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Trial profile HPV=human papillomavirus. CIN2+=cervical intraepithelial neoplasia grade 2 or worse. *The major reason for women not to be enrolled in our study was lack of time for general practitioners to explain the objectives of the study.
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Treatment of cervical intraepithelial neoplasia
Citations
... Identification of hrHPV as the aetiological factor of CC enabled elaboration of very sensitive molecular technologies which may replace cytology as a primary screening test and potentially provide better outcomes of screening. A number of randomised controlled trials comparing hrHPV testing to cytology, specifically the detection of high grade CIN (CIN 2 + and CIN 3 +), have been executed [22][23][24][25]. Based on meta-analyses, hrHPV primary screening has higher sensitivity than cytology primary screening in detecting precancerous cervical lesions (CIN2 + and CIN3 +), so it gives increased protection against development of CC [2, 26]. ...
... Many triage strategies are being tested, however amongst them, two most common ones can be distinguished. First is based on performing reflex LBC after detection of any hrHPV type (Netherlands) and second uses HPV 16/18 genotyping to identify women with the highest risk for high-grade precancerous lesions and the need for direct referral for colposcopy (Australia, Italy) [22,30]. The Netherlands was the first country to switch to hrHPV screening (January 2017). ...
Background
An Organised Cervical Cancer Screening Programme (OCCSP) was started in Poland in 2006/2007. Each woman aged 25 to 59 is eligible for a free Pap test every 3 years in OCCSP. Despite implementation of the OCCSP, the age-standardised cervical cancer (CC) incidence and mortality rates in 2019 were 7.3/100 000 and 3.9/100 000 respectively and were still higher than those in Western European countries with well-organised screening programmes. Apart from low coverage of the OCCSP, suboptimal performance of the screening test (conventional cytology) may be partially responsible for this situation. Several countries have already incorporated high risk Human Papillomavirus (hrHPV) testing in CC screening as a more sensitive tool reducing the risk of missing precancerous lesions and allowing for extension of screening intervals. The European Guidelines for Quality Assurance in Cervical Cancer Screening recommend pilot evaluation of a new screening test in country-specific conditions before its implementation.
Methods
The HIPPO project (HPV testing In Polish POpulation-based cervical cancer screening program) is a randomised health services study nested in the OCCSP in Poland. The project will randomise 33 000 women aged 30–59 years to cytology or hrHPV testing (ratio: 1:1) with age stratification. In the cytology arm women with repeated Atypical Squamous Cells of Undetermined Significance (ASC-US) or ≥ Low–Grade Squamous Intraepithelial Lesions (LSIL) are referred for colposcopy. In the other arm, hrHPV ( +) women with ≥ ASC-US reflex Liquid-Based Cytology (LBC) are referred for colposcopy. Primary endpoints include detection rates of histologically confirmed high grade intraepithelial lesions or worse (CIN2 +) in each arm.
Discussion
This pilot randomised healthcare study nested in the OCCSP in Poland will assess and compare the performance of hrHPV testing to current standard—cytology in order to make decisions on implementation of HPV-based screening in the country.
Trial registration
This randomised healthcare service study was prospectively registered at https://clinicaltrials.gov/ (identifier: NCT04111835, protocol ID 28/2019) on 19th of September 2019.
... The recognition that a persistent HPV infection is causative for the vast majority of cervical cancers has led to a transition from cytology-based to HPV-based screening programs in an increasing number of countries, either as a stand-alone screening method or in combination with cytology (cotesting) [1,2]. Several large randomized controlled trials comparing HPV-based screening with cytology have shown that HPV-based screening is more effective in detecting CIN 3 in the first screening round with a reduced occurrence of CIN 3 in the second round of screening, thus resulting in earlier detection of clinically relevant precancerous lesions [3][4][5][6][7]. Additionally, a pooled analysis of follow-up data of four European randomized controlled trials demonstrated that HPV-based screening provides 60-70% greater protection against invasive cervical cancer compared with cytology alone [8]. ...
Purpose
According to the recently implemented organized cervical cancer screening program in Germany, women older than 35 years with negative cytology but persistent high-risk human papilloma virus (hrHPV) infection > 12 months should be referred to colposcopy for further evaluation. This study aimed to present and dissect colposcopic and histopathological findings with particular focus on associated hrHPV genotypes.
Methods
This study is a retrospective analysis of clinical data from 89 hrHPV positive patients with normal cytology who underwent colposcopic examination at a certified dysplasia outpatient clinic in Germany in 2021.
Results
While 38 (43%) women had a normal colposcopic finding, 45 (51%) had minor and 6 (7%) major changes. Thirty-one (35%) of the women were HPV 16 and/or HPV 18 positive and 58 (65%) women were positive for other hrHPV only. Among patients who underwent colposcopy with biopsies (in case of an abnormal finding or type 3 transformation zone, n = 68), eight (12%) had cervical intraepithelial neoplasia (CIN) 3 and six (9%) had CIN 2. The proportion of women diagnosed with CIN 3 varied among different hrHPV genotypes (HPV 16: 11%, HPV 18: 33%, HPV 31: 27%, HPV 33: 33%, HPV 52: 33%).
Conclusion
Persistently hrHPV positive women with negative cytology are at increased risk of being diagnosed with CIN 3. As CIN 3 prevalence seems to differ with regard to hrHPV strain, immediate HPV genotyping for risk stratification and subsequent early referral for colposcopy might constitute a feasible strategy.
... Mainly, viral infections are associated with increased genomic instability due to induction of changes at cellular, genetic and epigenetic levels resulting in tumor formation and progression . A growing number of pathogenic infections promote carcinogenesis including, hepatitis B virus (hepatocellular carcinoma) (Poh et al., 2015), human herpesvirus 8 (linked to Kaposi's sarcoma) (Memar et al., 1995), human papillomavirus (cervical carcinoma) (Rijkaart et al., 2012), Epstein-Barr virus and Helicobacter pylori (associated with gastric carcinoma) (Souza et al., 2018), Streptococcus bovis (colorectal carcinoma) (Ellmerich et al., 2000;Krishnan and Eslick, 2014), Salmonella enterica (gastrointestinal cancers) (Mughini-Gras et al., 2018), Chlamydia pneumoniae (lung cancer) (Chaturvedi et al., 2010), human T-cell lymphotropic virus (HTLV-1) (leukemia/lymphoma) (Kataoka et al., 2015) and SV40-Polyomavirus of the rhesus macaque (brain/osteosarcoma) (Mazzoni et al., 2015). Due to the involvement of a large population of pathogens in the tumorigenesis, it is emerging to control the immune responses against invaders (Deretic et al., 2013). ...
Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.
... Randomised trials have shown that cervical screening for high risk human papillomavirus (hrHPV) achieves greater sensitivity than cytology in the detection of cervical intraepithelial neoplasia and greater protection against cervical cancer. [1][2][3][4][5] Because of the enhanced sensitivity, screening intervals can be safely extended. 5 6 However, hrHPV testing has reduced specificity compared with cytology, due to the high prevalence of hrHPV. ...
Objective
To provide the first report on the main outcomes from the prevalence and incidence rounds of a large pilot of routine primary high risk human papillomavirus (hrHPV) testing in England, compared with contemporaneous primary liquid based cytology screening.
Design
Observational study.
Setting
The English Cervical Screening Programme.
Participants
578 547 women undergoing cervical screening in primary care between May 2013 and December 2014, with follow-up until May 2017; 183 970 (32%) were screened with hrHPV testing.
Interventions
Routine cervical screening with hrHPV testing with liquid based cytology triage and two early recalls for women who were hrHPV positive and cytology negative, following the national screening age and interval recommendations.
Main outcome measures
Frequency of referral for a colposcopy; adherence to early recall; and relative detection of cervical intraepithelial neoplasia grade 2 or worse from hrHPV testing compared with liquid based cytology in two consecutive screening rounds.
Results
Baseline hrHPV testing and early recall required approximately 80% more colposcopies, (adjusted odds ratio 1.77, 95% confidence interval 1.73 to 1.82), but detected substantially more cervical intraepithelial neoplasia than liquid based cytology (1.49 for cervical intraepithelial neoplasia grade 2 or worse, 1.43 to 1.55; 1.44 for cervical intraepithelial neoplasia grade 3 or worse, 1.36 to 1.51) and for cervical cancer (1.27, 0.99 to 1.63). Attendance at early recall and colposcopy referral were 80% and 95%, respectively. At the incidence screen, the 33 506 women screened with hrHPV testing had substantially less cervical intraepithelial neoplasia grade 3 or worse than the 77 017 women screened with liquid based cytology (0.14, 0.09 to 0.23).
Conclusions
In England, routine primary hrHPV screening increased the detection of cervical intraepithelial neoplasia grade 3 or worse and cervical cancer by approximately 40% and 30%, respectively, compared with liquid based cytology. The very low incidence of cervical intraepithelial neoplasia grade 3 or worse after three years supports extending the screening interval.
... In recent years, HPV DNA tests (hereafter HPV test or testing) capable of identifying high-risk HPV types have been developed. Multiple studies have shown that HPV testing is more sensitive than cytology in detecting cervical intraepithelial neoplasia in primary cervical cancer screening (hereafter primary screening) (Bulkmans et al., 2007;Naucler et al., 2007;Ronco et al., 2010;Anttila et al., 2010) and has similar specificity compared to Pap testing in women aged 30 and older (Rijkaart et al., 2012). Overwhelming evidence suggests that a negative HPV test provides more reassurance to a woman that she is at low-risk for cervical lesions than a negative Pap test and supports the extension of intervals in primary screening beyond 5 years (Franco et al., 2009;Crosbie et al., 2013;Ronco et al., 2014). ...
Primary screening for cervical cancer is transitioning from the longstanding Pap smear towards implementation of an HPV-DNA test, which is more sensitive than Pap cytology in detecting high-risk lesions and offers greater protection against invasive cervical carcinomas. Based on these results, many countries are recommending and implementing HPV testing-based screening programs. Understanding what factors (e.g., knowledge, attitudes) will impact on HPV test acceptability by women is crucial for ensuring adequate public health practices to optimize cervical screening uptake. We used mixed methods research synthesis to provide a categorization of the relevant factors related to HPV primary screening for cervical cancer and describe their influence on women's acceptability of HPV testing. We searched Medline, Embase, PsycINFO, CINAHL, Global Health and Web of Science for journal articles between January 1, 1980 and October 31, 2017 and retained 22 empirical articles. Our results show that while most factors associated with HPV test acceptability are included in the Health Belief Model and/or Theory of Planned Behavior (e.g., attitudes, knowledge), other important factors are not encompassed by these theoretical frameworks (e.g., health behaviors, negative emotional reactions related to HPV testing). The direction of influence of psychosocial factors on HPV test acceptability was synthesized based on 14 quantitative studies as: facilitators (e.g., high perceived HPV test benefits), barriers (e.g., negative attitudes towards increased screening intervals), contradictory evidence (e.g., sexual history) and no impact (e.g., high perceived severity of HPV infection). Further population-based studies are needed to confirm the impact of these factors on HPV-based screening acceptability.
... These results support the use of hrHPV DNA testing for pri- mary cervical screening, leading to recommendations from the US, Australia, and Europe to implement HPV screening in nation- wide programs (20)(21)(22). In the US, screening guidelines provided by the American College of Obstetricians and Gynecologists (23) and the U.S. Preventive Services Task Force (USPSTF) (24) rec- ommend women visit their healthcare provider every 3-5 years, depending on age and risk factors, for a Pap smear, often with HPV co-testing. ...
In most industrialized countries, screening programs for cervical cancer have shifted from cytology (Pap smear or ThinPrep) alone on clinician-obtained samples to the addition of screening for human papillomavirus (HPV), its main causative agent. For HPV testing, self-sampling instead of clinician-sampling has proven to be equally accurate, in particular for assays that use nucleic acid amplification techniques. In addition, HPV testing of self-collected samples in combination with a follow-up Pap smear in case of a positive result is more effective in detecting precancerous lesions than a Pap smear alone. Self-sampling for HPV testing has already been adopted by some countries, while others have started trials to evaluate its incorporation into national cervical cancer screening programs. Self-sampling may result in more individuals willing to participate in cervical cancer screening, because it removes many of the barriers that prevent women, especially those in low socioeconomic and minority populations, from participating in regular screening programs. Several studies have shown that the majority of women who have been underscreened but who tested HPV-positive in a self-obtained sample will visit a clinic for follow-up diagnosis and management. In addition, a self-collected sample can also be used for vaginal microbiome analysis, which can provide additional information about HPV infection persistence as well as vaginal health in general.
... Cervical screening is changing globally from a cytology based approach to the molecular detection of hrHPV types [6][7][8][9]. While the sensitivity of hrHPV testing for CIN2+ has been demonstrated, the specificity of hrHPV testing to detect disease is sub-optimal. ...
Background:
The ability to distinguish which hrHPV infections predispose to significant disease is ever more pressing as a result of the increasing move to hrHPV testing for primary cervical screening. A risk-stratifier or "triage" of infection should ideally be objective and suitable for automation given the scale of screening.
Results:
CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL12 emerged as the strongest, candidate biomarkers to detect underlying disease [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)]. For CIN2+, CCL2 had the highest area under the curve (AUC) of 0.722 with a specificity of 82%. A combined biomarker panel of six chemokines CCL2, CCL3, CCL4, CXCL1, CXCL8, and CXCL12 provides a sensitivity of 71% and specificity of 67%.
Conclusion:
The present work demonstrates that the levels of five chemokine-proteins are indicative of underlying disease. We demonstrate technical feasibility and promising clinical performance of a chemokine-based biomarker panel, equivalent to that of other triage options. Further assessment in longitudinal series is now warranted.
Methods:
A panel of 31 chemokines were investigated for expression in routinely taken archived and prospective cervical liquid based cytology (LBC) samples using Human Chemokine Proteomic Array kit. Nine chemokines were further validated using Procartaplex assay on the Luminex platform.
... 5 When cytology and HPV tests are used together (co-testing), sensitivity approaches 100 %, 6 and the 5year risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) after a negative co-test is far below that with negative cytology alone, supporting longer testing intervals. 7,8 For this age group, multiple organizations now recommend co-testing every 5 years as an alternative to cytology. 5,[9][10][11] The American Cancer Society, The American Society of Colposcopy and Cervical Pathology (ASCCP) and the American Society of Clinical Pathology recommend co-testing as a Bpreferredŝ creening strategy, 5 although the appropriateness of this recommendation has been questioned. ...
... An additional cytology test after 6 to 12 months decreased the risk to less than 1%, which seemed an acceptable strategy when considering the risk of CIN 3+. 23 In the United States, a positive result for either HPV 16 or 18 was found to bear a CIN 3+ risk high enough to justify direct referral to colposcopy, skipping cytology triaging. 24 In conclusion, our data suggest that cytology interpreted with prior knowledge of the HPV status is more sensitive than blinded cytology. ...
Objectives: This study aimed to evaluate the influence of prior knowledge of human papillomavirus (HPV) status in cervical cytopathology readings. Methods: Participants comprised 2,376 women who underwent parallel cytology and HPV-DNA testing. Smears were read twice by the same team, first with previous knowledge of HPV-DNA status. Results: Overall, 239 (10.2%) smears had their cytology classification altered by the HPV-informed review. Cytology readings with prior knowledge of the HPV status revealed 10.5% of abnormal smears (atypical squamous cells of undetermined significance or higher), while without prior knowledge, this rate dropped to 7.6%. When HPV status was informed, a significant increase in all categories of altered smears was observed. Cytology with prior knowledge of HPV status detected more cervical intraepithelial neoplasia grade 2 or higher (CIN 2+) compared with blinded: 86.7% vs 60.0%. Conclusions: Our data indicate that cytology interpreted with prior knowledge of the HPV status provides higher sensitivity for CIN 2+ lesions while marginally reducing the overall specificity compared with HPV status blinded cytology. Cervical cancer (CC) remains the most important human papillomavirus (HPV)-related human cancer, with an estimated 530,000 new cases and 275,000 deaths annually. 1 Cytology-based CC screening was introduced in the early 1950s and has led to substantial reductions in CC incidence and mortality, but it is well recognized that the interpretation of cervical cytology is relatively subjective and associated with high rates of interobserver and intraobserver variability. A single test has low sensitivity, of approximately 50% to 70%, requiring repeat testing throughout women's lives, bringing complexity and costs to the strategy. 2 Cytology laboratories are constantly making efforts to improve screening for the provision of better patient care, moving beyond the Papanicolaou (Pap) test. 3 In the past decade, new and more effective technologies for cervical cancer control have emerged-namely, molecular testing for HPV, which was demonstrated to have great efficacy in large randomized screening trials, 4,5 and liquid-based cytology (LBC), addressed to reduce cells' overlapping and artifacts of preparation, potentially improving results while providing some practical advantages (eg, quicker interpretation, ancillary molecular testing). 6,7 In addition, LBC analysis guided by a computerized system can select fields of view that facilitate the recognition of abnormal cells, potentially reducing the false-negative rates. 8 In Brazil, the SUS (Public Unified Health System) recommends cytology-based CC screening, conducted with a 3-year interval after two consecutive annual negative examinations for women aged between 25 and 64 years. For several reasons, estimates of cancer incidence and mortality Downloaded from https://academic.oup.com
... An additional cytology test after 6 to 12 months decreased the risk to less than 1%, which seemed an acceptable strategy when considering the risk of CIN 3+. 23 In the United States, a positive result for either HPV 16 or 18 was found to bear a CIN 3+ risk high enough to justify direct referral to colposcopy, skipping cytology triaging. 24 In conclusion, our data suggest that cytology interpreted with prior knowledge of the HPV status is more sensitive than blinded cytology. ...
Objectives: This study aimed to evaluate the influence of prior knowledge of human papillomavirus (HPV) status in cervical cytopathology readings. Methods: Participants comprised 2,376 women who underwent parallel cytology and HPV-DNA testing. Smears were read twice by the same team, first with previous knowledge of HPV-DNA status. Results: Overall, 239 (10.2%) smears had their cytology classification altered by the HPV-informed review. Cytology readings with prior knowledge of the HPV status revealed 10.5% of abnormal smears (atypical squamous cells of undetermined significance or higher), while without prior knowledge, this rate dropped to 7.6%. When HPV status was informed, a significant increase in all categories of altered smears was observed. Cytology with prior knowledge of HPV status detected more cervical intraepithelial neoplasia grade 2 or higher (CIN 2+) compared with blinded: 86.7% vs 60.0%. Conclusions: Our data indicate that cytology interpreted with prior knowledge of the HPV status provides higher sensitivity for CIN 2+ lesions while marginally reducing the overall specificity compared with HPV status blinded cytology. Cervical cancer (CC) remains the most important human papillomavirus (HPV)-related human cancer, with an estimated 530,000 new cases and 275,000 deaths annually. 1 Cytology-based CC screening was introduced in the early 1950s and has led to substantial reductions in CC incidence and mortality, but it is well recognized that the interpretation of cervical cytology is relatively subjective and associated with high rates of interobserver and intraobserver variability. A single test has low sensitivity, of approximately 50% to 70%, requiring repeat testing throughout women's lives, bringing complexity and costs to the strategy. 2 Cytology laboratories are constantly making efforts to improve screening for the provision of better patient care, moving beyond the Papanicolaou (Pap) test. 3 In the past decade, new and more effective technologies for cervical cancer control have emerged-namely, molecular testing for HPV, which was demonstrated to have great efficacy in large randomized screening trials, 4,5 and liquid-based cytology (LBC), addressed to reduce cells' overlapping and artifacts of preparation, potentially improving results while providing some practical advantages (eg, quicker interpretation, ancillary molecular testing). 6,7 In addition, LBC analysis guided by a computerized system can select fields of view that facilitate the recognition of abnormal cells, potentially reducing the false-negative rates. 8 In Brazil, the SUS (Public Unified Health System) recommends cytology-based CC screening, conducted with a 3-year interval after two consecutive annual negative examinations for women aged between 25 and 64 years. For several reasons, estimates of cancer incidence and mortality Downloaded from https://academic.oup.com
