BRIEF REPORT Lupus Erythematosus–Like Reaction in Imiquimod-Treated Skin: A Report of 2 Cases May P. Chan, MD and Mary Jane Zimarowski, MD Abstract: Imiquimod (Aldara) is a topical immune response modifier effective against a variety of cutaneous tumors. Post therapy histologic reaction patterns have not been well characterized. Here, we present 2 patients treated with imiquimod, whose biopsies showed interface dermatitis of the epidermis and the adnexae with prominent periadnexal and perivascular lymphocytic inflammation. Without the clinical history, these histologic findings may be misinterpreted as lupus erythematosus. This report describes a new finding in imiquimod-treated skin and supports the diversity of reaction patterns that may be seen in association with imiquimod treatment. Key Words: imiquimod, Aldara, lupus erythematosus, reaction (Am J Dermatopathol 2011;33:523–527) INTRODUCTION Topical imiquimod 5% cream (Aldara) is an immuno- modulator that has been approved for the treatment of genital warts, actinic keratoses, and basal cell carcinomas. 1 It has also been used off-label for other malignancies, including mycosis fungoides, 2 Bowen disease, 3 and lentigo maligna. 4 Upon penetration of the epidermis, imiquimod binds to dermal dendritic cells and macrophages through Toll-like receptor (TLR)-7, resulting in the release of proinflammatory cytokines including interferon (IFN)-a, tumor necrosis factor-a, inter- leukin (IL)-2, IL-6, and IL-8. 5,6 These mediators in turn recruit and stimulate cytotoxic T lymphocytes 7 and natural killer cells, 8 thereby eliciting a strong cellular immune response. In addition, several studies have illustrated both direct and indirect pro-apoptotic activities of imiquimod leading to the apoptosis of tumor cells. 9 Together, these mechanisms work synergistically to contribute to the antitumoral effect of imiquimod. Although a clinically significant inflammatory response is often associated with successful clearance of tumor, 10,11 the histologic response to imiquimod seems variable and has not been fully characterized. Lentigo maligna is a variant of melanoma in situ that affects sun-damaged skin, most commonly on the face, of elderly individuals. Although surgical excision is the gold standard treatment, obtaining clear margins without significant disfiguration is often challenging. Several uncontrolled studies and case reports on the use of imiquimod 5% cream for lentigo maligna have shown a composite clearance rate of 88%. 12,13 Imiquimod has been approved for the treatment of actinic keratosis a precursor of squamous cell carcinoma. 14 Here, we present a case of lentigo maligna and a case of multiple actinic keratoses treated with imiquimod, both of which demonstrated a lymphocytic reaction pattern, closely resembling that of lupus erythematosus. CASE REPORTS Case 1 A 91-year-old woman with lentigo maligna on the nose tip was treated with topical imiquimod due to her advanced age. She applied 5% imiquimod cream 5 times a week for a total of 8 weeks. A month after completion of therapy (3 months after initiation of therapy), the area remained pigmented and was rebiopsied to rule out residual lentigo maligna or malignant melanoma. The repeat biopsy showed prominent perivascular and deep perifollicular lymphocytic inflam- mation (Fig. 1) and an interface dermatitis with clusters of colloid bodies at the dermoepidermal junction (Fig. 2). The follicular epithelium demonstrated basal vacuolar degeneration (Fig. 3). A dilated follicle filled with keratin debris was present (Fig. 1). Dermal melanophages accounted for the pigmentation (Fig. 2); no viable atypical melanocytic proliferation was identified. No increase in dermal mucin was observed with colloidal iron stain. Periodic acid– Schiff stain demonstrated normal thickness of the epidermal basement membrane. By immunohistochemistry, the lymphocytic infiltrates were comprised of predominantly CD3 + T cells and a smaller subset of CD20 + B cells. Few lymphoid cells were positive for CD56. These inflammatory changes were not seen in the prior biopsy from the area (Fig. 4), and the patient did not have a history of lupus erythematosus. Case 2 A 75-year-old man with a history of squamous cell carcinoma and basosquamous carcinoma status post Mohs excisions was monitored closely for multiple actinic keratoses on the scalp. These lesions had been treated with imiquimod 5% cream 3 times a week for several months. On follow-up examination at 3 months after initiation of therapy, multiple new papules with dark crusts were noted on the parietal and occipital scalp, clinically concerning for hypertrophic actinic keratoses or squamous cell carcinomas. Four of these lesions were biopsied, which revealed superficial and deep perivascular lymphocytic infiltrates (Fig. 5) with focal exocytosis into the eccrine duct epithelium (Fig. 6). One of the lesions also showed lichenoid interface dermatitis (Fig. 7). Two other biopsies demonstrated From the Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Presented as a poster at the 46th American Society of Dermatopathology Annual Meeting in Chicago, IL, on October 1–4, 2009. Reprints request: May P. Chan, MD, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston MA 02215 (e-mail: mchan3@bidmc.harvard.edu). Copyright Ó 2011 by Lippincott Williams & Wilkins Am J Dermatopathol  Volume 33, Number 5, July 2011 www.amjdermatopathology.com | 523