Freija Verdoodt

Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis

BACKGROUND Screening for human papillomavirus (HPV) infection is more effective in reducing the incidence of cervical cancer than screening using Pap smears. Moreover, HPV testing can be done on a vaginal sample self-taken by a woman, which offers an opportunity to improve screening coverage. However, the clinical accuracy of HPV testing on self-samples is not well-known. We assessed whether HPV testing on self-collected samples is equivalent to HPV testing on samples collected by clinicians. METHODS We identified relevant studies through a search of PubMed, Embase, and CENTRAL. Studies were eligible for inclusion if they fulfilled all of the following selection criteria: a cervical cell sample was self-collected by a woman followed by a sample taken by a clinician; a high-risk HPV test was done on the self-sample (index test) and HPV-testing or cytological interpretation was done on the specimen collected by the clinician (comparator tests); and the presence or absence of cervical intraepithelial neoplasia grade 2 (CIN2) or worse was verified by colposcopy and biopsy in all enrolled women or in women with one or more positive tests. The absolute accuracy for finding CIN2 or worse, or CIN grade 3 (CIN3) or worse of the index and comparator tests as well as the relative accuracy of the index versus the comparator tests were pooled using bivariate normal models and random effect models. FINDINGS We included data from 36 studies, which altogether enrolled 154 556 women. The absolute accuracy varied by clinical setting. In the context of screening, HPV testing on self-samples detected, on average, 76% (95% CI 69-82) of CIN2 or worse and 84% (72-92) of CIN3 or worse. The pooled absolute specificity to exclude CIN2 or worse was 86% (83-89) and 87% (84-90) to exclude CIN3 or worse. The variation of the relative accuracy of HPV testing on self-samples compared with tests on clinician-taken samples was low across settings, enabling pooling of the relative accuracy over all studies. The pooled sensitivity of HPV testing on self-samples was lower than HPV testing on a clinician-taken sample (ratio 0·88 [95% CI 0·85-0·91] for CIN2 or worse and 0·89 [0·83-0·96] for CIN3 or worse). Also specificity was lower in self-samples versus clinician-taken samples (ratio 0·96 [0·95-0·97] for CIN2 or worse and 0·96 [0·93-0·99] for CIN3 or worse). HPV testing with signal-based assays on self-samples was less sensitive and specific than testing on clinician-based samples. By contrast, some PCR-based HPV tests generally showed similar sensitivity on both self-samples and clinician-based samples. INTERPRETATION In screening programmes using signal-based assays, sampling by a clinician should be recommended. However, HPV testing on a self-sample can be suggested as an additional strategy to reach women not participating in the regular screening programme. Some PCR-based HPV tests could be considered for routine screening after careful piloting assessing feasibility, logistics, population compliance, and costs. FUNDING The 7th Framework Programme of the European Commission, the Belgian Foundation against Cancer, the International Agency for Research on Cancer, and the German Guideline Program in Oncology.

Triage of women with minor abnormal cervical cytology: Meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types: ASC-US/LSIL Triage: mRNA Test Accuracy

High‐risk human papillomavirus (hrHPV) DNA detection is generally accepted for the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC‐US). However, no consensus has been reached on the optimal management of low‐grade squamous intraepithelial lesions (LSIL).

Reply to triage of women with minor abnormal cervical cytology: Meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types.

We welcome the comment of Benevolo et al concerning our meta-analysis of the accuracy of a 5type human papillomavirus (HPV) messenger ribonucleic acid (mRNA) assay and the 13-type HPV DNA test (Hybrid Capture 2 [HC2]) to detect cervical precancerous lesions (grade 2 cervical intraepithelial neoplasia or worse [CIN21] or CIN31) in women with a cytology result of atypical squamous cells of undetermined significance (ASC-US) or lowgrade squamous intraepithelial lesions (LSIL). We did not include their study because of incomplete verification with a reference test, and because the randomness of the verification of triage test positive and negative results was not assured. However, we agree that the positive predictive values (PPVs), if they result from the verification of the large majority of positive cases, do not suffer from verification bias. Moreover, intrastudy PPV ratios depend mainly on test accuracy because the underlying prevalence of disease is constant within a given study. In our meta-analysis, the test positivity rates pooled from the 5 studies that were included that evaluated both tests were 37% and 72%, respectively, for the mRNA and HC2 test (ratio, 0.51) in ASC-US and 39% and 73%, respectively, (ratio, 0.47) in LSIL. RNA triage reduced the burden for colposcopy referral to approximately onehalf compared with triage with HC2. The pooled PPVs of the mRNA testing for underlying high-grade CIN were similar in ASC-US and LSIL (43% and 41%, respectively). The PPVs of HC2 were substantially lower (34% and 29%, respectively, in ASC-US and LSIL). Moreover, the PPV (posttest probability) of HC2 in the triage of LSILs hardly differed from the pretest probability (25%), thereby underscoring the generally low efficiency of this test to triage women with this cytological abnormality, as also concluded by Benevolo et al and from previous reviews. Another clinically relevant parameter, derived from diagnostic test accuracy reviews, is the risk of precancerous lesions among negative triage test findings (the complement of the negative predictive value). In our meta-analysis, the pooled risk for CIN21 was 3% and 5%, respectively, when negative on HC2 and 8% and 10%, respectively, when RNA negative in women with ASC-US or LSIL cytology. Only in women with ASC-US and a negative HC2 test might the risk of underlying precancer be considered low enough to refer them back to the screening program. Women with a negative 5-type RNA test cannot be reassured that they are free of precancer and therefore should be kept under surveillance. Contrary to what Benevolo et al state, the range in interstudy variation of the PPV was not lower than for specificity, reflecting variability in local cytological standards and the inherent underlying prevalence of the disease. In primary screening for a rare disease, test negativity (the complement of test positivity) (FN 1 TN)/(TN1FN1FP1TP) approximates specificity (TN/ [FP1TN]) since the FN and TP are small. However, in triage of cytological abnormalities, this approximation does not hold. (Abbreviations: FN, TN, TP, FP: number of false-negatives, true-negatives, true-positives, falsepositives).

Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis

BACKGROUND Incomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure. METHODS We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models. FINDINGS 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4-25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9-23·2] for laser conisation to 25·9% [22·3-29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9-8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2-7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8-65·5) and 84·4% (79·5-88·4), respectively, for the margin status, and 91·0% (82·3-95·5) and 83·8% (77·7-88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free. INTERPRETATION The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status. FUNDING European Federation for Colposcopy and Institut national du Cancer (INCA).

Genotyping for human papillomavirus types 16 and 18 in women with minor cervical lesions: A systematic review and meta-analysis

Background High-risk human papillomavirus (hrHPV) testing to triage women with minor cervical lesions generates many referrals. Purpose To evaluate the accuracy of genotyping for HPV types 16 and 18 and its utility as a second triage step after hrHPV testing in women with minor cervical lesions. Data Sources Searches of 4 bibliographic databases, without language restrictions, from 1 January 1999 to 1 February 2016. Study Selection Studies involving women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL) who were triaged with tests for hrHPV and HPV 16/18 to find cervical intraepithelial neoplasia (grade ≥2 [CIN2+] or grade ≥3 [CIN3+]). Data Extraction Independent study selection, extraction of data, and quality assessment by 2 reviewers. Data Synthesis Twenty-four moderate- to good-quality studies involving 8587 women with ASC-US and 5284 with LSIL were found. The pooled sensitivity of HPV 16/18 genotyping for CIN3+ was about 70% for women with either ASC-US or LSIL. The pooled specificity (with a threshold of grade <2 CIN) was 83% (95% CI, 80% to 86%) for women with ASC-US and 76% (CI, 74% to 79%) for those with LSIL. The average risk for CIN3+ was 17% and 19% in HPV 16/18-positive women with ASC-US and LSIL, respectively, and was 5% in hrHPV-positive but HPV 16/18-negative women with either ASC-US or LSIL. Limitation Methodological and technical heterogeneity among studies; insufficient data to assess accuracy of separate assays. Conclusion Testing for HPV 16/18 to triage women with minor abnormal cytology is poorly sensitive but may be useful as a second triage test after hrHPV testing, with direct referral if the woman is positive for HPV 16/18. Whether colposcopy or repeated testing is recommended for hrHPV-positive but HPV 16/18-negative women depends on local decision thresholds that can be derived from pretest-posttest probability plots. Primary Funding Source 7th Framework Programme of the European Commission.

Triage of ASC-H: A meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer.

Women with a cytological diagnosis of atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion (ASC‐H) are usually immediately referred for colposcopy. However, triage may reduce the burden of the diagnostic workup and prevent overtreatment.

Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva: A systematic review and meta-analysis

In this updated systematic review and meta‐analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR‐based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I2 statistic was used to describe the amount of heterogeneity. In meta‐regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1–44.4%). Overall, 76.3% (95% CI: 70.1–82.1%) of VIN lesions tested HPV‐positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5–95.5%) and 2.0% (95% CI: 0–10.0%), respectively. Substantial between‐study heterogeneity was observed (vulvar cancer: I2 = 88.4%; VIN: I2 = 90.7%) with the largest variation between geographical regions. Among HPV‐positive cases, the predominant high‐risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions.

High‐risk HPV testing in the management of atypical glandular cells: A systematic review and meta‐analysis

Whereas the utility of high‐risk HPV (hrHPV) testing is widely accepted in triage of women with atypical squamous lesions, its role in managing atypical glandular cells (AGC) is not fully elucidated. A systematic review and meta‐analysis were performed to evaluate the accuracy of hrHPV testing in the management of women with AGC to detect underlying high‐grade intraepithelial neoplasia or worse, and adenocarcinoma in situ or worse (AIS+). Additionally, the diagnosis of extra‐cervical cancer was considered as an outcome in this review. A bibliographic database search (PubMed, EMBASE, CENTRAL) identified twelve eligible studies. The occurrence of cervical intraepithelial neoplasia grade two or worse including AIS+ (CIN2+/AIS+), was 19.8% among women with AGC, and 55.7% among women with AGC and concurrent squamous lesions (atypical squamous cells of undetermined significance or worse, ASC‐US+). The pooled sensitivity and specificity of hrHPV‐testing with Hybrid Capture 2 (HC2) to detect CIN2+/AIS+ in women with AGC was 90.0% (95% CI = 85.1–93.4%) and 75.1% (95% CI = 64.8–83.2%), respectively. Women who were hrHPV‐negative, demonstrated an increased risk for extra‐cervical malignancy (endometrium, fallopian tube, ovary). In women of 50y and older, a hrHPV‐negative result was linked with a 18.0% chance of extra‐cervical malignancy, while the chance of cervical pre‐cancer and cancer was 0.4 and 0.0%, respectively. In conclusion, given the high risk of underlying CIN2+/AIS+, women with AGC should be referred directly to colposcopy. However, hrHPV test results in combination with the age, appears to improve the diagnostic process by distinguishing the risk for cervical versus non‐cervical lesions.

Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study

Background:Increasing data suggest that aspirin use may improve cancer survival; however, the evidence is sparse for ovarian cancer.Methods:We examined the association between postdiagnosis use of low-dose aspirin and mortality in a nationwide cohort of women with epithelial ovarian cancer between 2000 and 2012. Information on filled prescriptions of low-dose aspirin, dates and causes of death, and potential confounding factors was obtained from nationwide Danish registries. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer-specific or other-cause mortality associated with low-dose aspirin use.Results:Among 4117 patients, postdiagnosis use of low-dose aspirin was associated with HRs of 1.02 (95% CI: 0.87–1.20) for ovarian cancer mortality and 1.06 (95% CI: 0.77–1.47) for other-cause mortality. Hazard ratios remained neutral according to patterns of low-dose aspirin use, including prediagnosis use or established mortality predictors.Conclusions:Low-dose aspirin use did not reduce mortality among ovarian cancer patients.

Statin use and mortality among endometrial cancer patients: a Danish nationwide cohort study: Statin use and endometrial cancer mortality

Statin use has been linked to improved prognosis of some cancer types, however, for endometrial cancer, the results are equivocal. We therefore examined the effect of statin use on endometrial cancer mortality. From the Danish Cancer Registry, we identified all women in Denmark aged 30–84 years with primary endometrial cancer during 2000–2012. Data on drug use, mortality outcomes and potential confounders were retrieved from nationwide registries. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer‐specific and other‐cause mortality associated with statin use. Among 6,694 endometrial cancer patients, 753 died from endometrial cancer and 765 from other causes during a median follow‐up of 4.5 year (interquartile range: 1.9–8.1). We observed an inverse association between time‐varying postdiagnosis statin use (≥2 prescriptions) and endometrial cancer mortality (HR: 0.61, 95% CI: 0.48–0.77) compared to non‐use (<2 prescriptions). The associations did not differ substantially by intensity or cumulative amount of statin use. In secondary analyses including prediagnosis statin use, we observed reduced mortality among both continuing (pre‐ and postdiagnosis) users (HR 0.70, 95% CI 0.53–0.92) and new (postdiagnosis only) users (HR 0.43, 95% CI 0.29–0.65) compared to “never users.” In sensitivity analyses with fixed exposure periods after the endometrial cancer diagnosis, the inverse association was more pronounced more than 5 years after the diagnosis. Our findings suggest that statin use may be associated with improved survival in endometrial cancer patients.