Low-grade Cervical Abnormalities Research Articles

Hidden mover-stayer model for disease progression accounting for misclassified and partially observed diagnostic tests: Application to the natural history of human papillomavirus and cervical precancer.

Hidden Markov models (HMMs) have been proposed to model the natural history of diseases while accounting for misclassification in state identification. We introduce a discrete time HMM for human papillomavirus (HPV) and cervical precancer/cancer where the hidden and observed state spaces are defined by all possible combinations of HPV, cytology, and colposcopy results. Because the population of women undergoing cervical cancer screening is heterogeneous with respect to sexual behavior, and therefore risk of HPV acquisition and subsequent precancers, we use a mover-stayer mixture model that assumes a proportion of the population will stay in the healthy state and are not subject to disease progression. As each state is a combination of three distinct tests that characterize the cervix, partially observed data arise when at least one but not every test is observed. The standard forward-backward algorithm, used for evaluating the E-step within the E-M algorithm for maximum-likelihood estimation of HMMs, cannot incorporate time points with partially observed data. We propose a new forward-backward algorithm that considers all possible fully observed states that could have occurred across a participant's follow-up visits. We apply our method to data from a large management trial for women with low-grade cervical abnormalities. Our simulation study found that our method has relatively little bias and out preforms simpler methods that resulted in larger bias.

Population-level impact and herd effects following HPV vaccination programs: a global view

Prophylactic HPV-vaccination programs constitute major public-health initiatives worldwide. HPV vaccines have been introduced into national immunization programs in over 80 countries, although most are in high income countries. Now that these vaccines have been implemented just over 10 years, the impact and effectiveness on HPV infection and disease has been reported in various observational studies. Underpinning outcomes, is high coverage of target populations before HPV exposure, as well as those where catchup programs have been initiated. Recently reported are maximal reductions of ∼90% for HPV related infections such as 6/11/16/18, ∼90% for genital warts, ∼45% for low-grade cytological cervical abnormalities, ∼60% for high-grade histologically-proven cervical abnormalities (HSIL), in addition to reductions in colposcopic referrals, plus ablative therapy. With these reductions in HSIL, the positive predictive value of cervical cytology for underlying precancer has reduced: thus countries are adopting more sensitive HPVDNA screening methods. Where catchup programs have extended to high coverage and to up to 26 years of age, herd protection for vaccine-related infections and disease has been seen in unvaccinated women, as well as in similar age males, all from the female only vaccine programs. Modelling suggests that the incremental benefit of vaccinating boys where female coverage is high will be small. However, that does not address gender neutral (male) vaccination.

Adherencia al seguimiento y evolución de la lesión en mujeres con Neoplasia intra epitelial cervical escamosa grado 1

ObjectiveTo determine adherence to follow-up and outcome of lesions in women diagnosed with grade 1 cervical intraepithelial neoplasia (CIN 1). MethodologyThe study included non-pregnant women aged 18 or older, referred for colposcopy, with a colposcopy directed biopsy diagnosis of CIN 1, with no history of prior CIN, hysterectomy or cervical ablative therapy. Participants answered a questionnaire on risk factors, and the outcome of previous cytology and colposcopy was documented. All women should have been followed up for 1 year with cytology and colposcopy every six months. Those who did not have cytology and colposcopy / colposcopy assessments or documented treatments after 15 months were considered as non-adherent. ResultsA total of 40 patients with CIN 1 were included. The loss to follow-up rate of loss was 17/40 (42.5%). The demographic and clinical variables most frequently associated with non-adherence to follow-up were null parity and early initiation of sexual intercourse. The progression of low-grade to high-grade lesion was observed in 4.3%. 22.5% failed Conservative treatment failed conservative treatment and moved to invasive therapy. ConclusionThe rate of loss to follow-up was high, with a considerable referral from conservative to invasive therapy. A large percentage of patients had regression of CIN 1. This study should help clarify the optimal strategies for the treatment of women with low-grade cervical abnormalities in populations of low sociocultural conditions and high risk of cervical cancer.

Outcome of Persistent Low-Grade Cervical Intraepithelial Neoplasia Treated With Loop Electrosurgical Excision Procedure

The aim of the study was to evaluate the outcome of persistent (≥2 years) low-grade cervical intraepithelial neoplasia (CIN 1) treated with loop electrosurgical excision procedure (LEEP). A study of 252 subjects with persistent biopsy-confirmed CIN 1 diagnosed after low-grade squamous intraepithelial lesions or atypical squamous lesions of undetermined significance on Papanicolaou test and treated with LEEP. Post-LEEP follow-up cytological, colposcopic, and molecular diagnostic examinations were scheduled at 6 months, 1 year, and yearly thereafter. The 252 subjects enrolled had a total number of 1,008 visits per colposcopies (median = 3, range = 1-7) during a median post-LEEP follow-up of 25 months (range = 12-121). The cumulative incidence of CIN 2+ at 2 years and at 3 years of follow-up was 2.3% (4/176) and 5.5% (7/128), respectively, or 1.7 cases (95% CI = 1-2.8) per 100 woman-years. Low-grade cervical lesions during post-LEEP follow-up were diagnosed in 70 subjects (27.8%) or 10 cases (95% CI = 7.9-12.6) per 100 woman-years. Overall, persistent and multiple high-risk HPV infections during follow-up were associated with increased rates of CIN persistence or progression. Women with persistent CIN 1 after atypical squamous lesions of undetermined significance/low-grade squamous intraepithelial lesion treated with LEEP had a low rate of progression to CIN 2+ but remained at a high risk of low-grade cervical abnormalities during follow-up. This information should be taken into account when deciding on the treatment strategy and counseling women with persistent CIN 1.

Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience.

Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.

Outcomes of a Decade of Routine Cervical Screening in a Canadian Adolescent Obstetrics Clinic

New recommendations from the Ontario Cervical Cancer Screening Program indicate that initiation of screening should be delayed to age 21. However, there is sparse evidence pertaining to pregnant adolescents. Our objective was to determine whether early cervical cancer screening in pregnant adolescents confers an advantage over delayed screening in the prevention of cervical carcinoma. We conducted a retrospective cohort study of cervical cancer screening in all pregnant adolescents receiving antenatal care through an obstetrics clinic for adolescents between 2000 and 2010. Clinic attendees had an antenatal and/or postpartum Pap smear, with follow-up according to standard recommendations. Results were recorded together with information on regression, persistence, or progression of abnormal cytology, colposcopy referrals, and cervical biopsies. There is a single regional colposcopy clinic. At least one Pap smear result was documented in 365 of the 388 patients. Of these 365 smears, 88 had abnormal cytology, 76 (86.4%) of which were reported as atypical cells of undetermined significance/low-grade squamous intraepithelial lesion, 11 (12.5%) high-grade squamous intraepithelial lesion (HSIL), and one atypical glandular cells (1.1%). Follow-up cytology was available for 78 patients. No patient lost to follow-up had subsequent referrals for colposcopic assessment in the region. Overall, cytologic abnormalities regressed in 75 (96.1%), persisted in two (2.6%), and progressed in one patient (1.3%). Twenty-three patients (of 365) required a total of 68 colposcopy visits and 17 biopsies, but ultimately only three loop electrosurgical excision procedures (LEEPs) and one laser vaporization were performed. Only one LEEP in a 20-year-old demonstrated HSIL. This population of pregnant adolescents had a high incidence of low-grade cervical abnormalities with a high rate of regression. Routinely screening these pregnant adolescents resulted in numerous repeat visits, repeat Pap smears, and colposcopy referrals, and led to patient anxiety and systemic costs. Not a single case of cervical cancer was prevented that would not otherwise have been identified by adherence to the new guidelines.

Patterns of care of women with low-grade cervical cytologic abnormalities

Patterns of care of women with low-grade cervical cytologic abnormalities

Psychosocial Impact of Alternative Management Policies for Low-Grade Cervical Abnormalities: Results from the TOMBOLA Randomised Controlled Trial

BackgroundLarge numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination.MethodsWomen attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20–59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥8) and significant anxiety (≥11; “30-month percentages”). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance.ResultsThere was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80–1.21) or anxiety (OR = 0.97, 95% CI 0.81–1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38–0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54–0.84). Neither anxiety nor depression differed between arms at subsequent time-points.ConclusionsThere was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost.Trial RegistrationControlled-Trials.com ISRCTN 34841617

Cervical Squamocolumnar Junction–specific Markers Define Distinct, Clinically Relevant Subsets of Low-grade Squamous Intraepithelial Lesions

Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.

Association between carotenoids and outcome of cervical intraepithelial neoplasia: a prospective cohort study

It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self-administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78-2.01, p=0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p=0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95% confidence interval (CI) 0.11-0.71, p=0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95% CI 0.24-1.13, p=0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95% CI 0.97-5.42, p=0.058). Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids.

Human papillomavirus infection and the risk of cervical cancer in Japan

Infection with a high-risk human papillomavirus (HPV) is established as a major risk factor for cervical cancer. In Japan, eight HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58) confer a much higher risk of cervical cancer and its immediate premalignant lesions (cervical intraepithelial neoplasia grade 3 [CIN 3]) than do other high-risk and the low-risk HPV types. However, only a small fraction of infected women develop CIN 3 or invasive cervical cancer, suggesting the involvement of additional cofactors in cervical carcinogenesis. A multicenter prospective cohort study of Japanese women with low-grade cervical abnormalities has demonstrated that tobacco smoking is significantly associated with an increased risk of persistent low-grade cervical lesions, while the presence of human leukocyte antigen Class II DRB1*1302 protects against progression to CIN 3. Understanding the epidemiology of HPV infections and cervical cancer may improve prevention and lead to novel clinical management strategies for cervical precursor lesions. Viral and host factors that affect the risk of cervical cancer are discussed in this review.

Do neutralizing antibody responses generated by human papillomavirus infections favor a better outcome of low‐grade cervical lesions?

To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low-grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n = 42), abnormal cytology persisted longer in those positive for HPV 16-specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16-specific neutralizing antibodies (P = 0.03, log-rank test). In women infected with types other than HPV 16 (n = 200), detection of HPV 16-specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low-grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression.

Women's preferences regarding options for management of atypical, borderline and low-grade cervical abnormalities

Women's preferences regarding options for management of atypical, borderline and low-grade cervical abnormalities

What women want. Women’s preferences for the management of low‐grade abnormal cervical screening tests: a systematic review

If human papillomavirus (HPV) testing will replace cytology in primary cervical screening, the frequency of low-grade abnormal screening tests will double. Several available alternatives for the follow-up of low-grade abnormal screening tests have similar outcomes. In this situation, women's preferences have been proposed as a guide for management decisions. To determine women's preferences for the follow-up of low-grade cervical screening abnormalities. Using Medical Subject Headings (MeSH) terms, PubMed was searched for articles published up to December 2010. The reference lists of the retrieved studies were consulted. Studies asking women to state a preference between active follow-up and observation for the management of low-grade abnormalities on screening cytology or HPV tests. Information on study design, participants and outcomes was retrieved using a prespecified form. Studies were sorted by design. Thirteen studies were included in the review. In all five studies that surveyed women with abnormal tests before any management had started, two-thirds preferred active follow-up, predominantly as immediate colposcopy, to observation, predominantly as repeated Pap smears. In all but two studies testing other situations, women more often expressed a preference for active follow-up than for observation; however, women appeared to be somewhat more willing to accept observation if reassured of the low risk of cervical cancer. Even for low-grade abnormal cervical tests, women tend to prefer active management strategies. It may be a challenge to meet their expectations of optimal follow-up when HPV testing is used in primary screening.

Current Views and Practices in the Management of Low-Grade Cervical Abnormalities-Results of a British Society for Colposcopy and Cervical Pathology Study

To determine current views and practice of the management of low-grade cervical abnormalities. A questionnaire survey was distributed to all accredited colposcopists whose details were available on the British Society for Colposcopy and Cervical Pathology database. Of the 1292 colposcopists contacted, 470 responded to the questionnaire. Of these respondents, 57% were obstetricians/gynecologists, 16% were nurse colposcopists, and 12% were gynecological oncologists. Most colposcopists would only advise a woman to undergo treatment of low-grade cytology (atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion) with low-grade colposcopic findings if the disease was persistent for 24 months or more. There was significant diversity in the management between colposcopists working in different medical specialties. Gynecological oncologists and nurse colposcopists were less likely to be influenced by poor compliance (p <.01) or immunosuppression (p <.01) into offering treatment earlier for low-grade disease. Also, community gynecologists were more likely to routinely offer ablative treatment of low-grade disease compared with colposcopists based on secondary care, p <.01. The need for conservative management with low-grade cervical abnormalities and the accurate diagnosis of disease progression seem to be well understood. The reported management of low-grade cervical abnormalities seem to follow the National Health Service Cervical Screening Programme guidelines; however, there is diversity in practice between colposcopists working in different medical specialties.

Immediate colposcopy referral in women with low-grade abnormal results on cervical cytology detects more CIN2 or worse lesions than cytological surveillance in primary care, but might lead to overtreatment

Commentary on: TOMBOLA Group. Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial. BMJ2009;339:b2546.

Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial

Objectives To examine the effectiveness of cytological surveillance in primary care compared with immediate referral for colposcopic examination in women with low grade abnormal results on cervical cytology tests.Design Multicentre...

Options for managing low grade cervical abnormalities detected at screening: cost effectiveness study

Objective To estimate the cost effectiveness of alternative methods of managing low grade cervical cytological abnormalities detected at routine screening.Design Cost analysis within multicentre individually randomised controlled trial.Setting Grampian, Tayside,...

High-Grade Cervical Disease in Adolescents With HIV

Infection by genital types of human papillomavirus (HPV), carcinogenic HPV infection, and cervical cancer precursors all are more frequent in HIV-positive women. HPV infections are particularly common in young women. Young women with HIV are more likely than older subjects to have abnormal Pap test results and to develop incident Pap abnormalities. This study was planned to determine the frequency of high-grade squamous intraepithelial lesions (HSIL) and grade 2 or grade 3 cervical intraepithelial neoplasia (CIN 2,3) in 45 HIV-seropositive and 87 HIV-seronegative women aged 20 years or less. Colposcopy was recommended for all grades of epithelial abnormality. None of the 121 adolescents evaluated had either HSIL or CIN 2,3 when enrolled in this study. During a median follow-up interval of 2.6 years, 8 women (7%) developed high-grade disease. The incidence of HSIL/CIN 2,3 was 2.5 per 100 person-years. The figure was 4.8 per 100 person-years in HIV-seropositive women and 1.6 per 100 person-years in those who were HIV-seronegative. The relative risk was 3.1 with a 95% confidence interval of 0.76 to 12.74. None of the women developed cancer during the study. These findings indicate that, in young, HIV-seropositive women, rapid progression of cervical lesions to high-grade disease is unlikely. This would seem to dictate a policy of observation by cytology and colposcopy rather than preventive treatment of low-grade cervical abnormalities.

Human Papillomavirus testing for the management of low-grade cervical abnormalities in the UK—Influence of age and testing strategy

Background The results of the UK pilot studies were encouraging with respect to the introduction of Human Papillomavirus (HPV) testing as a means to improve the management of low-grade cytological abnormalities. However, several important unresolved issues related to HPV triage remain, two of which are: what type of HPV test should be used and what age group should be targeted. Objectives To perform an evaluation of two commercial HPV detection tests and to correlate disease persistence and clearance with age and HPV status by the two tests. Study design We performed an evaluation of two commercial HPV tests in a cross-sectional analysis of 322 cervical cytology specimens with low-grade abnormalities. A subset of these specimens were then examined longitudinally, in order to correlate disease persistence and clearance with age and HPV status by the two detection tests. Results The two tests performed similarly with respect to the longitudinal identification/prediction of high-grade cervical disease. Age did not appear to be a factor in determining which cases went on to manifest high-grade disease within 3 years of a low-grade result ( p = 0.678). Conclusions This study weakens the case for age-adjusted HPV triage of low-grade cervical abnormalities.