Abstract
Extramammary Paget’s disease (EMPD) is a rare skin cancer arising in the anogenital area. Most EMPD tumors remain dormant as in situ lesions, but the outcomes of patients with metastatic EMPD are poor because of the lack of effective systemic therapies. Nectin cell adhesion molecule 4 (NECTIN4) has attracted attention as a potential therapeutic target for some cancers. Urothelial cancer is one such cancer, and clinical trials of enfortumab vedotin, a drug-conjugated anti-NECTIN4 antibody, are ongoing. However, little is known regarding the role of NECTIN4 in EMPD. In this study, we conducted immunohistochemical analysis of NECTIN4 expression in 110 clinical EMPD samples and normal skin tissue. In normal skin, positive signals were observed in epidermal keratinocytes (particularly in the lower part of the epidermis), eccrine and apocrine sweat glands, inner and outer root sheaths, and matrix of the hair follicles. The most EMPD lesions exhibited strong NECTIN4 expression, and high NECTIN4 expression was significantly associated with increased tumor thickness, advanced TNM stage, and worse disease-specific survival. These results support the potential use of NECTIN4-targeted therapy for EMPD. Our report contributes to the better understanding of the pathobiology of NECTIN4 in the skin and the skin-related adverse effects of NECTIN4-targeted therapy.
Highlights
Extramammary Paget’s disease (EMPD), first reported by Crocker in 1889, is an uncommon skin cancer that mainly affects apocrine sweat gland-rich areas [1,2]
Nectin cell adhesion molecule 4 is expressed during fetal development, and its expression is attenuated in adulthood, contrary to the extensive expression of other nectins in adult tissue [29]
Low nectin cell adhesion molecule 4 (NECTIN4) expression has been reported in various adult normal tissues [20,22]
Summary
Extramammary Paget’s disease (EMPD), first reported by Crocker in 1889, is an uncommon skin cancer that mainly affects apocrine sweat gland-rich areas [1,2]. Extramammary Paget’s disease most frequently arises in the anogenital area in elderly people and less commonly in the axillary area [2,3,4]. This disease typically affects Caucasian woman and Asian men older than 60 years [3,4,5,6]. Most EMPD tumors remain restricted to the epidermis as in situ lesions, and they carry a good prognosis because of their slow-growing nature [1,7]. Approximately 15–40% of EMPD lesions display dermal invasion, increasing the risk of lymph node and distant metastases [2,4]. New treatment modalities are required [4,12,13,14]
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