Immune activation enhances epithelial nerve growth in provoked vestibulodynia.

BACKGROUND: Provoked vestibulodynia manifests as allodynia of the vulvar vestibular mucosa. The exact mechanisms that result in altered pain sensation are unknown. Recently, we demonstrated the presence of secondary lymphoid tissue, which is the vestibule-associated lymphoid tissue in the vestibular mucosa, and showed that this tissue becomes activated in provoked vestibulodynia. OBJECTIVE: The purpose of this study was to examine whether expression of intraepithelial nerve fibers and nerve growth factor are related to immune activation in provoked vestibulodynia. STUDY DESIGN: Vestibular mucosal specimens were obtained from 27 patients with severe provoked vestibulodynia that was treated by vestibulectomy and from 15 control subjects. We used antibodies against the protein gene product 9.5, the neuron specific neurofilament, and nerve growth factor for immunohistochemistry to detect intraepithelial nerve fibers and nerve growth factor expressing immune cells in the vestibular mucosa. For intraepithelial nerve fibers, we determined their linear density (fiber counts per millimeter of the outer epithelial surface, protein gene product 9.5) or presence (neuron specific neurofilament). Nerve growth factor was analyzed by counting the staining-positive immune cells. Antibodies against CD20 (B lymphocytes) and CD3 (T lymphocytes) were used to identify and locate mucosal areas with increased density of lymphocytes and the presence of germinal centers (ie, signs of immune activation). B-cell activation index was used to describe the overall intensity of B-cell infiltration. RESULTS: We found more protein gene product 9.5-positive intraepithelial fibers in vestibulodynia than in the control samples (6.3/mm [range, 0.0-15.8] vs 2.0/mm [range, 0.0-12.0]; P=.006). Neuron specific neurofilament -positive intraepithelial fibers were found in 17 of 27 vestibulodynia cases (63.0%) and in none of the control cases. Protein gene product 9.5-positive intraepithelial fibers were more common in samples with more pronounced immune activation. The density of these fibers was higher in samples with than without germinal centers (6.1/mm [range, 4.3-15.8] vs 3.0/mm [range, 0.0-13.4]; P=.020). A positive correlation between the fiber density and B-cell activation index score of the sample was found (Spearman's Rho, 0.400; P=.004; R2=0.128). No significant difference, however, was found in the density or presence of nerve fibers between samples with high and low T-cell densities. We identified areas of minor and major vestibular glands in 16 of the patient samples and in 1 control sample. Protein gene product 9.5-positive nerve fibers were found more often in glandular epithelium surrounded by B-cell infiltration than in glands without B cells (P=.013). Also, the presence of neuron specific neurofilament-positive fibers in glandular epithelium was associated with B-cell infiltrates (P=.053). Nerve growth factor-positive immune cells were more common in mucosal areas with than without B-cell infiltration and intraepithelial nerve fibers. CONCLUSION: Excessive epithelial nerve growth in provoked vestibulodynia is associated with increased B-cell infiltration and the presence of germinal centers. This supports the fundamental role of immune activation in provoked vestibulodynia.

Activation of vestibule-associated lymphoid tissue in localized provoked vulvodynia.

OBJECTIVE: Localized provoked vulvodynia (LPV) may have inflammatory etiology. We wanted to find out whether the cell-mediated immune system becomes activated in the vestibular mucosa in LPV. STUDY DESIGN: This was a controlled cross-sectional study. Vestibular mucosal specimens were obtained from 27 patients with severe LPV and 15 controls. Detailed clinical history of the patients was obtained. For immunohistochemistry, antibodies against CD3 (T cells), CD20 (B cells), IgA (mucosal plasma cells), CD163 (dendritic cells [DCs]), CD68 (macrophages), and CD117 (mast cells) were employed. Mann-Whitney U test and χ(2) test were used for statistical analyses. RESULTS: More B lymphocytes and mature mucosal IgA-plasma cells were found in patients than in controls (P < .001 and P < .001, respectively). In LPV samples, B and T cells were arranged into germinal centers representing local immune activation. Germinal centers were not seen in controls. Antigen-presenting DCs and macrophages were found both in patients and controls with similar densities. DCs were found to extend their dendrites into the luminal space through an intact epithelium. Similar amounts of mast cells were found evenly scattered throughout the stroma of vestibular mucosa of both patients and controls. CONCLUSION: We demonstrate here local organized vestibule-associated lymphoid tissue analogous to mucosa-associated lymphoid tissue. Vestibule-associated lymphoid tissue may emerge as a response to local infection or inflammation in LPV.

Long-term well-being after surgical or conservative treatment of severe vulvar vestibulitis.

OBJECTIVE: To compare long-term well-being of women who needed surgery or did not need surgery in the treatment of severe vulvar vestibulitis syndrome. We also attempted to identify factors explaining differences in the treatment response. DESIGN: An observational case-control study. SETTING: University Hospital Vulva clinic. POPULATION: Sixty-six women diagnosed with severe vulvar vestibulitis and treated initially by conservative management during 1994-2005. Thirty-nine women did not respond and underwent posterior vestibulectomy and 27 were managed without surgery. METHODS: Baseline patient characteristics, degree of dyspareunia, and details of management were collected from hospital charts. At the follow-up visit current dyspareunia, sexual well-being, somatic and mental health, and social support were analyzed. Vestibular tenderness was measured by swab-touch test. MAIN OUTCOME MEASURES: Visual analogue scale for dyspareunia, sexual well-being, vestibular tenderness, and overall patient satisfaction at follow-up. RESULTS: Dyspareunia decreased significantly in both groups. The visual analogue scale decreased 66.7% in the surgery group and 78.1% in the conservative treatment group (p= 0.407). Posterior swab-touch test was negative more frequently after vestibulectomy. Long-term sexual well-being did not differ between the two groups. Overall, 89% of the women in both groups were satisfied with the treatment. Women with atopic skin problems were less likely to need surgery (odds ratio 0.2; 95% confidence interval 0.1-0.7). CONCLUSION: Women with severe vulvar vestibulitis syndrome who do not respond to conservative management achieve good long-term well-being and decrease of dyspareunia by posterior vestibulectomy. The response is comparable to that achieved by conservative management among women who do not need surgery.

Long-term follow up of posterior vestibulectomy for treating vulvar vestibulitis.

OBJECTIVE: To evaluate the safety and the effectiveness of posterior vestibulectomy in the treatment of vulvar vestibulitis syndrome. DESIGN: A retrospective cohort study. SETTING: University Hospital, tertiary referral center. POPULATION: Seventy women treated by posterior vestibulectomy for severe vulvar vestibulitis syndrome during 1995-2007 at the Department of Obstetrics and Gynecology, University Hospital, Helsinki. METHODS: All operated women were invited to a long-term follow-up study. Patient characteristics, baseline visual analog scale (VAS) for dyspareunia and data from the postoperative period were collected. Of the 70 women, 57 attended the follow-up visit including face-to-face interview, gynecological examination with swab-touch test for vestibular tenderness, current VAS score for dyspareunia and McCoy questionnaire for sexual problems. MAIN OUTCOME MEASURES: Short-term and long-term complication rates, dyspareunia by VAS score, vestibular tenderness, sexual problem index and overall patient satisfaction. RESULTS: Ninety-one per cent were satisfied with the outcome. The VAS for dyspareunia decreased from a median of 9 to 3 (66.7% decrease; p<0.001). Posterior vestibular tenderness was absent in 34 patients (64.2%). Six (8.6%) patients developed postoperative bleeding and 11 (15.7%) mild wound infection. Bartholin's cysts occurred in four (5.7%) patients. CONCLUSIONS: Posterior vestibulectomy is effective and safe in the treatment of severe vulvar vestibulitis syndrome and provides long-term patient satisfaction.

Surgical treatment of vulvar vestibulitis: a review.

Vulvar vestibulitis syndrome, a subset of vulvodynia, is a complex pain syndrome. It causes severe dyspareunia and affects mainly young women. The etiology is unknown and no uniformly effective treatment exists. Surgery has been considered as 'the last resort' in the management of patients not responding to conservative treatment modalities. For this review, all studies of surgical treatment of vulvar vestibulitis were evaluated. We describe the evolution of vestibulectomy techniques through the years. Our aim was also to find out whether any surgical technique is better than others providing better patient satisfaction and lower complication rates. We conclude that surgical technique as such plays a relatively small role. Surgery seems to be effective. However, lack of randomized trials and insufficient data on complication rates must be emphasized.