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

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.

CO2 laser colposcopic guided surgery for the see and treat management of VHSIL: a preliminary experience.

The purpose of this study is to evaluate the efficiency of CO2 laser colposcopic guided surgery performed in an outpatient see and treat setting in the management of VHSIL. Women with a suspected diagnosis of VHSIL and no vulvoscopic suspicion of vSCC were enrolled. An electronic register of CO2 laser treatment was created where description of performing parameters (excision or ablation) was specified and personal history was recorded. Statistical analysis was performed by Fisher's exact test. Relative risks (RR) of risk factor were calculated and expressed in odds. From September 2014 to September 2018, we enrolled a total of 63 patients who underwent CO2 laser procedure and had a minimum follow-up time of 2 years at Careggi University Hospital in Florence. Forty-eight (76.2%) patients underwent laser excision and 15 (23.8%) patients underwent ablative treatment without histological results. Undertreatment was performed in 3 cases (6.3%) with definitive histology of vSCC. Therapeutical appropriateness of CO2 laser excision was reached in 85.4% of the cases (41/48). No volunteer loss to follow-up was registered; thus, fidelity to treatment was assess at 100%. Recurrence rate within 2 years attested in 8/60 followed patients (13.3%). No personal factor was found to influence the VHSIL course. CO2 laser excision may represent an excellent therapeutic option to VHSIL because it provides adequate oncological purpose with good cosmetic and functional results and high patients' loyalty to treatment. An expert team could allow to undergo patients with VHSIL suspicion to unique diagnostic and therapeutic procedure with significant benefits.

Vulvar intraepithelial neoplasia: Classification, epidemiology, diagnosis, and management.

Vulvar intraepithelial neoplasia (VIN) is classified into two entities: differentiated (dVIN) and vulvar high-grade squamous intraepithelial lesions (vH-SIL). dVIN is a premalignant lesion that develops on an existing vulvar lesion such as lichen sclerosus, while vH-SIL is associated with HPV infection. The two entities differ in terms of pathophysiology, background, prognosis, and management. The incidence of VIN in young women is rising and recurrence is common, even after radical surgery, which can cause significant disfigurement. Alternative strategies include topical treatments, ablation, and a watch-and-wait approach. There is currently no consensus on how these lesions should be managed. We review the literature in this field.

Incidence of vulvar high-grade precancerous lesions and cancer in Denmark before and after introduction of HPV vaccination.

OBJECTIVE: To assess the incidence of vulvar high-grade precancerous lesions and cancer in Denmark during 1997-2018. METHODS: We identified incident vulvar cancer cases in the Danish Cancer Registry and incident cases of vulvar precancerous lesions in the Danish Pathology Register. We calculated age-standardized incidence rates of vulvar squamous cell carcinoma (VSCC), non-SCC and precancerous lesions, and age-specific incidence rates of VSCC and precancerous lesions. Incidence trends were evaluated using linear Poisson regression to estimate the average annual percentage change (AAPC). For vulvar precancerous lesions, trends were evaluated in the period before (1997-2007) and after (2008-2018) implementation of HPV vaccination. RESULTS: In the 22-year study period, the age-standardized incidence rate of VSCC increased from 1.23 (1997-1998) to 1.98 per 100,000 (2017-2018), corresponding to an average yearly increase of 2.95% (95%CI: 2.15-3.75). The incidence of non-SCC increased only slightly. Overall, the incidence of vulvar precancerous lesions increased (AAPC = 2.38%; 95%CI: 1.75-3.02). After implementation of HPV vaccination, the incidence of vulvar precancerous lesions decreased significantly in women aged <20 (AAPC = -22.10% (95%CI: -35.27 to -6.26)) and 20-29 years (AAPC = -6.57, 95% CI: -10.63 to -2.33), whereas the incidence increased in the majority of age groups ≥50 years. CONCLUSIONS: Overall, the incidence of VSCC and vulvar precancerous lesions increased during 1997-2018. However, after introduction of HPV vaccination, the incidence of vulvar precancerous lesions decreased among women aged <20 and 20-29 years, pointing towards a possible effect of HPV vaccination in this group. This development should be followed in the future.

The immune microenvironment in vulvar (pre)cancer: review of literature and implications for immunotherapy.

INTRODUCTION: Vulvar squamous cell carcinoma (VSCC) develops via two different pathways: TP53 mutations in a background of lichen sclerosus or a persistent infection with high-risk human papilloma virus (HPV). The latter group of tumor responds better to treatment than the non-virally induced VSCC. This may be explained by a difference in the tumor immune microenvironment (TME). AREAS COVERED: This review summarizes literature on TME of VSCC and its precursors, and extrapolates this to foster the development of new therapeutic strategies. EXPERT OPINION: Both types of VSCC and their precursors are infiltrated with variable numbers of M2 macrophages, regulatory T cells and CD8+ T cells, indicating that they express targetable tumor antigens. Type 1 T cell immunity in precursor lesions is associated with fewer recurrences and better clinical responses to immunotherapy. Escape of these lesions and progression toward VSCC is associated with the downregulation of HLA Class I, increased expression of co-inhibitory molecules, infiltration with immunosuppressive cells and the local production of immunosuppressive enzymes and cytokines. More in-depth studies of the VSCC TME are required to fully comprehend the impact of the immune system on VSCC, and subsequently to identify patients who will benefit from immunotherapeutic strategies.

Therapeutic assessment of vulvar squamous intraepithelial lesions with CO2 laser vaporization in immunosuppressed patients / Avaliação terapêutica das lesões intraepiteliais escamosas da vulva com vaporização a laser CO2 em pacientes com imunossupressão

Abstract Objective A vulvar squamous intraepithelial lesion is deemed to be a preceding lesion to vulvar cancer, especially in women aged under 40 years, holders of an acquired or idiopathic immunosuppression. Several treatments have been used to treat these lesions. One of the aesthetically acceptable therapeutic methods is the CO2 laser vaporization. Methods In a transversal study, 46 records of immunosuppressed women bearing a vulvar low grade and/or high grade squamous intraepithelial lesion were selected out of the retrospective analysis, computing age, date of record, date of vulvar lesion treatment with CO2 laser, the time elapsed between the first and the last visit (in months), the number of visits, the presence or absence of condylomatous lesions in other female lower genital tract sites and whether or not recurrences and persistence of intraepithelial lesions have been noticed during the follow-up. Results Patients bearing vulvar high-grade squamous intraepithelial lesion and immunosuppressed (serumpositive forhumanimmunodeficiency virus [HIV] or with solid organs transplantation) have shown a higher level of persistence of lesions and a higher chance of having other areas of the female lower genital tract involved. Conclusion While the CO2 laser vaporization is the most conservative method for the treatment of vulvar high-grade intraepithelial lesions, it is far frombeing the ideal method, dueto the intrinsic infection features considered. The possibility of persistence, recurrences and spontaneous limited regression indicates that a closer surveillance in the long-term treated cases should be considered, in special for immunosuppressed patients.

Resumo Objetivo A lesão intraepitelial escamosa da vulva é considerada uma lesão precursora do câncer vulvar, emespecial emmulheres com idade inferior a 40 anos, portadoras de imunossupressão adquirida ou idiopática. Vários tratamentos têm sido utilizados para tratar esse tipo de lesão. Um dos métodos terapêuticos esteticamente aceitáveis é a vaporização a laser CO2. Métodos Em um estudo transversal, foram selecionados da análise retrospectiva de prontuários arquivados no setor de patologia do trato genital inferior 46 prontuários de mulheres comimunossupressão e portadoras de lesão intraepitelial escamosa de baixo grau e/ou alto grau computando-se: idade, data de registro, data do tratamento da lesão vulvar com laser CO2, tempo entre a primeira e a última consulta (em meses), número de consultas, presença ou ausência de lesões condilomatosas em outros locais do aparelho reprodutor feminino e a ocorrência ou não de recidivas e persistência de lesões intraepiteliais durante o período de acompanhamento. Resultados Pacientes com lesão intraepitelial de alto grau vulvar e imunocomprometidas (soropositivas para HIV ou com transplante de órgãos sólidos) mostraram maior índice de persistência das lesões e maior chance de ter outras áreas do órgão genital feminino comprometidas. Conclusão Embora a vaporização a laser CO2 seja o método mais conservador para o tratamento das lesões intraepiteliais vulvares de alto grau, está longe de ser o método ideal pelas características intrínsecas da afecção em foco. A possibilidade de persistência, recidivas e regressão espontânea limitada recomenda maior vigilância para os casos tratados a longo prazo, em especial para as pacientes com imunossupressão.

Risk factors for unrecognized invasive carcinoma in patients with vulvar high-grade squamous intraepithelial lesion at vulvoscopy-directed biopsy.

OBJECTIVE: To evaluate the prevalence and risk factors for unrecognized invasive carcinoma in a series of patients undergoing surgical excision after an office biopsy of vulvar high-grade squamous intraepithelial lesion (VHSIL). METHODS: Two hundred and sixteen consecutive patients treated in a tertiary-level referral center for vulvar disease in north-western Italy were recruited. Patients' records were reviewed by trained personnel. Factors showing a statistically significant (p<0.05) association with detection of stromal invasion at excisional surgery in univariate analysis were further examined in a backward stepwise multiple logistic regression model. RESULTS: The median patient age was 50 years (range, 19-88). More than 25% patients with VHSIL at biopsy had associated cervical/vaginal intraepithelial neoplasia, and more than 35% had a multifocal lesion. Invasive carcinoma was detected in surgical specimens from 24 patients (11%). The depth of stromal invasion varied between 0.1 mm and 3.0 mm with a median of 0.5 mm. In multivariate analysis, the risk of invasive carcinoma detection was greater for patients in the highest tertile of age (p=0.008), for patients with a lesion ≥20 mm in size (p=0.013) and with clitoral involvement (p<0.001), and for patients presenting with a nodular lesion (p=0.078). CONCLUSION: Our study suggests that patient age, lesion size, clitoral involvement and nodular appearance in patients with VHSIL at vulvoscopy-directed biopsy are independently associated with the risk of unrecognized invasive carcinoma.

Risk factors for unrecognized invasive carcinoma in patients with vulvar high-grade squamous intraepithelial lesion at vulvoscopy-directed biopsy / 부인종양

OBJECTIVE: To evaluate the prevalence and risk factors for unrecognized invasive carcinoma in a series of patients undergoing surgical excision after an office biopsy of vulvar high-grade squamous intraepithelial lesion (VHSIL). METHODS: Two hundred and sixteen consecutive patients treated in a tertiary-level referral center for vulvar disease in north-western Italy were recruited. Patients' records were reviewed by trained personnel. Factors showing a statistically significant (p<0.05) association with detection of stromal invasion at excisional surgery in univariate analysis were further examined in a backward stepwise multiple logistic regression model. RESULTS: The median patient age was 50 years (range, 19–88). More than 25% patients with VHSIL at biopsy had associated cervical/vaginal intraepithelial neoplasia, and more than 35% had a multifocal lesion. Invasive carcinoma was detected in surgical specimens from 24 patients (11%). The depth of stromal invasion varied between 0.1 mm and 3.0 mm with a median of 0.5 mm. In multivariate analysis, the risk of invasive carcinoma detection was greater for patients in the highest tertile of age (p=0.008), for patients with a lesion ≥20 mm in size (p=0.013) and with clitoral involvement (p<0.001), and for patients presenting with a nodular lesion (p=0.078). CONCLUSION: Our study suggests that patient age, lesion size, clitoral involvement and nodular appearance in patients with VHSIL at vulvoscopy-directed biopsy are independently associated with the risk of unrecognized invasive carcinoma.