Development of a technical external quality assurance scheme in non-gynaecological cytology in UK.

Technical external quality assurance (EQA) schemes are well established for histopathology and cervical cytology but, to date, sadly lacking for diagnostic cytology (DC). This timely review redresses the balance by describing the development and evaluation of a technical EQA scheme for DC available to the UK, Europe and beyond.

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

AIM: This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. METHODS: We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. RESULTS: HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. CONCLUSIONS: HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.

Uterine corpus metastasis in stage IA1 squamous carcinoma of the cervix.

•Treatment of stage 1A1 cancer of the cervix often involves preservation of the corpus.•Rarely metastasis to the corpus can occur in these cases.

Subclinical infection and asymptomatic carriage of gastrointestinal zoonoses: occupational exposure, environmental pathways, and the anonymous spread of disease.

Asymptomatic carriage of gastrointestinal zoonoses is more common in people whose profession involves them working directly with domesticated animals. Subclinical infections (defined as an infection in which symptoms are either asymptomatic or sufficiently mild to escape diagnosis) are important within a community as unknowing (asymptomatic) carriers of pathogens do not change their behaviour to prevent the spread of disease; therefore the public health significance of asymptomatic human excretion of zoonoses should not be underestimated. However, optimal strategies for managing diseases where asymptomatic carriage instigates further infection remain unresolved, and the impact on disease management is unclear. In this review we consider the environmental pathways associated with prolonged antigenic exposure and critically assess the significance of asymptomatic carriage in disease outbreaks. Although screening high-risk groups for occupationally acquired diseases would be logistically problematical, there may be an economic case for identifying and treating asymptomatic carriage if the costs of screening and treatment are less than the costs of identifying and treating those individuals infected by asymptomatic hosts.

High-grade vaginal intraepithelial neoplasia: can we be selective about who we treat?

OBJECTIVE: To determine the role of conservative management in high-grade vaginal intraepithelial neoplasia (HG VaIN). DESIGN: Retrospective observational study. SETTING: Northern Gynaecological Oncology Centre, Gateshead, UK. POPULATION: A total of 100 women with histologically-proven HG VaIN. METHODS: Review of patient records from 1995 to 2011. MAIN OUTCOME MEASURES: Rates of progression to cancer, treatment remission, and disease recurrence, particularly post-treatment when vaginoscopy is normal but cytology is abnormal. RESULTS: Of 100 women referred, 69 underwent initial treatment of whom 47 (68%) went into remission: of these, seven developed a recurrence after a median follow-up of 29 months (range 15-214 months). Of the 31 women managed conservatively with cytological and vaginoscopic surveillance, no cancers developed after a median follow-up of 35 months (range 2-230 months). Rate of overall progression to cancer was 3% and all were detected among the initial treatment group after a median of 59 months (range 8-249 months). Post-treatment, when normal vaginoscopy was accompanied by abnormal cytology, two categories existed. Of 24 cases with low-grade cytological abnormality, recurrence of HG VaIN occurred in seven (29%) after a median follow-up of 12 months (range 2-110 months). Of 19 cases with HG cytological abnormality, 15 (79%) developed recurrence at a median follow-up of 7 months (range 2-21 months), giving a hazard ratio 5.6 (95% confidence interval 2.0-15.5, P = 0.001). CONCLUSIONS: It is possible to select women with HG VaIN for conservative surveillance with excellent results. The majority of women undergoing initial treatment will enter remission. Post-treatment, if cytological abnormality develops in the presence of normal vaginoscopy, the majority of women will develop histological HG VaIN recurrence.

Tumour-free distance from serosa is a better prognostic indicator than depth of invasion and percentage myometrial invasion in endometrioid endometrial cancer.

OBJECTIVE: To evaluate the prognostic performance of tumour-free distance (TFD) compared with depth of invasion (DOI) and percentage of myometrial invasion (MI). DESIGN: Retrospective cohort study. SETTING: Regional gynaecological oncology centre. POPULATION: All women identified with stage I-III endometrioid endometrial carcinoma from January 2000 to December 2007, who had surgery at the Northern Gynaecological Oncology Centre (NGOC). METHODS: Surgicopathological, follow-up and survival data were collected. Univariate and multivariate analyses were performed comparing TFD, DOI and MI with known prognostic factors. The prognostic accuracy of TFD was assessed by receiver operating characteristic (ROC) curve analyses, and an optimum cut-off was proposed. MAIN OUTCOME MEASURES: Death from disease, recurrence and pelvic lymph node involvement. RESULTS: A total of 288 women were identified. The median follow-up time was 67 months, with 40 recurrences and 32 disease-related deaths. When TFD, DOI and MI were separately examined in multivariate analyses with other covariates, TFD was an independent predictor of death from disease (HR 1.22; 95% CI 1.00-1.48; P = 0.05). In multivariate analyses including all three measures together (TFD, DOI and MI), TFD was an independent predictor of death from disease (HR 1.49; 95% CI 1.03-2.16; P = 0.04) and recurrence (HR 1.39; 95% CI 1.01-1.91; P = 0.05). TFD was also an independent predictor of lymph node involvement when examined separately (OR 0.74; 95% CI 0.56-0.96; P = 0.03), and together with DOI and MI (OR 0.67; 95% CI 0.49-0.92; P = 0.01), in women who had pelvic lymphadenectomy (n = 86). A TFD cut-off of 1.75 mm showed good prognostic performance. CONCLUSIONS: The TFD measure may be a more accurate method of representing myometrial invasion in the staging for endometrial cancer.

Intra-operative frozen section analysis for suspected early-stage ovarian cancer: 11 years of Gateshead Cancer Centre experience.

OBJECTIVE: In centres in which intra-operative frozen section (FS) analysis is not performed, 'apparent' early-stage ovarian cancer diagnosed after surgery on paraffin section may require further restaging laparotomy or adjuvant chemotherapy. Previous studies on FS analysis have reported high sensitivity, specificity and overall accuracy. The objective of this article is to present the largest published dataset on the accuracy of FS analysis over an 11-year period from a single institution. DESIGN: Diagnostic test accuracy. SETTING: Northern Gynaecological Oncology Centre and Department of Cellular Pathology, Gateshead, UK. POPULATION: 1439 intra-operative FS analyses performed between January 2000 and December 2010 for suspected ovarian cancer. METHODS: Prospectively collected data on FS analysis were compared with gold standard paraffin section. MAIN OUTCOME MEASURES: Sensitivity, specificity, likelihood ratios and post-test probability. RESULTS: The overall sensitivity and specificity of FS analysis were 91.2% and 98.6%, respectively. Positive and negative likelihood ratios were 64.7% and 0.09%, respectively. The pre-test probability of an ovarian tumour being borderline or malignant was 45.8%. When FS analysis was reported to be positive, the post-test probability increased to 98% (confidence interval, 97-99%). Conversely, when FS analysis was reported to be negative, the post-test probability decreased to 7% (confidence interval, 6-9%). The majority of false test results were either borderline tumours or of mucinous differentiation. CONCLUSIONS: Intra-operative FS analysis has excellent diagnostic test accuracy and assists gynaecological oncologists to perform the appropriate surgery in 95% of cases, thereby preventing the morbidity of surgical staging in benign cases and the morbidity of restaging procedures or chemotherapy in early-stage malignant tumours.

Laparoscopic assisted radical vaginal hysterectomy versus radical abdominal hysterectomy--a randomised phase II trial: perioperative outcomes and surgicopathological measurements.

OBJECTIVE: To evaluate perioperative surgical outcomes and resection size for laparoscopically assisted radical vaginal hysterectomy (LARVH) compared with radical abdominal hysterectomy (RAH). DESIGN: A prospective randomised phase II trial. POPULATION: Early stage IB cervical cancer requiring radical surgical treatment. SETTING: Northern Gynaecological Oncology Centre, Gateshead, UK. METHODS: Fifteen women were randomised to LARVH and to RAH. MAIN OUTCOME MEASURES: Outcomes included requirement in days for bladder catheterisation after surgery, operating time, blood loss, hospital stay, opiate pain relief, complication rate, time to normal activities and resection size of major ligaments and vaginal cuff. Results Statistically significant differences were found between LARVH and RAH, respectively: median duration of bladder catheterisation, 4 days versus 21 days (P = 0.003); median operating time, 180 minutes versus 138 minutes (P = 0.05); median blood loss, 400 ml versus 1000 ml (P = 0.05), median hospital stay, 5 days versus 7 days (P = 0.04) and median opiate requirement in the first 36 hours postoperatively, 30 mg versus 53 mg (P = 0.004). The mean resected lengths for LARVH versus RAH, respectively, were: mean resected vaginal cuff, 1.26 cm versus 2.16 cm (P = 0.014); mean resected cardinal ligament length, 1.30 cm versus 2.79 cm (P = 0.013) and mean resected uterosacral ligament length, 1.47 cm versus 4.68 cm (P = 0.034). CONCLUSIONS: This study confirms the short-term surgical benefits of LARVH. In addition, LARVH has been shown to be a less radical procedure than RAH, supporting the need for strict patient selection and to restrict the procedure to small tumours.

An audit of cervical cytology in HIV-positive women.

OBJECTIVE: To investigate whether a cohort of human immunodeficiency virus-positive (HIV+) women were having annual cervical cytology as recommended by the English National Health Service cervical screening programme (NHSCSP) guidelines. METHODS: An audit of cervical cytology in an HIV+ cohort of 187 women by obtaining their last cervical cytology result and recall from local cytology services. RESULTS: Of the 187 women in the audit, two were ineligible, leaving 185 women, 167 (90.3%) of whom were aged 25-64 years and eligible for screening. Of the 185 women, 126 (68.1%) had a cytology history, 50 (27%) had never had cervical cytology and nine (4.9%) had inadequate details to ascertain whether or not they had a cytology history. Of the 126 with a cytology record, 34 (27%) had a current cytological abnormality, which was low grade in 25 (19.8%) and high grade in nine (7.1%). Among women aged 25-64 years attending the clinic, these percentages were significantly higher than expected for England as a whole (P < 0.001). Of 126 women with a cytology record, 29 (23%) were overdue for their recall date and of these the previous test was abnormal in 14 (48.3%). Cytology tests were taken within the community setting in 61 (48.4%), whereas 65 (51.6%) were seen either at an HIV sexual health clinic or were under colposcopy follow-up. Of 91 women with negative cytology only 50 (54.9%) were recommended for repeat in 12 months. CONCLUSION: This audit demonstrates a high rate of cytological abnormalities among HIV+ women compared with the screening population at large. Implementation of NHSCSP guidelines has been difficult and requires improved care pathways between HIV clinics, primary care and laboratories.

BSCC Code of Practice--fine needle aspiration cytology.

The British Society for Clinical Cytology Code of Practice on fine needle aspiration cytology complements that on exfoliative cytopathology, which was published in the last issue (Cytopathology 2009;20:211-23). Both have been prepared with wide consultation within and outside the BSCC and have been endorsed by the Royal College of Pathologists. A separate code of practice for gynaecological cytopathology is in preparation. Fine needle aspiration (FNA) cytology is an accepted first line investigation for mass lesions, which may be targeted by palpation or a variety of imaging methods. Although FNA cytology has been shown to be a cost-effective, reliable technique its accurate interpretation depends on obtaining adequately cellular samples prepared to a high standard. Its accuracy and cost-effectiveness can be seriously compromised by inadequate samples. Although cytopathologists, radiologists, nurses or clinicians may take FNAs, they must be adequately trained, experienced and subject to regular audit. The best results are obtained when a pathologist or an experienced and trained biomedical scientist (cytotechnologist) provides immediate on-site assessment of sample adequacy whether or not the FNA requires image-guidance. This COP provides evidence-based recommendations for setting up FNA services, managing the patients, taking the samples, preparing the slides, collecting material for ancillary tests, providing rapid on-site assessment, classifying the diagnosis and providing a final report. Costs, cost-effectiveness and rare complications are taken into account as well as the time and resources required for quality control, audit and correlation of cytology with histology and outcome. Laboratories are expected to have an effective quality management system conforming to the requirements of a recognised accreditation scheme such as Clinical Pathology Accreditation (UK) Ltd.

The BSCC code of practice--exfoliative cytopathology (excluding gynaecological cytopathology).

Exfoliative cytopathology (often referred to as non-gynaecological cytology) is an important part of the workload of all diagnostic pathology departments. It clearly has a role in the diagnosis of neoplastic disease but its role in establishing non-neoplastic diagnoses should also be recognised. Ancillary tests may be required to establish a definitive diagnosis. Clinical and scientific teamwork is essential to establish an effective cytology service and staffing levels should be sufficient to support preparation, prescreening, on-site adequacy assessment and reporting of samples as appropriate. Routine clinical audit and histology/cytology correlation should be in place as quality control of a cytology service. Cytology staff should be involved in multidisciplinary meetings and appropriate professional networks. Laboratories should have an effective quality management system conforming to the requirements of a recognised accreditation scheme such as Clinical Pathology Accreditation (UK) Ltd. Consultant pathologists should sign out the majority of exfoliative cytology cases. Where specimens are reported by experienced biomedical scientists (BMS), referred to as cytotechnologists outside the UK, this must only be when adequate training has been given and be defined in agreed written local protocols. An educational basis for formalising the role of the BMS in exfoliative cytopathology is provided by the Diploma of Expert Practice in Non-gynaecological Cytology offered by the Institute of Biomedical Science (IBMS). The reliability of cytological diagnoses is dependent on the quality of the specimen provided and the quality of the preparations produced. The laboratory should provide feedback and written guidance on specimen procurement. Specimen processing should be by appropriately trained, competent staff with appropriate quality control. Microscopic examination of preparations by BMS should be encouraged wherever possible. Specific guidance is provided on the clinical role, specimen procurement, preparation and suitable staining techniques for urine, sputum, semen, serous cavity effusion, cerebrospinal fluid, synovial fluid, cyst aspirates, endoscopic specimens, and skin and mucosal scrapes.

Expression of gonadotrophin releasing hormone receptor I is a favorable prognostic factor in epithelial ovarian cancer.

The majority of epithelial ovarian cancers originate in the ovarian surface epithelium. The ovarian surface epithelium is a hormonally responsive tissue, and hormones are thought to play a key role in the development of this type of cancer. Gonadotrophin releasing hormone II is one of 2 isoforms which are thought to act through gonadotrophin releasing hormone receptor I, and gonadotrophin releasing hormone II has been shown to cause growth inhibition of cultured ovarian surface epithelium. The aim of this study was to investigate the expression levels and prognostic significance of gonadotrophin releasing hormone II and the gonadotrophin releasing hormone receptor I in epithelial ovarian cancer. Gonadotrophin releasing hormone II and gonadotrophin releasing hormone receptor I messenger RNA expression was examined in 23 cancers and 7 normal ovarian surface epithelium samples by quantitative real time polymerase chain reaction. An ovarian cancer tissue microarray containing 139 cases was constructed and immunohistochemical analysis of gonadotrophin releasing hormone II and gonadotrophin releasing hormone receptor I protein expression was performed and correlated with clinical outcome data. Gonadotrophin releasing hormone II messenger RNA expression was lower in cancer samples compared to normal ovarian surface epithelium samples (P < .05). Gonadotrophin releasing hormone II protein expression correlated with histologic subtype (25% serous versus 45% nonserous, P < .05) but not with overall survival. Gonadotrophin releasing hormone receptor I messenger RNA expression was highest in serous tumors when compared to non serous (P < .05) and normal tissue (P < .001). Expression of the gonadotrophin releasing hormone receptor I protein was also found to correlate with patient survival (P < .05). We have demonstrated gonadotrophin releasing hormone II and its receptor, gonadotrophin releasing hormone receptor I, are present in clinical ovarian samples, and that gonadotrophin releasing hormone receptor I protein expression is a favorable prognostic factor, suggesting these proteins play an important role in the development of epithelial ovarian cancer.

Comparison of examination of the entire uterine cervix with routine cervical sampling in hysterectomy specimens from women with endometrial cancer.

BACKGROUND: Cervical involvement by endometrial cancer alters the FIGO stage and determines clinical management, but there are no accepted guidelines for cervical sampling of these cases. AIM: To assess whether sampling more than two "routine" blocks of the cervix (anterior and posterior) alters the pathological staging of hysterectomy specimens for endometrial cancer. METHODS: Histological involvement of the cervix was prospectively compared in hysterectomies performed for proven endometrial cancer (n = 61). Specimens had two "routine" blocks taken from anterior and posterior cervix; all of the remaining cervix was also processed for histological assessment. RESULTS: 61 cases of endometrial cancer had the entire uterine cervix processed. There were 54 cases of endometrioid adenocarcinoma and 7 special types. Twelve cases had cervical involvement (stage 2A or 2B), and seven cases were stage 3A or above, of which three also had cervical involvement. In none of the 61 cases did the additional cervical blocks (n = 544) taken alter the staging made on the "routine" blocks. CONCLUSION: Sampling of two blocks from the cervix appears sufficient for histological staging of endometrial cancer in hysterectomy specimens.

Vulvar intraepithelial neoplasia--the need for auditable measures of management.

OBJECTIVES: Surgical excision is currently the standard treatment for vulvar intraepithelial neoplasia (VIN). To date it has proved difficult to evaluate the management of VIN in reported series due to heterogeneity in datasets. The objective of this study was to justify standardised data presentation to permit comparison between series and facilitate determination of an optimal strategy for management of VIN. We propose auditable indicators of performance to benchmark management and outcomes. This may also enable definition of a surgical control arm for future novel therapy studies. STUDY DESIGN: Data from the Northern Gynaecological Oncology Centre (NGOC), UK on women with proven VIN diagnosed between 1989 and 2004 who attended the vulvar review clinic are presented and analysed alongside three large retrospective series by Jones et al. [Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women. Obstet Gynecol 2005;106(6):1319-26], Herod et al. [Herod JJ, Shafi MI, Rollason TP, Jordan JA, Luesley DM. Vulvar intraepithelial neoplasia: long term follow up of treated and untreated women. Br J Obstet Gynaecol 1996;103(5):446-52], McNally et al. [McNally OM, Mulvany NJ, Pagano R, Quinn MA, Rome RM. VIN 3: a clinicopathologic review. Int J Gynecol Cancer 2002;12(5):490-5] against proposed performance indicators to illustrate the deficiencies in current data presentation. RESULTS: Demographics and indicators such as degree of pathological expertise, definition of early stromal invasion and use of International Society for the study of Vulvovaginal Disease (ISSVD) classification were usually well documented. The description of lesions including size and focality were not always documented, nor the proportion examined by co-specialists. Numbers of primary treatments were well described but the indications for treatment, completeness of excision and VIN subclassification were not. Subsequent surgical treatments were inconsistently reported including the pathological details and intervals between treatments. Symptomatology was not well reported. Information on follow-up intervals and duration of follow-up with an indication of patient compliance was inadequate. Outcome data on recurrence of VIN and progression to carcinoma (early stromal invasion or frankly invasive carcinoma) were included in all series. CONCLUSIONS: Consensus on the ideal management of VIN or evaluation of new strategies will prove impossible without standardised data presentation. We propose a number of performance indicators that will facilitate evaluation of future studies or series against the current benchmark of surgical treatment for VIN.

Conservative surgical management of small-volume stage IB1 cervical cancer.

OBJECTIVE: To determine outcomes of women with small-volume stage IB1 disease managed by conservative surgical treatment. DESIGN: A retrospective review. SETTING: The Northern Gynaecological Oncology Center, Queen Elizabeth Hospital, Gateshead, UK. POPULATION: Women with stage IB1 cervical cancer who were managed by conservative surgery over a 6-year period between 1 January 2000 and 31 December 2005. MAIN OUTCOME MEASURES: Pelvic lymph node metastases, recurrence rates and outcome survival. RESULTS: A total of 17 women with conservatively managed stage IB1 cervical cancer were identified. Their ages were 25-67 years, median 37 years, 4 women were nulliparous. All women presented with an abnormal screening smear showing at least severe dyskaryosis. Estimated tumour volumes ranged from 16 to 640 mm3, median 72 mm3. Four women showed multifocal invasion. All four nulliparous women and one parous woman underwent fertility-sparing treatment, i.e. loop cone +/- laparoscopic pelvic node dissection. The other 12 women underwent laparoscopic assisted vaginal hysterectomy/total abdominal hysterectomy +/- pelvic lymph node dissection. There were no cases of residual disease in any of the definitive treatment specimens. There were no cases of metastatic spread to pelvic lymph nodes. To date, no women have developed recurrent disease, and all women are alive and well (median follow up, 29 months). CONCLUSIONS: The conservative surgical management of small-volume stage IB1 cases in this series showed an excellent outcome with no cases showing pelvic lymph node involvement and no cases developing recurrent disease. A more formal assessment of tumour volume with a more active approach to determining the third dimension will allow more women the option of conservative treatment, thereby minimising the adverse effects of radical surgery.