Calendar-period trends in cervical precancer and cancer diagnoses since the introduction of human papillomavirus and cytology co-testing into routine cervical cancer screening at Kaiser Permanente Northern California.

OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

Risk of recurrent disease following conization of cervical intraepithelial neoplasia grade 3 according to post-conization HPV status and surgical margins.

OBJECTIVE: To examine the absolute risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) following conization according to post-conization HPV status and surgical margins. METHODS: A total of 11,006 women with CIN3 on the cone were followed for up to 14 years using nationwide registries. We estimated absolute risks of recurrent CIN2+ and sensitivity and specificity of HPV testing and margin status in predicting CIN2+ 4 years after conization. RESULTS: Altogether, 2537 women were HPV positive and 8469 were HPV negative. During follow-up, 306 and 140 women were diagnosed with CIN2+ among HPV positive and negative women, respectively. HPV positive women had higher absolute risk of CIN2+ compared to HPV negative women. Specifically, the 8-year absolute risk of CIN2+ was 12.5% (95% CI: 11.2-13.9) for HPV positive women and 1.8% (95%CI: 1.5-2.1) for HPV negative women. Among HPV negative women, the 8-year absolute risk was 2.7% (95%CI: 2.1-3.5) and 1.3% (95%CI: 1.0-1.7) for women with positive and negative margins, respectively. The same pattern was seen among HPV positive women. Combined testing with HPV and margins had a higher sensitivity but lower specificity than HPV testing alone. CONCLUSION: Our results add knowledge on long-term risk assessment of women treated with conization as taking both HPV and margin status into account added further stratification of the risk of recurrent disease compared to HPV status alone. Additionally, combined testing with HPV and margin status had higher sensitivity than HPV testing alone, which is important in high-risk populations, however, the specificity was lower.

Long-term risk of cervical cancer following conization of cervical intraepithelial neoplasia grade 3-A Danish nationwide cohort study.

Using nationwide Danish registries we examined the long-term risk of cervical cancer in women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3) (including adenocarcinoma in situ (AIS)) on the cone compared to women with a normal cytology test. Initially, we identified women born 1918-1990, who were recorded as living in Denmark between January 1, 1978 and December 31, 2012. From the Pathology Data Bank information on CIN3 on the cone, margins status, histological type of CIN3 and cervical cytology results was extracted. Cox proportional hazard model was used to estimate the relative risk of subsequent cervical cancer. We included 59,464 women with CIN3 on the cone and 1,918,508 women with a normal cytology test. Overall, women diagnosed with CIN3 had a higher risk of subsequent cervical cancer compared to women with normal cytology (HR = 2.06; 95%CI: 1.81-2.35). Analyses according to time since conization showed elevated risks in all time periods, and 25 years or more after conization the relative risk was significantly increased (HR = 2.56; 95%CI: 1.37-4.77). Twenty years or more after conization, also women with negative margins had an increased relative risk (HR = 2.49; 95%CI: 1.12-5.57). In addition, the long-term relative risk of cervical cancer varied with the different histological types of CIN3 and was highest for AIS (HR = 7.50; 95%CI: 1.87-30.01, 10-14 years after conization). In conclusion, women diagnosed with CIN3 on the cone have a long-lasting increased risk of cervical cancer even when the margins on the cone are negative.

Triage by PAX1 and ZNF582 Methylation in Women With Cervical Intraepithelial Neoplasia Grade 3: A Multicenter Case-Control Study.

Background: The colposcopy-conization inconsistency is common in women with cervical intraepithelial neoplasia grade 3 (CIN3). No adequate method has been reported to identify the final pathology of conization. In this study, we explored the ability of PAX1 and ZNF582 methylation to predict the pathological outcome of conization in advance. Methods: This was a multicenter study and included 277 histologically confirmed CIN3 women who underwent cold knife conization (CKC) from January 2019 to December 2020. The methylation levels of PAX1 (PAX1m) and ZNF582 (ZNF582m) were determined by quantitative methylation-specific polymerase chain reaction (qMSP) and expressed in ΔCp. Receiver operating characteristic curves were used to evaluate predictive accuracy. Results: The final pathological results in 48 (17.33%) patients were inflammation or low-grade squamous intraepithelial lesion (LSIL), 190 (68.59%) were high-grade squamous intraepithelial lesion (HSIL), and 39 (14.08%) were squamous cervical cancer (SCC). PAX1m and ZNF582m increased as lesions progressed from inflammation/LSIL, HSIL, to SCC. PAX1 and ZNF582 methylation yielded better prediction performance compared with common screening strategies, whether individually or combined. A 4.33-fold increase in the probability of inflammation/LSIL was observed in patients with lower ZNF582 methylation levels (ΔCpZNF582 ≥ 19.18). A 6.53-fold increase in SCC risk was observed in patients with elevated ZNF582 methylation (ΔCpZNF582 < 7.09). Conclusions: DNA methylation would be an alternative screening method to triage and predict the final outcome of conization in CIN3 cases.

Comparison of CINtec PLUS cytology and cobas HPV test for triaging Canadian patients with LSIL cytology referred to colposcopy: A two-year prospective study.

OBJECTIVES & METHODS: CINtec PLUS and cobas HPV tests were compared for triaging patients referred to colposcopy with a history of LSIL cytology in a 2-year prospective study. Cervical specimens were tested once at enrollment, and test positivity rates determined. Test performance was ascertained with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3 or worse (CIN3+) serving as clinical endpoints. RESULTS: In all ages, (19-76 years, n= 598), 44.3% tested CINtec PLUS positive vs. 55.4% HPV positive (p< 0.001). To detect CIN2+ (n= 99), CINtec PLUS was 81.8% sensitive vs. 93.9% for HPV testing (p= 0.009); genotype 16/18-specific sensitivity was 46.5%. Specificity was 52.9% vs. 36.6%, respectively (p< 0.001). In all ages, to detect CIN3+ (n= 44), sensitivity was 93.2% for both tests; genotype 16/18-specific sensitivity was 52.3%. Specificity was 48.4% for CINtec PLUS vs. 31.1% for HPV testing (p< 0.001). In patients < 30 years, CINtec was 91.7% sensitive vs 95.8% for HPV testing (p= 0.549). CONCLUSIONS: CINtec PLUS or cobas HPV test could serve as a predictor of CIN3+ with high sensitivity in patients referred to colposcopy with a history of LSIL regardless of age while significantly reducing the number of LSIL referral patients requiring further investigations and follow-up in colposcopy clinics.

Association of menopause, aging and treatment procedures with positive margins after therapeutic cervical conization for CIN 3: a retrospective study of 8,856 patients by the Japan Society of Obstetrics and Gynecology.

OBJECTIVE: The Japan Society of Obstetrics and Gynecology conducted a retrospective multi-institutional survey of patients who underwent cervical conization in Japan. This study aimed to determine the predictive factors for positive surgical margins in cervical intraepithelial neoplasia grade 3 (CIN 3) patients after therapeutic cervical conization and those for positive margins in patients who did not experience recurrence and did not undergo additional treatment. METHODS: In 2009 and 2013, 14,832 patients underwent cervical conization at 205 institutions in Japan. Of these, 8856 patients who underwent therapeutic conization fulfilled the inclusion criteria. Their histologic findings and clinical outcomes were evaluated based on standard statistical procedures and clinical and demographic characteristics. RESULTS: Negative and positive margins were observed in 7,585 and 1,271 (14.4%) patients, respectively. The predictors of positive margins were menopausal status (p<0.001), loop electrosurgical excision procedure (p<0.001), and Shimodaira-Taniguchi (S-T) conization (p<0.001). Of 1,271 patients with positive margins, 1,060 underwent no additional treatment; among those 1,060 patients, 129 (12.2%) experienced recurrence. The predictors of positive margins in patients who did not undergo additional treatment and did not experience recurrence were age, parity, gravidity, S-T conization, and laser scalpel conization. CONCLUSION: Menopausal status and treatment procedures were associated with positive margins after therapeutic conization of CIN 3. It is important to understand the characteristics of treatment procedures and select an appropriate procedure for each case. For elderly or menopausal patients with positive margins, immediate additional treatment is recommended.

Risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) among women with HPV-test in 1990-1992, a 30-year follow-up study.

BACKGROUND/OBJECTIVE: Having a 30-year follow-up of a cohort of women tested for HPV is a unique opportunity to further study long-term risk of CIN3+. The study objective was to compare HPV status at baseline with the risk of CIN3+ in the follow-up period of 30 years. METHODS: All women (n = 642) referred to the HPV outpatient clinic at the University Hospital of North Norway (UNN) in 1990-1992, with an HPV test at baseline, were included in a prospective cohort. HPV-testing was performed by two different HPV-DNA tests, and genotypes 6, 11, 16, 18, 31 and 33 were identified. High-risk (HR) HPV genotypes (16, 18, 31 and 33) were classified as HPV positive, whereas low-risk (LR) genotypes (6 and 11) in addition to absent HPV were classified as HPV negative. A single cohort in which women were classified for their HPV status underwent follow-up prospectively to the last time-point of observation of 30 years. RESULTS: During follow-up, 148 (148/642) cases of CIN3+ were detected, of whom 70.3% (104/148) were HPV positive and 29.7% (44/148) were HPV negative at baseline. The proportions of women who developed CIN3+ following a positive and a negative test were 46.6% (104/223) and 10.5% (44/419), respectively. Most cases of CIN3+ were seen shortly after the baseline HPV test, with 112 cases of CIN3+ diagnosed within the first year. In total, 48.6% (72/148) with HPV 16 and 57.6% (19/33) with HPV 33 developed CIN3+. Within the first year, CIN3+ was detected in 37.8% (56/148) with HPV 16, and 51.5% (17/33) with HPV 33. The long-term risk of CIN3+ was significantly lower than the short-term risk, and mainly associated with HPV 16. Overall, eight cases of cervical cancer were detected. Five were HPV positive, harboured HPV 16 at baseline and developed cervical cancer after 3, 4, 5, 11 and 24 years of follow-up. CONCLUSION AND CONSEQUENCES: HPV status at baseline is predictive for the subsequent risk of developing CIN3+. Women with a positive HPV test in 1990-1992 had a significantly higher risk of CIN3+ during 30 years of follow-up than those with a negative test. HPV 16 was associated with the greatest long-term risk of cervical cancer. All patients with a positive HPV test at baseline should be followed up until negative. TRIAL REGISTRATION: ISRCTN, ISRCTN10836802 . Registered 14 December 2020 - Retrospectively registered.

Clinical significance of atypical squamous cells of undetermined significance after treatment for cervical intraepithelial grade 3 neoplasia: A retrospective single-center cohort study.

The aim of the present study was to evaluate the clinical significance of atypical squamous cells of undetermined significance (ASC-US) following cervical conization for cervical intraepithelial neoplasia (CIN) grade 3. This study was a retrospective cohort analysis. The medical records of women treated with conization for CIN 2-3 were reviewed and 142 patients with CIN 3 who had been diagnosed using the conization specimens were selected. The mean follow-up period after conization was 41.8 months. Cytological abnormalities after conization were observed in 19.0% of the patients and consisted of ASC-US (13.4%) and worse than low-grade squamous intraepithelial lesion (LSIL; 5.6%). Recurrence was defined as a diagnosis worse than CIN 2, and the recurrence rate was 29.6% among patients with abnormal cytology. The recurrence rate was 15.7% in the ASC-US group and 71.4% in the worse than LSIL group. There was no significant difference in the time of initial identification of abnormal cytology after treatment between the worse than LSIL and the ASC-US groups (P=0.054). However, the ASC-US group had a significantly better cumulative recurrence-free rate compared with the worse than LSIL group (P<0.05). Women with ASC-US following treatment for CIN appear to be at a relatively high risk. Regarding the risk stratification of women following treatment for CIN, if surveillance cytology shows ASC-US, immediate colposcopy is recommended, along with long-term follow-up.