Metastatic EMPD is an aggressive skin adenocarcinoma with poor prognosis. Since current chemotherapeutic regimens are only moderately effective, improving clinical outcomes is imperative. The basic and translational research to date has provided an insight into the mechanisms promoting metastasis of EMPD that provide potential therapeutic targets for new drug development. Seemingly, Paget cells augment the ability of proliferation and survival by activating the RAS–RAF–MEK–ERK signaling, PI3K–AKT–mTOR signaling, or androgen–AR signaling. In addition, the interaction of Paget cells with other cells, such as LECs and CD163+Arg1+ macrophages in a tumor through the CXCR4–SDF-1 signaling and RANKL–RANK signaling, respectively, could establish a favorable tumor microenvironment to promote metastasis of Paget cells. Furthermore, recent genomic analysis of MMR has revealed that a decent percentage of EMPD comprises MMR-deficient EMPD cases that might achieve durable clinical response by an anti-PD-1 antibody. Hence, we are now beginning to understand multiple aspects involved in the pathogenesis of metastatic EMPD, and these findings will be sure to lead to better treatments for patients with metastatic EMPD in the future.

Chemokines are involved in many aspects of oncogenesis, including regulation of cancer cell growth, dissemination and host-tumor response. However, the potential of the chemokine receptors, CXCR4 and CXCR7, in serving as biomarkers in extramammary Paget's disease (EMPD) has been rarely examined. Expressions of CXCR4 and CXCR7 were evaluated in 92 EMPD specimens by immunohistochemistry. High expression of CXCR4 and CXCR7 were both correlated with regional lymph node metastasis and presence of lymphovascular invasion. High expression of CXCR7 also correlated with the depth of invasion. The prognostic value of these two chemokines were also investigated in progression-free survival (PFS) and cancer-specific survival (CSS). Both high expression of CXCR4 and CXCR7 were indicative of shorter PFS and CSS. In the combined prognostic model, concomitant high expression of CXCR4 and CXCR7 were suggestive of poor prognosis compared with the other two groups. In the multivariate analysis, depth of invasion, combined prognostic model and regional lymph node metastasis at diagnosis were the independent prognostic factors for EMPD patients for PFS, and the former two factors independently impacted CSS. Our results demonstrated that CXCR4 and CXCR7 can be used as prognostic biomarkers and prediction of aggressiveness of EMPD. Therapy targeting CXCR4 and CXCR7 may helpful to prevent EMPD progression and improve the prognosis of EMPD.

mmune evasion by cancer is a well-recognized mechanism that promotes tumour growth and metastases which in recent years has been shown to be amenable to therapeutic exploitation. Extramammary Paget disease (EMPD) is a rare form of skin cancer affecting apocrine glands in anogenital regions. The prognosis of the disease is good if treated early by surgical removal of the tissue, with a 5-year survival rate close to 95%.[1] The prognosis is worse for invasive disease, partly due to the lack of definitive treatment options in this setting.[2] Understanding the mechanisms of EMPD evolution has the potential to identify new treatment targets for this entity. In this edition of the BJD, Fujimura et al.[3] have looked into a suspected link between Langerhans cells (LCs) and regulatory T-cell (Treg) activity in EMPD that could contribute to the immunosuppressive environment that supports tumour growth and invasion by immune evasion.