical excision is achieved.

Recurrent cervical cancer detection using DNA methylation markers in self‐collected samples from home

AbstractEarly detection of recurrent cervical cancer is important to improve survival rates. The aim of this study was to explore the clinical performance of DNA methylation markers and high‐risk human papillomavirus (HPV) in cervicovaginal self‐samples and urine for the detection of recurrent cervical cancer. Cervical cancer patients without recurrence (n = 47) collected cervicovaginal self‐samples and urine pre‐ and posttreatment. Additionally, 20 patients with recurrent cervical cancer collected cervicovaginal self‐samples and urine at time of recurrence. All samples were self‐collected at home and tested for DNA methylation and high‐risk HPV DNA by PCR. In patients without recurrent cervical cancer, DNA methylation levels decreased 2‐years posttreatment compared to pretreatment in cervicovaginal self‐samples (p < .0001) and urine (p < .0001). DNA methylation positivity in cervicovaginal self‐samples was more frequently observed in patients with recurrence (77.8%) than in patients without recurrence 2‐years posttreatment (25.5%; p = .0004). Also in urine, DNA methylation positivity was more frequently observed in patients with recurrence (65%) compared to those without recurrence (35.6%; p = .038). Similarly, high‐risk HPV positivity in both cervicovaginal self‐samples and urine was more frequent (52.6% and 55%, respectively) in patients with recurrence compared to patients without recurrence (14.9% and 8.5%, respectively) (p = .004 and p = .0001). In conclusion, this study shows the potential of posttreatment monitoring of cervical cancer patients for recurrence by DNA methylation and high‐risk HPV testing in cervicovaginal and urine samples collected at home. The highest recurrence detection rate was achieved by DNA methylation testing in cervicovaginal self‐samples, detecting 77.8% of all recurrences and, specifically, 100% of the local recurrences.

Optimal follow-up strategy using high-risk human papillomavirus testing and cytology after conservative treatment for cervical adenocarcinoma in situ

After treatment for cervical adenocarcinoma in situ, patients remain a risk for recurrent adenocarcinoma in situ, cervical intraepithelial grade 3, or cervical cancer. This study aimed to determine the optimal follow-up strategy for high-risk human papillomavirus and cytology testing in conservatively treated patients with adenocarcinoma in situ. Patients were selected from a nationwide, retrospective cohort that included pathology reports from the Dutch Nationwide Pathology Databank (Palga) and survival data from the Central Bureau for Genealogy for patients conservatively treated for adenocarcinoma in situ between 1990 and 2021. The main outcome was the 5-year cumulative incidence of recurrent adenocarcinoma in situ, cervical intraepithelial neoplasia grade 3, or cervical cancer stratified by single and consecutive human papillomavirus test and/or cytology results at 6, 12, 18, and 24 months. A total of 3411 patients were eligible for analysis. High-risk human papillomavirus test and/or cytology results in the first 5 years of follow-up were available in 3312 of 3411 patients (97.1%), including 5207 high-risk human papillomavirus test results of 1928 patients and 13,369 cytology results of 3306 patients. Up to 5 years after a single high-risk human papillomavirus test at 6 months after treatment, the incidence of recurrent adenocarcinoma in situ, cervical intraepithelial neoplasia grade 3, or cervical cancer was lower among high-risk human papillomavirus-negative patients (2.3%; 95% confidence interval, 0.8-3.7) compared with high-risk human papillomavirus-positive patients (20.1%; 95% confidence interval, 14.2-25.5). Patients with normal cytology results 6 months after treatment for adenocarcinoma in situ had a lower incidence of recurrent adenocarcinoma in situ, cervical intraepithelial neoplasia grade 3, or cervical cancer (3%; 95% confidence interval, 2.2-3.8) compared with patients with low-grade (5.9%; 95% confidence interval, 3.4-8.4) or high-grade cytology (52.1%; 95% confidence interval, 42.7-59.9). The 5-year cumulative incidence of recurrent adenocarcinoma in situ, cervical intraepithelial neoplasia grade 3, or cervical cancer among patients testing negative for high-risk human papillomavirus consecutively at 6 and 12, 6 and 18, and 6 and 24 months was 0.6% (95% confidence interval, 0-1.8), 1.1% (95% confidence interval, 0-3.4), and 0% (95% confidence interval not applicable), respectively. Similarly, for patients with consecutive normal cotest results (high-risk human papillomavirus-negative with normal or low-grade cytology) at 6 and 12, 6 and 18, and 6 and 24 months, the 5-year cumulative incidence of recurrent adenocarcinoma in situ, cervical intraepithelial neoplasia grade 3, or cervical cancer was 0.6% (95% confidence interval, 0-1.8), 1.2% (95% confidence interval, 0-3.5), and 0% (95% confidence interval not applicable), respectively. After 2 consecutive negative high-risk human papillomavirus or normal cotests within 2 years after conservative adenocarcinoma in situ treatment, the risk of recurrent adenocarcinoma in situ, cervical intraepithelial neoplasia grade 3, or cervical cancer is low, and it seems acceptable to refer patients back to the national cervical cancer screening program, if applicable.