Successful treatment of high-grade vulval intra-epithelial neoplasia with imiquimod 5% in a renal transplant recipient

Abstract

Organ transplant recipients are at a higher risk of pre-malignant human papillomavirus-associated lesions due to immunosuppression. The efficacy of immunomodulants such as imiquimod 5% is not yet fully evaluated in this population. We describe a case of vulval intra-epithelial neoplasia in a renal transplant recipient which was successfully treated with topical imiquimod.

Keywords

Vulval intra-epithelial neoplasia imiquimod immunosuppressants transplant recipient human papillomavirus

Introduction

Vulval intra-epithelial neoplasia (VIN) is a pre-cancerous condition of the vulval skin with increasing prevalence.¹ VIN is diagnosed histologically and can be classified as low-grade squamous intra-epithelial lesion (LSIL; previously known as VIN 1) or high-grade squamous intra-epithelial lesion (HSIL; previously known as VIN 2/3) depending on the thickness of the affected squamous epithelium.² Human papillomavirus (HPV)-related type is described as usual type VIN and is most common in women under 45. More than 80% of VIN lesions are associated with the high-risk HPV subtypes 16, 18 and 33.³ Smoking and immunosuppression are additional risk factors. In contrast, differentiated type VIN generally occurs in older women and is typically associated with lichen sclerosus.⁴

Organ transplant recipients (OTR) are at higher risk for developing HPV-associated pre-malignant and malignant lesions due to chronic immunosuppression. Imiquimod is an immunomodulatory drug with an ability to stimulate the innate and acquired cellular immune responses. The safety, efficacy and tolerability of imiquimod has been evaluated for a range of skin conditions such as actinic keratosis, Bowen’s disease, basal cell carcinoma and recalcitrant cutaneous warts in OTR.

There is a growing body of evidence for the efficacy and safety of topical imiquimod for VIN although data are limited for managing VIN in OTR. Here, we present a case of a renal transplant recipient on systemic immunosuppressants with high-grade VIN treated with 5% imiquimod cream with complete response.

Case report

A 49-year-old white Caucasian female presented to the sexual health clinic with a three-month history of intense vulval itching. She was a renal transplant recipient on tacrolimus, mycophenolate mofetil and prednisolone. She was a non-smoker. Her cervical smears had been normal to date.

Clinically, she had extensive raised warty plaques on the anterior vulva extending to perianal skin (Figure 1). This raised a high suspicion of VIN. She was referred to Gynae-oncology for tissue diagnosis. Mapping biopsies confirmed VIN (usual type) grade 1–3 with extensive field change. There was no evidence of invasion. In view of the extent of disease, she was referred to a dermatologist for medical management.

Figure 1.

Pink and white warty papules over whole external vulva, perineum and perianal area prior to treatment.

Treatment was initiated with imiquimod 5% cream starting with one application at night per week and slowly increased to five nights a week. The patient was advised to use emollients for vulval skin care. At eight-week follow-up, she had an excellent response with no apparent local inflammatory or systemic side effects. There was one residual area which she continued to treat for another eight weeks. At three months and seven months post treatment, the patient was symptom free with complete clinical resolution. She subsequently defaulted from further follow-up. Renal function was stable with no increase in serum creatinine observed during the course of treatment.

Discussion

Imiquimod is an immune response-modifying drug which enhances local skin immune responses by activating toll-like receptor-7 and -8 on macrophages and dendritic cells. This results in release of pro-inflammatory T-helper cell type 1 cytokines and upregulation of cell-mediated immunity.⁵ This induces an antiviral and proapoptotic effect on HPV-infected abnormal cells. Common patient-reported side effects include local pruritus, burning, pain, irritation and soreness. Erythema is often seen on examination. Potential systemic side effects can include flu-like symptoms.

Imiquimod has emerged as a promising agent for the conservative treatment of VIN in a number of studies as surgery does not guarantee cure and can be potentially disfiguring. Three randomised controlled trials of imiquimod compared to placebo showed a combined complete response in 58% of patients.⁶ A recent multicentre randomised phase 2 trial showed a response rate in over 45% of patients treated with imiquimod.⁷ Two retrospective studies of treatment outcomes with imiquimod showed response rates of 76% and 31%.^8,9 The response rates in these studies were based on both clinical and histological assessment.

The use of imiquimod for treating VIN in OTR presents some important dilemmas to physicians because of the theoretical risk of jeopardising the viability of the grafted organ through the systemic immunostimulation from imiquimod. The imiquimod Summary of Product Characteristics advises caution in OTR and that the benefit of treatment must be balanced with the possibility of organ rejection or graft-versus-host disease. No graft rejection or deterioration of graft function was seen in 43 transplant recipients (kidney, liver and heart) who used a double dose of imiquimod for the treatment of actinic keratosis at a dosing of three times/week for 16 weeks.¹⁰ Specifically, in renal transplant recipients who used imiquimod for the treatment of skin dysplasia, no more than a 20% increase in serum creatinine was observed during treatment suggesting that localised application did not significantly affect graft function.¹¹ Pharmacokinetic data suggest that there is insignificant systemic absorption of topically-applied imiquimod.¹²

However, there has been a report of acute renal failure in a renal transplant recipient with extra genital warts treated with imiquimod.¹³

A number of studies have supported the efficacy of imiquimod in OTR for the treatment of a range of skin conditions such as basal cell carcinoma,¹⁴ actinic keratosis,¹⁵ carcinoma in situ¹¹ and warts.¹⁶ This suggests that the cutaneous immune system in OTR when stimulated by imiquimod is able to mount a response against viral or tumour antigens resulting in lesion clearance. Therefore, this concept should also apply in the treatment of high-grade VIN in OTR. Imiquimod upregulates the immune system not only at the site of application but also in adjacent areas which can be useful in treating skip lesions. Evidence also exists for the efficacy of imiquimod in patients with HIV-induced immunosuppression.¹⁷

The most common adverse event from imiquimod use in OTR is application site reaction with severe erythema seen in 30% of renal transplant recipients.¹⁵ Other studies have shown that the local skin reaction profile is similar in intensity but slightly protracted in OTR.^11,18,19 In our patient, this may have been mitigated by the slow dose escalation of imiquimod application which was carefully planned to improve tolerability. Clearance appears to have been achieved despite no clinical evidence of an inflammatory response.

There are currently no data regarding VIN recurrence rates after complete response in OTR. It seems prudent to follow up these individuals at 3, 6 and 12 months with annual visits thereafter to monitor for recurrence.

This case report shows that topical imiquimod was a safe and effective treatment for the management of high-grade VIN in a renal transplant recipient. Further research is needed to evaluate the long-term safety of imiquimod use in OTR with the ever-increasing burden of skin infection and dysplasia.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Baandrup

Varbo

Munk

et al . In situ and invasive squamous cell carcinoma of the vulva in Denmark 1978–2007 – a nationwide population-based study. Gynecol Oncol 2011; 122: 45–49.

Bornstein

Bogliatto

Haefner

et al . The 2015 international society for the study of vulvovaginal disease (ISSVD) terminology of vulvar squamous intraepithelial lesions. Obstet Gynecol 2016; 127: 264–268.

Faber

Sand

Albieri

et al . Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva. Int J Cancer 2017; 141: 1161–1169.

Sideri

Jones

Wilkinson

et al . Squamous vulvar intraepithelial neoplasia – 2004 modified terminology, ISSVD vulvar oncology subcommittee. J Reprod Med 2005; 50: 807–810.

Sauder

DN.

Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol 2000; 43: S6–S11.

Pepas

Kaushik

Bryant

et al . Medical interventions for high grade vulval intraepithelial neoplasia. Cochrane Database Syst Rev 2011; 4: CD007924.

Tristram

Hurt

Madden

et al . Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT³ VIN): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2014; 15: 1361–1368.

van Seters

van Beurden

ten Kate

FJW

et al . Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med 2008; 358: 1465–1473.

Westermann

Fischer

Clad

Treatment of vulvar intraepithelial neoplasia with topical 5% imiquimod cream. Int J Gynaecol Obstet 2013; 120: 266–270.

10.

Rowert-Huber

Patel

Forschner

et al . Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol 2007; 156: 8–12.

11.

Brown

Atkins

Ghali

et al . Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients – randomized, double-blind, placebo-controlled trial. Arch Dermatol 2005; 141: 985–993.

12.

Owens

Bridson

Smith

et al . Percutaneous penetration of Aldara cream, 5% during the topical treatment of genital and perianal warts. Prim Care Update Ob Gyns 1998; 5: 151.

13.

Santos-Juanes

Esteve

Mas-Vidal

et al . Acute renal failure caused by imiquimod 5% cream in a renal transplant patient: review of the literature on side effects of imiquimod. Dermatology 2011; 222: 109–112.

14.

Vidal

Matias-Guiu

Alomar

Open study of the efficacy and mechanism of action of topical imiquimod in basal cell carcinoma. Clin Exp Dermatol 2004; 29: 518–525.

15.

Stockfleth

Meyer

Benninghoff

et al . Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases. Br J Dermatol 2001; 144: 1050–1053.

16.

Harwood

Perrett

Brown

et al . Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals. Br J Dermatol 2005; 152: 122–129.

17.

Toby

Conway

Sethi

et al . Usual vulval intraepithelial neoplasia in HIV-positive women – a case series. Int J STD AIDS 2016; 27: 1253–1256.

18.

Gayed

SL.

Topical imiquimod cream 5% for resistant perianal warts in a renal transplant patient. Int J STD AIDS 2002; 13: 349–351.

19.

Ulrich

Bichel

Euvrard

et al . Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 2007; 157: 25–31.