Extra-mammary Paget’s disease (EMPD) is a rare neoplasm of epithelial origin, whose precise incidence is not clear. Starting from what is already known, we performed a systematic review and meta-analysis to investigate in male and female patients the immunohistochemical expression of biological markers that could serve as potential prognostic/therapeutic factors, including only human epidermal growth factor receptor 2 (HER2/neu), Estrogen Receptor (ER), Progesterone Receptor (PR), and Androgen Receptor (AR). Methods. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2000 to June 2020. Results. A total of 27 studies with 713 patients assessed the role of HER2/neu, AR, ER, and PR expression in male and female with EMPD. The overall rate of HER2/neu expression was 30%, the expression’s rate for ER and AR was 13% and 40%, respectively, and the overall rate for PR was 8%. The subgroup analysis revealed that there is a different expression of molecular markers between male and female patients. Conclusions. This study revealed that AR status and HER2/neu overexpression/amplification have been shown as two fundamental pathogenetic pathways in both female and male patients affected by EMPD.

Extramammary Paget disease (EMPD) was first described by Crocker in 1889 in a man affected from bladder carcinoma and presented with an eczematous lesion involving the penoscrotal region, that was diagnosed as Paget disease in an extramammary site [1]. Subsequently EMPD has been reported involving more frequently the external female genitalia and less commonly, the perianal/perineal region, groin, axilla, umbilicus, eyelids, and also external ear canal [2–4].

EMPD has been defined by World Health Organization (WHO) as an intraepithelial neoplasm of epithelial origin expressing apocrine or eccrine glandular-like features and characterized by distinctive large cells with prominent cytoplasm, referred to as Paget cells’ [5].

The pathogenesis of EMPD is not fully understood; the stem cell compartment of the epidermis and hair follicle as well as Toker cells and mammary-like glands have been reported as possible sites of origin of Paget cells [6–8].

Over time, different attempts to classify EMPD have been made and, in particular, at the vulvar site, a histopathological classification of VPD has been conceived, distinguishing primary/cutaneous VPD (type 1) from secondary/non-cutaneous VPD [9]. In detail, cutaneous VPD (type 1) is further subdivided according to the presence or absence of dermal invasion: type 1a (intraepithelial disease arising within the epidermis and extending into the epithelium of skin appendages and less commonly arising from the skin appendages and migrate to the overlying epidermis by epidermotropism); type 1b when focal invasion can be observed; type 1c when there is a cutaneous “pagetoid spread” from an underlying vulvar adenocarcinoma of the skin appendage or subcutaneous vulvar glands.

The 5-year survival is highly variable, depending on the entity of infiltration, being, respectively, 100% and 88% for intraepithelial and micro-invasive disease (<1 mm), and only 15% when neoplastic invasion exceeds 1 mm [10].

On the other hand, secondary VPD can originate by epidermotropic metastases or by direct extension from a malignancy of the gastrointestinal tract (type 2) or the uro-genital tract (type 3) [11,12]. More recently, the WHO Classification of Tumours of Female Reproductive Organs (4th edition)

considers to use the subdivision of cutaneous and non-cutaneous EMPD in routinary diagnosis [5]. Given the rarity of EMPD, data on genetic alterations are largely unexplored. Findings regarding the hormonal status including Her2/Neu amplification are probably the most studied genetic alteration, likely because of their therapeutic potential but the clinical significance of these abnormalities still remains to be fully understood [13]. Being aware that at present the need of a tailored treatment for EMPD is a critical clinical goal, but its concrete availability is still too far to achieve, we reviewed the current literature in order to study the impact of IHC expression in VPD and EMPD in both genders of biological markers that could serve as potential prognostic/therapeutic factors, including human

epidermal growth factor receptor 2 (HER2/neu), Estrogen Receptor (ER), Progesterone Receptor (PR), and Androgen Receptor (AR).