Existence of Staphylococcus aureus correlates with the progression of extramammary Paget's disease: potential involvement of interleukin-17 and M2-like macrophage polarization.

BACKGROUND: The microbiome plays an important role in the tumour microenvironment (TME). OBJECTIVES: In this study, we investigated the clinical significance of the microbiota in extramammary Paget's disease (EMPD). MATERIALS & METHODS: Patients with EMPD, treated between March 2007 and September 2019 at Kumamoto University Hospital, were investigated retrospectively. Inclusion criteria included: histological diagnosis of EMPD, inspection of the bacterial culture of the cancer lesion using swab sampling, and availability of sufficient tissue in paraffin blocks for immunohistochemistry. For the latter, primary antibodies against IL-17, CD163 and ionized calcium-binding adapter molecule 1 (Iba1) were used. RESULTS: Bacterial cultures of the cancer lesion revealed that Staphylococcus aureus (S. aureus) was highly prevalent in EMPD patients, with dermal invasion or lymph node metastasis, compared to patients without these findings. Furthermore, the number of IL-17-positive cells and CD163-positive M2-like macrophages (pro-tumour macrophages) were increased in EMPD tissues with S. aureus. Moreover, the number of IL-17-producing cells in EMPD tissues positively correlated with the accumulation of CD163-positive M2-like macrophages. In addition, the percentage of CD163-positive cells within Iba-1-positive macrophages (total macrophages) was also significantly elevated in EMPD tissues with S. aureus. CONCLUSION: Based on these findings, S. aureus may exacerbate the pathological condition of EMPD via the accumulation of IL-17 and M2-like macrophages.

Malassezia-derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra-mammary Paget's disease.

Malassezia yeast play 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 (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, 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. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs.

[Extra-mammary Paget's disease. An HPV-correlated neoplasia?]. / La malattia di Paget extramammaria. Neoplasia HPV correlata?

Eight cases of Paget's disease of the vulva and anogenital region are presented. Seven cases presented intraepithelial lesions and only one showed superficial intraepidermal diffusion. The average age of the patients in our series was 58.8 years. In all cases histochemical and immunohistochemical reactions were positive, except for the CEA reaction (only one case was positive). Specimens from our series were tested for presence of HPV 6, 11, 16, 18, 31, 33, 35 by in situ DNA hybridization. All cases were negative. Paget's disease, at the moment, is the only tumor of the low female genital tract non HPV-associated. Recurrences are very frequent even many years after radical surgery treatment.

Failure to detect human papillomavirus DNA in extramammary Paget's disease.

Ten genital skin specimens, biopsy proven to be Paget's disease, were examined by human papillomavirus (HPV) in situ hydridization in an effort to detect DNA of HPV types 6, 11, 16, 18, 31, 33, and 35. All ten specimens showed no evidence of DNA of these HPV types. Extra-mammary Paget's disease is probably not a result of infection with HPV types 6, 11, 16, 18, 31, 33, or 35.

[Human papillomavirus DNA in vulvar lesions].

In order to study the role of human papillomavirus (HPV) in genital cancer, we attempt to determine the presence of HPV in tumors of the genital tract. In the current study, we have examined 35 histologically diagnosed cases of vulvar lesions in attempts to compare the sensitivities of various methods of detecting HPV. All but 7 vulvar lesions contained HPV DNA by Southern blot DNA hybridization. Detectability of HPV by immunocytochemistry and koilocytosis significantly declined as compared to DNA hybridization. The detection of HPV DNA by in situ hybridization is discussed.

Paget's disease of the vulva: search for herpes simplex virus antigens and human papillomavirus antigen and DNA.

Specimens from three women with Paget's disease of the vulva were tested for presence of herpes simplex virus type 2 (HSV2) antigens and human papillomavirus (HPV) antigen and DNA. In one of the lesions, the HSV2-associated antigen ICSP 34/35 was demonstrated. Neither HPV antigens nor HPV DNA were detected in the lesions.