Treatment of Vulvar Intraepithelial Neoplasia with Topical Imiquimod

Seters, Manon van; Beurden, Marc van; Kate, Fiebo J.W. ten; Beckmann, Ilse; Ewing, Patricia C.; Eijkemans, Marinus J.C.; Kagie, Marjolein J.; Meijer, Chris J.M.; Aaronson, Neil K.; KleinJan, Alex; Heijmans-Antonissen, Claudia; Zijlstra, Freek J.; Burger, M. P. M.; Helmerhorst, Theo J.M.

doi:10.1056/nejmoa072685

Cited by 342 publications

(267 citation statements)

References 22 publications

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“…This is in line with previous studies, the focus of which was mainly on T cell infiltrates and LCs/DCs in uVIN in relation to responses to immunotherapy. 5,7,8,16,17,21,43,44 From these studies it was concluded that the epithelium of uVIN lesions was suppressed as it lacked a strong CD81 infiltration and displayed lower numbers of Langerhans cells. 16,17,21 In contrast, the dermis of uVIN lesions was thought to be the most active region as there was abundant infiltration of CD41 and CD81 T cells as well as mature DCs.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] Conventional treatment consistent of potential disfiguring surgical interventions is associated with psychosexual problems and is increasingly replaced by either standardized immunotherapy with imiquimod or immunotherapy in experimental setting by therapeutic vaccination or photodynamic therapy, with promising clinical successes. [2][3][4][5][6][7][8] The incidence of hrHPV-induced dysplasia is increased in immunocompromised patients highlighting the essential role of the immune system in viral clearance. 9,10 Spontaneous regression of HPV is associated with systemic HPV-specific CD41 and CD81 immune responses, however in most of the patients with uVIN these T cell responses are either weak or absent.…”

mentioning

confidence: 99%

“…20 The type of myeloid cells infiltrate could influence the uVIN microenvironment and as such may also influence the outcome of immunotherapeutic approaches for HPV-induced vulvar neoplasia. [5][6][7][8]21 Current knowledge of the character of uVIN infiltrating myeloid cells is limited. In this study, we aimed to characterize intraepithelial and stromal (im)mature myeloid cells in uVIN lesions, HPV-induced vulvar carcinoma and healthy vulvar tissue and determine their influence on the clinical course of disease.…”

mentioning

confidence: 99%

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Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

Esch

Poelgeest

Trimbos

et al. 2014

Intl Journal of Cancer

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Human papilloma virus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) is infiltrated by myeloid cells but the type and role of these cells is unclear. We used triple immunofluorescent confocal microscopy to locate, identify and quantify myeloid cells based on their staining pattern for CD14, CD33 and CD163 in a cohort of 43 primary and 20 recurrent uVIN lesions, 21 carcinomas and 26 normal vulvar tissues. The progressive course of uVIN is characterized by an increase in both intraepithelial and stromal mature M1 and M2 macrophages. While the M2 macrophages outnumber M1 macrophages in healthy controls and uVIN, they are matched in number by M1 macrophages in cancer. Importantly, uVIN patients with a dense intraepithelial infiltration with mature CD141 macrophages (irrespective of M1 or M2 type) displayed approximately a six times higher risk to develop a recurrence and a high number of these cells constituted an independent prognostic factor for recurrence. In addition, a dense intraepithelial CD141 cell infiltration was associated with high numbers of intraepithelial CD41 Tregs and low numbers of stromal CD81TIM31 T cells. Patients with low numbers of intraepithelial CD141 cells and high numbers of stromal CD81TIM31 cells showed the best recurrence-free survival. These data clearly show the importance of the local immune response in HPV-induced vulvar neoplasia and may be of help in predicting the prognosis of patients or their response to immunotherapy.Usual-type vulvar intraepithelial neoplasia (uVIN) lesions are caused by a persistent high-risk human papilloma virus (HPV) infection (mainly HPV 16) and are characterized by high recurrences, a low spontaneous regression rate of 1.5% and a malignant potential of 3-4% in treated patients. [1][2][3] Treatment of uVIN lesions is indispensable since 80% of patients suffer from symptoms as pruritis and pain. 2-4 Conventional treatment consistent of potential disfiguring surgical interventions is associated with psychosexual problems and is increasingly replaced by either standardized immunotherapy with imiquimod or immunotherapy in experimental setting by therapeutic vaccination or photodynamic therapy, with promising clinical successes. [2][3][4][5][6][7][8] The incidence of hrHPV-induced dysplasia is increased in immunocompromised patients highlighting the essential role of the immune system in viral clearance. 9,10 Spontaneous regression of HPV is associated with systemic HPV-specific CD41 and CD81 immune responses, however in most of the patients with uVIN these T cell responses are either weak or absent. 11,12 In addition, the local innate immune cell environment is known to influence innate and adaptive immune responses in tumors. 13,14 Monocytes are innate immune cells which can differentiate into dendritic cells (DCs) or macrophages in response to local factors. 13 DCs process and present antigens to T cells, stimulate cytotoxicity of NK cells and initiate the adaptive immune response. 15 Studies of the microenvironment in uVIN revealed that ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

Esch

Poelgeest

Trimbos

et al. 2014

Intl Journal of Cancer

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“…Recently, different forms of immunotherapyvaccination to enhance the HPV16-specific T cells response, imiquimod to enhance the local innate immune response, and combination hereof-have been successful in the treatment of HPV16-induced lesions of the vulva. 19,20,43 Similar to HPV-induced lesions of the vulva, the HPV-induced HNSCC are relatively accessible and one could envisage that these strategies might be applicable to tumors of the oropharynx.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of HPV in the diluted samples was determined by genotyping the samples that demonstrated 65 basepair PCR amplimers on a 3% agarose gel using an INNOLiPA Genotyping Extra test (Innogenetics, Ghent, Belgium), according to the manufacturer's instruction. This assay allows the detection of the following HPV types: HPV 6,11,16,18,26,31,33,35,39,40,43,44,45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 69/71, 73 and 74. Hybridization patterns were visually inspected and interpreted using a grid.…”

Section: Hpv Typingmentioning

confidence: 99%

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

Heusinkveld

Goedemans

Briët

et al. 2011

Intl Journal of Cancer

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Squamous cell carcinomas of the head and neck (HNSCC), in particular those of the oropharynx, can be caused by human papilloma virus Type 16 (HPV16). Whereas these HPV-induced oropharyngeal carcinomas may express the HPV16 E6 and E7 oncoproteins and are associated with better survival, the nonvirally induced HNSCC are associated with overexpression of p53. In this study we assessed the presence of systemic and local T cells reactive against these oncoproteins in HNSCC. An exploratory study on the presence, type and function of HPV16-and/or p53-specific T cells in the blood, tumor and/or metastatic lymph node as measured by several immune assays was performed in an unselected group of 50 patients with HNSCC. Tumor tissue was tested for HPV DNA and the overexpression of p53 protein. Almost all HPV161 tumors were located in the oropharynx. Circulating HPV16-and p53-specific T cells were found in 17/47 and 7/45 tested patients. T cells were isolated from tumor cultures and/or lymph nodes of 20 patients. HPV16-specific T cells were detected in six of eight HPV1 tumors, but in none of the 12 HPV-tumors. Tumor-infiltrating p53-specific T cells were not detected. In depth analysis of the HPV16-specific T-cell response revealed that this response comprised a broad repertoire of CD41 T-helper Type 1 and 2 cells, CD41 regulatory T cells and CD81 T cells reactive to HPV16. The local presence of HPV16-specific T-cell immunity in HPV16-induced HNSCC implicates a role in the antitumor response and support the development of immunotherapy for HNSCC.

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Medical interventions for high grade vulval intraepithelial neoplasia

Pepas¹,

Kaushik²,

Bryant³

et al. 2011

Cochrane Database of Systematic Reviews

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Background Vulval intraepithelial neoplasia (VIN) is a pre-malignant condition of the vulval skin; its incidence is increasing in women under 50 years. VIN is graded histologically as low grade or high grade. High grade VIN is associated with infection with human papilloma virus (HPV) infection and may progress to invasive disease. There is no consensus on the optimal management of high grade VIN. The high morbidity and high relapse rate associated with surgical interventions call for a formal appraisal of the evidence available for less invasive but effective interventions for high grade VIN. Objectives To evaluate the effectiveness and safety of medical interventions for high grade VIN. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE (up to September 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Selection criteria Randomised controlled trials (RCTs) that assessed medical interventions, in adult women diagnosed with high grade VIN. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis. Main results Four trials met our inclusion criteria: three assessed the effectiveness of topical imiquimod versus placebo in women with high grade VIN; one examined low versus high dose indole-3-carbinol in similar women. Meta-analysis of three trials found that the proportion of women who responded to treatment at 5 to 6 months was much higher in the group who received topical imiquimod than in the group who received placebo (relative risk (RR) = 11.95, 95% confidence interval (CI) 3.21 to 44.51). A single trial showed similar results at 12 months in (RR = 9.10, 95% CI 2.38 to 34.77). Only one trial reported adverse events, which were more common in the imiquimod group. One trial found no significant differences in quality of life (QoL) or body image between the imiquimod and placebo groups. Authors’ conclusions Imiquimod appears to be effective, but its safety needs further examination. Its use is associated with side effects which are tolerable, but more extensive data on adverse effects are required. Long term follow-up should be mandatory in view of the known progression of high grade VIN to invasive disease. Alternative medical interventions, such as cidofovir, should be explored.

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Treatment of Vulvar Intraepithelial Neoplasia with Topical Imiquimod

Abstract: Imiquimod is effective in the treatment of vulvar intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN11290871 [controlled-trials.com].).

Cited by 342 publications

References 22 publications

Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

Medical interventions for high grade vulval intraepithelial neoplasia

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