The impact of loss to follow-up in the Dutch organised HPV-based cervical cancer screening programme

Loss to follow-up (LTFU) within cervical screening programmes can result in missed clinically relevant lesions, potentially reducing programme effectiveness. To examine the health impact of losing women during the screening process, we determined the proportion of women LTFU per step of the Dutch hrHPV-based screening programme. We then determined the probability of being LTFU by age, screening history and sampling method (self- or clinician-sampled) using logistic regression analysis. Finally, we estimated the number of missed CIN2+/3+ lesions per LTFU moment by using the CIN-risk in women compliant with follow-up. Data from the Dutch nationwide pathology databank (Palga) was used. Women eligible for screening in 2017 and 2018 were included (N = 840,428). For clinician collected (CC) samples, the highest proportion LTFU was found following ‘referral advice for colposcopy’ (5.5% after indirect referral; 3.8% after direct referral). For self-sampling, the highest proportions LTFU were found following the advice for repeat cytology (13.6%) and after referral advice for colposcopy (8.2% after indirect referral; 4.3% after direct referral). Self-sampling users and women with no screening history had a higher LTFU-risk (OR: 3.87, CI: 3.55–4.23; OR: 1.39, CI: 1.20–1.61) compared to women that used CC sampling and women that have been screened before, respectively. Of all women LTFU in 2017/18, the total number of potentially missed CIN2+ was 844 (21% of women LTFU). Most lesions were missed after ‘direct referral for colposcopy’ (N = 462, 11.5% of women LTFU). So, this indicates a gap between the screening programme and clinical care which requires further attention, by improving monitoring of patients after referral.     

HPV检测与细胞学检查在宫颈癌前病变诊断中的比较

目的:探讨人乳头瘤状病毒DNA检测与细胞学检查在宫颈癌前病变早期诊断中的比较。方法:病例来源于我院门诊及住院病人,均已在普通门诊做巴氏涂片(采用TBS细胞分类法)和高危型HPV-DNA检测,任何一项检查异常均在阴道镜下行多点活检。巴氏涂片以≥ASCUS/AGUS为阳性,HPV-DNA≥1.0pg/ml,宫颈活检病理作为金标准,以≥CIN2为阳性。结果:高危型HPV-DNA检测的敏感性为97.3%;特异性为71.6%;巴氏涂片的敏感性为62.2%;特异性为83.8%;两者相比高危型HPV-DNA检测方法有较高的敏感度和阴性预测值。结论:HPV-DNA检测在宫颈癌前病变早期诊断中的敏感度和阴性预测值都很高,是一种有效的初筛手段。     

Value of routine follow-up procedures for patients with stage I/II cervical cancer treated with combined surgery-radiation therapy.

BACKGROUND: The aim of this study was to determine the value of routine follow-up for the detection of recurrence in patients treated for cervical cancer. PATIENTS AND METHODS: From 1986 to 1998, 583 women with stage I and II cervical carcinoma were treated with combined surgery-radiation therapy. After treatment, follow-up was based on clinical examination, a systematic Pap smear and radiography (chest X-ray and abdomino-pelvic ultrasonography). RESULTS: Forty-five patients had recurrence observed with a delay > or = 6 months following the end of treatment. Thirty-eight patients had symptoms and seven were asymptomatic at the time of their recurrence. Among asymptomatic patients only two recurrences were diagnosed following routine examinations. Survival is similar in asymptomatic and symptomatic recurrent patients. CONCLUSIONS: In conclusion, follow-up of patients treated for cervical cancer based on routine Pap smears and systematic radiography does not permit earlier detection of recurrence and does not increase survival.     

A simplified and reliable HPV testing of archival Papanicolaou-stained cervical smears: application to cervical smears from cancer patients starting with cytologically normal smears

The efficacy of four methods to recover DNA from Papanicolaou (Pap)-stained archival cervical smears for optimal detection of human papillomavirus (HPV) DNA by GP5+/bioGP6+ polymerase chain reaction (PCR) was investigated. Two of the methods were based on proteinase K treatment and two based on treatment with guanidinium thiocyanate (GTC). The quality of the DNA as measured by PCR assays amplifying different sizes of the beta-globin gene appeared to be superior for the GTC-based assays. Using competitive beta-globin PCR assays, one of the GTC-based, assays, provisionally named High Pure PCR Template Preparation (HPPTP) assay, yielded by far the highest quantity of amplifiable DNA. It allowed the recovery of 2.2 x 10(5) to 3 x 10(5) genome equivalents in smears containing 5 x 10(5) to 20 x 10(5) nucleated cells, indicating a mean efficiency of 26% (range of 15-44%). In contrast, the other methods revealed markedly lower efficiencies varying from 1% to 10%. The use of the HPPTP assay as a reliable processing procedure was validated by demonstrating a complete agreement in HPV detection and 93% agreement in HPV typing between 39 archival Pap-stained and paired fresh-frozen cervical smears. This method was applied to 40 archival smears from ten cervical cancer patients (selected from a group of 200 patients) which had a history of 3-6 smears with the first smear being Pap 1 or 2 taken at least 5 years before cancer was diagnosed. The average time period between the first Pap 1/2 smear that contained the same HPV type as in the corresponding carcinoma and diagnosis of cervical cancer was 12.0 +/- 2.9 years. All subsequent smears were invariably positive for the same HPV type which was also found in the cervical cancer biopsy. In conclusion, the HPPTP assay provides a reliable and efficient means to extract DNA from Pap-stained archival cervical smears for the detection of HPV DNA by PCR and would be the method of choice for future HPV analysis of archival Pap-stained cervical smears.     

Human papillomavirus testing and genotyping in cervical screening

Mass vaccination against human papillomavirus (HPV) genotypes 16 and 18 will, in the long term, reduce the incidence of cervical cancer, but screening will remain an important cancer control measure in both vaccinated and unvaccinated women. Since the 1960s, cytology screening has helped to reduce the incidence of cervical cancer, but has a low sensitivity for high-grade cervical intraepithelial neoplasia (CIN) and requires frequent testing. Several HPV tests have become available commercially. They appear to be more sensitive for high-grade CIN, and may further reduce the incidence of cervical cancer compared with cytology. However, they are associated with an increased frequency of positive tests without underlying CIN, and therefore increase the need for colposcopy and repeated testing. This problem will pose a major challenge for switching from cytology-based to HPV-based screening. The aim of this article is to discuss the role and the use of HPV tests and HPV genotyping in unvaccinated women.     

Liquid-based cytology for primary cervical cancer screening: a multi-centre study

The aim of this six-centre, split-sample study was to compare ThinPrep fluid-based cytology to the conventional Papanicolaou smear. Six cytopathology laboratories and 35 gynaecologists participated. 5428 patients met the inclusion criteria (age > 18 years old, intact cervix, informed consent). Each cervical sample was used first to prepare a conventional Pap smear, then the sampling device was rinsed into a PreservCyt vial, and a ThinPrep slide was made. Screening of slide pairs was blinded (n = 5428). All non-negative concordant cases (n = 101), all non-concordant cases (n = 206), and a 5% random sample of concordant negative cases (n = 272) underwent review by one independent pathologist then by the panel of 6 investigators. Initial (blinded) screening results for ThinPrep and conventional smears were correlated. Initial diagnoses were correlated with consensus cytological diagnoses. Differences in disease detection were evaluated using McNemar's test. On initial screening, 29% more ASCUS cases and 39% more low-grade squamous intraepithelial lesions (LSIL) and more severe lesions (LSIL+) were detected on the ThinPrep slides than on the conventional smears (P = 0.001), including 50% more LSIL and 18% more high-grade SIL (HSIL). The ASCUS:SIL ratio was lower for the ThinPrep method (115:132 = 0.87:1) than for the conventional smear method (89:94 = 0.95:1). The same trend was observed for the ASCUS/AGUS:LSIL ratio. Independent and consensus review confirmed 145 LSIL+ diagnoses; of these, 18% more had been detected initially on the ThinPrep slides than on the conventional smears (P = 0.041). The ThinPrep Pap Test is more accurate than the conventional Pap test and has the potential to optimize the effectiveness of primary cervical cancer screening.     

Value of colposcopy in the early diagnosis of cervical cancer in patients with abnormal pap smears at Shahid Sadoughi hospital, Yazd

Background and objectives: Cervical cancer is preventable, although it is common in developing countries and Iran, where there is no defined approach to “atypical squamous cells of undetermined significance” (ASCUS) on Pap smears. This study determined the value of colposcopy in the early diagnosis of cervix cancer in females with ASCUS. Materials and methods: This accuracy study examined 213 ASCUS cases referred from different cities from 2007 to 2009. All patients underwent a repeated conventional Pap smear, colposcopy, endocervical curettage, and a cervical biopsy, considered the gold-standard diagnostic test. Results: There was no significant relationship between age, age of first intercourse, smoking, or number of children and a positive cervical biopsy. The sensitivity and specificity of a repeat Pap smear for ASCUS were 15 and 93%, respectively, while the respective values for diagnosing cervical cancer with colposcopy were 80 and 80%. Endocervical curettage had 64% sensitivity and 100% specificity for diagnosing cervical cancer, and 11 positive neoplastic or malignant lesions reported on endocervical curettage were confirmed by biopsy. Discussion: Based on the low accuracy of the Pap smear in Iran as a developing country and the need for an early diagnosis of cervical cancer, a cervical biopsy and colposcopy are recommended for these patients. Colposcopy and endocervical curettage alone are better diagnostic tools than a repeat Pap smear for unsatisfactory Pap smears.     

Human papillomavirus testing and cervical cytology in primary screening for cervical cancer among women in rural China: Comparison of sensitivity,specificity, and frequency of referral

The causal relationship between persistent high‐risk human papillomavirus infection and cervical cancer is widely accepted. HR‐HPV DNA testing, alone or in combination with Pap smear testing, may have a role in primary screening. The screening results (VIA, VILI, Pap, and HR‐HPV DNA) of 9,057 women in rural China were analyzed to determine the screening performance for the detection of CIN3+. All screening strategies had comparable AUCs (0.9). Cotesting strategies had the overall highest sensitivity for CIN3+ (99.4%), followed by HR‐HPV DNA testing alone (96.3%), Pap alone (80.2%), and reflex testing (75.4%). Reflex testing had the highest specificity (96.7%), followed by Pap alone (93.3%), HR‐HPV DNA testing alone (85.5%), and both cotesting strategies (LSIL: 84.8%, HSIL: 84.8%). Of the single‐test strategies, HR‐HPV DNA testing had a higher sensitivity (96.3% vs. 80.2%) compared with Pap testing. The specificity of the Pap test was higher (93.3% vs. 85.5%) and it had a lower percent referred for colposcopy (7.8% vs. 15.8%) than HR‐HPV DNA testing. HR‐HPV DNA testing with a 10.0 cutoff point (relative light units/cutoff ratio) had a sensitivity (85.2%) and specificity (90.6%) estimate comparable to Pap testing. A single‐test primary screening strategy with adequate performance would permit less frequent screening and be most appropriate. Of the primary screening strategies investigated in this setting in China, the performance of HR‐HPV DNA testing with an increased cutoff‐point might best meet these criteria.     

Pooled analysis of the accuracy of five cervical cancer screening tests assessed in eleven studies in Africa and India

Cervical cancer is the main cancer among women in sub-Saharan Africa, India and other parts of the developing world. Evaluation of screening performance of effective, feasible and affordable early detection and management methods is a public health priority. Five screening methods, naked eye visual inspection of the cervix uteri after application of diluted acetic acid (VIA), or Lugol's iodine (VILI) or with a magnifying device (VIAM), the Pap smear and human papillomavirus testing with the high-risk probe of the Hybrid Capture-2 assay (HC2), were evaluated in 11 studies in India and Africa. More than 58,000 women, aged 25-64 years, were tested with 2-5 screening tests and outcome verification was done on all women independent of the screen test results. The outcome was presence or absence of cervical intraepithelial neoplasia (CIN) of different degrees or invasive cervical cancer. Verification was based on colposcopy and histological interpretation of colposcopy-directed biopsies. Negative colposcopy was accepted as a truly negative outcome. VIA showed a sensitivity of 79% (95% CI 73-85%) and 83% (95% CI 77-89%), and a specificity of 85% (95% CI 81-89%) and 84% (95% CI 80-88%) for the outcomes CIN2+ or CIN3+, respectively. VILI was on average 10% more sensitive and equally specific. VIAM showed similar results as VIA. The Pap smear showed lowest sensitivity, even at the lowest cutoff of atypical squamous cells of undetermined significance (57%; 95% CI 38-76%) for CIN2+ but the specificity was rather high (93%; 95% CI 89-97%). The HC2-assay showed a sensitivity for CIN2+ of 62% (95% CI 56-68%) and a specificity of 94% (95% CI 92-95%). Substantial interstudy variation was observed in the accuracy of the visual screening methods. Accuracy of visual methods and cytology increased over time, whereas performance of HC2 was constant. Results of visual tests and colposcopy were highly correlated. This study was the largest ever done that evaluates the cross-sectional accuracy of screening tests for cervical cancer precursors in developing countries. The merit of the study was that all screened subjects were submitted to confirmatory investigations avoiding to verification bias. A major finding was the consistently higher sensitivity but equal specificity of VILI compared with VIA. Nevertheless, some caution is warranted in the interpretation of observed accuracy measures, since a certain degree of gold standard misclassification cannot be excluded. Because of the correlation between visual screening tests and colposcopy and a certain degree of over-diagnosis of apparent CIN2+ by study pathologists, it is possible that both sensitivity and specificity of VIA and VILI were overestimated. Gold standard verification error could also explain the surprisingly low sensitivity of HC2, which contrasts with findings from other studies.     

HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears

In a retrospective case-control study, we investigated high-risk HPV DNA presence by general primer GP5+/6+ PCR in the last normal cervical smear in the patient archives (i.e. baseline smear) of 57 women who later developed cervical cancer. Also, normal cervical smears of 114 age-matched control women were analysed. High-risk HPV DNA was detected in 37 of the 57 (65%) baseline smears of the case women, and 7 (6%) of 114 smears of the control women (OR 28, 95% Cl 11-72). The HPV positive subsequent smears and cervical cancer biopsies of the case women contained the same HPV type as was detected in the baseline smear. After cytological revision, the baseline smears of 48 case women (84%) were reclassified as abnormal, 33 (69%) of which scored high-risk HPV DNA positive. Ultimately, an undisputable normal baseline smear was found in only 10 case women. In 7 (70%) of them this smear was HPV positive, whereas only 7 (7%) of 104 revised, undisputable normal smears of control women were high-risk HPV positive (OR 32, 95% Cl 6.8-153). The results showed that (1) high-risk HPV presence precedes abnormal cytology in women who develop cervical cancer, and (2) high-risk HPV testing signals false-negative smears of women at risk of cervical cancer.     

Cost-effectiveness of cervical cancer screening with primary human papillomavirus testing in Norway

Background:

New screening technologies and vaccination against human papillomavirus (HPV), the necessary cause of cervical cancer, may impact optimal approaches to prevent cervical cancer. We evaluated the cost-effectiveness of alternative screening strategies to inform cervical cancer prevention guidelines in Norway.

Methods:

We leveraged the primary epidemiologic and economic data from Norway to contextualise a simulation model of HPV-induced cervical cancer. The current cytology-only screening was compared with strategies involving cytology at younger ages and primary HPV-based screening at older ages (31/34+ years), an option being actively deliberated by the Norwegian government. We varied the switch-age, screening interval, and triage strategies for women with HPV-positive results. Uncertainty was evaluated in sensitivity analysis.

Results:

Current cytology-only screening was less effective and more costly than strategies that involve switching to primary HPV testing in older ages. For unvaccinated women, switching at age 34 years to primary HPV testing every 4 years was optimal given the Norwegian cost-effectiveness threshold ($83 000 per year of life saved). For vaccinated women, a 6-year screening interval was cost-effective. When we considered a wider range of strategies, we found that an earlier switch to HPV testing (at age 31 years) may be preferred.

Conclusions:

Strategies involving a switch to HPV testing for primary screening in older women is expected to be cost-effective compared with current recommendations in Norway.     

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25–65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56–1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43–1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14–65) and intervention 43 (95% CI: 25–73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1–0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.     

High risk HPV types in southern Iranian patients with cervical cancer

This study was undertaken to assess the rate of HPV infection in cervical carcinoma among southern Iranian patients. 101 archival cervical carcinoma tissue samples of a 10 year period were studied for the presence of HPV DNA in southern Iran by a polymerase chain reaction method. In addition, the presence of high risk HPV-16 and HPV-18 genotypes was investigated. In total, 88 (87.1%) of the samples were HPV DNA positive, of which 83 were squamous cell carcinomas and 5 were adenocarcinomas. HPV-16 genotype was detected in 26.7% of HPV positive cervical carcinomas; however, none of the samples were positive for the existence of HPV-18 genotype. Collectively, these results suggest that HPV-16 and HPV-18 are not the frequent high risk HPV types in our patients and circulating HPV types in southern Iranian population are different from many other populations.     

The cervical cancer screening program in Mexico: problems with access and coverage

A cross-sectional study was carried out in two geographic regions of Mexico - Oaxaca (rural area) and Mexico City (urban area) - to determine the main factors for predicting participation in Cervical Cytology Screening Programs (CCSP), in populations with high mortality due to cervical cancer. We included 4,208 women aged between 15 and 49 years, randomly selected through a national household-sample frame. Knowledge of what the Pap test is used for strongly predisposes use of CCSP in Mexico City (odds ratio [OR] = 46.1, 95 percent confidence interval [CI] = 33.1-64.1) and Oaxaca state (OR = 61.5, CI = 42.0-89.9), as well as high socioeconomic level (Mexico: OR = 2.0, CI = 1.1-7.6; Oaxaca: OR = 4.1, CI = 3.1-5.3), high education level (Mexico: OR = 3.6, CI = 1.5-8.8; Oaxaca: OR = 5.3, CI = 2.8-10.0), and access to social security (Mexico: OR = 1.7, CI = 1.4-2.2; Oaxaca: OR = 2.2, CI = 1.8-2.7). Low coverage of the CCSP is confirmed as an important problem in Mexico.     

Testing for human papillomavirus in cervical cancer screening: a review of indications and methodology

High‐risk human papillomavirus (hrHPV) testing has become an integral component of cervical cancer screening, given that persistent infection with hrHPV was recognized as a significant risk factor for most precancers and cancers of the cervix. Particularly, testing for hrHPV types (in conjunction with cervical cytology) has been approved for primary screening in women over 30 years of age and for cost‐effective triaging of equivocal cervical cytology results. HPV was a small double‐stranded DNA virus that cannot be cultured in vitro; so, different types of tests have been developed to detect its presence. Various molecular techniques were available for detecting the presence and/or quantity of hrHPV. In this review, the testing options for hrHPV and its surrogates, with an emphasis on those approved by the US Food and Drug Administration (FDA), were detailed. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

Effectiveness of novel,lower cost molecular human papillomavirus‐based tests for cervical cancer screening in rural china

This study examined the efficacy of the OncoE6? Cervical Test, careHPV? and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1‐year follow‐up. In a population of 7,543 women living in rural China, women provided a self‐collected and two clinician‐collected specimens and underwent VIA. All screen positive women for any of the tests, a ～10% random sample of test‐negative women that underwent colposcopy at baseline, and an additional ～10% random sample of test‐negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1‐year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPV? on clinician‐collected and self‐collected specimens, respectively, and 54.4% for OncoE6? test. The OncoE6? test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1‐year follow‐up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5–6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer.     

人乳头瘤病毒与人类宫颈癌

鉴于人乳头瘤病毒（HPV）与人类宫颈上皮内瘤样病变以至宫颈癌的发病有密切的关系，为此作者复习相关文献，就HPV的结构、女性生殖道HPV感染的流行病学、HPV感染与宫颈癌的关系等方面加以扼要的综述。     

Negative human papillomavirus testing in normal smears selects a population at low risk for developing high-grade cervical lesions

High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas and there is an increasing interest in using HR-HPV DNA detection in adjunction to cytological examination for primary cervical screening. To determine whether women with a normal smear negative for HR-HPV DNA detection with the Hybrid Capture II assay might represent a low-risk population for developing a high-grade squamous intraepithelial lesion (HSIL), 4401 women have been followed in a period of 12-72 months (median=34 months). During this follow-up, four HSIL and one microinvasive carcinoma have been detected in this cohort (three in the cohort of 3526 women >29 years). The global negative predictive value (NPV) of double-negative tests is thus of 99.9% (ninety-five percent confidence interval (95% CI): 99.8-100%), whereas cytology alone gives an NPV of 99.2% (95% CI: 98.9-99.5%). If we obtain a second negative HR-HPV test 1-2 years after the initial test, the NPV is 100%. The NPV is also of 100% in the cohort of women >49 years. We conclude that all these women could be safely screened at longer intervals between 3 and 5 years. This policy will offset the increased costs induced by an additional HR-HPV testing in primary screening.