High-grade Vulvar Intraepithelial Neoplasia Research Articles

Multicentricity and the Risk of Recurrence/Persistence After Laser Vaporization for High-Grade Vulvar and Vaginal Intraepithelial Neoplasia.

The aim of the study was to assess the effect of multicentricity on the recurrence/persistence of high-grade vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN) after laser vaporization. A retrospective cohort study was conducted on patients diagnosed with high-grade VIN/VAIN, who had undergone laser vaporization between 1997 and 2014. Recurrence/persistence rates and factors affecting recurrence/persistence were analyzed, and a life table analysis of recurrence-free intervals was conducted. Among the 65 patients, the recurrence/persistence rate following laser vaporization was 22.3 per 100 person-years, with a median time to recurrence/persistence of 31.2 months (95% confidence interval (CI): 0.0 - 71.9 months). Patients with multicentricity and unicentricity had a recurrence/persistence rate of 49.1 per 100 person-years, with a median time to recurrence/persistence of 11.4 months, and 7.4 per 100 person-years, with a median time to recurrence/persistence of 96.5 months, respectively (P = 0.0002). The difference in recurrence-free survival between the multicentricity and unicentricity groups was significant (P = 0.00035). Patients with multicentricity had a 4.7-fold higher risk of recurrence/persistence (hazard ratio (HR): 4.71, 95% CI: 1.87 - 11.88, P = 0.001). Multivariate analysis showed that multicentricity was an independent risk factor for recurrence/persistence (odds ratio (OR): 4.16, 95% CI: 1.56 - 11.06, P = 0.004). Treatment of multicentric, high-grade VIN/VAIN with laser vaporization is strongly associated with treatment failure, with approximately half of patients experiencing recurrence/persistence.

Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3

ObjectiveTo evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. MethodsParticipants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. ResultsFifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. ConclusionsTopical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

Vulvar squamous intraepithelial neoplasia epithelial thickness in hairy and non-hairy sites: a single center experience from China.

A large-sample study focusing on VIN lesions of a more precise thickness is needed to help guide clinical treatment. This study aimed to investigate the depth of vulvar intraepithelial neoplasia (VIN) and involved skin appendages to provide evidence for laser surgery. The study retrospectively enrolled and analyzed the clinical characteristics of VIN patients in the obstetrics and gynecology department of a university hospital between January 1, 2019 and December 30, 2021. The study further explored the thickness of epithelium and skin appendages of 285 women with low-grade VIN (VIN1) and 285 women with high-grade VIN (VIN2/3). The study included 1,139 (80%) VIN1 and 335 (20%) VIN2/3 cases. The VIN1 and VIN2/3 groups showed a significant difference in human papillomavirus infection (P<0.01) but not in cytology (P = 0.499). Most (89.90%, 1,325) cases occurred in one area of the vulva, whereas 10.11% were multifocal. VIN commonly occurred on the posterior fourchette (76.85%), labia majora (11.61%), and labia minora (9.92%). The VIN2/3 group reported a significantly higher positive rate for concurrent cervical and vaginal intraepithelial neoplasia (160 of 285) than the VIN1 group (321 of 953) (P=0.000). The involved epithelial thicknesses in VIN2/3 and VIN1 were 0.69 ± 0.44 and 0.49 ± 0.23mm, respectively, both of which were greater than the corresponding noninvolved epithelial thickness (0.31 ± 0.19 and 0.32 ± 0.10mm, P<0.001 and P<0.001, respectively). In cases of appendage involvement, the VIN thickness was 1.98 ± 0.64mm. VIN thickness was generally ≤1 mm for the superficial lesions in non-hairy areas. However, for lesions extending onto hairy areas, the thickness was approximately 3mm, leading to the destruction of involved skin appendages.

High-grade vulvar intraepithelial neoplasia: comprehensive characterization and long-term vulvar carcinoma risk.

Adequate diagnosis of human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population-based series of vulvar lesions, originally reported as high-grade VIN, and assessed the cancer risk. Baseline high-grade VIN of 751 patients were categorized by histopathological reassessment, integrating the results of immunohistochemistry (p16INK4a , p53, Ki-67) and HPV DNA testing. Integrated analyses resulted in 88.4% HPV-associated lesions (77.0% HSIL, 10.9% low-grade SIL [LSIL], and 0.4% vulvar squamous cell carcinoma [VSCC]), 10.9% HPV-independent lesions (6.1% HPV-independent VIN, 4.7% nondysplastic lesions, and 0.1% VSCC) and 1.1% inconclusive lesions. HSIL demonstrated p16INK4a block-positivity in 99.0%, increased Ki-67 in ≥2/3rd of the epithelium in 93.6%, and HPV positivity in 99.6%. In HSIL, a p53 wildtype mid-epithelial staining pattern was common (51.6%) while this was not observed in HPV-independent lesions. HPV-independent VIN harboured mutant p53 patterns in 65.2% and showed a wide morphological spectrum, ranging from differentiated to nondifferentiated ('HPV-associated-like', in 41.3%). Kaplan-Meier analyses showed a 10-year cancer risk of 8.0% in HPV-associated HSIL, 67.4% in HPV-independent VIN/p53mutant, and 27.8% in HPV-independent VIN/p53wildtype. Strikingly, the 10-year cancer risk was 73.3% in HPV-independent VIN with nondifferentiated ('HPV-associated-like') morphology. Immunohistochemistry by p16INK4a and p53 is highly recommended for optimal categorization into HPV-associated and HPV-independent VIN, which is of utmost importance given the different cancer risk. The high cancer risk of HPV-independent VIN underscores the need for surgical treatment and close follow-up, especially in case of a p53 mutant pattern and/or nondifferentiated morphology.

Oncoguía de cáncer de vulva 2023

Vulvar cancer is a rare neoplasm. Risk factors for the development of vulvar cancer include advanced age, human papillomavirus infection leading to high-grade squamous intraepithelial lesions, smoking, inflammatory conditions affecting the vulva, immunodeficiencies such as human immunodeficiency virus infection, and the presence of well-differentiated vulvar intraepithelial neoplasia (VIN) in patients from 65 to 70 years. VIN may be asymptomatic or present with a mixed variety of symptoms, including itching, discomfort, burning, pain during sexual intercourse, and whitish spots over the vulva. The most common histologic subtype is squamous cell carcinoma. The 5-year survival is 86 % for early clinical stages (CS) I-II, 53 % for locally advanced CS III-IVA, and 19 % for metastatic disease CS IVB. The classic treatment for high-grade VIN is surgical excision and, in the case of multifocal lesions, vulvectomy. Treatment is predominantly surgical in the early stages.

The distribution of HPV subtype in vulvar intraepithelial neoplasia and the association with recurrent VIN and vulva cancer in Taiwan.

e17635 Background: Vulvar intraepithelial neoplasia (VIN) is a precursor lesion of vulvar cancer. Human papillomavirus (HPV) is causative for part of VIN lesions. This retrospective study aimed to investigate HPV distribution in patients with vulvar intraepithelial neoplasia (VIN) and the factor associated with the recurrence of high-grade vulvar intraepithelial neoplasia (VIN2+), high-grade vaginal intraepithelial neoplasia (VAIN) , cervical intraepithelial neoplasia(CIN) or progression to vulvar cancer. Methods: We retrospectively analyzed patients who diagnosed as vulvar squamous intraepithelial lesions between 1990 and 2014 in our institution. All the diagnoses and classifications were confirmed by two pathologists in 2015 ISSVD terminology. HPV DNA was extracted from formalin-fixed and paraffin-embedded samples. SPF1/GP6+ polymerase chain reaction (PCR) followed by HPV Blot and E6 type-specific PCR were performed. Results: Ninety-eight VIN patients were included in our analysis. Ninety-three percent were positive for HPV and HPV16 (43.9%), HPV6 (11.38%), HPV11 (8.94%), and HPV58 (4.88%) were the most prevalent types. Patients with positive HPV were diagnosed younger than those with negative results (43.0 years vs. 61.1 years, P = 0.049). In 15 patients who with recurrent VIN (n = 11) or progression to vulvar cancer (n = 4), had positive HPV. All 4 patients who had progression to cancer were positive for HPV16 in their initial VINs. High risk type HPV infection, positive HPV16, and positive alpha-9 types are significant risk factors for recurrent VIN and progression to cancer. Conclusions: Positive HPV was detected in 92.8% of VINs and was related to younger age at diagnosis. HPV16 was the most prevalent type and was significantly related to recurrence/ progression. Other significant risk factors for recurrent VIN or progression to cancer were high-risk HPV and alpha-9 types. Closely monitor of those patients with risk factors was indicated for early detection and treatment of recurrent VIN and vulvar cancer.

Clinical validation of methylation biomarkers for optimal detection of high-grade vulvar intraepithelial neoplasia.

The precursor lesions of vulvar squamous cell carcinoma (VSCC) include human papillomavirus (HPV)-associated and HPV-independent squamous neoplasia with a varying cancer risk. Our study aimed to validate the accuracy of previously identified DNA methylation markers for detection of such high-grade vulvar intraepithelial neoplasia (VIN). A large clinical series of 751 vulvar lesions, originally diagnosed as high-grade VIN, were reassessed and categorized into HPV-associated or HPV-independent vulvar disease categories. Together with 113 healthy vulvar controls, all samples were tested for 12 methylation markers with quantitative multiplex methylation-specific PCR (qMSP). Performance of individual markers and selection of an optimal marker panel for detection of high-grade VIN was determined by logistic regression analysis. SST was the best-performing individual marker (AUC 0.90), detecting 80% of high-grade VIN cases, with excellent detection of HPV-independent VIN (95%), known to have the highest cancer risk. Merely 2% of controls tested methylation positive for SST. Selection of a marker panel, including ZNF582, SST and miR124-2, resulted in a comparably high accuracy for detection of high-grade VIN (AUC 0.89). In conclusion, we clinically validated the accuracy of 12 DNA methylation markers for detection of high-grade VIN. SST, as a sole marker or in a panel, provides an optimal diagnostic tool to distinguish high-grade VIN in need of treatment, particularly HPV-independent VIN, from low-grade or reactive vulvar lesions. These findings warrant further prognostic validation of methylation biomarkers for cancer risk stratification of patients with VIN.

Vulvar High-Grade Squamous Intraepithelial Lesions Treated with Imiquimod: Can Persistence of Human Papillomavirus Predict Recurrence?

Simple SummaryVulvar high-grade intraepithelial lesion (vulvar HSIL) is a premalignant vulvar condition that requires intervention, usually surgery. It recurs frequently, and its treatment involves repeated disfiguring surgeries. Vulvar HSIL is associated with human papillomavirus. Imiquimod is a medical treatment option currently attracting attention because vulvar high-grade intraepithelial neoplasia is frequent in young women with multiple vulvar lesions. Few studies have evaluated the long-term effects of the response to imiquimod and the association of human papillomavirus with response and recurrence. We describe a retrospective (with cases already treated) study designed to determine the long-term response to imiquimod in patients with vulvar HSIL, and also to analyze the role of human papillomavirus (HPV), and different HPV types, in the persistence or recurrence of vulvar HSIL after imiquimod treatment.Objectives: Vulvar high-grade squamous intraepithelial lesion (vulvar HSIL) or vulvar intraepithelial neoplasia (VIN) is a premalignant condition that can progress to carcinoma. Imiquimod is a topical drug with high effectiveness and low morbidity. We aimed (1) to assess the long-term response to imiquimod in a cohort of patients with vulvar HSIL and (2) and to analyze the role of HPV determined in pre- and post-imiquimod treatment biopsies in the persistence or recurrence of vulvar HSIL. Design: Retrospective study between 2011 and 2022. Setting: Referrals from the primary care area of Baix Llobregat treated in the gynecology department of a university hospital in Barcelona, Spain. Population: 20 women with vulvar HSIL treated with imiquimod. Methods: The inclusion criteria were vulvar HSIL, vulvar HPV determination by pre- and post-treatment biopsy, acceptance of medical treatment, at least one follow-up and 4 weeks of treatment. Main outcome measures: Histological diagnosis of vulvar HSIL with pre- and post-imiquimod HPV determination. Response to treatment (complete, partial, no response, recurrence). Results: After imiquimod, 10 (50%) and 6 (30%) cases had complete and partial responses, respectively. Another 4 cases (20%) did not respond. Before treatment, 19 (95%) cases were positive for vulvar HPV (16 cases had HPV type 16). After treatment, 10 cases (50%) were positive for HPV (8 cases with HPV type 16): 2 cases (20%) with a complete response, 5 cases (83.3%) with a partial response and 3 cases (75%) with no response. Eight of the 10 HPV-negative cases (80%) post-treatment showed a complete response. HPV type 16 was present in 16 cases (84.2%) pre-treatment and in 8 cases (80%) post-treatment. Ten patients underwent additional treatments following a partial response, no response or recurrence. The 2 HIV and 3 immunosuppressed patients treated with imiquimod showed a partial response and required additional treatment. All these patients were HPV-positive pre- and post-treatment (100%). Response to imiquimod was associated with post-treatment vulvar HPV positivity (p = 0.03). The median time to a complete response in HPV-negative cases was 4.7 months versus 11.5 months in HPV-positive cases post-imiquimod treatment. Recurrence of vulvar HSIL was observed in 7 patients (35%), with a median time to recurrence of 19.7 months (range 3.2–32.7). Recurrence was experienced in 10% of cases with a complete response, in 4/6 (66.6%) cases with a partial response, and in 2/4 (50%) women with no response. Four of the 7 recurrent cases (57%) were infected with HIV or immunosuppressed. Six (85%) of the recurrent cases were HPV-positive post-treatment (all were HPV type 16). Four (30.7%) of the non-recurrent cases were HPV-positive post-treatment with imiquimod (p = 0.05), two of which were HPV type 16 (50%). Conclusions: Imiquimod effectively treats vulvar HSIL. Cases with a complete response showed less HPV positivity post-treatment than partial or non-response cases. Recurrences were more frequent in those with a partial or no response to imiquimod, and in immunosuppressed patients. In recurrent cases, 85% were HPV-positive post-treatment, while 30.7% of non-recurrent cases were HPV-positive. HPV positivity in the post-treatment biopsy suggests the need for stricter follow-up of patients.

Changes in vulvar cancer incidence from before COVID-19 through the first year of the pandemic (350)

Objectives: The primary objective of this study was to evaluate the trend in vulvar cancer incidence before and during the COVID-19 pandemic.Methods: A retrospective analysis was conducted of patients diagnosed with new high-grade vulvar intraepithelial neoplasia 3 (VIN3) or stage I-IV squamous cell carcinoma of the vulva between January 2015 and June 2021 at a single institution. All diagnoses were confirmed by histologic identification of invasive squamous cell carcinoma on either biopsy or surgical excision. Incidence rate ratios were calculated before and after the April 2020 - June 2020 COVID- 19 lockdown. U charts were created to identify the change in incidence before and after the COVID-19 lockdown. Nominal variables and continuous variables associated with increased risk for vulvar cancer were analyzed using Fisher’s exact test and two-sample tests, respectively.Results: The incidence of stage I vulvar cancer and stage II-IV vulvar cancer was 2.13 and 2.19 times as high following the COVID-19 lockdown compared to the incidence prior to the COVID-19 lockdown, respectively. Cumulatively, the incidence of invasive vulvar cancer (stage I-IV) was 2.14 times as high following the COVID-19 lockdown. Comparatively, the incidence of high-grade VIN3 in the year following the COVID-19 lockdown was 0.7 times the incidence of VIN3 in the five years prior to the lockdown. Using a U chart, three of the four consecutive quarters following the lockdown had incidence values greater than the centerline, with an incidence in 2020 quarter-4 greater than two standard deviations from the centerline proportion. No differences existed between pre- and post-COVID-19 lockdown groups in terms of age, BMI, gravidity, parity, race, history of HIV/AIDS, chronic immunosuppression, lichen sclerosus, or smoking history.Conclusions: The incidence of invasive squamous cell carcinoma of the vulva increased following the COVID-19 lockdown. Vulvar cancer development and progression have been shown to be time-sensitive and delayed care has been broadly reported during the COVID-19 pandemic. However, the etiology of the increase in the diagnosis of vulvar cancer during the pandemic is most likely multifactorial, given the overall rapid increase.Fig. 1

High Grade Vulvar Intraepithelial Neoplasia in women under 30-year old: Report of Two Cases

High Grade Vulvar Intraepithelial Neoplasia in women under 30-year old: Report of Two Cases

Efficacy of a New Therapeutic Option for Vulvar Intraepithelial Neoplasia: Superficial Shaving Combined With Photodynamic Therapy.

Vulvar intraepithelial neoplasia (VIN), a precancerous lesion, is difficult to treat by excision or ablation due to high recurrence rates. Photodynamic therapy (PDT) is a minimally invasive therapeutic procedure and is now widely used to treat non-melanoma skin diseases. However, the clinical response rates of VIN to single PDT are unstable. The reason may be the limited light penetration into deep tissues. To retrospectively evaluate the clinical response and recurrence of VIN after combined treatment with superficial shaving and PDT. Seventeen patients with VIN were enrolled. All patients had multifocal high-grade VIN that had failed to respond to various therapies. Superficial shaving was performed only once and prior to the first 5-aminolaevulinic acid (5-ALA)-PDT cycle. Generally, the procedure of 5-ALA PDT for each patient was performed in three sessions. Clinical response, recurrence, cosmetic outcomes, adverse events, patient satisfaction, quality of life, and mental health were assessed. The expression of p16 and Ki-67 in pre- and post-treatment tissue was detected. A clinical response of 94% was observed in 17 patients, who were administered combination therapy, over an observation period of 12 months. Approximately, 71% of patients had excellent cosmetic outcomes. All patients had satisfactory therapeutic effects and significant improvements in quality of life and mental health. Downregulation of p16 and Ki-67 may have been correlated with recurrence after 5-ALA-PDT. Combined treatment with superficial shaving and 5-ALA-PDT is a safe and effective option for VIN. In particular, combination therapy is recommended for patients with large, multifocal, high-grade lesions; repeated recurrence; and strong willingness to maintain vulvar configuration and function. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Risk of cervical and vaginal dysplasia after surgery for vulvar intraepithelial neoplasia or cancer: A 6 year follow-up study

ObjectivesTo estimate the frequency of abnormal surveillance cytology leading to high-grade dysplasia after surgical management for high-grade vulvar intraepithelial neoplasia (VIN) and vulvar cancer and to determine whether prior hysterectomy reduces this risk. MethodsWomen who underwent surgery for high-grade VIN or vulvar cancer between 2006 and 2014 were identified retrospectively. Patients who underwent prior hysterectomy for any indication were included. Univariate and multivariate logistic regression analyses were used to identify clinical correlates of abnormal cytology after surgical treatment for VIN and vulvar cancer. ResultsDuring a median follow-up for 72 months, 302 women underwent surveillance with cytologic screening after vulvar surgery including 99 (33%) women with prior hysterectomy. 75 (25%) women had abnormal cytology results. Of those, 47 (63%) were low-grade and 28 (37%) were high-grade, including 2 (3%) cases of invasive cancer. The rates of high-grade vaginal intraepithelial neoplasia (VAIN), cervical intraepithelial neoplasia (CIN), or cancer were not significantly different despite prior hysterectomy (9% VAIN 2+, 7% CIN 2+). Multivariate analysis showed that correlates of high-grade cytology following treatment for VIN or vulvar cancer included non-white race [odds radio (OR) 3.6, 95% confidence interval (CI) 1.7–7.8], prior abnormal cytology (OR 3.5, 95% CI 1.6–7.6), and immunodeficiency (OR 3.4, 95% CI 1.3–8.8). Prior hysterectomy did not significantly decrease risk of high-grade cytology (OR 0.87, 95% CI 0.5–1.6). ConclusionsWomen treated surgically for VIN/vulvar cancer have an 8% risk of at least high-grade dysplasia from surveillance screening and prior hysterectomy does not mitigate the risk. Extrapolating from current guidelines, we recommend surveillance cytology screening at least 6–12 months after treatment.

Classic Vulvar Intraepithelial Neoplasia With Superimposed Lichen Simplex Chronicus: A Unique Variant Mimicking Differentiated Vulvar Intraepithelial Neoplasia.

High-grade vulvar intraepithelial neoplasia, a precursor lesion to vulvar squamous cell carcinoma, is subdivided into 2 types, classic or usual vulvar intraepithelial neoplasia (CVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). CVIN, which is a human papilloma virus (HPV)-dependent lesion, is typically distinguished from DVIN, a p53 mutation-dependent process, by its distinct histomorphologic and immunohistochemical characteristics. However, distinguishing between the 2 entities becomes challenging in cases of CVIN with superimposed inflammatory changes, especially lichen simplex chronicus (LSC). Twelve cases of DVIN, 9 cases of LSC, and 9 cases of CVIN with superimposed LSC were assessed for a number of morphologic features, including hyperkeratosis, hypergranulosis, acanthosis, hypercellularity, abnormal maturation (i.e. abnormal keratinization close to the base and/or dyskeratosis), hyperchromasia, and basal atypia. Immunohistochemistry for p53, p16, and MIB-1 was performed for all cases. When sufficient tissue was available, HPV genotyping was performed for cases of CVIN with superimposed LSC. DVIN uniformly demonstrated abnormal maturation, and atypia involving the basal cell layer; they were all p16 negative and demonstrated p53 positivity of moderate to strong intensity in a basal and parabasal distribution. CVIN with superimposed LSC frequently displayed hyperchromasia involving the basal 3 to 4 cell layers, basal to full-thickness atypia, and apoptosis. CVIN with superimposed LSC demonstrated intense p16 positivity extending from the basal cells to the mid-epithelium and a reduction or loss of staining in maturing keratinocytes. P53 staining revealed a unique pattern of parabasal and mid-epithelial weak to moderate staining with sparing of the basal layer. Cases of LSC demonstrated heterogenous p53 positivity and were negative for p16. MIB-1 staining showed a similar range of positivity for all diagnoses. HPV genotyping revealed HPV 16 in all 5 cases of CVIN with LSC that underwent testing. We conclude that, although CVIN with superimposed LSC can closely resemble DVIN, morphologic features such as nuclear hyperchromasia uniformly involving the basal 3 to 4 cell layers, apoptosis, and absent or less pronounced cytoplasmic maturation are more suggestive of CVIN with superimposed LSC. In cases where the morphology remains ambiguous, immunohistochemistry for both p16 and p53 can be helpful. In particular, p53 parabasal and mid-epithelial staining without involvement of the basal layer appears to be a characteristic finding in CVIN with superimposed LSC. MIB-1 staining is of little utility in distinguishing between these entities and should not be routinely performed.

Superficially invasive stage IA vulvar squamous cell carcinoma-therapy and prognosis.

Superficially invasive stage IA squamous vulvar cancer (VSCC) is defined as a single lesion measuring ≤2 cm with a depth of invasion of ≤1.0 mm (FIGO stage IA). This article examines the natural course and prognosis of superficially invasive VSCC. This is a retrospective case series of 46 patients (median age 58 years) with superficially invasive stage IA VSCC receiving wide local excision between January 1996 and November 2014 in the University Medical Center Hamburg-Eppendorf. Median tumor size was 4 mm. In 39/46 (84.8%) patients peri-tumoral high-grade intraepithelial neoplasia (HSIL) and/or lichen sclerosus (LS) of the vulva were histologically detected: 34 (74.0%) usual type high-grade vulvar intraepithelial neoplasia (uVIN, HSIL), 4 (8.7%) LS with simultaneous VIN (3 uVIN, 1 differentiated VIN (dVIN)), 1 (2.2%) with LS only. 37/46 (80.4%) patients had a R0 resection; in 2 (4.3%) a high-grade VIN was detected in the margin and in 7 (15.2%) the resection status was unknown. The mean follow-up was 58 (range 10-185) months. Four patients (8.7%) suffered from an invasive recurrence after 4, 17, 40, and 54 months, three in the vulva and one in the groin. All local recurrences occurred in women with LS in a combination with high-grade VIN (3 uVIN, 1 dVIN). Two were treated surgically again including inguino-femoral lymphadenectomy (ifLAE) (no regional lymph node metastasis histologically) as invasion depth exceeded 1 mm. The third patient refused treatment. Inguinal recurrence was treated with a bilateral ifLAE, revealing one positive lymph node, followed by adjuvant radiotherapy (groins, pelvis). None of these patients had experienced further recurrences at last follow-up. Superficially invasive VSCC is characterized by having a very good prognosis. Sole surgical therapy is highly effective. Patients with LS might benefit additionally from intensified surveillance and adequate maintenance therapy in specialized centers.

A case of high-grade vulvar dysplasia with underlying spherules of amyloid deposition

Introduction: High-grade vulvar intraepithelial neoplasia (VIN3) is a common pathologic diagnosis. Usually, the lesions are associated with human papillomavirus (HPV), as demonstrated by block positivity on p16 staining. The lesions are not typically associated with amyloid deposition. It is even more rare to find amyloid spherules associated with high-grade vulvar dysplasia. The clinicopathologic significance of the amyloid spherules is unclear.

Genital Dysplasia and Immunosuppression: Why Organ-Specific Therapy Is Important

Background: Young patients with Crohn’s disease (CD) show a high prevalence of human papillomavirus (HPV) which is the main cause of high-grade squamous intraepithelial lesions (HSIL). A major complication for patients undergoing immunocompromising therapy is the development of genital dysplasia. Methods: We report the case of a 32-year-old patient with recurrent genital dysplasia under long-term therapy for CD with a focus on different drug-related, immunosuppressive mechanisms. Results: Gynecological examination and biopsy revealed high-grade vulvar intraepithelial neoplasia (VIN) positive for HPV 16 treated with laser vaporization. Due to the combination of HPV positivity, intraoperative multilocularity, and CD, follow-up examinations were performed every 6 months. One year later, the patient showed a VIN at a new location and additionally, a cervical intraepithelial neoplasia (CIN), which were surgically treated. Catch-up HPV vaccination was applied accessorily. After the switch from a TNF-α blocker to vedolizumab, which acts as a gut-selective anti-integrin, the subsequent PAP smear, vulvoscopy, and colposcopy showed no more evidence of dysplasia. Conclusions: This case report highlights that gut-selective immunosuppression with vedolizumab might be favorable in young HPV-positive patients due to a good side effect profile. Regular screening and HPV vaccination are a mainstay of dysplasia prevention and control. The risk for HPV-associated dysplasia in immunosuppressed patients is highly dependent on the choice of immunosuppressive therapy.

Abstract 5050: Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia

Abstract Vulvar squamous cell carcinoma (VSCC) and precancerous high-grade vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinical and histological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in 24 VSCC and 41 VIN lesions. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during &amp;gt;10 year follow-up (VINnoVSCC). HPV-testing resulted in 41 HPV-positive lesions (16 VINVSCC, 14 VINnoVSCC and 11 VSCC) and 24 HPV-negative lesions (11 VINVSCC and 13 VSCC). HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than VSCC (P = 0.009), mainly 8q gains and 8p losses. In HPV-positive lesions, CNA frequencies were lower in VINnoVSCC than in VINVSCC (P = 0.022) and VSCC. Interestingly, a 1pq gain was detected in 81% of VINVSCC and only 29% of VINnoVSCC. In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Progression risk in VIN is reflected by the extent of CNA, in particularly chromosome 1 gain. Citation Format: Maaike CG Bleeker, Dorian RA Swarts, Quirinus JM Voorham, Saskia M. Wilting, Marc van Beurden, Renske DM Steenbergen. Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5050.

Is cidofovir a better treatment than imiquimod for high-grade vulval intraepithelial neoplasia?

Is cidofovir a better treatment than imiquimod for high-grade vulval intraepithelial neoplasia?

Vulvar intraepithelial neoplasia: Risk factors for recurrence

ObjectiveWe studied a large population of women with high-grade vulvar intraepithelial neoplasia (VIN) in order to identify patient and treatment-related risk factors for recurrence and progression to cancer. MethodsFor this retrospective cohort study of women with a histologic diagnosis of VIN within Southern California Permanente Medical Group between 1995 and 2007 medical records were reviewed; clinical, demographic and pathologic data were collected. Statistical analyses included Chi-squared and Student's t-tests, univariate and multivariate logistic regression, and cumulative incidence analysis. Results914 patients with high-grade VIN were identified; 784 met inclusion criteria. We found 26.3% recurrences among treated women, with 2.2% progression to cancer (8.2% among those with recurrence). Risk factors for recurrence on multivariate analysis were: age >50years (OR, 1.44; 95%CI 1.01–2.07), immunosuppression (OR 2.08; 95%CI 1.42–3.06), metasynchronous VAIN or CIN (OR 1.76; 95%CI 1.08–2.88) in addition to margin status (OR 8.17; 95%CI 4.60–14.51) and adjacent LSA (OR 9.91; 95%CI 1.53–31.32) or HPV (OR 2.15; 95%CI 1.13–3.37) with excisional treatment. Recurrence rates did not differ significantly by smoking status and treatment modalities. Median time to recurrence was 16.9months; 25% had late recurrences (44–196months). Cumulative incidence analyses of time to recurrence shows a significantly higher risk among patients over age 50 (log-rank p=0.0031). ConclusionWe identified independent risk factors for recurrence including age >50years, immunosuppression, metasynchronous vaginal or intraepithelial neoplasia, positive excision margins, and adjacent lichen sclerosus or human papilloma-virus. Regardless of treatment modality, 25% of recurrences occurred late, highlighting the need for long-term surveillance in women treated for VIN.

Diagnostic and Management Challenges Associated With Vulvar Crohnʼs Disease

Crohn's disease(CD) is an IBD with extra intestinal manifestations such as arthritis, uveitis, erythema nodosum. Crohn's disease of the vulva is a rare and under recognized condition, particularly because it may not involve GI tract. The diagnosis and treatment of this condition remains a challenge. We present a case of Vulvar Crohn's which has been an extremely difficult case to manage. Our patient is a 29 y/o female with 10 year h/o vulvar Crohn's disease presenting as painful fissures, perirectal and labial masses. On physical exam, there was erythema, induration and severe edema of labia majora, minora and perianal area. She underwent biopsy of the lesions which was confirmed to be Crohn's disease. Even though she had no GI symptoms, she underwent colonoscopy to determine the extent of her disease and it was normal. Patient was tried on several medications including metronidazole, steroids, 6-MP, infliximab, adalimumab, methotrexate, azathioprine, certolizumab,ustekinumab and vedolizumab. However, she failed to respond to any of these therapies. Patient was referred to plastic surgery for partial vulvectomy, biopsy of which showed high grade vulvar intraepithelial neoplasia (VIN) in addition to Crohn's (dermal chronic inflammation with granulomas). She was then referred to colorectal surgery for management of perianal disease, and gynecology for evaluation of VIN. She also underwent excision of anal skin tags and anal mapping, with pathology demonstrating positive P16 in squamous epithelium consistent with high grade AIN. Vulvar Crohn's is an under-recognized condition with about 100 cases reported to date. It can occur by direct extension from perianal region or by metastatic spread from bowel. Vulvar CD may precede intestinal involvement in about 25% of cases. It usually presents with edema, ulcerations and fissures of the vulva. Patients may be asymptomatic or present with pain, pruritis, discharge and dyspareunia. Diagnosis requires a high degree of suspicion as it could be mistaken for other conditions like infections, sarcoidosis etc. Diagnosis is confirmed by biopsy. Treatment remains a challenge and no treatment guidelines exist. A multidisciplinary approach is recommended and medications including steroids, thiopurines, TNF-α antagonists could be used. However, patients may not respond to any medications and surgery remains an option. Clinicians must be astute to consider neoplasia in this situation, as was seen in our patient.Figure: Microscopic findings of the epiglottis biopsy demonstrating in the high- and low-power fields ulcerated squamous mucosa with chronic inflammatory changes.