Usual-type Vulvar Intraepithelial Neoplasia Research Articles

Vulvar cancer in young woman—case report

Vulvar cancer is rare with incidence of 45,240 new cases globally which account for 4% of all genitourinary tract neoplasma. It is considered as a postmenopausal disease, however incidence age has decreased over the years because of high prevalence of persistent high-risk human papillomavirus (hrHPV) infection. Vulvar cancer diagnosis in young women is challenging. Prompt and adequate diagnosis, and treatment can ensure the life quality. A 23 years old patient was admitted to Department of Operative Gynecology for treating malignant vulvar neoplasma. She was reffered to our clinic for electrocauterization after being diagnosed of condylomata accuminata. Physical examination revealed vulva atrophy with smooth discolored skin patches on both sides. A 2 cm exophytic lesion was noted ~10 mm from clitoris on right labia majora. Multifocal biopsy was performed for suspect finding which proved invasive vulvar squamous keratinizing cancer. Positron emission tomography-computed tomography (PET/CT) scan showed individual lymph nodes on right inguinofemoral region which were moderately metabolically active. Wide excision of cancer was performed with unilateral inguinofemoral lymphadenectomy. Macroscopic evaluation of entire specimen depicted 2.4 × 2.2 × 0.5 cm HPV associated invasive vulvar squamous keratinizing cancer, vulvar high grade squamous intraepithelial lesion (vHSIL) or usual type vulvar intraepithelial neoplasia (uVIN3) and lichen sclerosus. Healthcare professionals in primary care centers should be adequately trained, aware of and familiar with vulvar malignancies in younger women despite their rarity. Early diagnosis can improve outcomes in vulvar cancer via reducing morbidity and mortality. The individualized surgical treatment is the preferred strategy for patients at present.

Оцінка ефективності клініко-дерматоскопічного та вульвоскопічного дослідження при вульварній інтраепітеліальній неоплазії

High grade squamous intraepithelial lesions of the vulva of the usual type are associated with infection caused by human papillomavirus, while differentiated intraepithelial neoplasia of the vulva develops most often on the background of vulvar lichen sclerosus et atrophicus in postmenopausal women. These types of intraepithelial neoplasia can be analyzed using dermoscopy and vulvoscopy methods. Purpose - to evaluate the effectiveness of clinical dermatoscopy and vulvoscopic examination in vulvar intraepithelial neoplasia. Materials and methods. This research paper presents the results of using dermoscopy and vulvoscopy examination methods, their comparison with the histological result and determining the most effective of these methods taking into account a higher probability of suspected precancerous lesions of the vulva. Results. The study involved 170 patients who were examined in the outpatient department of the National Cancer Institute in 2017-2021. 100 (58.82%) patients were diagnosed with the usual type vulvar intraepithelial neoplasia, 70 (41.17%) patients - of the differentiated type. Conclusions. The study results proved that dermoscopy was more exact to suspect precancer and a more accurate biopsy taking was fixed. The detection of НSIL was 98% in patients who underwent dermoscopy and those who had vulvoscopy - 75%, compared with histological findings. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Topical imiquimod as first-line treatment for vulvar intraepithelial neoplasia

Human papillomavirus (HPV)-induced vulvar high-grade squamous intraepithelial lesions (vHSIL), formerly known as usual-type vulvar intraepithelial neoplasia (VIN), has a cancer risk of approximately 10% and treatment is aimed at relieving symptoms and preventing progression towards cancer.1 New therapeutic options have emerged to provide alternative non-surgical management strategies, including immune-response modulators, anti-viral agents, photodynamic therapy, and prophylactic HPV vaccination.

Vulvar intraepithelial neoplasia. Literature review

Vulvar intraepithelial neoplasia (VIN) is the proliferation of atypical basal cells in the vulvar epithelium. The global VIN incidence has recently doubled; its incidence among white women under 35 years of age has almost tripled with a tendency for further growth. Such an increase in the number of usual-type VIN cases in young women is primarily attributed to infection with highly oncogenic human papillomavirus. The second type of dysplasia, namely differentiated VIN, is usually found in older women and is associated with chronic dystrophic diseases of the vulva, most frequently with lichen sclerosus of the vulva. VIN diagnosis is quite challenging; no screening programs for this disorder have been developed so far. Patients with VIN practice self-treatment for a long time, which aggravates their condition and might trigger the development of vulvar cancer. Several treatment options are currently available; however, their efficacy worldwide is not high.

Anal Intraepithelial Neoplasia Associated with High-Grade Vulva Injury (Usual-Type Vulvar Intraepithelial Neoplasia): Surgical Treatment with Cutaneous Flap Advancement

AbstractThe aim of the present article is to report the case of a young patient with bowenoid papulosis who was a carrier of other sexually-transmitted infections (STIs), such as HIV and high-grade vulva lesion (usual-type vulvar intraepithelial neoplasia, VIN), and to demonstrate the strategy used to manage the case, as well as to discuss important issues regarding the standardization of intraepithelial lesions.8

Programmed Death Ligand-1 (PD-L1) expression is up-regulated and related to the pattern of invasion in FIGO Stage I vulvar squamous cell carcinomas

The immune checkpoint protein programmed death ligand-1 (PD-L1) is expressed in different types of cancer and is a potential prognostic factor as well as therapeutic target. This study evaluated PD-L1 expression in the neoplastic progression of vulvar epithelia with respect to the pattern of infiltration in FIGO stages I keratinizing squamous cell carcinomas (SCC). Normal squamous vulvar epithelia (n=20), usual type vulvar intraepithelial neoplasia (uVIN, n=23), differentiated VIN (dVIN, n=21) and FIGO stage I SCC (n=35) were immunostained for PD-L1. In SCC a cohesive growth with well-delineated borders was considered as pushing, dissociative growth in small groups or single cells was defined as diffuse pattern of infiltration. Immunostaining was done with a monoclonal anti PD-L1 antibody (clone SP263, Ventana) and scored to determine up-regulation and overexpression (score 0/1+, 0-5% immunoreactive cells; score 2+, >5 to 50% immunoreactive cells; score 3+, >50% immunoreactive cells). PD-L1 immunoexpression was comparable in normal epithelia and VINs (score 0/1+, n=59; score 2+, n=5, in VINs only; score 3+, n=0), was significantly increased (P<0.0001) in SCC (score 0/1+, n=13; score 2+, n=16; score 3+, n=6), and was related to a diffuse pattern of infiltration (P<0.0001). Staining was accentuated at the invasive margins of SCC frequently. PD-L1 expression is up-regulated in the neoplastic cells of vulvar low stage SCC, related to the development of an invasive phenotype reflecting the initiation of cancer immunoediting, and to an aggressive diffuse type of stromal invasion.

Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome.

Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC) is an aggressive clinical entity. Current diagnostic guidelines for premalignant lesions are ambiguous, and their molecular profile and progression events are still unclear. We selected 75 samples, from 40 patients, including 33 VSCC, 8 verrucous carcinomas (VC), 13 differentiated-type vulvar intraepithelial neoplasia (dVIN), 11 suspicious for dVIN (?dVIN), 6 differentiated exophytic vulvar intraepithelial lesions (DE-VIL), 2 vulvar acanthosis with altered differentiation (VAAD), and 2 usual-type vulvar intraepithelial neoplasia (uVIN/HSIL). Invasive and precursor lesions were matched in 29 cases. Clinical information, p16 immunohistochemistry, and mutation analysis were performed on all lesions. All dVIN, ?dVIN, DE-VIL, and VAAD were p16 negative, all uVIN/HSIL were p16 positive. In the HPV-independent group, mutations were identified in 6 genes: TP53 (n = 40), PIK3CA (n = 20), HRAS (n = 12), MET (n = 5), PTEN (n = 4), and BRAF (n = 1). TP53 mutations occurred in 73% (22/30) VSCC, 85% (11/13) dVIN, 70% (7/10) ?dVIN and no VC (0/8), DE-VIL (0/6) nor VAAD (0/2). Basal atypia was the only reliable feature of TP53 mutations. ?dVIN lesions that were non-acanthotic and atypical but obscured by inflammation, all harbored TP53 mutations. In lesions without TP53 mutations, PIK3CA (50% VC, 33% DE-VIL, 100% VAAD, 40% VSCC) and HRAS (63% VC, 33% DE-VIL, 0% VAAD, 20% VSCC) mutations were found. Mutational progression from in situ to invasive was seen (7/26, 27%) and usually involved TP53 (4/26, 15%). Cases with TP53 and PIK3CA co-mutations had the worse clinical outcomes (p < 0.001). We recommend testing for p53 in all HPV-independent lesions suspicious for dVIN, even in the presence of marked inflammation or non-acanthotic skin, particularly when close to a margin. VC, VAAD, and DE-VIL, were almost never mutated for TP53, but instead often harbored PIK3CA and HRAS mutations. In VSCC, combined TP53 and PIK3CA mutations may inform prognosis.

Vulval squamous cell carcinoma and its precursors.

Vulval squamous cell carcinoma (VSCC) can arise through two distinct pathways [human papillomavirus (HPV)-associated and HPV-independent], and these VSCC variants are recognised as different disease entities on the basis of different aetiologies, morphological features, molecular events during oncogenesis, precursor lesions, prognosis, and response to treatment. The precursor of HPV-associated VSCC, variously referred to as high-grade squamous intraepithelial lesion (HSIL) [vulvar intraepithelial neoplasia (VIN) 2/3] or usual-type VIN, is morphologically identical to the more common HSIL (cervical intraepithelial neoplasia 2/3) of the cervix. The precursor lesions of HPV-independent VSCC include differentiated VIN, differentiated exophytic vulvar intraepithelial lesion, and vulvar acanthosis with altered differentiation; these have been under-recognised by pathologists in the past, leading to delays in treatment. This review will discuss the recent advances in diagnostic surgical pathology of VSCC and its precursors, and how these diagnoses can impact on patient management.

Abstract B091: Vulvar squamous cell carcinoma: Comprehensive genomic profiling of HPV(+) versus HPV(–) forms reveals a different set of potentially actionable biomarkers

Abstract Introduction: One major form of vulvar squamous cell carcinoma (vSCC) is associated with detectable high-risk strains of human papillomavirus (hrHPV) and is often accompanied by usual-type vulvar intraepithelial neoplasia (VIN). The second major form of vSCC is often associated with chronic dystrophic or inflammatory lesions in postmenopausal women, does not harbor detectable HPV infection, and is often preceded by p53-mutant differentiated VIN. While studies have examined the two subtypes, no large-scale genomic study has been performed to our knowledge. We sought to assess the genomics of a large cohort of aggressive vSCCs, with an aim to identify distinct mutational signatures based on the presence or absence of hrHPV genome reads. Methods: 280 vSCC were tested by hybridization capture of up to 406 cancer-related genes evaluated for base substitutions, small indels, amplification (amp), and rearrangements. HPV genome sequences were detected by de novo assembly of non-human sequencing reads and BLASTn comparison against all viral nucleotide sequences in the NCBI RefSeq database. Tumor mutational burden (TMB, mutations/Mb) was determined on ~1.1 Mbp of sequenced DNA. PD-L1 status was determined by IHC (Dako 22C3), with ≥50% tumor proportion score defined as high positive. Results: 102/280 vSCCs contained hrHPV sequences. Of these, 90 were HPV-16, 7 HPV-18, 1 HPV-31, 3 HPV-33, 1 HPV-58, and 1 HPV-67. Patients were significantly younger in the HPV(+) group (median 59 v. 64 years, p=0.001). Compared with the HPV(–) cohort, HPV(+) cases showed significantly more pathogenic genomic alterations (GA) in PIK3CA (31% vs. 17%, p=0.004), PTEN (14% vs. 2%, p&amp;lt;0.0001), EP300 (14% vs. 1%, p&amp;lt;0.0001), STK11 (14% vs. 1%, p&amp;lt;0.0001), AR (5% vs. 0%, p=0.006), and FBXW7 (10% vs. 3%, p=0.03). In contrast, HPV(–) cases showed significantly more alterations in TP53 (82% vs. 3%, p&amp;lt;0.0001), TERTp (71% vs. 8%, p&amp;lt;0.0001), CDKN2A (55% vs. 2%, p&amp;lt;0.0001), CCND1 (23% vs. 2%, p&amp;lt;0.0001), FAT1 (25% vs. 4%, p&amp;lt;0.0001), NOTCH1 (19% vs. 6%, p=0.002), and EGFR (amp: 12% vs. 0%, p&amp;lt;0.0001), as well as a higher rate of 9p24.1 (PDL1/PDL2) amp (7% vs. 1%) and PD-L1 IHC high-positive tumor staining (33% vs. 9%, p=0.04). Differences in alterations were observed between known primary and metastatic sites in cases with similar HPV status but did not reach significance (table). HPV(+)HPV(–) PrimaryMetastasisPrimaryMetastasis # of cases504112442 Age (range)58 (36-81)60 (29-83)64 (25-89)63 (45-89) Median TMB (range)5.2 (0-18.3)6.1 (0-47.8)3.5 (0-90.5)5.0 (0-13) PIK3CA GA26%37%17%17% PTEN GA18%10%2%2% STK11 GA10%22%1%2% FBXW7 GA10%10%5%0% TP53 GA0%5%82%81% TERTp GA6%10%73%64% CDKN2A GA0%5%55%52% CCND1 GA2%2%20%29% EGFR amp0%0%12%14% CD274(PD-L1) amp*0%0%6%10% PD-L1 IHC high*8%11%30%33% TMB &amp;gt;10*6%24%3%19% Conclusions: vSCCs show significant differences in molecular profile based on HPV status. 63% of metastatic HPV(+) cases (54% overall) have a potentially actionable alteration in the PI3K/mTOR pathway, and 42% of metastatic HPV(–) cases (39% overall) have at least one potential predictive biomarker* for response to immunotherapy. Our findings provide compelling rationale for tandem comprehensive genomic profiling and HPV assessment of advanced vulvar SCCs to more fully inform therapeutic options and stratification in clinical trials. Citation Format: Erik A Williams, Adrienne J Werth, Meagan Montesion, Ethan S Sokol, Dean C Pavlick, Nikunj A Shah, Jo-Anne Vergilio, Natalie A Danziger, Jonathan K Killian, Douglas A Lin, Vincent A Miller, Jeffrey S Ross, Julia A Elvin. Vulvar squamous cell carcinoma: Comprehensive genomic profiling of HPV(+) versus HPV(–) forms reveals a different set of potentially actionable biomarkers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B091. doi:10.1158/1535-7163.TARG-19-B091

Differential expression patterns of GATA3 in usual and differentiated types of vulvar intraepithelial neoplasia: potential diagnostic implications

AbstractThe two main precursors of vulvar squamous cell carcinoma, usual and differentiated vulvar intraepithelial neoplasia (VIN), have distinctive etiology, pathogenesis, and natural history. Usual type VIN is often associated with high-risk HPV and differentiated VIN has de novo p53 genetic alterations that are unrelated to HPV infection. GATA-binding protein 3 (GATA3) is a tumor suppressor that shows increased expression in several types of human malignancies including breast and bladder carcinomas. Little is known regarding the expression of GATA3 in vulvar squamous neoplasms. We have systematically examined the expression of GATA3 in 119 vulvar lesions and neoplasms including 20 cases of lichen sclerosus, 12 cases of lichen simplex chronicus, 30 cases of usual type VIN, 34 cases of differentiated VIN, and 23 cases of squamous cell carcinoma. Similar to adjacent non-neoplastic epidermis, moderate to strong GATA3 expression was retained in all cases of lichen sclerosus, lichen simplex chronicus, and usual type VIN. However, in comparison, the GATA3 immunostaining pattern in differentiated VIN was distinct. Partial/complete loss of GATA3 expression in the basal layer with or without loss in the parabasal layer was observed in 30/34 (88%) of differentiated VIN cases. Significant loss of GATA3 expression was also observed in all (7/7) squamous cell carcinomas associated with usual type VIN and in 13/16 (81%) of those associated with differentiated VIN. There was no significant correlation between loss of GATA3 expression and overexpression of p53 in differentiated VIN. Our study shows that loss of GATA3 expression is seen in the vast majority (87%) of vulvar squamous cell carcinomas. Downregulation of GATA3 may be an early event during tumorigenesis in differentiated VIN but not in HPV-related usual type VIN. Our data suggests that application of GATA3 immunohistochemistry along with p53 may be a useful tool in facilitating the accurate diagnosis of VIN.

Differentiated Vulvar Intraepithelial Neoplasia-like and Lichen Sclerosus-like Lesions in HPV-associated Squamous Cell Carcinomas of the Vulva.

Most human papillomavirus (HPV)-associated vulvar squamous cell carcinomas (VSCCs) originate from high-grade squamous intraepithelial lesions, also named usual type vulvar intraepithelial neoplasia. However, growing evidence suggests that morphologic studies have limitations in predicting HPV status in vulvar lesions. We aimed to evaluate adjacent intraepithelial lesions in a series of DNA HPV-positive VSCCs, focusing on unusual histologic patterns mimicking differentiated vulvar intraepithelial neoplasia (dVIN) or lichen sclerosus (LS). We identified 326 DNA HPV-positive VSCC with at least 1 cm of skin adjacent to the invasive tumor and analyzed HPV typing, HPV E6*I mRNA, and p16 immunohistochemistry in all cases. A careful histologic evaluation was conducted. A conclusive association with HPV was based on a positive p16 or HPV E6*I mRNA result or both in addition to the HPV DNA, whereas cases negative for both markers were classified as nonconclusively associated with HPV. One hundred twenty-one tumors (37.1%) had normal adjacent skin, 191 (58.6%) had only high-grade squamous intraepithelial lesions, also named usual type vulvar intraepithelial neoplasia, and unusual intraepithelial lesions were identified in 14 (4.3%) tumors. Seven cases showed dVIN-like features, 5 showed adjacent LS-like lesion, and in 2 cases dVIN-like and LS-like lesions were identified simultaneously. Six of them were conclusively associated with HPV (3 dVIN-like, 2 LS-like, 1 with combined dVIN/LS-like features). All 6 tumors were associated with HPV16 and were positive for both p16 and HPV mRNA, and p16 was also positive in the dVIN-like and LS-like lesions. In summary, a small subset of VSCCs conclusively associated with HPV may arise on intraepithelial lesions, mimicking precursors of HPV-independent VSCC.

Vulvar cancer is not a disease of the elderly: Treatment and outcome at a tertiary referral centre in South Africa.

An increase in vulvar cancer in young women is attributed to infection with oncogenic human papillomavirus (HPV). South Africa (SA) has a high prevalence of HPV, and it was therefore hypothesised that women with vulvar cancer here would be younger than in high-income countries (HICs). To describe age, cancer stage, treatment and outcome of patients with vulvar cancer at a tertiary referral centre in SA. In a retrospective observational study, patient records of women diagnosed with vulvar cancer between 2001 and 2014 were reviewed and demographic and surgical details captured. Histology results of vulvar biopsies and resected specimens were checked for HPV changes, koilocytes and usual-type vulval intraepithelial neoplasia. Patients were restaged using the International Federation of Gynecology and Obstetrics(FIGO) 2009 staging system to allow for comparison of outcomes. Five-year disease-specific survival probability curves were generated using Kaplan-Meier analysis. The mean age of the 180 patients in the study was 52.5 years. Those who had documented HPV changes on histological specimens had a mean age of 50.4 years. More than 50% of the patients had advanced-stage disease, and 62.7% were treated with primary surgery. Five-year disease-specific survival probabilities were similar to those reported in the literature. Vulvar cancer should not be regarded as a disease of the elderly in SA, as women with vulvar cancer are 10 - 15 years younger than in HICs. A large proportion of patients present with advanced-stage disease. Health professionals should be alert to vulvar lesions, especially in women with abnormal Pap smears, to reduce the morbidity and mortality of this disease.

The Natural History of Vulvar Intraepithelial Neoplasia, Differentiated Type: Evidence for Progression and Diagnostic Challenges.

Squamous cell carcinoma of the vulva (SCCV) develops through either human papillomavirus (HPV)-dependent or HPV-independent pathways. Approximately 60% of SCCV arise independently of HPV, commonly in a background of an inflammatory dermatosis, particularly lichen sclerosus. The likely direct precursor to most of these lesions is vulvar intraepithelial neoplasia (VIN), differentiated type (dVIN), although the evidence is largely circumstantial. There are few reports of progression to carcinoma, and the natural history of this pathway is not well understood. Nevertheless, dVIN is widely regarded as a potentially aggressive lesion. We identified dVIN adjacent to SCCV in 97 of 212 women (45.8%). Twenty-four of the 97 women (24.7%) had biopsies performed at least 6 mo before presentation with SCCV; slides for 47 biopsies from 21 women were available for review. dVIN was identified in 18 biopsies from 8 women (38.1%), which in 14 biopsies had been previously unrecognized. The subsequent cancer developed in the same region as the previous biopsy showing dVIN in 6 of the 8 women. The median interval between biopsy and invasive cancer was 43.5 mo (range, 8-102 mo). dVIN-associated SCCV was strongly associated with both lichen sclerosus, and HPV-negative status compared with usual type VIN (relative risk=38.35 (9.755-150.8) and 0.06485 (0.02764-0.1522), respectively). This study adds to the evidence linking dVIN with SCCV, and indicates that both clinical and histologic underrecognition contribute to the apparent rarity of dVIN as a solitary diagnosis. The morphologic spectrum of dVIN is likely to be wider than commonly appreciated; however, histologically defining the lower threshold is difficult and controversial.

Committee Opinion No.675: Management of Vulvar Intraepithelial Neoplasia.

Vulvar intraepithelial neoplasia (VIN) is an increasingly common problem, particularly among women in their 40s. Although spontaneous regression has been reported, VIN should be considered a premalignant condition. Immunization with the quadrivalent or 9-valent human papillomavirus vaccine, which is effective against human papillomavirus genotypes 6, 11, 16, and 18, and 6, 11, 16, 18, 31, 33, 45, 52, and 58, respectively, has been shown to decrease the risk of vulvar high-grade squamous intraepithelial lesion (HSIL) (VIN usual type) and should be recommended for girls aged 11-12 years with catch-up through age 26 years if not vaccinated in the target age. There are no screening strategies for the prevention of vulvar cancer through early detection of vulvar HSIL (VIN usual type). Detection is limited to visual assessment with confirmation by histopathology when needed. Treatment is recommended for all women with vulvar HSIL (VIN usual type). Because of the potential for occult invasion, wide local excision should be performed if cancer is suspected, even if biopsies show vulvar HSIL. When occult invasion is not a concern, vulvar HSIL (VIN usual type) can be treated with excision, laser ablation, or topical imiquimod (off-label use). Given the relatively slow rate of progression, women with a complete response to therapy and no new lesions at follow-up visits scheduled 6 months and 12 months after initial treatment should be monitored by visual inspection of the vulva annually thereafter.

A case series of young women with spontaneous regression of vulval intraepithelial neoplasia: Demographics and associated HPV genotypes.

To review the clinical features, demography and human papillomavirus (HPV) genotype in a group of young women with usual type vulval intraepithelial neoplasia (VIN) whose lesions regressed spontaneously. A retrospective case note review was made of the records of women with a diagnosis of usual type VIN whose lesions resolved spontaneously. The clinical features, demography, associated conditions, time to regression and follow-up data were extracted. Stored paraffin-embedded biopsy tissue was tested for the presence and genotype of HPV. Fifty-four women were identified. The median age at diagnosis was 19 years. Forty-four women (81%) were of non-European ethnicity. The median time to regression was 9 months. In 44 (81%) cases, the lesion was an incidental finding during clinical examination. The majority of lesions were multifocal and pigmented (44 (81%) and 48 (89%), respectively). HPV was detected in 40 (87%) of the 46 available biopsy samples, and HPV genotype 16 was identified in 33 (82.5%). Recurrences of usual type VIN occurred in three women, and these all resolved spontaneously. Women diagnosed with usual type VIN which resolves spontaneously are very young, mainly non-European, and usually present with multiple, asymptomatic pigmented lesions. HPV genotypes and their frequencies are similar to those detected in older women with usual type VIN. This clinically defined group of women may be managed by observation alone if follow-up is assured.

The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions.

The impact of terminology for vulvar intraepithelial lesions has been significant over the years, because it has affected diagnosis, treatment, and research. The introduction of the Lower Anogenital Squamous Terminology (LAST) in 2012 raised 2 concerns in relation to vulvar lesions: firstly, the absence of reference to "differentiated vulvar intraepithelial neoplasia" (differentiated VIN) could lead to its being overlooked by health care providers, despite its malignant potential. Secondly, including the term "low-grade squamous intraepithelial lesion" (LSIL) in LAST recreated the potential for overdiagnosis and overtreatment for benign, self-limiting lesions. The International Society for the Study of Vulvovaginal Disease (ISSVD) assigned the terminology committee the task of developing a terminology to take these issues into consideration. The committee reviewed the development of terminology for vulvar SILs with the previous 2 concerns in mind and reviewed several new terminology options. The final version accepted by the ISSVD contains the following: 1) Low-grade SIL of the vulva or vulvar LSIL, encompassing flat condyloma or human papillomavirus effect. 2) High-grade SIL or vulvar HSIL (which was termed "vulvar intraepithelial neoplasia usual type" in the 2004 ISSVD terminology). 3) Vulvar intraepithelial neoplasia, differentiated type. The advantage of the new terminology is that it includes all types of vulvar SILs, it provides a solution to the concerns in relation to the application of LAST to vulvar lesion, and it is in accordance with the World Health Organization classification as well as the LAST, creating unity among clinicians and pathologists.

Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia.

Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia.

The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions.

The impact of terminology for vulvar intraepithelial lesions has been significant over the years, because it has affected diagnosis, treatment, and research. The introduction of the Lower Anogenital Squamous Terminology (LAST) in 2012 raised 2 concerns in relation to vulvar lesions: firstly, the absence of reference to "differentiated vulvar intraepithelial neoplasia" (differentiated VIN) could lead to its being overlooked by health care providers, despite its malignant potential. Secondly, including the term "low-grade squamous intraepithelial lesion" (LSIL) in LAST recreated the potential for overdiagnosis and overtreatment for benign, self-limiting lesions. The International Society for the Study of Vulvovaginal Disease (ISSVD) assigned the terminology committee the task of developing a terminology to take these issues into consideration. The committee reviewed the development of terminology for vulvar SILs with the previous 2 concerns in mind and reviewed several new terminology options. The final version accepted by the ISSVD contains the following:•Low-grade SIL of the vulva or vulvar LSIL, encompassing flat condyloma or human papillomavirus effect.•High-grade SIL or vulvar HSIL (which was termed "vulvar intraepithelial neoplasia usual type" in the 2004 ISSVD terminology).•Vulvar intraepithelial neoplasia, differentiated type. The advantage of the new terminology is that it includes all types of vulvar SILs, it provides a solution to the concerns in relation to the application of LAST to vulvar lesion, and it is in accordance with the World Health Organization classification as well as the LAST, creating unity among clinicians and pathologists.

Medical interventions for high-grade vulval intraepithelial neoplasia.

This is an updated version of a review first published in theCochrane Database of Systematic Reviews, Issue 4, in 2011. Vulval intraepithelial neoplasia (VIN) is a pre-cancerous condition of the vulval skin and its incidence is increasing in women under 50 years. High-grade VIN (also called usual-type VIN (uVIN) or VIN 2/3 or high-grade vulval intraepithelial lesion) is associated with human papilloma virus (HPV) infection and may progress to vulval cancer, therefore is usually actively managed. There is no consensus on the optimal management of high-grade VIN; and the high morbidity and relapse rates associated with surgical interventions make less invasive interventions highly desirable. To evaluate the effectiveness and safety of medical (non-surgical) interventions for high-grade VIN. We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 3), MEDLINE and EMBASE (up to 30 March 2015). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Randomised controlled trials (RCTs) that assessed non-surgical interventions in women diagnosed with high-grade VIN. We used Cochrane methodology with two review authors independently abstracting data and assessing risk of bias. Where possible, we synthesised data in meta-analyses using random effects methods. Five trials involving 297 women with high-grade VIN (defined by trial investigators as VIN 2/3 or VIN 3 or 'high-grade' lesions) met our inclusion criteria: three trials assessed the effectiveness of topical imiquimod versus placebo; one assessed topical cidofovir versus topical imiquimod; and one assessed low- versus high-dose indole-3-carbinol in similar types of participants.Three trials were at a moderate to low risk of bias, two were at a potentially high risk of bias.Meta-analysis of the three trials comparing topical imiquimod 5% cream to placebo found that women in the active treatment group were more likely to show an overall response (complete and partial response) to treatment at five to six months compared with the placebo group (Risk Ratio (RR) 11.95, 95% confidence interval (CI) 3.21 to 44.51; participants = 104; studies = 3; I(2) = 0%; high-quality evidence). A complete response at five to six months occurred in 36/62 (58%) and 0/42 (0%) participants in the active and placebo groups, respectively (RR 14.40, 95% CI 2.97 to 69.80; participants = 104; studies = 3; I(2) = 0%). A single trial reported 12-month follow-up, which revealed a sustained effect in overall response in favour of the active treatment arm at 12 months (RR 9.10, 95% CI 2.38 to 34.77; moderate-quality evidence), with 9/24 (38%) and 0/23 (0%) complete responses recorded in the active and placebo groups respectively. Progression to vulval cancer was also documented in this trial (one versus two participants in the active and placebo groups, respectively) and we assessed this evidence as low-quality. Only onetrial reported adverse events, including erythema, erosion, pain and pruritis at the site of the lesion, which were more common in the imiquimod group. Dose reductions occurred more frequently in the active treatment group compared with the placebo group (19/47 versus 1/36 participants; RR 7.77, 95% CI 1.61 to 37.36; participants = 83; studies = 2; I(2) = 0%; high-quality evidence). Only one trial reported quality of life (QoL) and there were no significant differences between the imiquimod and placebo groups.For the imiquimod versus cidofovir trial, 180 women contributed data. The overall response at six months was similar for the imiquimod and cidofovir treatment groups with 52/91 (57%) versus 55/89 (62%) participants responding, respectively (RR 0.92, 95% CI 0.73 to 1.18). A complete response occurred in 41 women in each group (45% and 46%, respectively; RR 1.00, 95% CI 0.73 to 1.37). Although not statistically different, total adverse events were slightly more common in the imiquimod group of this trial with slightly more discontinuations occurring in this group. Longer term response data from this trial are expected.The small trial comparing two doses of indole-3-carbinol contributed limited data. We identified five ongoing randomised trials of various interventions for VIN. Topical imiquimod appears to be a safe and effective treatment for high-grade VIN (uVIN), even though local side-effects may necessitate dose reductions. However, longer term follow-up data are needed to corroborate the limited evidence that response to treatment is sustained, and to assess any effect on progression to vulval cancer. Available evidence suggests that topical cidofovir may be a good alternative to imiquimod; however, more evidence is needed, particularly regarding the relative effectiveness on longer term response and progression. We await the longer-term response data and the results of the five ongoing trials.

No viral association found in a set of differentiated vulvar intraepithelial neoplasia cases by human papillomavirus and pan-viral microarray testing.

Vulvar Intraepithelial Neoplasia (VIN) is the precursor lesion of Vulvar Squamous Cell Carcinoma (VSCC), and the differentiated type (dVIN) is more frequently observed in relation to VSCC. In contrast to usual-type VIN (uVIN), which is related to infection by human papillomavirus (HPV), a germline mutation in the p53 gene is thought to be associated with ~90% of dVIN cases. To date, no infectious agent has been identified in association with dVIN, and studies investigating this possibility have been hindered by the difficulty in accurately diagnosing dVIN from small biopsies. Here, we used immunostaining for p16ink4a, a biomarker for HPV infection, to study 14 uVIN high-grade VIN and 14 dVIN cases, and to select 10 dVIN cases to broadly screen for all known viruses using a pan-viral microarray platform (ViroChip). All of the uVIN tissue samples, including 8 warty and 6 basaloid cases, showed positivity with the p16ink4a immunostain. The staining pattern was full-thickness for all except two cases in which positive staining was localized in the lower 1/3 of the epidermis. In contrast, immunostaining for p16ink4a was negative in all dVIN cases. ViroChip analysis of 10 pure dVIN samples confirmed the absence of human papillomavirus subtypes or any other virus with the exception of a single sample that showed a weak microarray signature to a porcine herpesvirus. Follow-up PCR testing of the sample was negative for herpesvirus, and in-depth metagenomic next-generation sequencing revealed only sequences corresponding to non-pathogenic viral flora and bacterial contamination. In this study, we demonstrated lack of a virus association in 10 dVIN cases. Alternative pathways for carcinogenesis such as the p53 mutation should be considered for investigation of potential treatment options in dVIN.