Albert G. Siebers

Risk of Gynecologic Cancer after Atypical Glandular Cells Found on Cervical Cytology: A Population-Based Cohort Study

Abstract Background: Atypical glandular cells (AGC) are rare abnormalities found on cervical cytology associated with a range of lesions of the female reproductive system. We compared the risk of cervical and other gynecologic cancers following AGC on cervical cytology with the risk following squamous cell abnormalities of comparable severity. Methods: We used data from the Dutch Pathology Archive (PALGA) from 2000 to 2015 to categorize cervical cytology tests into groups based on most severe cytologic abnormality and correlated follow-up advice (normal cytology and “no follow-up” advice, squamous-cell–based, AGC-based, and combined AGC/squamous-cell based each with either repeat testing or referral advice). Cancer data were linked from the Netherlands Cancer Registry. Cox proportional hazard models were calculated stratified by age [younger (<50 years) and older (50+ years)], adjusted for number of previous primary cytology tests. Results: 8,537,385 cytology smears and 9,061 cancers were included. When repeat cytology testing was advised, HRs of cervical cancer (younger women: HR, 6.91; 95% CI, 5.48–8.71; older women: HR, 3.98; 95% CI, 2.38–6.66) or other gynecologic cancer diagnosis in younger women (HR, 2.82; 95% CI, 1.39–5.74) were significantly higher after an AGC-based abnormality compared with squamous-based abnormalities. Hazards were also significantly higher for “referral” advice cytology, except for cervical cancer among older women (HR, 0.88; 95% CI, 0.63–1.21). Conclusions: AGC indicates an increased risk of gynecologic cancer compared with squamous-based abnormalities of comparable severity. Impact: Gynecologists should be alert for cervical and endometrial cancers when examining women referred following AGC.

Cervical intraepithelial neoplasia and the risk of spontaneous preterm birth: A Dutch population-based cohort study with 45,259 pregnancy outcomes

BackgroundExcisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease.Methods and findingsThis Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or ≥100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age ≥16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth.In total, 29,907, 5,940, and 9,412 pregnancies were included in the control, untreated CIN, and treated CIN group, respectively. The control group showed a 4.8% (1,002/20,969) proportion of spontaneous preterm birth, which increased to 6.9% (271/3,940) in the untreated CIN group, 9.5% (600/6,315) in the treated CIN group, and 15.6% (50/321) in the group with multiple treatments. Women with untreated CIN had a 1.38 times greater odds of preterm birth compared to women without CIN (95% confidence interval (CI) 1.19 to 1.60;P< 0.001). For women with treated CIN, these odds 2.07 times increased compared to the control group (95% CI 1.85 to 2.33;P< 0.001). Treated women had a 1.51 times increased odds of preterm birth compared to women with untreated CIN (95% CI 1.29 to 1.76;P< 0.001). Independent from cervical disease, a volume excised from the cervix of 0.5 to 0.9 cc increased the odds of preterm birth 2.20 times (37/379 versus 1,002/20,969; 95% CI 1.52 to 3.20;P< 0.001). These odds further increased 3.13 times and 5.93 times for women with an excised volume of 4 to 8.9 cc (90/724 versus 1,002/20,969; 95% CI 2.44 to 4.01;P< 0.001) and ≥9 cc (30/139 versus 1,002/20,969; 95% CI 3.86 to 9.13;P< 0.001), respectively. Limitations of the study include the retrospective nature, lack of sufficient information to calculate odds of preterm birth <24 weeks, and that the excised volume could only be calculated for a select group of women.ConclusionsIn this study, we observed a strong correlation between preterm birth and a volume of ≥0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.

Long-term cervical cancer risk following negative hrHPV-based versus negative cytology-based screening: A population-based study

Randomized trials have shown that hrHPV-testing provides better protection against cervical cancer than cytology. However, long-term assessment of programme sensitivity remains essential. In the Netherlands, hrHPV-screening replaced cytology in 2017. We estimated the long-term cervical cancer risk following negative results in hrHPV- versus cytology-based screening. Screening and histology data from the nationwide Dutch pathology databank (Palga) were used to identify 469,116 women without referral in 2014 (cytology-based) and 362,128 in 2017 (hrHPV-based), representing 4,071,690 person-years. Cervical cancer risk following non-referral, including interval cancers (IC) and those detected in the next screening round were analysed. The incidence rate per 100,000 person-years was 3.3 IC following non-referral in cytology-based versus 2.7 following non-referral in hrHPV-based screening. Including next-round cancers, these numbers increase to 5.7 and 4.5. HrHPV-test negative women had a 50 % lower IC risk compared to those with normal cytology (HR 0.5; 95 % CI: 0.3-0.8), and 60 % lower when including next-round cancers (HR 0.4; 95 % CI: 0.3-0.5). HrHPV-positive women without referral had the highest cancer risk: 24 IC per 100,000 person-years, rising to 45 when including next-round cancers. Their risk was 3.4 times higher than for women with positive primary cytology without referral (HR: 3.4; 95 % CI: 1.1-8.1 for IC and HR: 3.4; 95 % CI: 1.4-8.1 including next-round cancers). A negative hrHPV test was linked to lower long-term risk of cervical cancer than normal cytology, supporting longer screening intervals for hrHPV-negative women. However, hrHPV-positivity with negative cytology was associated with increased risk, suggesting the possible need for alternative triage guidelines.