Malassezia yeast plays a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget’s disease (EMPD) is an adenocarcinoma of apocrine origin and, except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate 1) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/chemokines (IL-23, IL-36, CCL20), 2) the expression of these factors in lesion-affected skin in EMPD, and 3) the activation of tumor-associated macrophages (TAMs) by the productions of IL-17 induced factors. In the lesion-affected skin of EMPD patients, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17–producing cells were distributed adjacent to Paget cells. In addition, Th17 related stromal factors, which could stimulate TAMs, were significantly increased in invasive EMPD compared to non-invasive EMPD. Indeed, compared to healthy donors, EMPD patients exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10, and CCL20, suggesting that the activation of CD163+ TAMs in EMPD. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signaling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs.

Possible immunological mechanisms of developing extramammary Paget’s disease through Malassezia-derived aryl hydrocarbon receptor ligands pathways.