Diede L. Loopik

The relative risk of noncervical high‐risk human papillomavirus‐related (pre)malignancies after recurrent cervical intraepithelial neoplasia grade 3: A population‐based study

Women with cervical intraepithelial neoplasia grade 3 (CIN3) have a long‐lasting increased risk for noncervical high‐risk human papillomavirus (hrHPV)‐related (pre)malignancies. The aim of our study was to estimate this risk in women with recurrent CIN3 compared to women without a history of CIN3 and women with a single episode of CIN3. Women with a CIN3 diagnosis between 1990 and 2010 were obtained from the Dutch Pathology Registry (PALGA) and matched with a control group of women without CIN3. Analysis has been conducted in a subset of women with recurrent CIN3, defined as reoccurrence minimally 2 years post‐treatment. Cases of noncervical hrHPV‐related (pre)malignancies of the anus, vulva, vagina and oropharynx were identified until 2015 and incidence rate ratios (IRRs) were estimated. Then, 1,797 women with recurrent CIN3 were included with a median age of 34 years (range 18–76) and 31,594 person‐years of follow‐up. Women with recurrent CIN3 had an increased risk of developing noncervical hrHPV‐related (pre)malignancies compared to women without CIN3 with an IRR of 25.96 (95%CI 6.32–106.58). The IRR was 2.48 (95% CI 1.87–3.30) compared to women with a single episode of CIN3. Studies on posttreatment follow‐up and prophylactic hrHPV vaccination are warranted.

Benefit and burden in the Dutch cytology-based vs high-risk human papillomavirus-based cervical cancer screening program

In 2017, the Dutch cervical cancer screening program had replaced the primary cytology-based screening with primary high-risk human papillomavirus-based screening, including the opportunity to participate through self-sampling. Evaluation and balancing benefit (detection of high-grade cervical intraepithelial neoplasia) and burden of screening (unnecessary referrals, invasive diagnostics, and overtreatment) is needed. This study aimed to compare the referral rates, detection of high-grade cervical intraepithelial neoplasia, overdiagnosis, and overtreatment in the new high-risk human papillomavirus-based screening program, including physician-sampled and self-sampled material, with the previous cytology-based screening program in the Netherlands. A retrospective cohort study was conducted within the Dutch population-based cervical cancer screening program. Screenees with referrals for colposcopy between 2014 and 2015 (cytology-based screening) and 2017 and 2018 (high-risk human papillomavirus-based screening) were included. Data were retrieved from the Dutch Pathology Registry (PALGA) and compared between the 2 screening programs. The main outcome measures were referral rate, detection of high-grade cervical intraepithelial neoplasia or worse, overdiagnosis (cervical intraepithelial neoplasia grade 1 or less in the histologic specimen), and overtreatment (cervical intraepithelial neoplasia grade 1 or less in the treatment specimen). Of the women included in the study, 19,109 received cytology-based screening, and 26,171 received high-risk human papillomavirus-based screening. Referral rates increased from 2.5% in cytology-based screening to 4.2% in high-risk human papillomavirus-based screening (+70.2%). Detection rates increased to 46.2% for cervical intraepithelial neoplasia grade 2 or worse, 32.2% for cervical intraepithelial neoplasia grade 3 or worse, and 31.0% for cervical cancer, and overdiagnosis increased to 143.4% with high-risk human papillomavirus-based screening. Overtreatment rates were similar in both screening periods. The positive predictive value of referral for detection of cervical intraepithelial neoplasia grade 2 or worse in high-risk human papillomavirus-based screening was 34.6% compared with 40.2% in cytology-based screening. Women screened through self-sampling were at higher risk of cervical intraepithelial neoplasia grade 2 or worse detection (odds ratio, 1.38; 95% confidence interval, 1.20-1.59) and receiving treatment (odds ratio, 1.31; 95% confidence interval, 1.16-1.48) than those screened through physician-sampling. Compared with cytology-based screening, high-risk human papillomavirus-based screening increases detection of high-grade cervical intraepithelial neoplasia, with 462 more cervical intraepithelial neoplasia grade 2 or worse cases per 100,000 women but at the expense of 850 more cases per 100,000 women with invasive diagnostics indicating cervical intraepithelial neoplasia grade 1 or less.

RNA-based high-risk HPV genotyping and identification of high-risk HPV transcriptional activity in cervical tissues

Nearly all cervical cancers are initiated by a persistent infection with one of the high-risk human papillomaviruses (high-risk HPV). High-risk HPV DNA testing is highly sensitive but cannot distinguish between active, productive infections and dormant infections or merely deposited virus. A solution for this shortcoming may be the detection of transcriptional activity of viral oncogenes instead of mere presence of high-risk HPVs. In this study, fresh-frozen cervical tissues (n = 22) were subjected to high-risk HPV DNA detection using the line probe assay and to targeted RNA next-generation sequencing using single-molecule molecular inversion probes. Targeted RNA sequencing was applied for (1) RNA-based genotyping of high-risk HPV, giving information on specific HPV-subtype (2) discrimination of E2, E6, and E7 transcripts and (3) discovery of possible non-HPV cancer biomarkers. Data were analyzed using computational biology. Targeted RNA sequencing enabled reliable genotyping of high-risk HPV subtypes and allowed quantitative detection of E2, E6, and E7 viral gene expression, thereby discriminating cervical lesions from normal cervical tissues. Moreover, targeted RNA sequencing identified possible cervical cancer biomarkers other than high-risk HPV. Interestingly, targeted RNA sequencing also provided high-quality transcription profiles from cervical scrape samples, even after 1 week of dry storage or storage in Preservcyt fixative. This proof of concept study shows that targeted RNA sequencing can be used for high-risk HPV genotyping and simultaneous detection of high-risk HPV gene activity. Future studies are warranted to investigate the potential of targeted RNA sequencing for risk assessment for the development of cervical lesions, based on molecular analysis of cervical scrapes.

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.