Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience.

Cervico-vaginal (CV) localization of extra-mammary Paget's disease (EMPD) of the vulva is extremely rare. In order to investigate the incidence risk and the pathognomonic clinical and pathological features of this condition, a retrospective analysis was conducted including 94 women treated for vulvar EMPD at the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020. Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively. All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms. The colposcopic findings were heterogeneous and could sometimes be misdiagnosed. Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma. Most patients developed invasive EMPD (5/9) of the cervix and/or vagina and underwent hysterectomy with partial or total colpectomy. CV involvement from EMPD should not be underestimated in women with a long-standing history of vulvar Paget's disease. Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up.

SIIV position paper: clinical approach to vulval diseases. Need for quality standards.

This paper summarizes the position of the Italian Society of Vulvology on the clinical approach to vulval disease. A thorough history (general medical, gynaecological, and vulval history) is essential for a successful and fruitful vulvological examination. Characteristics of pruritus (itch) and pain, that are the two main vulval symptoms, should be collected and reported with precision, according to duration, temporal course, location, provocation, and intensity. Physical examination must consider both the general condition of the patient and the specific vulval region, that must be examined following a standardized methodology. The physical examination of the vulva is carried out with naked eye and adequate natural or halogen lighting. The subsequent use of instrumental magnification can be considered on particular parts of skin/mucosa, already highlighted with the first inspection. Also, palpation is essential, allowing to appreciate physical features of vulval lesions: consistency, surface, soreness, adherence to underlying plans. Finally, the five-step approach of the International Society for the Study of Vulvo-vaginal Disease about Terminology and Classification of Vulvar Dermatological Disorders (2012) is summarized. A vulval biopsy may be useful in the following situations: when clinical diagnosis is uncertain, lesion not responding to treatment; histologic confirmation for a clinical diagnosis and exclusion or confirmation of a suspected neoplastic intraepithelial or invasive pathology.

Diagnostic Criteria for Differentiated Vulvar Intraepithelial Neoplasia and Vulvar Aberrant Maturation.

OBJECTIVE: The aim of the study was to describe the features required for diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar aberrant maturation (VAM). MATERIALS AND METHODS: The International Society of the Study of Vulvovaginal Diseases tasked the difficult pathologic diagnoses committee to develop consensus recommendations for clinicopathologic diagnosis of vulvar lichen planus, lichen sclerosus, and dVIN. The dVIN subgroup reviewed the literature and formulated diagnostic criteria that were reviewed by the committee and then approved by the International Society of the Study of Vulvovaginal Diseases membership. RESULTS: Differentiated vulvar intraepithelial neoplasia is the immediate precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma and shows a spectrum of clinical and microscopic appearances, some overlapping with HPV-related neoplasia. The histopathologic definition of dVIN is basal atypia combined with negative or nonblock-positive p16 and basal overexpressed, aberrant negative, or wild-type p53. The most common pattern of dVIN is keratinizing with acanthosis, aberrant rete ridge pattern, and premature maturation. The morphologic spectrum of keratinizing dVIN includes hypertrophic, atrophic, acantholytic, and subtle forms. A few dVIN cases are nonkeratinizing, with basaloid cells replacing more than 60% of epithelium. Vulvar aberrant maturation is an umbrella term for lesions with aberrant maturation that arise out of lichenoid dermatitis and lack the basal atypia required for dVIN. CONCLUSIONS: Evaluation of women at risk for dVIN and VAM requires a collaborative approach by clinicians and pathologists experienced in vulvar disorders. Close surveillance of women with lichen sclerosus and use of these recommendations may assist in prevention of HPV-independent squamous cell carcinoma through detection and treatment of dVIN and VAM.

The International Classification of Diseases, 11th Revision: A Step-Back for Women With Vulvodynia?

OBJECTIVE: The aim of the study was to compare the International Classification of Diseases, 11th revision, (ICD-11) with current terminology of vulvodynia, approved by a broad-based consensus of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS). METHODS: The diagnostic criteria and descriptions of vulvodynia as well as the definition and classification of chronic pain in ICD-11 were reviewed and compared with the Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia, endorsed in 2015 by the ISSVD, ISSWSH, and IPPS. RESULTS: Diagnostic criteria and descriptors of vulvodynia in the ICD-11 are outdated. Moreover, vulvodynia is not identified among chronic pain diagnoses, despite fulfilling the diagnostic criteria of chronic primary pain. Specifically, vulvodynia is a vulvar pain of at least 3-month duration, which is associated with significant emotional distress and functional disability, and is not better accounted for by another specific condition. CONCLUSIONS: The ICD-11 is not aligned with current vulvodynia diagnostic criteria and terminology, approved by the ISSVD, ISSWSH, and IPPS. Collaboration among the International Association for the Study of Pain Task Force on Classification of Chronic Pain, ICD team, ISSVD, ISSWSH, and IPPS is needed to harmonize terminologies, codes, and clinical approach regarding vulvar pain and vulvodynia classification.

Descriptors of Vulvodynia: A Multisocietal Definition Consensus (International Society for the Study of Vulvovaginal Disease, the International Society for the Study of Women Sexual Health, and the International Pelvic Pain Society).

OBJECTIVES: Three scientific societies, the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) developed the "2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia" (referred to as the "2015 consensus terminology").The terminology included 11 descriptors of vulvodynia. However, the definitions of the descriptors were not included in the 2015 consensus terminology publications. The objective of this article was to provide these definitions. MATERIALS AND METHODS: The ISSVD led a discussion on the definitions for the 11 vulvodynia descriptors, with participation from the ISSWSH and IPPS. The definitions were created through a consensus process. RESULTS: The definitions are described and the rationale for their choice is elucidated. CONCLUSIONS: The definitions of vulvodynia descriptors were determined by a multistaged process of discussion among health care providers with expertise in the pathophysiology, evaluation, and treatment of vulvodynia. The definitions were approved by the ISSVD, ISSWSH, and IPPS. It is recommended that these definitions of vulvodynia descriptors as well as the 2015 consensus terminology be used for the classification of vulvodynia.

Vulvar Lichen Sclerosus and Neoplastic Transformation: A Retrospective Study of 976 Cases.

OBJECTIVE: The aim of the study was to estimate the neoplastic potential of vulvar lichen sclerosus (VLS). MATERIALS AND METHODS: This was a retrospective study of 976 women with VLS. We recorded age at diagnosis of VLS, length of follow-up, and type of neoplasia, categorized as the following: (1) vulvar intraepithelial neoplasia (VIN), further subdivided in differentiated VIN (dVIN) and high-grade squamous intraepithelial lesion; (2) superficially invasive squamous cell carcinoma; and (3) frankly invasive squamous cell carcinoma. Neoplasia incidence risk, neoplasia incidence rate, and cumulative probability of progression to neoplasia according to the Kaplan-Meier method were estimated. Log-rank test was used to compare the progression-free survival curves by age at diagnosis of VLS. RESULTS: The mean age at diagnosis of VLS was 60 (median = 60; range = 8-91) years. The mean length of follow-up was 52 (median = 21; range = 1-331) months. The following 34 patients developed a neoplasia: 8 VIN (4 dVIN, 4 high-grade squamous intraepithelial lesions), 6 keratinizing superficially invasive squamous cell carcinoma (5 with adjacent dVIN), and 20 keratinizing invasive squamous cell carcinoma (1 with adjacent dVIN). The neoplasia incidence risk was 3.5%. The neoplasia incidence rate was 8.1 per 1,000 person-years. The cumulative probability of progression to neoplasia increased from 1.2% at 24 months to 36.8% at 300 months. The median progression-free survival was significantly shorter in older women (≥70 years) when compared with that in younger women (p = .003). CONCLUSIONS: Vulvar lichen sclerosus has a nonnegligible risk of neoplastic transformation and requires a careful and lifelong follow-up in all patients, particularly in elderly women. Early clinical and histological detection of preinvasive lesions is essential to reduce the risk of vulvar cancer.

VIN usual type-from the past to the future.

Usual vulvar intraepithelial neoplasia (uVIN) is the most common VIN type, generally related to a human papillomavirus (HPV) infection, predominantly type 16. The incidence of uVIN has been increasing over the last decades, and a bimodal peak is observed at the age of 40-44 and over 55 years. Almost 40% of patients with uVIN have a past, concomitant or future HPV-associated lesion of the lower genital tract. HPV-related malignancies are associated with a persistent HPV infection. The host immune response is of crucial importance in determining clearance or persistence of both HPV infections and HPV-related VIN. About 60% of the patients present with symptoms. Clinical features of uVIN vary in site, number, size, shape, colour, and thickness of lesions. Multicentric disease is often present. Most uVIN lesions are positive at immunohistochemistry to p16(ink4a) and p14(arf), but negative to p53. Irrespective of surgical treatment used, uVIN recurrence rates are high. Positive margins do not predict the development of invasive disease and the need to re-excide the tissue around the scare remains to be demonstrated. Therefore, considering the low progression rate of uVIN and psycosexual sequelae, treatments should be as conservative as possible. Medical treatments available are mainly based on immunotherapy to induce normalisation of immune cell count in uVIN. None are approved by the food and drug administration (FDA) for the treatment of uVIN. If medical treatment is performed, adequate biopsies are required to reduce the risk of unrecognised invasive disease. Some studies suggest that failure to respond to immunotherapy might be related to a local immunosuppressive microenvironment, but knowledge of the uVIN microenvironment is limited. Moreover, our knowledge of the potential mechanisms involved in the escape of HPV-induced lesions from the immune system has many gaps. HPV vaccines have been demonstrated to be effective in preventing uVIN, with 94.9% efficacy in the HPV-naive population, while studies on therapeutic vaccines are limited. The low incidence of VIN requires large multicentre studies to determine the best way to manage affected patients and to investigate the immunological characteristics of the 'vulvar microenviroment' which leads to the persistence of HPV.

Vestibulodynia: synergy between palmitoylethanolamide + transpolydatin and transcutaneous electrical nerve stimulation.

OBJECTIVE: The study aimed to assess the effect of palmitoylethanolamide + transpolydatin combination in patients with vestibulodynia undergoing transcutaneous electrical nerve stimulation (TENS) therapy and to confirm the effectiveness of TENS also in a domiciliary protocol. The study is based on the premise that palmitoylethanolamide + transpolydatin combination may contribute to a down-regulation of mast cell hyperactivity, which is believed to be responsible for the proliferation and sprouting of vestibular pain fibers and the associated hyperalgesia and allodynia. MATERIALS AND METHODS: Twenty women with vestibulodynia were randomly assigned to receive oral palmitoylethanolamide (PEA) 400 mg and transpolydatin 40 mg or placebo, twice daily for 60 days. All patients underwent TENS therapy in a self-administered home protocol. Visual analogue scale (VAS), Marinoff score for dyspareunia, and current perception threshold obtained from the vulvar vestibule were assessed at baseline and at the end of treatment. RESULTS: The patients received a mean of 26.7 TENS sessions. All scores in the 2 groups improved significantly, although the level of improvement was similar between the groups (VAS, p < .57; dyspareunia, p < .38). Nevertheless, the analysis of regression of symptoms related to the duration of disease revealed the therapy to be more effective when PEA + transpolydatin is included in cases with more recent disease onset, as compared with the placebo group (PEA: VAS, p < .01; dyspareunia, p < .01) (placebo: VAS, p = nonsignificant; dyspareunia, p = nonsignificant). CONCLUSIONS: This study confirms that TENS is of significant benefit in the management of vestibulodynia, also in a home environment. PEA + transpolydatin can be a value-added treatment adjunct when the onset of vestibulodynia is more recent or when the disease relapses.

Electrodiagnostic functional sensory evaluation of patients with generalized vulvodynia: a pilot study.

OBJECTIVE: To objectively evaluate vulvodynia by the current perception threshold (CPT) neurometer. METHODS: Neuroselective CPT measures of the pudendal nerve were obtained at the perineum by a neurometer (Neurotron, Inc, Baltimore, MD), using constant alternating sinusoid waveform electrical stimulus at 2,000-, 250-, and 5-Hz frequencies, in 20 healthy volunteers and 38 women with vulvodynia. The mean +/- SD CPT values in vulvodynia and healthy (control) women were analyzed with the Student t test. RESULTS: Women with vulvodynia showed lower mean CPT values (p <.01). CONCLUSIONS: Results of this study support a neuroselective sensory dysfunction in generalized vulvodynia. The field is opened for CPT measures in vulvodynia in selecting therapy strategy, monitoring response to treatment, and assessing vestibulodynia. Assessment of threshold values in a greater number of controls is needed to set a cutoff in CPT values for diagnosis and to grade the severity of the diseases.

Capsaicin and the treatment of vulvar vestibulitis syndrome: a valuable alternative?

OBJECTIVE: To assess the efficacy of topical capsaicin in the treatment of vulvar vestibulitis syndrome. STUDY DESIGN: Thirty-three consecutive women referred for vulvar vestibulitis syndrome were treated with topical capsaicin 0.05 %. The capsaicin cream was applied twice a day for 30 days, then once a Day for 30 days, and finally 2 times a week for 4 months. RESULTS: In 19 patients (59%), improvement of symptoms was recorded, but no complete remission was observed. Symptoms recurred in all patients after the use of capsaicin cream was discontinued. A return to a twice-weekly topical application of the cream resulted in the improvement of symptoms. Severe burning was reported as the only side effect by all the patients. CONCLUSION: Response to treatment was only partial, possibly due to the concentration of the compound being too low, or to the need for more frequent than daily applications. The therapeutic role of capsaicin should hence be confined to a last-choice medical approach.