High-grade Precancerous Cervical Lesions Research Articles

HPV Vaccination and the Risk of Invasive Cervical Cancer

(Abstracted from N Engl J Med 2020;383:1340–1348) Because of the well-established association between oncogenic types of human papillomavirus (HPV) and cervical cancer, as of December 2019 a total of 124 countries and territories had implemented HPV vaccination programs. Studies have demonstrated that HPV vaccination protects against HPV infection, genital warts, and high-grade precancerous cervical lesions.

Low-cost, high-resolution imaging for detecting cervical precancer in medically-underserved areas of Texas

ObjectiveCervical cancer rates in the United States have declined since the 1940's, however, cervical cancer incidence remains elevated in medically-underserved areas, especially in the Rio Grande Valley (RGV) along the Texas-Mexico border. High-resolution microendoscopy (HRME) is a low-cost, in vivo imaging technique that can identify high-grade precancerous cervical lesions (CIN2+) at the point-of-care. The goal of this study was to evaluate the performance of HRME in medically-underserved areas in Texas, comparing results to a tertiary academic medical center. MethodsHRME was evaluated in five different outpatient clinical settings, two in Houston and three in the RGV, with medical providers of varying skill and training. Colposcopy, followed by HRME imaging, was performed on eligible women. The sensitivity and specificity of traditional colposcopy and colposcopy followed by HRME to detect CIN2+ were compared and HRME image quality was evaluated. Results174 women (227 cervical sites) were included in the final analysis, with 12% (11% of cervical sites) diagnosed with CIN2+ on histopathology. On a per-site basis, a colposcopic impression of low-grade precancer or greater had a sensitivity of 84% and a specificity of 45% to detect CIN2+. While there was no significant difference in sensitivity (76%, p = 0.62), the specificity when using HRME was significantly higher than that of traditional colposcopy (56%, p = 0.01). There was no significant difference in HRME image quality between clinical sites (p = 0.77) or medical providers (p = 0.33). ConclusionsHRME imaging increased the specificity for detecting CIN2+ when compared to traditional colposcopy. HRME image quality remained consistent across different clinical settings.

Human papillomavirus types in cervical high-grade lesions or cancer among Nordic women-Potential for prevention.

It is valuable to establish a population‐based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high‐grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high‐grade precancerous cervical lesions (n = 1240) during 2004‐2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0‐86.4) in CIN2, 91.6% (95% CI 89.7‐93.5) in CIN3, and 86.4% (95% CI 83.7‐89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2‐40.6; CIN3: 50.2%, 95% CI 46.8‐53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8‐13.9; CIN3: 12.1%, 95% CI 9.9‐14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9‐52.7 and 15.3%, 95% CI 12.5‐18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P < 0.0001). Elimination of HPV16/18 by vaccination is predicted to prevent 42% (95% CI 37.0‐46.7) of CIN2, 57% (95% CI 53.8‐60.5) of CIN3 and 64% (95% CI 60.3‐67.7) of cervical cancer. Prevention of the five additional HPV types HPV31/33/45/52/58 would increase the protection to 68% (95% CI 63.0‐72.2) in CIN2, 85% (95% CI 82.4‐87.2) in CIN3 and 80% (95% CI 77.0‐83.2) in cervical cancer. This study provides large‐scale and representative baselines for assessing and evaluating the population‐based preventive impact of HPV vaccination.

Spectrum of Cervical Cytological Lesions in Premenopausal and Postmenopausal Women

Background: Screening with Pap smear initially targets women with higher prevalence of high grade precancerous cervical lesions [Cervical Intraepithelial Neoplasia 2/3 (CIN2/CIN3)] - women mostly in their third and fourth decade. But different conditions affect uterine cervix, including non neoplastic & neoplastic diseases, at different age. Thus, the Pap smears findings should vary in premenopausal & post menopausal groups. Methods: A prospective study of two years was conducted to screen Pap smears in women who were categorised as premenopausal age group 60 years. Conclusion: It is suggested that the Pap screening should not be ceased, but be continued beyond 60 years of age. In premenopausal age, along with SIL, the possibility of malignancy should not be neglected & infections should also be paid more attention. Thus, irrespective of the age of female after 30 yrs, it is highly recommended for them to undergo PAP screening. DOI: 10.21276/APALM.1661

Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: Results of the Compass pilot randomised trial.

BackgroundUsing primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia’s HPV-vaccinated population (by 2014, resident women ≤33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%–77%).Methods and findingsCompass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25–64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology (‘LBC screening’), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types (‘HPV+LBC triage’), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types (‘HPV+DS triage’). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%–3.9%]) and 1/995 (0.1% [95% CI 0.0%–0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%–4.7%]) and 20/1,992 (1.0% [95% CI 0.6%–1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%–4.9%]) and 24/2,008 (1.2% [95% CI 0.8%–1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women’s vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available.ConclusionsIn this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%–44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12613001207707

Vaginal and Urine Self-sampling Compared to Cervical Sampling for HPV-testing with the Cobas 4800 HPV Test.

To compare human papillomavirus (HPV) DNA detection in self-collected vaginal and urine samples with clinician-taken cervical samples in relation to histology. Self-collected vaginal, urine and clinician-taken cervical samples were analyzed from 218 women with the Cobas 4800 HPV test (Roche Molecular Diagnostics). The sensitivity for detection of HPV in the vaginal self-sampling test was 96.4% and in urine was 83.9% relative to detection by clinician-taken cervical sample. The vaginal self-sampling and the clinician-taken HPV tests had the same sensitivity of 92.8% (95% confidence interval=86.3-96.8%) and specificity for detection of high-grade squamous intraepithelial lesion (HSIL) and adenocarcinoma in situ (AIS). Detection in urine samples had a sensitivity of 76.3% (95% confidence interval=67.9-84.2%) for HSIL/AIS. The Cobas 4800 HPV test detects high-grade pre-cancerous cervical lesions in self-collected vaginal samples with the same high sensitivity as in clinician-taken cervical samples.

The “See and Treat” Strategy for Identifying Cytologic High-Grade Precancerous Cervical Lesions Among Low-Income Brazilian Women

After cytologic identification of high-grade cervical squamous intraepithelial lesions (HSILs), the most common management procedure is colposcopy-guided biopsy and endocervical curettage. The “see and treat” approach using the loop electrosurgical excision procedure (LEEP) is an alternative strategy that provides immediate and concomitant diagnosis and treatment without a previous biopsy. The see-and-treat approach may result in overtreatment in women with cervical lesions who do not require treatment or adverse effects. However, this strategy circumvents the failure to diagnose or treat HSILs and is an important strategy in low-resource and low-income settings. The see-and-treat strategy has been adopted in some states and regions in Brazil, but the possible benefits of this strategy have not been fully investigated. This retrospective study assessed the strategy of see-and-treat by LEEP for HSIL precancerous cervical lesions and evaluated post-LEEP recurrence among low-income women in Brazil. A retrospective survey of data from medical records of the Department of Gynecology, Hospital of Public Health, in União da Vitória, Paraná, Brazil, identified women who underwent LEEP for cytologic HSILs without prior biopsy between 2004 and 2008. Follow-up of patients for LEEP sample histology was performed with Papanicolaou (Pap) smear. A total of 117 women underwent LEEP for cytologic HSILs during the study period. In these women, histologic examination of tissue excised by LEEP showed that 26.7% had no lesions, and 72.6% had either histologically proven cervical intraepithelial neoplasia 2/3 (67.5%) or microinvasive/invasive carcinomas (5.2%). At follow-up, there was no significant difference in the recurrence rate between women with histologic findings of cervical intraepithelial neoplasia 2/3 and those with no lesions (16.7% and in 25%, respectively; P > 0.05). The most frequent type of recurrence (78%) was HSILs (P < 0.001). The surgical margin status among patients with cytologic HSILs was as follows: ectopositive and endopositive margins (6.3%), ectopositive margins (3.8%), and endopositive margins (33.0%). No significant difference was found in recurrence rates for women with endopositive (26.3%), no margin (17.4%), and cautery artifact margin (25.0%) involvement (P > 0.05). These findings suggest that the benefits of the see-and-treat strategy for patients with cytologic HSILs outweigh the risk of overtreatment. The data demonstrate that margin involvement should not be the only prognostic indicator. All women with both positive and negative margins on LEEP should be carefully followed.

Patterns of Cervical Cancer Screening, Diagnosis, and Follow-up Treatment in a State Medicaid Fee-for-Service Population

Despite being a screening-amenable cancer, cervical cancer is the third most common genital cancer among white women and the most common among African American women. The study objective was to use administrative claims data for CC disease surveillance among recipients enrolled in a state Medicaid fee-for-service (FFS) program. West Virginia (WV) Medicaid FFS administrative claims data for female recipients aged 21-64 years from 2003 to 2008 were used for this study. All medical and prescription claims were aggregated to reflect each recipient's medical care and prescription drug utilization. The yearly prevalence of Pap smear testing declined from 23.9% in 2003 to 15.8% in 2008 in the Medicaid FFS population. During the 6-year study period, persistence with Pap smear testing was low; 41.8% of recipients received no Pap smear testing. Only 73.1% of recipients received Pap smear testing during the year prior to their CC or precancerous cervical lesions (PCL) diagnosis. The likelihood of a CC diagnosis increased with a decrease in Pap smear testing persistence. Only 10.1% of recipients received appropriate follow-up care following a diagnosis of high-grade PCL; only 31.5% of the recipients received appropriate follow-up care for low-grade PCL diagnosis. Although CC preventive services such as screening and PCL follow-up care are covered under Medicaid programs, underutilization of these services by recipients in the Medicaid FFS population is a concern. Results of this study emphasize the need to address disparities in screening and appropriate PCL follow-up care among recipients in the Medicaid FFS population.

The “see and treat” strategy for identifying cytologic high-grade precancerous cervical lesions among low-income Brazilian women

ObjectiveTo evaluate the strategy of “see and treat” by loop electrosurgical excision procedure (LEEP) for cytologic high-grade precancerous cervical lesions (squamous intraepithelial lesions; HSIL) and post-LEEP recurrence among low-income Brazilian women. MethodsIn a retrospective survey of women who underwent LEEP for cytologic HSIL without prior cervical biopsy between January 2004 and March 2008 at CISVALI, União da Vitória, Paraná, Brazil, LEEP sample histology and patient follow-up by Papanicolaou smear were assessed. ResultsAmong 117 women treated, 24% had no lesions, 67.5% had cervical intraepithelial neoplasia (CIN) grade 2/3, and 5.2% had squamous cell carcinoma or adenocarcinoma on LEEP histology. Among patients with follow-up, recurrences occurred in those with no lesions (16.7%) and CIN 2/3 (25%) (P>0.05). HSIL was the most frequent type of recurrence (87%) (P<0.001). In total, 6.3% of patients had positive ectocervical (ecto-positive) and endocervical (endo-positive) margins, 3.8% had ecto-positive, and 33.0% had endo-positive margins. Recurrences occurred in women with endo-positive (26.3%), no margin (17.4%), and cautery artifact margin (25.0%) involvement (P>0.05). ConclusionFor cytologic HSIL, the benefits of the strategy of “see and treat” by LEEP outweighed the risk of overtreatment. Patients with both positive and negative margins on LEEP should be followed carefully.

Abstract SY12-01: HPV vaccines: The opportunity to prevent multiple cancers

Abstract SY12-01: HPV vaccines: The opportunity to prevent multiple cancers

Screening for Malignancy After Augmentation Cystoplasty in Children With Spina Bifida: A Decision Analysis

Augmentation cystoplasty is the mainstay of surgical treatment for medically refractory neurogenic bladder in patients with spina bifida. Concerns regarding an increased risk of malignancy have prompted many centers to consider routine postoperative screening. We examine the potential cost-effectiveness of such screening. A Markov model was used to compare 2 screening strategies among patients with spina bifida after cystoplasty, namely annual screening cystoscopy and cytology and usual care. Model parameters were informed via a systematic review of post-augmentation malignancy and cost estimates from published reports or government sources. In a hypothetical cohort the individual increase in life expectancy for the entire cohort was 2.3 months with an average lifetime cost of $55,200 per capita, for an incremental cost-effectiveness ratio of $273,718 per life-year gained. One-way and two-way sensitivity analyses suggest the screening strategy could be cost effective if the annual rate of cancer development were more than 0.26% (12.8% lifetime risk) or there were a greater than 50% increase in screening effectiveness and cancer risk after augmentation. After adjusting for multiple levels of uncertainty the screening strategy had only an 11% chance of being cost effective at a $100,000 per life-year threshold or a less than 3% chance of being cost effective at $100,000 per quality adjusted life-year. Annual screening for malignancy among patients with spina bifida with cystoplasty using cystoscopy and cytology is unlikely to be cost effective at commonly accepted willingness to pay thresholds. This conclusion is sensitive to a higher than expected risk of malignancy and to highly optimistic estimates of screening effectiveness.

Preferences for surveillance strategies for women treated for high-grade precancerous cervical lesions

Objectives Data are lacking on how women view alternative approaches to surveillance for cervical cancer after treatment of high-grade cervical intraepithelial neoplasia. We measured and compared patient preferences (utilities) for scenarios with varying surveillance strategies and outcomes to inform guidelines and cost-effectiveness analyses of post-treatment surveillance options. Methods English- or Spanish-speaking women who had received an abnormal Pap test result within the past 2 years were recruited from general gynecology and colposcopy clinics and newspaper and online advertisements in 2007 and 2008. Participation consisted of one face-to-face interview, during which utilities for 11 different surveillance scenarios and their associated outcomes were elicited using the time tradeoff metric. A sociodemographic questionnaire also was administered. Results 65 women agreed to participate and successfully completed the preference elicitation exercises. Mean utilities ranged from 0.989 (undergoing only a Pap test, receiving normal results) to 0.666 (invasive cervical cancer treated with radical hysterectomy or radiation and chemotherapy). Undergoing both Pap and HPV tests and receiving normal/negative results had a lower mean utility (0.953) then undergoing only a Pap test and receiving normal results (0.989). Having both tests and receiving normal Pap but positive HPV results was assigned an even lower mean utility (0.909). 15.9% of the respondents gave higher utility scores to the Pap plus HPV testing scenario (with normal/negative results) than to the “Pap test alone” scenario (with normal results), while 17.5% gave the Pap test alone scenario a higher utility score. Conclusions Preferences for outcomes ending with normal results but involving alternative surveillance processes differ substantially. The observed differences in utilities have important implications for clinical guidelines and cost-effectiveness analyses.

Identification of human papillomavirus type 16 integration sites in high-grade precancerous cervical lesions

Objectives Infection with oncogenic human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. In many cases of cervical cancer and all cervical cancer derived cell lines oncogenic HPV DNA is found to be integrated, indicating the importance of integration in disease development. In this study, 176 HPV 16 positive precancerous cervical lesions were analyzed for the physical state of viral genome to determine the sites of integration into a host cell DNA and to evaluate the incidence of the integration in different stages of cervical lesions. Methods The detection of integrated papillomavirus sequences (DIPS) method in combination with the amplification by polymerase chain reaction (PCR) of E1/E2 region was used to identify the physical state of HPV 16 genome. The site of integration within a host cell genome was determined by sequencing of unusual sized DIPS amplicons. Results The combined results of DIPS and E1/E2 PCR revealed the integration of HPV 16 DNA in 7.4% samples. The integration was found only in high grade cervical lesions indicating that it is a late event in disease progression. Sequencing of 11 DIPS amplicons revealed HPV DNA from 6 samples (54.5%) to be integrated in cellular genes ( VMP1, PVRL1, CHERP, CEACAM5, AHR, MRF-2) and also 6 (54.5%) within the common fragile sites (CFS). Conclusions Although, the HPV integration is known to be a random event, this study indicates that HPV 16 integrates more than by chance within or close to CFSs. As most of the genes affected by HPV 16 integration can be linked with some aspects of tumor formation, this indicates that the site of HPV DNA integration might play a role in the rate and the nature of tumor development.

Cervical cancer screening in medically underserved California Latina and non-Latina women: Effect of age and regularity of Pap testing

Background: This study focuses on age, race/ethnicity and regular cervical cancer screening of medically underserved Latina and non-Latina women enrolled in California's Cancer Detection Programs: Every Woman Counts ( CDP: EWC). Methods: Data from a cohort of women were evaluated for regularity of screening and ethnicity utilizing multi-category logistic regression models to investigate Pap test and biopsy results. Results: There was no statistically significant difference among medically underserved Latina or non-Latina women in Pap test result and stage of cervical cancer after controlling for age and screening regularity. Rarely/never Pap-tested women were more likely to have ‘SIL/ASC’ (odds ratio = 1.19; 95% confidence interval = 1.08, 1.31) compared to women who were screened regularly. Medically underserved 25–39-year-old women were also more likely to be identified with ‘SIL/ASC’ (odds ratio = 1.64; 95% confidence interval = 1.50, 1.79) than women 50 and over. Younger were more likely to have low-grade ‘HPV/Condylomata, Atypia/CINI/LSIL’ (odds ratio = 2.48; 95% confidence interval = 1.66, 3.72) and high-grade ‘CIN II/III/HSIL/CI/Other Cancers’ (odds ratio = 1.53; 95% confidence interval = 1.08, 2.16) than women age 40 and above, similar to rarely/never Pap-tested women. Conclusions: Women were more likely to be identified with high-grade precancerous cervical lesions and cancer process when they did not have regular screening, Ethnic differences in screening outcomes seem to be minimized by participation in a program that provides consistent screening resources to the medically underserved women who enroll. These findings support prevention strategies that expand screening to all medically underserved younger women or that provide HPV vaccination at an early age.