This short review outlines our understanding of cervical cancer precursors, concentrating on the central etiologic role of persistent human papillomavirus infection. The stages of cervical ...carcinogenesis are better understood than for most other major cancers, providing a successful cancer etiology and prevention model.
Highlights • Evidence suggests that primary HPV testing can be more effective than cytology. • Additional triage tests are needed to decide who among the HPV-positive women requires further ...management or treatment. • Evaluation of triage test candidates is based on absolute risk estimates compared to established clinical action thresholds. • An optimal integrated screening and triage strategy should reassure the vast majority of women that they are at very low risk of cervical cancer while sending the women at highest risk to colposcopy and treatment.
Human papillomavirus (HPV) infection of the genital tract is very common and normally follows a benign clinical course; however,
in an unfortunate minority of infected individuals, it can cause ...disease that sometimes leads to cancer. It is accepted that
HPV DNA testing has a role in the management of cervical disease both in a prevaccination and postvaccination era; however,
to improve the specificity of this approach, there is a requirement to develop and validate tools/assays that can identify
women at risk for progressive disease. There is evidence to suggest that detection of viral gene expression both directly
and indirectly may constitute a more specific approach for delineating clinically significant infection compared with HPV
DNA–based assays. HPV oncogene expression and evidence of its deregulation can be monitored through direct detection of viral
mRNA transcripts or through detection of the cellular protein p16. For both approaches, commercial assays have been introduced
and numerous studies have been conducted. The present article describes the scientific theory underpinning these approaches,
their amenability to routine-diagnostic specimens/settings, and the clinical data that has been garnered through their application
thus far. Currently, there is promising data indicating that HPV mRNA and p16 might play an important role in future cervical
cancer screening scenarios. Still, large randomized studies are necessary to confirm the preliminary data.
Methods: PubMed and OVID were interrogated with search terms “HPV RNA;” “HPV mRNA;” “HPV transcript—detection, testing, and
methods;” “p16” AND “cervical cancer;” “p16” AND “CIN;” “p16” AND “histology”; “p16” AND “cytology;” “p16;” and “screening.”
(Cancer Epidemiol Biomarkers Prev 2008;17(10):2536–45)
Uterine corpus cancer incidence rates have been projected to increase, a prediction often attributed to the obesity epidemic. However, correct estimation of these rates requires accounting for ...hysterectomy prevalence, which varies by race, ethnicity, and region. Here, we evaluated recent trends in hysterectomy-corrected rates by race and ethnicity and histologic subtype and estimated differences in relative survival by race and ethnicity, subtype, and stage.
We estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System. Hysterectomy-corrected age-standardized uterine corpus cancer incidence rates from 2000 to 2015 were calculated from the SEER 18 registries. Incidence rates and trends were estimated separately by race and ethnicity, region, and histologic subtype. Five-year relative survival rates were estimated by race and ethnicity, histologic subtype, and stage.
Hysterectomy-corrected incidence rates of uterine corpus cancer were similar among non-Hispanic whites and blacks and lower among Hispanics and Asians/Pacific Islanders. Endometrioid carcinoma rates were highest in non-Hispanic whites, whereas nonendometrioid carcinoma and sarcoma rates were highest in non-Hispanic blacks. Hysterectomy-corrected uterine corpus cancer incidence increased among non-Hispanic whites from 2003 to 2015 and among non-Hispanic blacks, Hispanics, and Asians/Pacific Islanders from 2000 to 2015. Overall incidence rates among non-Hispanic blacks surpassed those of non-Hispanic whites in 2007. Endometrioid carcinoma rates rose among non-Hispanic blacks, Hispanics, and Asians/Pacific Islanders but were stable among non-Hispanic whites; however, nonendometrioid carcinoma rates rose significantly among all women. Non-Hispanic blacks had the lowest survival rates, irrespective of stage at diagnosis or histologic subtype.
Among all women, rates of nonendometrioid subtypes have been rising rapidly. Our analysis shows profound racial differences and disparities indicated by higher rates of nonendometrioid subtypes and poorer survival among non-Hispanic black women.
The COVID-19 pandemic has a major impact on a wide range of health outcomes. Disruptions of elective health services related to cervical screening, management of abnormal screening test results, and ...treatment of precancers, may lead to increases in cervical cancer incidence and exacerbate existing health disparities. Modeling studies suggest that a short delay of cervical screening in subjects with previously negative HPV results has minor effects on cancer outcomes, while delay of management and treatment can lead to larger increases in cervical cancer. Several approaches can mitigate the effects of disruption of cervical screening and management. HPV-based screening has higher accuracy compared to cytology, and a negative HPV result provides longer reassurance against cervical cancer; further, HPV testing can be conducted from self-collected specimens. Self-collection expands the reach of screening to underserved populations who currently do not participate in screening. Self-collection and can also provide alternative screening approaches during the pandemic because testing can be supported by telehealth and specimens collected in the home, substantially reducing patient-provider contact and risk of COVID-19 exposure, and also expanding the reach of catch-up services to address backlogs of screening tests that accumulated during the pandemic. Risk-based management allows prioritizing management of patients at highest risk of cervical cancer while extending screening intervals for those at lowest risk. The pandemic provides important lessons for how to make cervical screening more resilient to disruptions and how to reduce cervical cancer disparities that may be exacerbated due to disruptions of health services.
•The pandemic increases disparities in cervical cancer prevention.•HPV self-sampling can extend the reach of cervical screening.•Screening and management visits should be prioritized by risk.•The pandemic provides an opportunity to make cervical screening more resilient.
Purpose
The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are inconclusive.
Methods
...We conducted a systematic review and meta-analysis of studies reporting associations between statin use and ovarian cancer risk in PubMed. Summary risk ratios (RRs) and confidence intervals (CIs) were calculated. Subgroup analyses by cancer histotype, statin class (lipo- or hydrophilic) and duration of statin use were conducted. Use of individual statins in populations was assessed to determine population-specific differences in statin types.
Results
Nine studies with 435,237 total women were included (1 randomized controlled trial (RCT); 4 prospective; 4 case–control). Statin use was associated with a reduced risk of ovarian cancer (RR 0.87, 95% CI 0.74–1.03) and risk was significantly reduced in populations with low pravastatin use (RR 0.83, 95% CI 0.70–0.99). Risk estimates varied by statin class (3 studies; lipophilic: RR 0.88, 95% CI 0.69–1.12; hydrophilic: RR 1.06, 95% CI 0.72–1.57) and cancer histotype (3 studies; serous: RR 0.95, 95% CI 0.69–1.30; clear cell: RR 1.17, 95% CI 0.74–1.86). Long-term use was associated with a reduced risk of ovarian cancer (RR 0.77, 95% CI 0.54–1.10) that further reduced when pravastatin use was low (RR 0.68, 95% CI 0.46–1.01). Between-study heterogeneity was high overall and in subgroups (
I
2
> 60%).
Conclusion
Statins may be associated with a reduced risk of ovarian cancer, but the effect likely differs by individual statin, duration of use and cancer histotype. Additional well-powered studies are needed to elucidate important subgroup effects.
Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates ...precancer for all 12 carcinogenic HPV types has not been evaluated.
In this nested case-control study, we tested up to 30 cases of precancer cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma
(AIS) and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies.
Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives.
HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women.
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Human papillomavirus vaccination and cervical screening are lacking in most lower resource settings, where approximately 80% of more than 500 000 cancer cases occur annually. Visual inspection of the ...cervix following acetic acid application is practical but not reproducible or accurate. The objective of this study was to develop a "deep learning"-based visual evaluation algorithm that automatically recognizes cervical precancer/cancer.
A population-based longitudinal cohort of 9406 women ages 18-94 years in Guanacaste, Costa Rica was followed for 7 years (1993-2000), incorporating multiple cervical screening methods and histopathologic confirmation of precancers. Tumor registry linkage identified cancers up to 18 years. Archived, digitized cervical images from screening, taken with a fixed-focus camera ("cervicography"), were used for training/validation of the deep learning-based algorithm. The resultant image prediction score (0-1) could be categorized to balance sensitivity and specificity for detection of precancer/cancer. All statistical tests were two-sided.
Automated visual evaluation of enrollment cervigrams identified cumulative precancer/cancer cases with greater accuracy (area under the curve AUC = 0.91, 95% confidence interval CI = 0.89 to 0.93) than original cervigram interpretation (AUC = 0.69, 95% CI = 0.63 to 0.74; P < .001) or conventional cytology (AUC = 0.71, 95% CI = 0.65 to 0.77; P < .001). A single visual screening round restricted to women at the prime screening ages of 25-49 years could identify 127 (55.7%) of 228 precancers (cervical intraepithelial neoplasia 2/cervical intraepithelial neoplasia 3/adenocarcinoma in situ AIS) diagnosed cumulatively in the entire adult population (ages 18-94 years) while referring 11.0% for management.
The results support consideration of automated visual evaluation of cervical images from contemporary digital cameras. If achieved, this might permit dissemination of effective point-of-care cervical screening.
Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this ...EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow‐up data; the existence of an HR‐HPV‐positive, cytology‐negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual‐staining with p16/Ki67 can mitigate inter‐operator/‐site disparities, clinician‐taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self‐taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.
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