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.
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.
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.
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.
European Federation for Colposcopy and Institut national du Cancer (INCA).
The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single‐nucleotide polymorphisms in a large ...case‐control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA‐DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79‐0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04‐1.31, P = .008) and with high‐grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70‐0.87, P = 7.1 × 10−6; rs2844511: OR 1.13, 95% CI 1.01‐1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75‐0.91, P = 6.9 × 10−5; rs2844511: OR 1.14, 95% CI 1.04‐1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low‐grade dysplasia (OR 1.26, 95% CI 1.04‐1.54, P = .019). In case‐only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA‐DQA1, suggesting extensive co‐regulation. All three genes were upregulated in HPV16‐positive samples. In stratified analyses, rs9272117 was associated with HLA‐DQA1 levels, specifically in HPV‐positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA‐DQA1. Altogether, our results support 6p21.32‐33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA‐DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.
What's new?
The HLA locus, on chromosome 6, appears to contribute to cervical cancer risk, according to some studies. Genome wide association studies have uncovered two candidate variants on that chromosome: rs2844511, at the HLA‐DQ1 gene, and rs9272117, located in an intron of lncRNA HCP5, downstream of the MICA gene. Here, the authors tested the contribution of the two variants through genotyping of 2500 cervical cancer cases and 1500 healthy controls. Both variants showed an association with cervical cancer and with high‐grade dysplasia, and they modulated the expression levels of nearby genes in cervical cells, providing evidence for the first cervical cancer susceptibility locus.
Human papillomavirus (HPV)-related screening technologies and HPV vaccination offer enormous potential for cancer prevention, notably prevention of cervical cancer. The effectiveness of these ...approaches is, however, suboptimal owing to limited implementation of screening programmes and restricted indications for HPV vaccination. Trials of HPV vaccination in women aged up to 55 years have shown almost 90% protection from cervical precancer caused by HPV16/18 among HPV16/18-DNA-negative women. We propose extending routine vaccination programmes to women of up to 30 years of age (and to the 45-50-year age groups in some settings), paired with at least one HPV-screening test at age 30 years or older. Expanding the indications for HPV vaccination and much greater use of HPV testing in screening programmes has the potential to accelerate the decline in cervical cancer incidence. Such a combined protocol would represent an attractive approach for many health-care systems, in particular, countries in Central and Eastern Europe, Latin America, Asia, and some more-developed parts of Africa. The role of vaccination in women aged >30 years and the optimal number of HPV-screening tests required in vaccinated women remain important research issues. Cost-effectiveness models will help determine the optimal combination of HPV vaccination and screening in public health programmes, and to estimate the effects of such approaches in different populations.
Objective To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade ...3 or cancer (CIN3+).Design Multinational cohort study with joint database analysis.Setting Seven primary HPV screening studies in six European countries.Participants 24 295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up.Main outcome measure Long term cumulative incidence of CIN3+.Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%.Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.
In human papillomavirus (HPV) cervical cancer screening, cytology is used as triage to counter the low specificity of HPV testing. VALID‐SCREEN is a EU‐multicenter, retrospective study conducted to ...evaluate the clinical performance of the FAM19A4/miR124‐2 methylation‐based molecular triage test as a substitute or addition to cytology as reflex testing of HPV screen positive women. FAM19A4/miR124‐2 methylation test (QIAsure Methylation Test) was evaluated in 2384 HPV‐positive cervical screening samples, from women 29‐76 years of age, derived from four EU countries. Specimens were collected in ThinPrep or SurePath media, HPV‐status, concurrent cytology, and histology diagnosis were provided by the parent institutes. The control population consisted of women with no evidence of disease within 2 years of follow‐up. A total of 899 histologies were retrieved; 527 showed no disease, 124 CIN2 (5.2%), 228 CIN3 (9.6%) and 20 cervical cancers (0.8%); 19 of 20 screen‐detected cervical cancers were found methylation‐positive (sensitivity 95%). Overall specificity of FAM19A4/miR124‐2 methylation test was 78.3% (n = 2013; 95%CI: 76‐80). The negative predictive value of hrHPV positive, methylation‐negative outcomes were 99.9% for cervical cancer (N = 1694; 95%CI: 99.6‐99.99), 96.9% for ≥CIN3 (95%CI: 96‐98), and 93.0% for ≥CIN2 (95%CI: 92‐94). Overall sensitivity for CIN3 using FAM19A4/miR124‐2 methylation test was 77% (n = 228; 95%CI: 71‐82). CIN3 sensitivity was uniform between centers independent of sample collection medias, DNA extraction methods and HPV screening tests. Being objectively reported compared to the subjectivity of cytology, equally performing across settings and screening methods, the FAM19A4/miR124‐2 methylation constitute an alternative/supplement to cytology as triage method to be investigated in real‐life pilot implementation.
What's new?
In HPV screening for cervical cancer, cytology has been used to triage those women who are hrHPV‐positive. However, cytology is subjective, and skilled cytologists are often in short supply. A molecular test using specific biomarkers might offer better results. In this large European study, the authors found that a new standardized test for the methylation biomarker combination FAM19A4/miR124‐2 did indeed yield results that were equal to or better than triage by cytology, in determining which hrHPV‐positive women should be referred for colposcopy.
Summary
Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV‐associated ...lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV‐associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus‐based guideline “Vaccination recommendations for the prevention of HPV‐associated lesions”, which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta‐analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus‐based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.
Widespread adoption of primary human papillomavirus (HPV)‐based screening has encouraged the search for a triage test which retains high sensitivity for the detection of cervical cancer and ...precancer, but increases specificity to avoid overtreatment. Methylation analysis of FAM19A4 and miR124‐2 genes has shown promise for the triage of high‐risk (hr) HPV‐positive women. In our study, we assessed the consistency of FAM19A4/miR124‐2 methylation analysis in the detection of cervical cancer in a series of 519 invasive cervical carcinomas (n = 314 cervical scrapes, n = 205 tissue specimens) from over 25 countries, using a quantitative methylation‐specific PCR (qMSP)‐based assay (QIAsure Methylation Test®). Positivity rates stratified per histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region were calculated. In total, 510 of the 519 cervical carcinomas (98.3%; 95% CI: 96.7–99.2) tested FAM19A4/miR124‐2 methylation‐positive. Test positivity was consistent across the different subgroups based on cervical cancer histotype, FIGO stage, hrHPV status, hrHPV genotype, sample type and geographical region. In conclusion, FAM19A4/miR124‐2 methylation analysis detects nearly all cervical carcinomas, including rare histotypes and hrHPV‐negative carcinomas. These results indicate that a negative FAM19A4/miR124‐2 methylation assay result is likely to rule out the presence of cervical cancer.
What's new?
Methylation analysis of host cell genes is a promising strategy for the triage of women who test positive for high‐risk human papillomavirus (hrHPV). Its ability to consistently detect cervical cancer, however, warrants further evaluation. In this retrospective cross‐sectional study of more than 500 cervical cancer cases worldwide, methylation analysis using FAM19A4 and miR124‐2 genes successfully detected the vast majority of cervical carcinomas. Detection by FAM19A4/miR124‐2 methylation analysis was consistent regardless of multiple factors, including hrHPV status and genotype, cancer histotype, sample type, and geographical region. The findings suggest that a negative FAM19A4/miR124‐2 methylation test result is likely to rule out cervical cancer.
The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first ...surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting.
Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability.
A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%.
This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer.
PDF
