Colposcopy telemedicine: live versus static swede score and accuracy in detecting CIN2+, a cross-sectional pilot study.

BACKGROUND: This cross-sectional pilot study evaluates diagnostic accuracy of live colposcopy versus static image Swede-score evaluation for detecting significant precancerous cervical lesions greater than, or equal to grade 2 severity (CIN2+). METHODS: VIA or HrHPV positive women were examined using a mobile colposcope, in a rural clinic in Kolkata, India. Live versus static Swede-score colposcopy assessments were made independently. All assessments were by gynecologists, junior or expert. Static image assessors were blinded to live scoring, patient information and final histopathology result. Primary outcome was the ability to detect CIN2+ lesions verified by directed biopsies. Diagnostic accuracy was calculated for live versus static Swede-score in detecting CIN2+ lesions, as well as for interclass correlation. RESULTS: 495 images from 94 VIA positive women were evaluated in this study. Thirteen women (13.9%) had CIN2+ on biopsy. No significant difference was found in the detection of CIN2+ lesions between live and static assessors (area under curve = 0.69 versus 0.71, p = 0.63). A Swede-score of 4+, had a sensitivity of 76.9% (95% CI 46.2-95.0%) and 84.6% (95% CI 54.6-98.1%), for live- and static-image assessment respectively. The corresponding positive predictive values were found to be 90.9% (95% CI 75.7-98.1%) and 92.6% (95% CI 75.7-99.1%). The interclass correlation was good (kappa statistic = 0.60) for the senior static assessors. CONCLUSIONS: Swede-score evaluation of static colposcopy images was found to reliably detect CIN2+ lesions in this study. Larger studies are needed to further develop the colposcopy telemedicine concept which may offer reliable guidance in management where direct specialist input is not available. TRIAL REGISTRATION: Ethical approval of the study was obtained by the Chittaranjan National Cancer Institute (CNCI) Human Research Ethics Committee (4.311/27/2014). The trial was retrospectively registered in the Clinical Trails Registry of India CTRI/2018/03/012470 .

Stratification of HPV-induced cervical pathology using the virally encoded molecular marker E4 in combination with p16 or MCM.

High-risk human papillomavirus (HPV) types cause cervical lesions of varying severity, ranging from transient productive infections to high-grade neoplasia. Disease stratification requires the examination of lesional pathology, and possibly also the detection of biomarkers. P16(INK4a) and MCM are established surrogates of high-risk HPV E6/E7 activity, and can be extensively expressed in high-grade lesions. Here we have combined these two cellular biomarkers with detection of the abundant HPV-encoded E4 protein in order to identify both productive and transforming lesions. This approach has allowed us to distinguish true papillomavirus infections from similar pathologies, and has allowed us to divide the heterogeneous CIN2 category into those that are CIN1-like and express E4, and those that more closely resemble nonproductive CIN3. To achieve this, 530 lesional areas were evaluated according to standard pathology criteria and by using a multiple staining approach that allows us to superimpose biomarker patterns either singly or in combination onto an annotated hematoxylin and eosin (H&E) image. Conventional grading of neoplasia was established by review panel, and compared directly with the composite molecular pathology visualized on the same tissue section. The detection of E4 coincided with the onset of vacuolation, becoming abundant in koilocytes as the MCM marker declined and cells lost their defined nuclear margins as visualized by standard H&E staining. Of the dual marker approaches, p16(INK4a) and E4 appeared most promising, with E4 generally identifying areas of low-grade disease even when p16(INK4a) was present. Extensive p16(INK4a) expression usually coincided with an absence of E4 expression or its focal retention in sporadic cells within the lesion. Our results suggest that a straightforward molecular evaluation of HPV life-cycle deregulation in cervical neoplasia may help improve disease stratification, and that this can be achieved using complementary molecular biomarker pairs such as MCM/E4 or, more promisingly, p16(INK4a)/E4 as an adjunct to conventional pathology.

Evaluation of a silver nitrate endometrial ablation fluid delivery system as a chemical treatment for menorrhagia.

STUDY OBJECTIVE: To explore the safety, feasibility, and effectiveness of silver nitrate-dextran paste delivered through the cervix as a simple and inexpensive endometrial ablation therapy for menorrhagia. DESIGN: Safety, feasibility, and effectiveness trials (Canadian Task Force classification II-3). SETTING: The trials were performed at the Whittington Hospital in London. PATIENTS: Seven women were treated for menorrhagia after prehysterectomy trials on 10 patients. Studies were first performed on rats and rabbits and human uterine specimens. INTERVENTION: We dissolved 10 g 75% silver nitrate/25% potassium nitrate and 15 g dextran 70 in 10 mL distilled water and delivered this paste through the cervix with a pressure-controlled syringe under fluroscopic monitoring. We planned silver nitrate doses of 500 mg in a 50-kg woman to remain in the uterus for 8 minutes after injection and then to be neutralized with normal saline and washed out. In uterine specimens, 8-minute treatment produced local necrosis to 4 mm. LD50 (lethal dose, 50%) studies in rats and mice ranged from 1100 to 2000 mg/kg. Prehysterectomy trials on 10 patients to evaluate safety revealed no penetration into the tubes and normal complete blood count, renal, cardiac, and liver tests with plasma silver rising to 20 to 30 µmoles/L and returning to baseline after 4 weeks. Finally, 7 patients were treated and followed for 6 months. We followed blood values, complications, and degree of flow reduction. Six patients were well and discharged the same day; of those, all blood values were similar to the safety studies, 5 reported varying degrees of flow reduction, and 1 patient continued with menorrhagia. The seventh patient had passage of paste into the left fallopian tube and peritoneal cavity producing immediate pain. Laparoscopy showed several burns on the back of the uterus, sigmoid colon, and cul de sac. After neutralization with saline, she made a complete, uneventful recovery and became oligoamenorrheic. CONCLUSION: Silver nitrate could be a simple, inexpensive, safe, and potentially effective agent for endometrial ablation. However, to ensure safety, the fluid delivery system described herein must be abandoned. An alternative delivery system is needed, one which precisely controls the locus of caustic action, and further testing is required for effectiveness and safety.

Biomarkers in cervical precancer management: the new frontiers.

The major cause of cervical cancer and its pre-invasive lesions is persistent infections with oncogenic human papillomavirus (HPV). Viral replication and integration in the cervix depends on the ordered expression of viral gene products, which can lead to overexpression of multiple molecular proteins or biomarkers. These novel biomarkers allow the monitoring of essential molecular events in histological or cytological specimens and are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings. This review focuses on these molecular markers and their role in the diagnosis and management of cervical dysplasia and cancer.

Visualization techniques (colposcopy, direct visual inspection, and spectroscopic and other visual methods). Summary of task force 7.

Visual screening techniques include both low-technology approaches, such as direct visual inspection (DVI), and high-technology approaches, such as those that utilize electrooptical detectors to identify cervical cancer precursors and invasive cervical cancer. Simple visual screening techniques, such as DVI, consist of washing the cervix with a solution of 5% acetic acid (e.g., vinegar) and then inspecting it using either the naked eye or with a low-power magnifying device to identify areas of acetowhitening, which frequently correspond to cervical squamous intraepithelial lesions (SILs). The simple visual screening methods are being evaluated as an alternative to cytology in low-resource settings where screening using cervical cytology is not feasible. Multiple studies have shown DVI to have sensitivity similar to that of cervical cytology for identifying women with high grade SIL but much lower specificity. The novel high-technology visual screening methods that utilize electrooptical sensors to identify cervical abnormalities are still in the developmental phases but offer considerable potential.

The HPV Cellular Transactivator Brn-3a Can Be Used to Predict Cervical Adenocarcinoma and Squamous Carcinoma Precancer Lesions in the Developed and Developing Worlds.

The cellular transactivator Brn-3a has previously been shown to be expressed at elevated levels in the cervix of women with squamous cell carcinoma of the cervix (SCC) and to activate the expression of HPV E6 mRNA. In this study, we show that common and rare cervical precancer lesions, including those of adenocarcinoma (AC), which are usually difficult to diagnose using classical procedures, also expressed high levels of Brn-3a and can be diagnosed by measuring the levels of Brn-3a and E6 mRNAs.

Detection of cervical abnormalities in a developing country using measurement of Brn-3a in cervical smears.

OBJECTIVE: We have previously shown that Brn-3a is elevated in biopsies from women in the United Kingdom with high grade cervical neoplasia, and that it specifically trans-activates the HPV URR in vitro and in vivo. The aim of this study is to establish the relationship of Brn-3a, HPV E6 and pathological diagnosis in cervical smear from women in a developing country with a high prevalence of cervical disease. This is a follow-up of our previous work in which for the first time Brn-3a and E6 levels in cervical smears from women in United Kingdom were shown to correlate with the histological diagnosis of cervical neoplasia and were even better in predicting underlying pre-malignant disease than conventional procedures. METHOD: Cervical smears from 295 women with cervical abnormalities attending gynecological clinics in Brazil were used to make RNA. The mRNA levels of Brn-3a and HPV E6 were measured and the data obtained were used to establish the relationship between Brn-3a and the histological diagnosis. RESULTS: The cellular transcription factor Brn-3a was readily measured in cervical smears from the Brazilian population. Its presence was shown to be frequently associated with the expression of HPV E6. The measured level of Brn-3a parallels the severity of the cervical ailment and predicts the pathological categories. CONCLUSIONS: The ability of Brn-3a to predict for cervical ailments is independent to the geographical characteristics of the population, and hence it could be used routinely as an adjunct to colposcopy and pathological diagnosis in developing and developed countries.

Tubal migration: a rare complication of an intrauterine contraceptive device leading to formation of a hydrosalpinx.

This is a case report of a unilateral hydrosalpinx caused by tubal migration of a copper intrauterine contraceptive device. A 33-year-old woman underwent laparoscopic right salpingectomy for a hydrosalpinx. During the procedure, a copper intrauterine contraceptive device was found protruding from the distal end of the hydrosalpinx.

Triage by HPV-DNA testing: is it useful in women with persistent minor smear abnormalities?

BACKGROUND: This study was carried out to evaluate the efficacy of HPV-DNA (Human Papilloma Virus) testing as a triage strategy for persistent borderline and mild cytological abnormalities. METHODS: A prospective cross-sectional study involving 321 women registered between January and December 2001 with two smears showing borderline or mild dyskaryosis, taken 6 months apart. This study was undertaken in a colposcopy unit in a large district general hospital in central London. RESULTS: Three hundred and twenty-one women referred with persistent borderline and mild dyskaryosis were recruited in this study. HPV-DNA testing was positive in 194 women (60.4%). Histology of colposcopically directed biopsy showed CIN2/3 in 57 women (18%). Fifty-one of these 57 women were detected by HPV-DNA testing (sensitivity for high-grade disease 89.5%). Specificity for high-grade disease was 45.8%. Negative predictive value was 95.3%. Women with a positive HPV-DNA result had a 7.2 times higher risk of having a high-grade cervical cancer precursor lesion. CONCLUSION: Negative predictive value of HPV-DNA testing for high-grade cervical lesion is very high. Hence, it can be used as a triage strategy for persistent borderline changes and mild dyskaryosis.

Asymptomatic vasculitis of the uterine cervix in presence of cervical intraepithelial neoplasia grade III.

CASE REPORT: A 34-year-old woman was diagnosed to have a high-grade cervical intraepithelial neoplasia and was treated by large loop excision of the transformation zone. Histology of the excised cone confirmed the diagnosis but also showed evidence of vasculitis of medium-sized vessels of the cervix. The woman was referred to a physician to rule out underlying systemic disease. Extensive laboratory and clinical screening was negative. DISCUSSION: The clinical significance and management of asymptomatic isolated vasculitis of the uterine cervix are discussed.

Human papillomavirus DNA detection in the management of women with twice mildly abnormal cytological smears.

This study was undertaken to investigate the value of HPV testing in women referred with two abnormal smears that were graded as mild dyskaryosis or less who attended for at least three follow-up visits. One hundred forty-nine women were included in the study and a total of 39 high-grade lesions including one cancer were detected. All of these were found to be associated with the persistent presence of one or more of 13 high-risk human papillomavirus types (HPV) as detected by a multiplex type specific PCR technique. Two high-grade lesions were initially missed by cytology. In contrast, no cytological or histological evidence of high-grade lesions was found during a follow-up period of up to 8 years in 62 women with no high-risk HPV infection or in 38 women with only transient high-risk HPV infection. The utility of high-risk HPV detection in the management of women presenting with mild cytological abnormalities is discussed.

Bilateral hematosalpinx in a case of ectopic pregnancy: a clinical dilemma.

A 31-year-old woman with a positive pregnancy test and a transvaginal ultrasound scan result that was suggestive of a right tubal ectopic pregnancy underwent a laparoscopy, which showed bilateral hematosalpinx. In the presence of active bleeding and deteriorating hemodynamic status of the patient, a minilaparotomy was performed that revealed a right-sided hematosalpinx and a left-sided ectopic gestation.

Measurement of Brn-3a levels in Pap smears provides a novel diagnostic marker for the detection of cervical neoplasia.

OBJECTIVES: We have previously demonstrated that Brn-3a cellular transcription factor activates transcription of the human papillomavirus (HPV) E6 and E7 oncogenes in human cervical cancer cells and that Brn-3a levels are dramatically elevated in biopsies from women with high-grade cervical neoplasia. The aim of this study was to establish the relationship between Brn-3a levels in Pap smears and the histological diagnoses. We also analysed whether Brn-3a levels can be used in combination with Pap smear to predict the presence of cervical intraepithelial lesion. METHODS: Two hundred thirty-eight women who were referred with abnormal Pap smear underwent a diagnostic colposcopy, repeat in-study Pap smear, colposcopically directed biopsy, and assessment of Brn-3a and HPV-16 E6 m-RNA levels. Data were analysed to assess the association between Brn-3a levels and the histological diagnosis. RESULTS: Brn-3a was readily measured in smears and showed a statistically significant correlation with the grade of cervical abnormality. Positive Brn-3a is associated with increased relative risk of higher-grade lesion. Moreover, measurement of Brn-3a levels in smears can be used to detect a significant proportion of cervical lesions that were missed by Pap smear. CONCLUSION: Measurement of Brn-3a levels in routinely taken Pap smears is a feasible technique that correlates with the severity of the epithelial abnormality and is a useful adjunct to cytology. Brn-3a appears to have great promise since it detects activation of oncogenic HPVs rather than simply detecting their presence, as is currently being done.

Video monitoring of smear-taking at colposcopy: relationship to cytology.

OBJECTIVE: To investigate the reasons why cervical smears occasionally fail to reflect the underlying pathology in the cervix even when the smear is taken at colposcopy. DESIGN: A randomised study of three different smear-taking devices. SETTING: A colposcopy clinic. POPULATION: Women attending the colposcopy clinic. METHODS: A smear was taken from 172 nulliparous and 100 multiparous women at colposcopy and the procedure was monitored on a video-imaging system. The cytological findings were compared with the biopsy report in 147 nulliparous and 85 multiparous women. MAIN OUTCOME MEASURES: Accuracy of cytology and the effect of a range of variables on the accuracy of cytology. RESULTS: Sampling of the transformation zone was incomplete in 15% of nulliparous women and 8% of multiparous women. Univariate analysis of a range of variables including parity, type of sampling devices, completeness of sampling of the transformation zone, size of the transformation zone, size of the lesion (aceto-white area) and location of the squamo-columnar junction showed that the accuracy of cytology was influenced by all these factors except for parity and smear-taking devices. Multivariate analysis showed that the location of the squamo-columnar junction, the size of the transformation zone area, the size of the aceto-white area and the ratio of the aceto-white area to the area of the transformation zone influenced the accuracy of cytology. CONCLUSIONS: Women with large transformation zone areas (>30.03 mm(2)) and/or small aceto-white lesions (<7.01 mm(2)) are more likely to have an inaccurate cytology reports than women with small transformation zone and women with larger aceto-white areas. A ratio of the aceto-white area to the area of the transformation zone of 0.22 or less increases the risk of disagreement between the cytological and histological findings.

Human papillomavirus detection for cervical cancer prevention with polymerase chain reaction in self-collected samples.

OBJECTIVE: We studied the usefulness of self-sampling in cervical cancer prevention. STUDY DESIGN: A cross-sectional study was undertaken at screening services in Recife (Brazil); 253 women aged 16 to 88 years were included. Participants were randomly selected from a high-risk population for cervical neoplasia. All participants collected a self-sample with a cotton-tipped swab by rotating it against the vaginal epithelium and, possibly, the cervix. Physician-collected samples from the ectocervix and endocervix, respectively, with an Ayre's spatula and a Cytobrush endocervical brush (Medscand) were followed by thorough colposcopy. Human papillomaviruses were detected by consensus polymerase chain reaction and typed by restriction fragment length polymorphism. RESULTS: The difference among human papillomavirus results in samples that were self-collected versus physician collected was significant (P <.03). The agreements were poor among patients with cervical intraepithelial neoplasia (CIN) grade 3 (kappa <0.29) and cervical cancer (kappa < 0.10). Self-sampling missed 50% more cancers than did physician sampling (P =.04). CONCLUSION: Self-sampling with a cotton-tipped swab for human papillomavirus detection is not a safe method for the collection of samples that are aimed at primary cervical cancer screening.

Cervical cancer control, priorities and new directions.

Cervical cancer is caused by infection with a range of high risk "oncogenic" human papillomavirus (HPV) types, and it is now accepted that >99% of cervical cancer is initiated by HPV infection. The estimated lifetime risk of cervical cancer is nevertheless relatively low (less than 1 in 20 for most community based studies). Although sensitivity and specificity of the available diagnostic techniques are suboptimal, screening for persistent HPV infection is effective in reducing the incidence of cervical cancer. Infection can be detected by molecular techniques or by cytological examination of exfoliated cervical cells. Persistent infection is the single best predictor of risk of cervical cancer. The latest findings of HPV and cervical cancer research need to be widely disseminated to the scientific and medical societies that are updating screening and management protocols, public health professionals, and to women and clinicians. This report reviews current evidence, clinical implications and directions for further research in the prevention, control and management of cervical cancer. We report the conclusions of the Experts' Meeting at the EUROGIN 2003 conference.