Dermatology Online Journal

Imiquimod for restoring local immunity in a renal transplant patient with persistent keratoacanthoma
Evelin Jasmine Paternò MD¹, Elena Campione MD¹, Laura Diluvio MD¹, Augusto Orlandi MD², Sergio Chimenti MD¹
Dermatology Online Journal 14 (3): 8

1. Department of Dermatology, University of Rome "Tor Vergata," Rome, Italy. evelin.paterno@libero.it
2. Department of Pathology, University of Rome "Tor Vergata" Rome," Italy

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Abstract

Keratoacanthoma (KA), a cutaneous neoplasm histologically resembling squamous cell carcinoma, is characterized by rapid growth and common spontaneous regression. The regression depends on an individual's immune response. We are reporting a case of a 53-year-old man who presented with an ulcerated tumor, which had arisen as a nodular lesion 9 months earlier. This was localized on the the left thumb. The patient had undergone a kidney transplant after severe glomerulonephritis. Following the operation, he was treated with systemic immunosuppressive drugs and developed multiple non-melanoma skin cancers. The histology examination of biopsy specimens was consistent with keratoacanthoma and showed low-density chronic inflammatory cells. Our patient refused surgical excision, so we prescribed imiquimod 5 percent cream once daily for 5 days a week. After 6 weeks of treatment the lesion had regressed completely, yielding an excellent cosmetic result. Continued resolution was documented 3 years after treatment. The patient had no signs of graft rejection related to the imiquimod treatment.

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Introduction

Keratoacanthomas (KAs) are epithelial tumors, characterized by a keratin-filled, rapidly growing papule, that develops in a crater produced by pilosebaceous follicles. Even though these lesions histologically resemble squamous cell carcinoma (SCC), they are considered to be immunologically well-controlled carcinoma cells, which usually regress spontaneously. The elective treatment is excisional surgery. However, given the possibility of a natural remission, a non-invasive medical therapy to treat this kind of cancer may be contemplated in certain situations. The medical therapies for the management of KAs include the use of 5-fluorouracil, retinoids, bleomycin, methotrexate, triamcinolone acetonide, radiotherapy and, recently, imiquimod [1-7]. Imiquimod is an immune response modifier, with significant antiviral and antitumor effects. It induces cytokines and cell-mediated cytolytic activity, stimulating both innate and acquired immune responses. Over the last few years, numerous clinical trials have reported the efficacy of imiquimod for the treatment of epithelial skin cancer, including in transplant patients.

Case Report

Figure 1
Figure 1. A 53-year-old man with two keratoacanthomas on the left hand before therapy

A 53-year-old man presented with a cutaneous lesion, which appeared 9 months before. It was characterized by an ulcerated nodule (20 mm in diameter) and was located on the left thumb (Fig 1.); no lymphoadenopathy was observed. The patient reported that the lesion was initially a nodule, which he repeatedly traumatized. The patient's past medical history revealed that he had been treated with dialysis for 13 years and then had undergone a kidney transplant due to renal insufficiency caused by glomerulonephritis. For this reason, he was given immunosuppressive treatment with cyclosporine (2mg/kg/per day) and prednisone (1mg/kg/per day).

Figure 2A	Figure 2B
Figure 2: (A) Histological examination of skin biopsy of lesional edge shows endophytic proliferations of squamous cells with (B) abundant cytoplasmic glycogen and minimal nuclear atypia, sometimes with abrupt keratinisation with abundant neutrophils forming intraepithelial microabscesses.

A punch biopsy was taken from the border of the lesion and the histopathological diagnosis was keratoacanthoma (KA) (Figs. 2A & 2B). The patient refused a surgical excision of the cutaneous tumor and requested medical treatment instead. He had previously undergone surgical removal of numerous cutaneous neoplasms that had appeared during immunosuppressive treatment. These surgical procedures caused painful and disfiguring scars. Therefore his KA was treated with imiquimod 5 percent cream for 5 consecutive days per week for 6 weeks.

Figure 2C	Figure 2D
Figure 2: (C) and (D) Histologic examination of skin biopsy at different magnifications after 6 weeks of therapy reveals flattened epidermis with focal hyperkeratosis, dermal reparative fibrosis and residual chronic inflammation and the absence of residual infiltrating squamous cells in the dermis. (Hematoxykin-Eosin, original magnification: A, C = 20X; B,D = 100X).

An informed written consent was obtained from the patient. Baseline full blood count, CD4/CD8 ratio, serum electrolytes, urea, creatinine and liver enzymes were measured before treatment and measurements were repeated every 2 weeks during his treatment period. Throughout and after the treatment with imiquimod 5 percent cream the patient maintained immunosuppressive therapy (cyclosporine 2mg/kg/daily). The dimension of the tumor was remarkably reduced after just 2 weeks of treatment. After 6 weeks of treatment, the lesion had completely regressed, as was confirmed by a second biopsy (Figs. 2C, 2D); the cosmetic result was excellent (Fig. 3). During treatment only local reactions, erythema and crusting, were observed. The patient continues follow-up visits every 6 months. No relapse has been observed after 36 months.

Figure 3
Figure 3. The clinical remission of the cutaneous lesions after therapy with Imiquimod 5% cream

Discussion

KAs are nodular cutaneous tumors that develop rapidly and simulate the histology of SCC. Some authors consider KA to be low-grade SCC and refer to the tumor as SCC/KA-type. KA, however, typically heals spontaneously, but the mechanism of resolution is not completely understood. Recent observations suggest that cutaneous tumor regression depends on an individual's immune response, mediated by CD8 and CD4 T lymphocytes. Batinac et al. described an elevated number of T cells expressing granzyme B in regressing KAs as compared with SCC [8]. Granzyme B and perforin released by CD8 cells could kill tumor cells, leading to the regression of the neoplasm. Moreover, in SCCs, imiquimod therapy causes a change in the local environment, with a recruitment of CD8 T cells, enriched by granzyme B [9]. This treatment potentiates the cytotoxic effect of the T cell population, inhibiting cancer progression. The successful results obtained by treating KAs in transplant patients with imiquimod 5 percent cream have recently been reported in several journals [7, 10].

Imiquimod has both an indirect antiviral action and an anti-tumoral action. The drug stimulates the synthesis and release of Th1-dependent cytokines (INF-α, TNF-α, IL-1α, IL-6, IL-8, IL-12, PGE2), thus leading to antigenic presentation and activation due to Langerhans cells (LCs) in regional lymph nodes. Immunohistochemistry studies quantified the LCs in benign and malignant cutaneous tumors, demonstrating the highest number in benign lesions, e.g. KA, as compared with malignant and with normal tissues [11]. Besides the acquired immunity (through cytotoxic T lymphocytes) and natural killer cell stimulation, imiquimod has been shown to induce apoptosis by downregulating the anti-apoptotic protein, Bcl-2, and inducing the pro-apoptotic Fas receptor (CD 92-receptor) [12, 13]. Inhibition of tumor angiogenesis was also observed [14]. These recent findings confirm the efficacy of the drug and its rational use in the management of cutaneous tumors. The use of imiquimod in transplant patients afflicted by epithelial skin growths has also been described [15]. This drug activates an immune response only at the site of application, without influencing the systemic immune response [16]. Harrison et al., in a recent study, measured serum levels of imiquimod in 58 non-immunosuppressed patients after local application. Low serum levels of the drug were measured and the immunological effects were limited to the area of application [17]. In our patient, systemic adverse effects did not occur. Positive results were observed near the beginning of therapy. The patient was visited every 2 weeks and photos of the lesions were taken. Repeated blood counts and chemistries remained in normal ranges. Imiquimod treatment of the KA resulted in complete remission. In fact, after only 2 weeks of treatment, we observed a rapid involution of the tumor; after 6 weeks, the lesion had totally healed and the cosmetic outcome was excellent. No relapse was observed after 36 months of follow-up. Future clinical trials could further validate the efficacy and safety of imiquimod in immunosuppressed patients who have undergone organ transplants. We have reported our case to demonstrate the efficacy of imiquimod treatment of KA in transplant patients. Our patient's tumor completely resolved without activating a systemic immune response.

ACKNOWLEDGMENTS: The Authors wish to thank Diana Saltarelli, for editing assistance.

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