Esther L. Moss

European Federation of Colposcopy quality standards Delphi consultation.

OBJECTIVE Optimization of colposcopy practice requires a program of quality assurance including the monitoring of performance indicators. The European Federation of Colposcopy (EFC) aimed to identify a list of quality indicators for colposcopic practice, which are relevant, reproducible and practical across all of the member countries. STUDY DESIGN A five-round Delphi consultation was conducted in 30 full, 5 associate and 4 potential member countries in order to determine a core list of quality indicators including optimal target ranges. RESULTS Six indicators were selected from a list of 37 proposed standards. Two further rounds of consultation were conducted to determine expert opinion on the target level for each of the standards. The six indicators identified and corresponding targets were: documentation of whether or not the squamocolumnar junction has been seen (100%); colposcopy prior to treatment for abnormal cervical cytology (100%); percentage of excisional treatments/conizations to contain cervical intra-epithelial neoplasia grade two or worse (≥85%); percentage of excised lesions/conizations with clear margins (≥80%); and two indicators concerned the number of cases to be colposcoped per year: ≥50 low-grade/minor and ≥50 high-grade/major cytological abnormalities. CONCLUSIONS A Delphi consultation identified six EFC quality indicators. These are a first step in an international attempt to optimize colposcopy practice throughout Europe. The current targets are based on expert opinion and may need adaptation in the future. Data are needed from European colposcopy settings to determine whether the indicators are achievable practice-based benchmarks and will help in improving and fine tuning the list of performance indicators and targets.

Knowledge of human papillomavirus and the human papillomavirus vaccine in European adolescents: a systematic review

Background The human papillomavirus (HPV) vaccine is recommended for adolescent girls in many European countries, however there is huge variation in vaccine uptake. Methods A mixed methods systematic review to ascertain the level of HPV and HPV vaccine knowledge that exists among European adolescents. Two electronic databases, Ovid Medline and PsychInfo, were searched from origin to September 2014. Meta-analysis was performed for the two primary outcome measures (‘have you heard of HPV?’ and ‘have you heard of the HPV vaccine?’), assessing for the correlation between gender and knowledge. This was supplemented with meta-synthesis for the remaining associations and secondary outcomes. Results 18 papers were included in the final review. Overall European adolescents had poor understanding of basic HPV and HPV vaccine knowledge. Meta-analysis identified that female adolescents are more likely to have heard of HPV (n=2598/5028 girls versus n=1033/3464 boys; OR 2.73, 95% CI 1.86–3.99) and the HPV vaccine (n=1154/2556 girls versus n=392/2074 boys; OR 5.64, 95% CI 2.43–13.07), compared to males. Age, higher education and a positive vaccination status were also associated with increased awareness. There was limited appreciation of more detailed HPV knowledge and uncertainty existed regarding the level of protection offered by the vaccine and the need for cervical screening post vaccination. Conclusions The delivery of HPV education to European adolescents needs to be re-evaluated, since at present there appears to be significant deficiencies in their basic knowledge and understanding of the subject. Increasing HPV knowledge will empower adolescents to make informed choices regarding participation with HPV related cancer prevention health strategies.

Is the colposcopically directed punch biopsy a reliable diagnostic test in women with minor cytological lesions

Objective The study aimed to determine the accuracy of the colposcopy-directed punch biopsy (punch) to detect or exclude high-grade cervical intraepithelial neoplasia (CIN 2 or 3) in women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) cytological result and minor colposcopic findings. Materials and Methods In a diagnostic test accuracy study, women with ASCUS or LSIL cytological result and minor colposcopic changes had a single colposcopy-targeted punch biopsy was performed immediately followed by a loop electrocautery excision procedure (LEEP) biopsy. The trial was powered to detect a level of &kgr; for a dichotomous outcome of 0.4 (i.e., fair-to-moderate agreement), with a two-sided significance level of 5% and a power of 90%. Accuracy parameters were computed using a cutoff for positive punch biopsy result of CIN 1+ and CIN 2+ for an outcome of CIN 2+ and CIN 3+ assessed in the LEEP specimen. Results Sixty-eight punch biopsy/LEEP–paired samples were analyzed. Of the 8 CIN 3 lesions, 6 and 4 were detected at cutoff CIN 1+ and CIN 2+, respectively (sensitivity, 50% and 75%). The corresponding specificities were 65% (39/60) and 97% (58/60). The punch biopsies identified only 14 (67%) or 6 (20%) of the 21 CIN 2+ lesions at cutoff CIN 1+ or CIN 2+, respectively. Of the punch biopsies, 31 (45.6%) accurately detected the severity of cervical abnormality. Conclusions A single colposcopically directed punch biopsy appears to be insufficient to exclude underlying CIN 2 or 3.

Surgical and oncological outcome of total laparoscopic radical hysterectomy in obese women with early-stage cervical cancer.

Objective To evaluate the clinical experience of the total laparoscopic radical hysterectomy (TLRH) for the surgical management of cervical cancer in obese (body mass index [BMI] >30 kg/m2) and nonobese (BMI <30 kg/m2) women. Methods Data were collected prospectively on intraoperative and postoperative parameters and complications for all women undergoing a TLRH for cervical cancer. Patients were classified as obese, BMI >30 kg/m2, or nonobese, BMI <30 kg/m2. Assessment of surgical radicality was made by comparing the excision specimens in the 2 groups with a cohort of open radical hysterectomy cases performed before the introduction of the TLRH. Results A total of 58 women underwent a TLRH; 15 (25.9%) were obese and 43 (74.1%) were in the nonobese group. There was no significant difference in intraoperative blood loss or median duration of surgery between the obese and nonobese groups. The median hospital stay in both groups was 3 days (range, 2–13 days). Four cases were converted to laparotomy (7%); all were in the nonobese group. Postoperatively, 3 patients developed ischemic ureterovaginal fistulae (5%) between days 5 and 7 after surgery; all were in the nonobese group. There was no significant difference in the parametrial length, maximum vaginal cuff length, and number of lymph nodes excised between the 2 groups. To date, there has been one recurrence during the median follow-up period of 19 months (range, 3–42 months). She belonged to the nonobese group. Conclusions The TLRH is a surgically safe procedure for early-stage cervical cancer. Obesity did not adversely affect the performance of TLRH or the radicality of the excision. In obese women, TLRH should be the favored route of surgery for all women who require a radical hysterectomy owing to its favorable perioperative outcome and short hospital stay.

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).

Neuroendocrine Carcinoma of the Cervix: Review of a Series of Cases and Correlation With Outcome.

Introduction. Neuroendocrine carcinoma (NEC) of the cervix is associated with a poor prognosis despite multimodal treatment. The correct diagnosis of this tumor type is imperative to provide clinicians and patients with prognostic information and ensure that appropriate treatment is provided. Methods. A clinicopathological study was undertaken on all cervical tumors registered as NEC with the West Midlands Cancer Intelligence Unit between January 1, 1998 and December 31, 2009. Of the 45 cases diagnosed during the study period, the tumor samples of 41 cases were traced, anonymized, and then independently reviewed by 2 gynecological pathologists. Results. The review confirmed 31/41 (78%) cases to be NEC, which overall, represented 1.3% of all the cervical cancers registered in the West Midlands over the period of the study. In the correct histological context, synaptophysin was the most sensitive and specific positive immunohistochemical marker of NEC differentiation. The cases that on review were confirmed as NEC had a significantly worse outcome than the non-NEC cases: median survival for NEC cases was 33.3 months versus 315.0 months for the non-NEC cases, P = .013. Conclusions. Histological review of a series of NECs has shown significantly reduced survival in those patients with confirmed NEC in comparison with those patients where a diagnosis of NEC was not confirmed. We propose morphological and immunohistochemical criteria for the diagnosis of cervical NEC; and discourage unqualified use of the term “small cell carcinoma” as this does not accurately convey the diagnosis of SCNEC. We urge pathologists to use the 2014 World Health Organization classification when reporting these tumors.

The diagnostic accuracy of colposcopy in previously treated cervical intraepithelial neoplasia.

Objective. To determine whether colposcopy is reliable in diagnosing cervical intraepithelial neoplasia in women who have undergone a previous cervical excision biopsy. Materials and Methods. A prospective study of women attending the colposcopy clinic at the University Hospital of North Staffordshire was performed between January 1998 and December 1999. Results. A clear histological diagnosis of the grade of cervical intraepithelial neoplasia was available for 469 in the treatment-naive group and 58 in the treatment group. &kgr; coefficients comparing the colposcopic impression (negative, low-grade, high-grade, or invasion) with histological diagnosis showed that there was no difference between the treatment-naive group, weighted &kgr; = 0.46, and the previous treatment group, weighted &kgr; = 0.47. The sensitivity, specificity, positive predictive value, and negative predictive value of colposcopy for any cervical diseasein the treatment-naive women were 93.9%, 51.9%, 96.7%, and 34.1%, respectively, compared with 77.6%, 66.7%, 86.4%, and 35.3% in previously treated women. The sensitivity of colposcopy fell when it was used to differentiate normal and low-grade disease from high-grade disease and invasion: 82.4%, 55.9%, 82.6%, and 49.6% for treatment-naive women, compared with 61.5%, 84.2%, 60.0% and 51.6%, respectively, for the previous treatment group. Conclusions. Previous treatment to the cervix does not seem to impair the ability of colposcopy to differentiate normal cervix from all grades of cervical abnormality in women where the squamocolumnar junction is visible. However, there is a suggestion that the sensitivity of colposcopy to differentiate negative/low-grade disease from high-grade disease/invasion is lower in previously treated women.

Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma

Real-time quantitative RT-PCR (qRT-PCR) is a powerful technique used for the relative quantification of target genes, using reference (housekeeping) genes for normalization to ensure the generation of accurate and robust data. A systematic examination of the suitability of endogenous reference genes for gene expression studies in endometrial cancer tissues is absent. The aims of this study were therefore to identify and evaluate from the thirty-two possible reference genes from a TaqMan(®) array panel their suitability as an internal control gene. The mathematical software packages geNorm qBasePLUS identified Pumilio homolog 1 (Drosophila) (PUM1), ubiquitin C (UBC), phosphoglycerate kinase (PGK1), mitochondrial ribosomal protein L19 (MRPL19) and peptidylpropyl isomerase A (cyclophilin A) (PPIA) as the best reference gene combination, whilst NormFinder identified MRPL19 as the best single reference gene, with importin 8 (IPO8) and PPIA being the best combination of two reference genes. BestKeeper ranked MRPL19 as the most stably expressed gene. In addition, the study was validated by examining the relative expression of a test gene, which encodes the cannabinoid receptor 1 (CB1). A significant difference in CB1 mRNA expression between malignant and normal endometrium using MRPL19, PPIA, and IP08 in combination was observed. The use of MRPL19, IPO8 and PPIA was identified as the best reference gene combination for the normalization of gene expression levels in endometrial carcinoma. This study demonstrates that the arbitrary selection of endogenous control reference genes for normalization in qRT-PCR studies of endometrial carcinoma, without validation, risks the production of inaccurate data and should therefore be discouraged.

FAU regulates carboplatin resistance in ovarian cancer.

The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel‐Biskis‐Reilly murine sarcoma virus (FBR‐MuSV)‐associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell lines sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short‐interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin‐induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal‐Wallis P = 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin‐induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real‐time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal‐Wallis P = 0.0261). These data support a role for FAU in the regulation of platinum‐resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer.

The invasive cervical cancer review: psychological issues surrounding disclosure

An audit of the screening history of all new cervical cancer cases has been a requirement since April 2007. While NHS cervical screening programmes (NHSCSP) guidance requires that women diagnosed with cervical cancer are offered the findings of the audit, as yet there has been no research to investigate the psychological impact that meeting to discuss the findings might have on patients. This is in spite of the fact that cytological under‐call may play a role in as many as 20% of cervical cancer cases. This review draws on the literature concerning breaking bad news, discussing cancer and disclosing medical errors, in order to gain insight into both the negative and positive consequences that may accompany a cervical screening review meeting. We conclude that while patients are likely to experience some distress at disclosure, there are also likely to be positive aspects, such as greater trust and improved perception of care.