Clonal Relationship Between Lichen Sclerosus, Differentiated Vulvar Intra-epithelial Neoplasia and Non HPV-related Vulvar Squamous Cell Carcinoma.

BACKGROUND/AIM: Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions. MATERIALS AND METHODS: DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. High-resolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53. RESULTS: Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%. CONCLUSION: Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS.

An alternative way to measure the depth of invasion of vulvar squamous cell carcinoma in relation to prognosis.

Depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma. The aim of this study was to identify the most optimal method of measuring the depth of invasion in relation to the individual outcome in patients with vulvar squamous cell carcinoma. Data of 175 consecutive patients with a primary vulvar squamous cell carcinoma with known lymph node status, treated in the Radboud University Medical Center, the Netherlands (2000-2010), were stored in a database. At pathology review of 148 (85%) cases, depth of invasion was measured using the conventional and alternative methods. Clinical and pathological characteristics of patients with a change in FIGO stage were compared with those without a change in stage. In 148 vulvar squamous cell carcinoma patients, the median depth of invasion was shown to be decreased from 5.5 mm (range 1.1-20) using the conventional method to 3.6 mm (range 0.2-20) using the alternative method (P<0.05). This led to a change in the FIGO stage in 13 of the 148 (9%) patients and a change in depth of invasion from 3.5 to 0.2 mm in one patient (1%) with FIGO stage IIIA. Of all 69 stage 1B patients, 13 (19%) were downstaged to stage IA. The downstaged patients developed less recurrences (15% vs 39%) and had a higher disease-specific survival (100% vs 84%) compared with the patients who remained FIGO stage IB. Using the alternative method for measuring the depth of invasion in tumors of vulvar squamous cell carcinoma patients, 19% of the patients with a FIGO stage IB tumor might be treated without groin surgery resulting in less treatment-related morbidity. The results are promising but more prospective data on a higher number of patients are necessary.

Lymph node count at inguinofemoral lymphadenectomy and groin recurrences in vulvar cancer.

OBJECTIVE: The objective of the study is to determine the risk factors for groin recurrence (GR) in patients with primary vulvar squamous cell carcinoma (SCC) after inguinofemoral lymphadenectomy (IFL) without lymph node metastases and/or adjuvant chemoradiotherapy. METHODS: The study is a multicenter retrospective review of clinical and histopathological data of patients with lymph node-negative vulvar SCC who underwent an IFL. Patients with and without GRs were compared to identify risk factors. RESULTS: In 134 patients, 252 groins were eligible for the analyses--16 patients underwent ipsilateral IFL and 118 patients underwent bilateral IFL. Groin recurrences occurred in 4 (1.6%) of the 252 dissected groins. Besides, 1 patient who underwent ipsilateral IFL had a recurrence in the nonoperated contralateral groin; this groin was left out of analysis. The median number of dissected nodes per groin was 9.8 (range, 1-38) in all patients and 6.5 (range, 5-8) in patients with GR. Multivariate analyses showed that GR was related to poor differentiation (P = 0.04), and node count less than 9 (P = 0.04), no association with age, tumor localization, tumor diameter, focality, invasion depth, or stage was found. Nineteen patients with both low node count and poor differentiation had 19% GRs. Survival analyses showed less favorable survival in patients with poor differentiation. CONCLUSIONS: The overall risk of developing GR after negative IFL in patients with vulvar SCC is low (1.6% per groin) but significantly higher in patients with tumors with a poor differentiation and lymph node count less than 9 at IFL. A large well-designed prospective study is needed to evaluate closer surveillance in patients at risk.

Medical students' perceptions of the physician's role in not allowing them to perform gynecological examinations.

PURPOSE: To determine how often medical students are not allowed to perform gynecological examinations during their obstetrics-gynecology clerkship, identify the barriers to participation related to physicians and patients, explore the role of the supervisory physician in not allowing medical student involvement, and explore differences between male and female students' experiences. METHOD: All medical students entering their obstetrics-gynecology clerkship at a medical school in the Netherlands between May and October 2011 were invited to participate in this study's questionnaire, which asked them to report the number of gynecological examinations they were allowed and not allowed to perform during their clerkship. Eighteen questionnaire respondents participated in three focus groups. RESULTS: Of the 139 medical students invited, 76 (55%) completed the questionnaire. Students reported a total of 2,196 instances in which they were not allowed to participate in the examination; 89% (n = 1,956) were related to the supervisory physician. Qualitative data from the focus group interviews showed that female supervisory physicians prioritized patients' autonomy above students' learning needs. Furthermore, female students were less assertive than male students in asking the supervisory physician for permission to participate. CONCLUSIONS: The physician's role in not allowing student involvement is substantial and results in fewer opportunities for students to perform gynecological examinations. For students to develop the necessary gynecological exam skills during their clerkship, medical educators need to improve the learning environment.

Interobserver variability and the effect of education in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia.

No published data concerning intraobserver and interobserver variability in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia (DVIN) are available, although it is widely accepted to be a subtle and difficult histopathological diagnosis. In this study, the reproducibility of the histopathological diagnosis of DVIN is evaluated. Furthermore, we investigated the possible improvement of the reproducibility after providing guidelines with histological characteristics and tried to identify histological characteristics that are most important in the recognition of DVIN. A total number of 34 hematoxylin and eosin-stained slides were included in this study and were analyzed by six pathologists each with a different level of education. Slides were reviewed before and after studying a guideline with histological characteristics of DVIN. Kappa statistics were used to compare the interobserver variability. Pathologists with a substantial agreement were asked to rank items by usefulness in the recognition of DVIN. The interobserver agreement during the first session varied between 0.08 and 0.54, which slightly increased during the second session toward an agreement between -0.01 and 0.75. Pathologists specialized in gynecopathology reached a substantial agreement (kappa 0.75). The top five of criteria indicated to be the most useful in the diagnosis of DVIN included: atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of rete ridges. In conclusion, the histopathological diagnosis of DVIN is difficult, which is expressed by low interobserver agreement. Only in experienced pathologists with training in gynecopathology, kappa values reached a substantial agreement after providing strict guidelines. Therefore, it should be considered that specimens with an unclear diagnosis and/or clinical suspicion for DVIN should be revised by a pathologist specialized in gynecopathology. When adhering to suggested criteria the diagnosis of DVIN can be made easier.

Successful centralisation of patients with vulvar carcinoma: a population-based study in The Netherlands.

INTRODUCTION: In general, centralisation of care for patients with rare malignancies is advised in order to improve outcome with respect to prognosis and treatment related morbidity. Therefore, centralisation of women with vulvar squamous cell carcinoma (SCC), which is an extremely rare tumour, has been advocated by the national guidelines of the Dutch Society of Obstetrics and Gynaecology in 2000. The objective of this study was to determine whether this advice has been adapted and has led to improved survival. METHODS: All patients diagnosed with vulvar malignancies between 1989 and 2008 in the Eastern part of the Netherlands were retrieved from the population-based cancer registry held by the Comprehensive Cancer Centre, The Netherlands. Patient- and tumour characteristics and vital status until January 2011 were retrieved. Data of patients diagnosed in two periods (before and after release of the guideline; 1989-1999 and 2000-2008) were compared. Relative survival rates were calculated as a good approximation of cause-specific survival. RESULTS: A total number of 382 patients with vulvar SCC with invasion > 1mm, who had an indication for groin surgery, were included in the analysis. In the first decade 62% (123 of 198 patients) were treated in a specialised oncology centre, which increased to 93% (172 of 184 patients) in the more recent period. Overall, the 5 year relative survival improved slightly from 69% (95% confidence interval (CI) 60-77%) to 75% (95% CI 65-83%). After adjustment for age and stage, being treated in a specialised oncology centre was an independent prognostic factor for survival. CONCLUSION: Centralisation of care for vulvar SCC patients has been well adopted in the Eastern part of the Netherlands. Being treated in a specialised oncology centre was associated with a better survival after adjustment for age and stage.