Topical imiquimod and in situ vulvar melanoma: A promising therapy?

Abstract

Objectives

Vulvar melanoma is a rare type of cancer that affects mainly postmenopausal women. There are no established protocols for the treatment of vulvar melanoma. From data extrapolated from the literature on cutaneous melanoma, surgical excision remains the best option for the resectable disease. Imiquimod, a topical immunomodulator, has been used in selected cases of in situ vulvar melanoma.

Methods and Results

We reported two cases of in situ vulvar melanoma treated with topical imiquimod 5%, either as first‐line therapy or adjuvant treatment, that showed a complete clinical response to topical treatment.

Conclusion

Imiquimod's beneficial and adverse effects in in situ vulvar melanoma treatment are examined.

Abbreviations

BCC

basal cell carcinoma

CCR

complete clinical response

FDA

Food and Drug Administration

HPV

human papilloma virus

VM

vulvar melanoma

1. INTRODUCTION

Vulvar melanoma (VM) is a rare type of cancer that accounts for 5% of all vulvar neoplasms and 1.4% of all melanomas. The exact incidence of VM is unknown, although a recent Spanish study showed that the age‐standardized incidence of vulvar‐vaginal melanoma in southern Spain from 1994 to 2018 was 0.09 cases/100 000 inhabitant‐year. ¹ The progression rate from in situ to invasive VM is unknown. However, it is common to find in situ VM at resection margins for invasive VM. ²

Vulvar melanoma typically affects postmenopausal women in their 50s to 80s; the median age at diagnosis of in situ VM is 63 years. ³ However, a few cases have been reported in children, too. ⁴ Approximately 20% of mucosal melanomas are believed to be multifocal and 40% are amelanotic, ⁵ while cutaneous melanomas have only 5% and 10% of such cases, respectively. ⁵ In most cases, the diagnosis is delayed until the advanced stage due to the absence of symptoms in the early stage or location, which might cause lower self‐awareness. In the advanced setting, VM often appears as a nodular lesion associated with symptoms like pain, bleeding, and discharge. ⁶ In situ VM might occur as an asymmetric, irregularly pigmented lesion, which can sometimes be mistaken for other conditions (e.g., genital nevi, vulvar melanosis, post‐inflammatory hyperpigmentation, squamous intraepithelial lesions, and pigmented seborrheic keratosis)s. The most commonly affected areas are the clitoral area and labia majora, followed by the labia minora and periurethral area; the vaginal introitus might be rarely involved. ⁷

Unfortunately, there are no established protocols for the treatment of VM. The gold‐standard treatment for resectable VM is a wide surgical excision with 1–2 cm negative margins. ⁸ However, VM has a high tendency for local recurrence, possibly due to its multifocal presentation and delayed diagnosis at an advanced stage of the disease. ⁹ , ¹⁰ Mucosal melanoma might also affect multiple anatomic sites at the same time, such as the vulva and anus or vulva and vagina.

In some cases of in situ VM, the large size of the lesion at diagnosis, the proximity to the urethra and anus, and the patient's comorbidities make non‐surgical treatment modalities suitable alternatives for the management of this condition. Because melanoma is one of the most immunogenic malignancies, imiquimod, an immune‐modulating agent, could be an appropriate antineoplastic treatment. ¹¹

In what follows, we present two cases of multifocal in situ VM that were successfully treated with topical imiquimod.

2. METHODS

2.1. Case 1

A 66‐year‐old patient followed at our clinic for a previous perianal squamous cell carcinoma, which had been treated with radiotherapy, presented a nodular lesion of the right labium major. The patient underwent surgical excision of the nodular lesion, and histopathology revealed an invasive, 5‐mm Breslow thickness melanoma. As a result, a right labium major wide excision and inguinal sentinel lymph node biopsy were performed. Histology revealed residual foci of in situ melanoma in the surgical specimen and the absence of nodal involvement. Five months later, the patient developed several hyperpigmented macules on the right labia. The dermoscopic exam showed brown macules with homogenous and structureless pigmentation (Figure 1a–c). Five 3‐mm‐punch biopsies of the suspect lesions were obtained, and histology confirmed in situ VM in all sites. Due to the large area involved and the multifocality of the disease, the suitable approach and treatment were evaluated within the multidisciplinary tumor board. Because the patient refused any further surgical procedures, after a thorough discussion, treatment with topical 5% imiquimod cream was started two times/week and, after 1 month, was switched to three times/week. The patient completed a 16‐week imiquimod course with some stops for significant local side effects, such as redness and irritations (Figure 1d). During the therapy, in addition to local symptoms, the patient experienced flu‐like symptoms that we treated with non‐steroidal anti‐inflammatory drugs with improvement. At the end of the treatment, clinical examination showed only post‐inflammatory signs without any residual melanoma features. The patient was monitored every 3 months for the first year and then every 6 months for 10 years, showing a complete clinical response (CCR) after an 11‐year‐long follow‐up (Figure 1e,f). Inguinal lymph node ultrasounds were performed every 6 months, and total‐body computed tomography scans were performed yearly.

FIGURE 1.

(a) Multifocal in situ vulvar melanoma of the right labium minor, labium major, and clitoris. (b, c) Dermatoscopy of one pigmented lesion on the right labium minor (original magnification 10×) shows structureless pigmentation. (d) Clinical aspect of the vulva during imiquimod treatment. (e) Dermatoscopy of one of the lesions treated with a residual brown pigmentation on a pinkish background (original magnification 20×). (f) Clinical aspect 1 month after treatment discontinuation with a complete clinical response.

2.2. Case 2

A 47‐year‐old patient had multiple surgeries for in situ VM over 4 years, leading to a left hemivulvectomy and flap reconstruction. The clinical and dermoscopic aspects are shown in Figure 2a–d. After a multidisciplinary consultation, adjuvant treatment with imiquimod was started twice weekly. After 8 weeks, the treatment schedule was increased to thrice a week because the topical therapy was well tolerated. However, 4 weeks later, the patient complained of severe burning and pain and stopped the therapy for 2 weeks. The treatment was switched to two applications weekly and continued for 12 months. After 12 months, no suspicious pigmentation was detected at the clinical and dermoscopic examination, and therefore, imiquimod therapy was discontinued. The patient continued her clinical and instrumental follow‐up. A CCR was observed after 24 months (Figure 2e,f). The patient is still under observation.

FIGURE 2.

(a, c) Clinical aspect of melanoma local recurrence at physical examination. (b, d) Dermatoscopy shows an atypical pigment network in (b) (first local recurrence) and a negative network with atypical vessels in (d) (second relapse) (original magnification 20×). (e, f) Clinical and dermoscopic aspects after 12 months of imiquimod adjuvant treatment.

3. DISCUSSION

Vulvar melanoma is a rare disease with a poor prognosis compared to cutaneous melanoma. Surgical excision remains the best approach for local disease control, but other treatments might be considered for unresectable lesions, multiple lesions, or patients who prefer non‐surgical options.

The Food and Drug Administration (FDA) approved topical imiquimod for treating genital warts in 1997. Imiquimod is a topical immune response modulator that stimulates the innate and adaptive immune system. ¹² The pleiotropic actions of imiquimod include TLR7‐dependent and TLR7‐independent effects. ¹² TLR7 is a membrane receptor expressed on multiple immune cell types recognizing pathogen antigens. Imiquimod binds to TLR7, activating an intracellular signaling cascade that stimulates the synthesis of pro‐inflammatory cytokines, chemokines, and interleukins, leading to a T‐helper 1 cellular immune response. Imiquimod also induces a direct apoptotic effect, leading to cell death ¹² (Figure 3).

FIGURE 3.

The intrinsic and extrinsic pathways of apoptosis induced by imiquimod. Scheme modified from Garcia‐Mouronte et al. ¹² BCC, basal‐cell carcinoma.

Moreover, imiquimod shows death‐receptor‐induced apoptosis, stimulating the cellular membrane expression of the CD95 ligand (FasL). ¹² In this way, CD4+ cells induce cellular apoptosis through the CD95‐CD95L binding. By upregulating CD95 and CD95L in basal cell carcinoma (BCC) cells, imiquimod induces apoptosis through BCC cell‐BCC cell contact. ¹² The above is the primary apoptotic mechanism of imiquimod observed in BCC. In 2004, imiquimod was approved by the FDA for treating BCC, and a recent meta‐analysis showed that imiquimod had a complete response rate of 77.8%. ¹³ , ¹⁴

In gynecologic diseases, imiquimod is often used as an off‐label treatment. In selected cases, it can be considered an alternative therapeutic choice to avoid repeated and mutilating surgery. Several clinical trials have shown promising results in human papilloma virus (HPV)‐associated vulvar intraepithelial neoplasia. The complete response rate for imiquimod‐treated women with HPV‐related vulvar intraepithelial neoplasia ranges from 35% to 81% from 2 to 6 months after treatment. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Different treatment schedules and heterogeneous populations included in the trials could explain the different response rates. A long‐term follow‐up at 7.2 years reported a persistent CCR in eight of nine patients who had responded to topical 5% imiquimod treatment.

Imiquimod has also been shown to be a safe, conservative treatment option for in situ vulvar Paget's disease with minimal adverse effects. Although surgical resection represents the gold standard of therapy, considering Paget's disease growth pattern with occult intradermal spread, surgical resection margin results are often involved. Thus, incomplete resection might lead to multiple and destructive surgeries. Topical 5% imiquimod minimized the morbidity of repeated surgery, achieving a CCR of 22% to 90% of cases. ¹⁹ , ²⁰ The treatment regimen varies among studies, from one to five applications weekly, according to patients' tolerability. Based on this data, imiquimod should be applied for at least 16 weeks.

In the last fifteen years, topical 5% imiquimod has been increasing as an adjuvant or complementary treatment post‐surgery, finding a wide field of application in cases where no radical removal is possible or surgical margins are positive. Imiquimod has been effective in treating cutaneous lentigo maligna of the face or the scalp when surgical options have not been feasible. ²¹ VM is biologically more similar to mucosal melanomas than cutaneous melanomas, and only limited case reports in the literature describe the experimental approach of imiquimod for VM.

Table 1 shows selected case reports on the efficacy of imiquimod therapy in situ VM. Lonsdale‐Eccles et al. reported the case of a 68‐year‐old patient who had experienced multiple recurrences of in situ VM. After numerous surgeries, the patient started a topical treatment with 5% imiquimod. She applied the cream every other day for 4 months with a CCR. No disease recurrence was evident at clinial follow‐up after 18 months. ²²

TABLE 1.

Studies ²² , ²³ , ²⁴ , ²⁵ , ²⁶ on the efficacy of imiquimod in treating in situ vulvar melanoma.

A. Y.	Type of article	Number of patients	Age	Histology	Location	Treatment	Treatment protocol	Discontinuation	Total treatment duration	Clinical outcome	Histological response	Follow‐up	Recurrence
Lonsdale, 2006	Case report	1	68	Mis	Vulva	Imi 5%	1/day, alternated days for 16 weeks	Yes	16 weeks	CR	No	4 months	No
Sadownik, 2010	Case report	1	72	Mis	Vulva	Imi 5%	1/day, 3/week for 6 weeks	NR	6 weeks	CR	Yes	10 months	No
Prescott, 2012	Case report	1	68	Mis	Vagina, vulva	Imi 5%	1/day, 1/week for 4 weeks, then 2/ week for 4 weeks, then3/week for 8 weeks	No	16 weeks	CR	No	18 months	No
Veraitch, 2019	Case report	1	75	Mis	Vulva	Imi 5%	1/day, 1–2/week for 8 weeks	No	18 months	PR	Yes	NR	NR
Fuchs, 2021	Case report	1	81	Mis	Vulva	Imi 5%	1/day, 3–7/week for 16 weeks	NR	16 weeks	CR	Yes	48 months	No

Abbreviations: CR, complete response; Imi, imiquimod; Mis, melanoma in situ; NR, not reported; PR, partial response.

Sadownik and Crawford described a 72‐year‐old patient with recurrent in situ VM who underwent wide local excision with positive margins. She was treated with imiquimod three times a week for 6 weeks with complete clinical and histological regression. She remained without evidence of recurrent disease after a 10‐month follow‐up after treatment completion. ²³ Veraitch et al. reported a similar case in a 75‐year‐old woman with multifocal in situ VM, whose wide resection had not been radical. The treatment schedule with imiquimod started with one application weekly and then increased to twice weekly for 8 weeks with excellent patient compliance. ²⁴

Prescott et al. reported a 68‐year‐old patient with a vaginal invasive melanoma. The surgical margin was positive for in situ melanoma, with no evidence of sentinel node or distant spread. Topical 5% imiquimod was started with a progressive increase in frequency application. An 18‐month follow‐up demonstrated a CCR. ²⁵ Similarly, in the case report of Fuchs et al., a 69‐year‐old patient underwent topical imiquimod therapy after multiple incomplete surgeries for in situ VM. The treatment regimen consisted of three times weekly application for 4 weeks and then every day with a weekend pause for 16 weeks. After a 48‐month follow‐up, the patient showed no disease recurrence. ²⁶

Even if imiquimod is not an approved treatment for in situ melanoma, studies have shown that it can be an effective and conservative option with reasonable response rates in selected cases. As it preserves the anatomy and function of the vulvar anatomy, imiquimod might improve patients' quality of life. However, side effects occur in over 50% of patients, and the treatment schedule needs to be standardized due to its off‐label use and variability in patient compliance. Local adverse effects, such as erythema, burning, erosion, or tenderness, are the most common, while systemic side effects include flu‐like symptoms, fever, myalgia, or arthralgia. There is a higher risk of systemic adverse effects in genital mucosa than in cutis due to the larger surface area treated and elevated inflammatory cytokines produced that spread into the systemic circulation. ²⁷

The rate of local symptoms observed during imiquimod therapy often leads to patients stopping the treatment or prematurely reducing the frequency of topical application. ²⁸ The duration of therapy is also variable, although most patients undergo a minimum of 16 weeks of treatment. In our two cases, there is a noticeable variation in the frequency of application and duration of therapy. The therapy's local and systemic side effects have certainly influenced patient compliance. In the first case, a more substantial interruption of topical therapy resulted in an extended duration of treatment. Additionally, the variation in therapy duration between our two cases can be attributed to multiple localizations in the first case, whereas the second case involved only a single localization.

Only one patient with vulvar in situ melanoma (vMIS) treated with topical imiquimod was found to have completed a response to treatment based on a histological examination. ²⁴ Clinicians generally prefer not to perform further biopsies in the absence of evident clinical lesions but instead rely on extended clinical and instrumental follow‐up to confirm a complete resolution of the disease.

Non‐invasive diagnostic techniques such as digital dermoscopy or reflectance confocal microscopy are widely used for an accurate diagnosis of cutaneous melanoma and non‐melanoma skin cancer. These non‐invasive diagnostic techniques have also been used in genital lesions to ameliorate the diagnosis or detect recurrence early. ²⁹ , ³⁰ Reflectance confocal microscopy allows for the non‐invasive epidermis and superficial dermis imaging at the quasi‐histologic resolution, monitoring the occurrence and evolution of small atypical melanocytic foci and identifying early high‐suspicious areas that require biopsy. Thus, it might help in evaluating large and multifocal vulvar pigmentations that are difficult to diagnose. ³⁰ Photography and digital dermoscopy during therapy can help detect the response to topical therapy, thus reducing unnecessary incisional biopsy. Not all genital pigmentations should be considered worrying, as some lesions might be benign. ³⁰ , ³¹

4. CONCLUSION

This paper highlights that imiquimod could be a promising option for treating in situ VM, owing to its positive response rate and the relatively low risk of severe adverse effects. However, drawing randomized controlled clinical trials using imiquimod in VM is difficult, mainly due to this disease's rarity. A multidisciplinary approach involving gynecologists, dermatologists, surgeons, radiotherapists, and pathologists is highly recommended to provide the best possible care for patients with this condition. Healthcare professionals can determine the most effective treatment approach and establish an appropriate clinical and instrumental follow‐up plan, which might help patients avoid unnecessary surgeries. Even if surgery remains the first treatment choice, establishing new protocols for treating genital melanoma is crucial to preserve the anatomy and function of genitalia and minimize the risk of recurrence.

AUTHOR CONTRIBUTIONS

Conceptualization EPP, PQ and GT; methodology, FP; validation EPP, GT and DAI; formal analysis, FP; investigation, FS; resources, FP; data curation, GR; writing—original draft preparation, FP, GT, SV; writing—review and editing, GT and FS; visualization, PQ, DAI, SV; supervision EPP; project administration, GT. All authors have read and agreed to the published version of the manuscript.

FUNDING INFORMATION

This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

INFORMED CONSENT STATEMENT

Informed consent was obtained from all subjects involved in the study.

Pepe F, Silvestri F, Preti EP, et al. Topical imiquimod and in situ vulvar melanoma: A promising therapy? Int J Gynecol Obstet. 2025;170:608‐613. doi: 10.1002/ijgo.70087

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.