Vaginoplasty: a modern approach: a report of 2 cases.

BACKGROUND: Split-thickness skin graft vaginoplasty is one of many methods for vaginal reconstruction. In its 130-year history it has been modified by numerous authors in attempts to improve graft viability and neovaginal function. We describe a modern approach that aims to improve outcomes and reduce complications. CASES: Two cases of split-thickness skin graft vaginoplasty are presented in which the traditional Abbé-McIndoe technique was supplemented by the combined use of vacuum-assisted closure and fibrin tissue sealant. In both cases 100% graft survival and normal neovaginal function were observed, with no recipient site complications. Both patients mobilized on postoperative day 3, and both were sexually active 4 months postoperatively. CONCLUSION: This approach has not been described previously in the literature. The impressive results seen in these cases suggest that the use of vacuum-assisted closure and fibrin tissue sealant in combination may improve graft survival and resulting neovaginal function.

Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis.

OBJECTIVE: The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing treatment. STUDY DESIGN: This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity. RESULTS: Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died. CONCLUSION: Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes.

Women's experience of colposcopy: a qualitative investigation.

BACKGROUND: The last comprehensive investigation of women's experience of the colposcopy service in the UK was conducted in the 1980's. It highlighted women's anxiety and lack of information, resulting in recommendations for improvements. Since then the colposcopy service has changed substantially. It is therefore time to re-visit women's experience of this service and reflect upon the success of service changes in improving experience and reducing anxiety. The aim of this study was to investigate women's experience of being referred for, and attending, colposcopy appointments, and identify potential service improvements. METHODS: Qualitative in-depth interviews were conducted with 18 women newly referred for colposcopy in the West Midlands, UK. The interviews were designed to elicit the experience of colposcopy from the patients' perspective. RESULTS: The eight emerging themes were categorised as three overarching concepts, which were: feelings of emotional reaction, choices being accommodated and time delays. Women felt very apprehensive before their appointment, but when attending, appreciated being consulted about their preferences. Delays in referral and feeling 'rushed' by staff impacted negatively on women's experience. CONCLUSIONS: Service changes in information provision and increased respect for dignity seem to have improved the experience that women have of colposcopy, however, this does not appear to have translated into decreased anxiety. Women still have strong emotional reactions to being referred for, and attending, colposcopy appointments. Staff taking time to explain the diagnosis fully, and discuss their preferences about aspects of their consultation can alleviate their anxiety.

Is gynaecological surgical training a cause for concern?: a questionnaire survey of trainees and trainers.

BACKGROUND: Concerns have been raised as to whether the current postgraduate training programme for gynaecological surgery is being detrimentally affected by changes in working practices, in particular the European Working Time Directive (EWTD). The purpose of this study was to investigate the surgical activity of obstetrics and gynaecology trainees and to explore trainees' and trainers' opinions on the current barriers and potential solutions to surgical training. METHODS: Two questionnaire surveys were conducted, one to obstetrics and gynaecology trainees working within the West Midlands Deanery and a second to consultant gynaecologists in the West Midlands region. RESULTS: One hundred and four trainees (64.3%) and 66 consultant gynaecologists (55.0%) responded. Sixty-six trainees (66.7%) reported attending up to one operating list per week. However, 28.1% reported attending up to one list every two weeks or less and 5 trainees stated that they had not attended a list at all over the preceding 8 weeks. Trainees working in a unit with less than 3999 deliveries attended significantly more theatre sessions compared to trainees in units with over 4000 deliveries (p = 0.007), as did senior trainees (p = 0.032) and trainees attached to consultants performing major gynaecological surgery (p = 0.022). In the previous 8 weeks, only 6 trainees reported performing a total abdominal hysterectomy independently, all were senior trainees (ST6 and above). In the trainers' survey, only two respondents (3.0%) agreed that the current program produces doctors competent in general gynaecological surgery by the end of training, compared to 48 (73.8%) respondents who disagreed. CONCLUSIONS: Trainees' concerns over a lack of surgical training appear to be justified. The main barriers to training are perceived to be a lack of team structure and a lack of theatre time.

Indication and outcome of repeat large loop excision biopsies of the cervix.

INTRODUCTION: To investigate the indications for performing a second large loop excision of the transformation zone (LLETZ) biopsy and to compare the associated colposcopic and pathological findings and treatment morbidity compared with 1 LLETZ. METHODS: This is a case-control study that reviewed case notes and histology reports on women who had undergone 1 LLETZ biopsy (control group) and women who had undergone 2 biopsies (index group). A comparison of referral cytology, colposcopic findings, and pathological and clinical outcomes was performed. RESULTS: Of the women who went on to have 2 LLETZ biopsies, 88% had histologically proven high-grade cervical intraepithelial neoplasia (CIN) or invasion on their first biopsy. A significantly greater proportion of high-grade cytologic and histologic diagnoses were associated with the first LLETZ compared with the second LLETZ biopsy, 76.5% and 69.1% versus 39.5% and 30.9%, respectively. A significantly greater proportion of women in the control group were referred with low-grade cytology (28.0%) and were diagnosed with human papillomavirus/low-grade CIN on histology (31.7%) compared with the first cytologic and LLETZ results in the index group, 9.9% and 8.6%, respectively. Complications were low in both groups; the immediate complication rate was 4% after the first LLETZ compared with 1% after the second LLETZ. CONCLUSIONS: Most second LLETZ biopsies are performed in women with a history of biopsy-proven high-grade CIN and are not associated with an increased risk of immediate complications.

Stage IA2 cervical carcinoma: how much treatment is enough?

OBJECTIVE: The current guidance for the management of women with stage IA2 cervical carcinoma is that whatever the primary surgical intervention, pelvic lymphadenectomy should be included. The role of lymphadenectomy in the management of cervical carcinoma remains somewhat confused, as the procedure has not been proven to be therapeutic, although it is claimed that the information gained is valuable in determining the need for adjuvant therapy. For lymphadenectomy to have clinical utility in the care of women with stage IA2 cervical carcinoma, a sufficiently high incidence of node positivity would be required to justify the morbidity of the procedure for the whole group. The objective of this paper was to establish the incidence of pelvic lymph node positivity in stage IA2 cervical carcinoma. METHODS: A PubMed search using the words "stage IA2 cervical carcinoma," "microinvasive cervical carcinoma," "stage IA cervical carcinoma," "stage I cervical carcinoma," and "lymphadenectomy in cervical carcinoma" was performed; the articles were divided into those that adhered to the International Federation of Gynecology and Obstetrics (FIGO) definition of a stage IA2 tumor and those that did not. Sentinel node studies were not included, as this procedure does not form part of the FIGO guidelines. RESULTS: Studies adhering to the FIGO definition showed a 0.5% incidence of lymph node metastases in stage IA2 cervical carcinomas, which is not as high as was previously believed (7.3%). CONCLUSIONS: The very low rate of positive lymph nodes in correctly staged IA2 cases cannot justify the inclusion of lymphadenectomy as part of standardized care for these patients.

Differentiated-type vulval intraepithelial neoplasia has a high-risk association with vulval squamous cell carcinoma.

OBJECTIVE: To assess the potential malignant risk of vulval premalignant conditions, in particular, to investigate whether there is a difference in the cancer risk between women with the 2 types of vulval intraepithelial neoplasia (VIN). METHODS: All vulval biopsy specimens taken for any reason in a single center for a 5-year period were identified. The histologic reports of 1309 biopsy specimens from 802 women were reviewed, and all pathologic conditions present were recorded for each woman. Reports of patients with biopsy specimens containing usual-type VIN, differentiated-type VIN, lichen sclerosus, and squamous hyperplasia were selected and analyzed for the presence of metachronous or subsequent carcinoma to give a proportional risk for each condition. RESULTS: Five hundred eighty women were identified with premalignant vulval conditions: 171 had usual-type VIN, 70 had differentiated-type VIN, 191 had lichen sclerosus, 145 had squamous hyperplasia, and 3 had other conditions not included in this analysis. Within these groups, the numbers of women with prior, synchronous, or subsequent vulval squamous cell carcinoma were 44 (25.7%), 60 (85.7%), 53 (27.7%), and 53 (31.7%), respectively (P = 0.000). CONCLUSIONS: Differentiated-type VIN is significantly more associated with vulval squamous cell carcinoma than usual-type VIN.

Is modified vestibulectomy for localized provoked vulvodynia an effective long-term treatment? A follow-up study.

OBJECTIVE: To determine whether vestibulectomy is an effective long-term treatment and investigate the levels of patient satisfaction in women with localized provoked vulvodynia, and to provide long-term follow-up data from a cohort of women whose short-term success rates have been published previously. STUDY DESIGN: A retrospective case note review of 110 women with localized provoked vulvodynia and follow-up patient questionnaire. Patients were asked to quantify their pain scores before surgery, at 2 months after surgery and 1 year after surgery and score their satisfaction levels. RESULTS: Mean pain scores continued to improve throughout the first postoperative year. The mean score was 9.17 preoperatively, 5.24 at 2 months after surgery and 2.48 at 1 year after surgery. Eighty-three percent of patients would recommend the procedure as effective treatment of localized provoked vulvodynia. The overall mean satisfaction score was 7.96, and long-term success appears to be reflected by short-term results. CONCLUSION: Vestibulectomy is an effective long-term treatment for women with provoked localized vulvodynia; the procedure is associated with high levels of patient satisfaction and low complication rates. Shortterm success appears to be a good indicator of long-term improvement, and improve- ment continues throughout the first postoperative year.

Vulval squamous cell carcinoma occurring on a background of differentiated vulval intraepithelial neoplasia is more likely to recur: a review of 154 cases.

OBJECTIVE: To assess the frequency of recurrence of vulval carcinoma, arising from the background of usual-type vulval intraepithelial neoplasia (uVIN), differentiated VIN (dVIN, and nonneoplastic epithelial disorders (NNEDs). STUDY DESIGN: A retrospective review was conducted of 200 pathology specimens of vulval squamous cell carcinoma (VSCC) from 154 women over a 5-year period. The pathologic findings were reviewed where information of the adjacent pathology and number of recurrences of carcinoma for each woman were recorded. The number of recurrences was then correlated with the adjacent pathology using logistical regression analysis. RESULTS: The overall recurrence rate for vulval carcinoma was 22.6%. A single recurrence occurred in 12.9% of patients, whereas 5.8% had 2 recurrences and 3.9% has 3 recurrences of vulval carcinoma. The odds ratio (OR) of having a recurrence of VSCC associated with dVIN alone is 3.85 (95% CI 0.52, 28.24) and 4.3 when associated with dVIN in combination with NNEDs (95% CI 0.84, 21.92), whereas with VSCC associated with uVIN the OR is 1.35 (95% CI 0.20, 9.01). CONCLUSION: Vulval cancers arising on a background of dVIN appear more likely to recur than cancers arising from undifferentiated VIN; this is compounded by the concurrent presence of NNEDs.

Medical management of vulvar intraepithelial neoplasia.

OBJECTIVE: To determine which nonsurgical treatments have been assessed for the treatment of vulvar intraepithelial neoplasia (VIN) and what the outcomes of such treatment might be. MATERIALS AND METHODS: The English literature over the last 25 years was searched on Medline. RESULTS: A wide variety of nonsurgical treatments was identified and the outcomes were very similar. These treatments showed responses rates varying between 10% and 60%. Responses were poorly defined, however, and few if any studies had large enough subject numbers or long enough follow-up to allow robust conclusions. CONCLUSIONS: Although VIN is a condition in which there would seem to be a pressing need for nonsurgical interventions, none of the nonsurgical treatments reviewed resulted in optimal outcomes. No one treatment seemed to be superior. There is a need for consensus on how outcomes are measured and a move toward large well-constructed studies is recommended. Because VIN is uncommon, there is a strong case for establishing research collaboratives.

Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis.

In this study, we describe the expression and function of CD40, a TNF receptor family member, in cervical carcinomas. CD40 was present at very low levels in normal cervical epithelium but was overexpressed in human papillomavirus-infected lesions and advanced squamous carcinomas of the cervix. The stimulation of CD40-positive cervical carcinoma cell lines with soluble CD40L (CD154) resulted in activation of the NF-kappaB and MAPK signaling pathways and up-regulation of cell surface markers and intracellular molecules associated with Ag processing and presentation. Concomitantly, the CD154-induced activation of CD40 in carcinoma cells was found to directly influence susceptibility to CTL-mediated killing. Thus, CD40 stimulation in cervical carcinoma cell lines expressing a TAP-dependent human papillomavirus 16 E6 Ag epitope resulted in their enhanced killing by specific CTLs. However, CD154 treatment of carcinoma cells expressing proteasome-dependent but TAP-independent Ags from the EBV-encoded BRLF1 and BMLF1 failed to increase tumor cell lysis by specific CTLs. Moreover, we demonstrate that chemotherapeutic agents that suppress protein synthesis and reverse the CD40-mediated dissociation of the translational repressor eukaryotic initiation factor 4E-binding protein from the initiation factor eukaryotic initiation factor 4E, such as 5-fluorouracil, etoposide, and quercetin, dramatically increase the susceptibility of cervical carcinoma cells to CD40L-induced apoptosis. Taken together, these observations demonstrate the functional expression of CD40 in epithelial tumors of the cervix and support the clinical exploitation of the CD40 pathway for the treatment of cervical cancer through its multiple effects on tumor cell growth, apoptosis, and immune recognition.

Characterizing T-cell response in low-grade and high-grade vulval intraepithelial neoplasia, study of CD3, CD4 and CD8 expressions.

OBJECTIVE: The objective of our study was to compare immunocyte infiltrates in vulval epithelium from low-grade and high-grade vulval intraepithelial neoplasia (VIN) lesions to determine if difference in T-cell presence reflected the grade of VIN. MATERIAL AND METHODS: Thirty-six vulval specimens were obtained from 24 patients who had previously undergone vulval biopsies for VIN, 14 high-grade diseases (VIN 3 with or without HPV) and 14 low-grade diseases (VIN 1 and VIN 2 with or without HPV). Eight samples of normal vulval tissue were selected from the excision margins of resected vulval biopsies. The lymphocyte surface markers included CD3 (Pan T-cell marker), CD4 (T helper cells), and CD8 (T cytotoxic cells). Each tissue section was visualized under high power magnification and cells were counted in 10 random areas at the dermo-epidermal junction. RESULTS: A significantly higher number of total mean T lymphocytes were detected in VIN specimens compared to normal vulval tissue (P = 0.002). In low-grade VIN, there were significantly more CD8 cells than CD4 when compared to high-grade VIN. This difference in CD4/CD8 ratio was significant (P = 0.001). CONCLUSIONS: This study suggests that increased CD8 response in VIN is a feature of low-grade disease and we speculate that this may be a protective mechanism. In high-grade disease, both CD4 cells and CD8 cells are equally present with preservation of normal CD4/CD8 ratio.

The effects of 5% imiquimod cream on high-grade vulval intraepithelial neoplasia.

OBJECTIVES: The aim of this study was to investigate the effects of topical 5% Imiquimod (3M Pharmaceuticals, St. Paul, Minnessota) on high-grade vulval intraepithelial neoplasia (VIN). METHODS: A prospective uncontrolled observational study was performed. Fifteen patients with histologically confirmed VIN 3 were asked to self-administer 5% Imiquimod cream to their vulval lesions up to three times weekly for 16 weeks. Review was conducted at 1, 2, 3, 4, 6, and 9 months postrecruitment. Lesions were photodocumented and at 4 months any areas demonstrating a clinical response were biopsied. RESULTS: Of 15 patients recruited, 4 demonstrated a clinical improvement in their disease, 3 of whom had negative biopsies posttreatment. Local side effects limited the frequency of application such that 7 patients applied the cream once weekly, 6 twice weekly, and 2 three times weekly. CONCLUSIONS: 5% Imiquimod cream appears to have an effect when used on high-grade VIN. The frequency of application was limited by local side effects which may have reduced the clinical responses seen. Measures to alleviate local side effects may allow more aggressive use of Imiquimod and lead to improved responses.

Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia.

OBJECTIVES: To investigate CD8+ T cell reactivity to human papillomavirus (HPV) 16 antigens in patients with high-grade vulval intraepithelial neoplasia (VIN) before, during and after treatment with 5% imiquimod cream. METHODS: CD8-enriched responder cell populations were obtained from 10 patients with high-grade VIN using imiquimod cream as a treatment. Overlapping synthetic peptides covering the entire primary sequences of the HPV16 E6, E7 and E4 proteins were used to screen for CD8+ T cell responses using an ELISPOT assay of interferon (IFN)-gamma release. RESULTS: Reactivity to the proteins was detected in all patients on at least one occasion. With the exception of one patient, CD8+ T cell reactivity generally increased at some stage during treatment. The magnitude and specificities of responses changed over the treatment period. This was particularly noticeable in response to peptides derived from the E4 protein. CD8+ T cell reactivity to HPV16 E7 appeared to be dominant amongst women with high-grade VIN. The magnitude and specificity of response had no correlation with clinical response to imiquimod. CONCLUSIONS: HPV16 specific CD8+ T cell activity was detected in patients with high-grade VIN. Imiquimod use appeared to increase the magnitude of the response and broaden the specificity of response in some patients. Despite the presence of these CD8+ T cells, the disease state persisted; therefore, a role for HPV-specific cytotoxic T cells (CTLs) in VIN resolution remains unproven.

Human papillomavirus (HPV) type 16-specific CD8+ T cell responses in women with high grade vulvar intraepithelial neoplasia.

Human papillomavirus (HPV)-associated vulvar intraepithelial neoplasia (VIN) has serious sequelae for the sufferer. Current treatments are associated with poor response and high relapse rates. The development of HPV-specific T cell immunotherapies offers a new approach to treatment. This will require a detailed understanding of the spectrum of T cell responses induced by HPV antigens, and how effectively viral antigens can be accessed by the immune system. We have investigated the frequency and spectrum of HPV16-specific CD8+ T cell responses to three HPV16 antigens in 9 women with high grade VIN (VIN3). CD4-depleted populations of responder cells were screened against overlapping 30-35mer peptides covering the sequences of HPV16 E6, E7 and E4 using ELISPOT assays of IFN-gamma release. We demonstrated CD8+ T cell reactivity to one or more of the proteins in 6 of 9 patient samples. All 6 of these responders recognised peptides covering the E7 protein, 3 of 9 women responded to E6 peptides, but no reactivity was seen to E4. Our results suggest that HPV16-specific cytotoxic T cells (CTLs) are relatively common in women with persistent VIN3. The HPV-specific CTL response, however, seems to be ineffective. There is some evidence that there are problems associated with the processing and presentation of HPV antigens by the infected vulvar epithelium. It will be crucial to address this in the design of any T cell based therapy for HPV-associated VIN and vulval cancer.