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• W3138281336 abstract "Cervical cancer remains the fourth most common cancer among women worldwide, accounting for more than 500 000 new cases annually. Cervical cancer can be effectively prevented through screening, which allows for detection and treatment of precursor lesions, thereby preventing their progression to cancer. Following the introduction of Papanicolaou smear cytology-based screening (and later liquid-based cytology [LBC]), cervical cancer incidence and mortality declined dramatically, and several studies have demonstrated that regular screening is associated with an 80%-90% reduced risk of cervical cancer and death from the disease.1 Acknowledging the central role of human papillomavirus (HPV) in the natural history of cervical cancer, many well-established screening programs in high-income countries are transitioning from morphology-based LBC to molecular HPV-based screening. Large randomized controlled trials and observational studies have demonstrated that HPV-based screening is significantly more sensitive for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+ compared with screening with cytology.2 A single HPV-negative test provides greater reassurance against CIN2+ and CIN3+ than a single normal cervical LBC, safely enabling longer intervals between screening tests.2 Furthermore, HPV-based screening is superior to LBC for detecting glandular lesions (ie, adenocarcinoma in situ) and for screening older women. Taken together, these findings suggest that HPV-based screening has the potential to prevent more cervical cancers and deaths from the disease compared with cytology-based screening. However, the downside of HPV-based screening is its low specificity for CIN2+ detection, resulting in a higher number of false-positive screens compared with cytology-based screening.2 The underlying reason for the lower specificity is that many HPV infections are only transiently detected and these short-duration detections are associated with a low 5- to 10-year risk of CIN2+. To improve the specificity of HPV-based screening and reduce the number of unnecessary colposcopies, different triage strategies have been explored. One of the most commonly used triage strategies is cytology, with atypical squamous cells of undetermined significance being the typical threshold for referral. Other triage strategies include the use of partial or complete HPV genotyping of cervical samples, as several studies have demonstrated a significant difference in risk of CIN2+ across genotypes, with HPV type 16 being associated with the highest risk of CIN2+.3 Depending on the selection of the test, further risk-stratification by genotype may be possible. This may be of clinical value because some non-HPV-16/18 types, such as HPV-31 and HPV-33, are associated with higher risk of CIN2+ compared with others (ie, HPV-66 and HPV-52). Choosing which triage strategy to use is challenging and depends on several factors. Ideally, you would want a triage strategy that is cheap, associated with high reproducibility, and increases the specificity for CIN2+ detection without compromising sensitivity. However, in practice substantial improvement in specificity almost always comes at a cost in the overall screening sensitivity. As a result, most countries balance the sensitivity/specificity trade-off when choosing a triage strategy, such as recommending a threshold for referral of atypical squamous cells of undetermined significance or worse. There is no universally “correct” choice; the appropriate balance is made based on the risk tolerance for missing cervical cancer cases and resource availability in each setting and health system. Choosing a strategy that maximizes sensitivity at the cost of specificity will miss fewer cases, but will increase the colposcopy and management burden. Alternatively, strategies that maximize specificity will reduce management burden in colposcopy clinics and increased surveillance of test-positive/disease-negative women at the expense of missing disease. The natural history of HPV and cervical cancer guides the age ranges recommended for HPV testing in routine cervical screening (30-65 years). HPV testing is typically not recommended for women under the age of 30 years, because the infections detected within the first several years after sexual debut are mostly transient with a very low risk of progressing to invasive cancer in the next 5-10 years. Screening women under age 30 years, typically starting at ages 21-25 years, is recommended using standard LBC methods. Screening during midlife is more likely to detect persistent or uncontrolled infections, which have a higher risk of progression to neoplasia. However, when counseling women screening positive for HPV, it is important to emphasize that the HPV test is just a “trigger” for the need to rule out disease with a more detailed colposcopic examination. In fact, most HPV detected in screening (like most ASC-US and low-grade squamous intra-epithelial lesion cytology or CIN1 histology) will not result in a CIN2+ diagnosis and will return to normal within 1-2 years. However, women with HPV that persists for more than 2 years without a diagnosis of neoplasia should be carefully evaluated, particularly if occurring in postmenopausal women where the epithelium is often atrophic and the transformation zone is retracted into the cervical canal. In these older women, sensitivity of cytology triage is low, suggesting a need for better triage strategies to identify the women at greatest risk of disease, including diagnostic cone biopsy in the case of persistent infection lasting ≥2 years. Given the significant decline in HPV-16-positive and HPV-18-positive cervical cancers with increasing age,4 performing risk stratification in older women using partial genotyping should be used with caution in the case of persistent non-HPV-16 or HPV-18 high-risk infection. Finally, it is important that clinicians are prepared for changes in disease prevalence and resource utilization associated with a switch from cytology-based screening once every 3 years to HPV-based screening every 5 years. For example, because of its higher sensitivity, HPV-based screening will identify lesions that have been missed in women attending cytology screening programs (if an appropriate threshold for referral is selected). This is supported by several studies reporting an increased risk of CIN2+ detection following the first HPV-based screening round or upon implementation of primary HPV screening.5, 6 This is also expected to result in an increased number of women in need of referral, subsequent treatment, and more intensive follow-up screening, and gynecology departments should anticipate and prepare for the increased burden of screening referrals, which will fluctuate with time in the initial decade following the program change.7 In subsequent screening rounds, the difference in detection rates for CIN2+ and colposcopy referrals between screening groups levels out. Furthermore, clinicians should be aware that risk of CIN2+ differs by duration of HPV infection, with risks being higher among women with prevalent versus newly detected infection. Given that most women entering HPV-based screening will have no record of previous HPV test results, it will be impossible to determine whether an infection is prevalent or newly detected. However, analysis of 15 years of HPV screening experience in the USA suggests that risk of CIN2+ in HPV-positive women with no previous information on HPV status (first ever test) is significantly higher compared with women with a documented HPV-negative test result, suggesting detection of a “prevalent persistent” infection at the initial screen.5 In summary, HPV-based screening is more sensitive but less specific for CIN2+ and CIN3+ detection compared with cytology. Therefore, triage is needed to separate the women in need of referral from those who can safely undergo repeat testing. Selecting which triage strategy to use and threshold for referral is a trade-off between sensitivity and specificity. Upon implementation, clinicians should be aware that CIN2+ and CIN3+ detection rates and colposcopy referrals might increase temporarily. The authors want to thank Professor Berit Andersen, Department of Public Health Programs, Randers Regional Hospital, Denmark, for commenting on the Editorial." @default.
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• W3138281336 date "2021-03-01" @default.
• W3138281336 modified "2023-09-23" @default.
• W3138281336 title "Clinical implications of transitioning from cytology to human papillomavirus‐based cervical cancer screening" @default.
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• W3138281336 doi "https://doi.org/10.1111/aogs.14107" @default.
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