A keratoacanthoma centrifugum marginatum (KACM) may pose a diagnostic and therapeutic challenge. Clinically and histologically, it may resemble mycobacterial or deep fungal infection or halogenoderma. Therapy can be challenging because the lesion can expand to a great size. We report on a patient with multiple lesions of KACM. The diagnostic difficulty and the therapeutic failure of imiquimod, intralesional methotrexate (MTX), and isotretinoin, as well as the therapeutic success of 5-fluorouracil (5-FU) cream, are discussed.
Although Belisario first referred to the large annular keratoacanthoma (KA) as keratoacanthoma centrifugum marginatum (KACM) in 1965, a variety of names have been applied to this entity, including squamous cell pseudoepithelioma, aggregated KA, coral-reef KA, nodulo-vegetating KA, KA centrifugum, and multinodular KA.1,2 KACM is characterized by central regression with concomitant growth and expansion of the periphery but no tendencies toward complete regression in contrast to other types of KAs. A proper diagnosis can be challenging because clinically and histologically the lesions may resemble halogenoderma or infections such as verrucous tuberculosis or deep fungal infection. Therapy can be challenging because the lesions can reach a great size. The present case illustrates this diagnostic and therapeutic conundrum in a patient with multiple KACM.
Case Report
A 78-year-old man being treated for more than 9 years for multiple KAs on his upper and lower extremities presented with an annular plaque with an elevated crusted keratotic border on the right ankle. Over the course of a year, the plaque enlarged to measure 20 cm (Figure 1). Additional annular and arciform plaques ranging from 13 to 16 cm developed on both legs over this period. The patient's medical history included type 2 diabetes mellitus, peripheral vascular disease, hyperlipidemia, coronary artery disease, and benign prostatic hypertrophy. There was no history of internal malignancy or family history of KAs. Chromoblastomycosis, verrucous tuberculosis, and KACM were considered in the differential diagnosis. No fungi or mycobacteria were isolated in any of the several skin biopsies or cultures performed. There were frequent secondary bacterial infections of the lesions, which were treated with appropriate antibiotics.
A wedge biopsy of the large annular plaque was performed. The area of regression showed fibrosis with an overlying flattened epidermis. The peripheral expanding area showed aggregations of large epithelial cells with abundant pink cytoplasm emanating from the epidermis (Figure 2), while the trailing clearing areas showed fibrosis. Some of the aggregations had jagged outlines that were lined by atypical epithelial cells (Figure 3). Within the aggregations, there were varying degrees of keratinization with presence of parakeratotic cornified cells and neutrophils centrally (Figure 3). Although the histopathologic changes were compatible for KACM, the differential diagnosis included halogenoderma and infectious etiology such as deep fungal or mycobacterial infection. The clinical and histopathologic findings, the lack of halogen exposure, the history of multiple KAs, and the absence of organisms in tissue biopsy and culture results led to the diagnosis of multiple KACM.
Once the frequent secondary bacterial infections were under control, the patient was treated with several therapeutic agents including imiquimod cream, intralesional methotrexate (MTX), and 5-fluorouracil (5-FU) cream. Because the lesions were multiple and large, surgery was not performed. As chemoprophylaxis, isotretinoin was initiated at 40 mg/d and then increased to 60 mg/d after 4 months. The total duration of isotretinoin therapy was 13 months. Along with the usual mucocutaneous side effects, the patient experienced back pain and mild mood alteration after the dose was increased. His complete blood count, liver function tests, and serum triglyceride levels all remained within reference range throughout the duration of therapy.
At the time of initiation of isotretinoin, MTX was injected into 2 different areas of the peripheral border of the largest lesion 3 weeks apart. The doses totaled 68 mg and 60 mg at each site, respectively. In addition, imiquimod under occlusion was applied every night to several of the lesions for the next 7 months. None of the lesions treated with either intralesional MTX or imiquimod resolved. Subsequent to the failure of imiquimod and MTX, 5-FU cream was applied to all of the annular lesions while the patient was still receiving isotretinoin therapy. Clinical response to 5-FU was apparent after 2 months. A complete clinical resolution, however, occurred over a period of 11 months (Figure 4). Isotretinoin was discontinued 5 months prior to the completion of the course of 5-FU cream.
While receiving isotretinoin therapy, the patient developed several more solitary KAs, and the annular lesions enlarged to varying sizes. The solitary KAs were managed either surgically or with liquid nitrogen, depending on the size. The new annular lesions were promptly eradicated with 5-FU cream.
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