Predictors of treatment failure for adenocarcinoma in situ of the uterine cervix: Up to 14 years of recorded follow-up.

The incidence of adenocarcinoma-in-situ (AIS) of the uterine cervix is rising, with invasive adenocarcinoma becoming increasingly common relative to squamous cell carcinoma. The present study reviewed a cohort of 84 patients first-time treated by conization for histologically-confirmed AIS from January 2001 to January 2017, to identify risk factors associated with recurrent/persistent AIS as well as progression to invasive cervical cancer. Nearly 80% of the patients were age 40 or younger at conization. Endocervical and ectocervical margins were deemed clear in 42 of the patients. All but two patients had ≥1 follow-up, with post-conization high-risk human papilloma virus (HPV) results documented in 52 patients. Altogether, 12 histopathologically-confirmed recurrences (14.3%) were detected; two of these patients had microinvasive or invasive carcinoma. In three other patients cytology showed AIS, but without recorded histopathology. Eight patients underwent hysterectomy for incomplete resection very soon after primary conization; they were not included in bivariate or multivariate analyses. Having ≥1 post-follow-up positive HPV finding yielded the highest sensitivity for histologically-confirmed recurrence: 87.5 [95% confidence interval (CI) 47.4-99.7]. Current or historical smoking status provided highest specificity: 94.4 (95% CI 72.7-99.9) and overall accuracy: 88.0 (95% CI 68.8-97.5) for histologically-confirmed recurrence. With multiple logistic regression (MLR), adjusting for age at conization and abnormal follow-up cytology, positive HPV18 was the strongest predictor of histologically-confirmed recurrence (P<0.005). Having ≥2 positive HPV results also predicted recurrence (P<0.02). Any unclear margin yielded an odds ratio 7.21 (95% CI 1.34-38.7) for histologically-confirmed recurrence adjusting for age, but became non-significant when including abnormal cytology in the MLR model. The strong predictive value of HPV, particularly HPV18 and persistent HPV positivity vis-à-vis detected recurrence indicated that regular HPV testing for patients treated for AIS is imperative. In conclusion, furthering a participatory approach, including attention to smoking with encouragement to attend needed long-term follow-up, can better protect these patients at high risk for cervical cancer.

Age, margin status, high-risk human papillomavirus and cytology independently predict recurrent high-grade cervical intraepithelial neoplasia up to 6 years after treatment.

The present study aimed to identify the factors that independently contribute to disease recurrence among women first-time treated for high-grade cervical intraepithelial neoplasia (CIN) during 4-6 years of follow-up. Overall, 529 of 530 eligible patients participated; these patients all attended a 1st follow-up appointment ~6 months post-conization, at which time high-risk human-papillomavirus (HPV) testing, liquid-based cytology and colposcopy were performed. Full data on margin excision status, other aspects of initial treatment and comorbidity were obtained. At least one subsequent follow-up was attended by 88% of patients. A total of 22 recurrent cases were detected during follow-up. Detected recurrence was the outcome of focus for multiple logistic regression analysis, with odds ratios (OR) and 95% confidence intervals (CI) computed. Four significant independent risk factors were identified: Age 45 years or above (OR=3.5, 95% CI=1.3-9.9), one or both unclear or uncertain margins (OR=5.3, 95% CI=2.0-14.2), positive HPV at 1st follow-up (OR=5.8, 95% CI=2.0-16.8), and abnormal cytology at 1st follow-up (OR=3.9, 95% CI=1.4-11.0). Bivariate analysis revealed that persistent HPV positivity was associated with recurrence (P<0.01). These findings indicated that incomplete excision of the CIN lesion may warrant more intensive subsequent screening, regardless of early post-conization HPV findings. Although early post-conization positive HPV was a powerful, independent predictor of recurrent high-grade CIN, over one-third of the patients with detected recurrence had a negative early post-conization HPV finding. These patients returned for routine screening, at which time, in most cases, HPV status was positive, thus indicating the need for repeated HPV evaluation. Especially during the on-going pandemic, home vaginal self-sampling is recommended. Particular attention is required for women aged ≥45 years. In addition, although not statistically significant, relevant comorbidities, especially autoimmune conditions, warrant consideration in clinical decision-making. Women who have been treated for high-grade CIN are at risk for recurrent disease and progression to cervical cancer; therefore, they require careful, individualized follow-up to avoid these adverse consequences.

Incomplete excision of cervical intraepithelial neoplasia as a predictor of the risk of recurrent disease-a 16-year follow-up study.

BACKGROUND: Women treated for high-grade cervical intraepithelial neoplasia (grade 2 or 3) are at elevated risk for developing cervical cancer. Suggested factors identifying women at highest risk for recurrence post-therapeutically include incomplete lesion excision, lesion location, size and severity, older age, treatment modality, and presence of high-risk human papilloma virus after treatment. This question has been intensively investigated over decades, but there is still substantial debate as to which of these factors or combination of factors most accurately predict treatment failure. OBJECTIVE: In this study, we examine the long-term risk of residual/recurrent high-grade cervical intraepithelial neoplasia among women previously treated for cervical intraepithelial neoplasia 2/3 and how this varies according to margin status (considering also location), as well as comorbidity (conditions assumed to interact with high-risk human papilloma virus acquisition and/or cervical intraepithelial neoplasia progression), posttreatment presence of high-risk human papilloma virus, and other factors. MATERIALS AND METHODS: This prospective study included 991 women with histopathologically confirmed cervical intraepithelial neoplasia 2/3 who underwent conization in 2000-2007. Information on the primary histopathologic finding, treatment modality, comorbidity, age, and high-risk human papilloma virus status during follow-up, and residual/recurrent high-grade cervical intraepithelial neoplasia was obtained from the Swedish National Cervical Screening Registry and medical records. Cumulative incidence of residual/recurrent high-grade cervical intraepithelial neoplasia was plotted on Kaplan-Meier curves, with determinants assessed by Cox regression. RESULTS: During a median of 10 years and maximum of 16 years of follow-up, 111 patients were diagnosed with residual/recurrent high-grade cervical intraepithelial neoplasia or worse. Women with positive/uncertain margins had a higher risk of residual/recurrent high-grade cervical intraepithelial neoplasia or worse than women with negative margins, adjusting for potential confounders (hazard ratio, 2.67; 95% confidence interval, 1.81-3.93). The risk of residual/recurrent high-grade cervical intraepithelial neoplasia or worse varied by anatomical localization of the margins (endocervical: hazard ratio, 2.72; 95% confidence interval, 1.67-4.41) and both endo- and ectocervical (hazard ratio, 4.98; 95% confidence interval, 2.85-8.71). The risk did not increase significantly when only ectocervical margins were positive or uncertain. The presence of comorbidity (autoimmune disease, human immunodeficiency viral infection, hepatitis B and/or C, malignancy, diabetes, genetic disorder, and/or organ transplant) was also a significant independent predictor of residual/recurrent high-grade cervical intraepithelial neoplasia or worse. In women with positive high-risk human papilloma virus findings during follow-up, the hazard ratio of positive/uncertain margins for recurrent/residual high-grade cervical intraepithelial neoplasia or worse increased significantly compared to that in women with positive high-risk human papilloma virus findings but negative margins. CONCLUSION: Patients with incompletely excised cervical intraepithelial neoplasia 2/3 are at increased risk for residual/recurrent high-grade cervical intraepithelial neoplasia or worse. Margin status combined with high-risk human papilloma virus results and consideration of comorbidity may increase the accuracy for predicting treatment failure.