Metastatic Extramammary Paget's Disease: Pathogenesis and Novel Therapeutic Approach

Abstract

Extramammary Paget's disease (EMPD) is a rare, slow-growing, cutaneous adenocarcinoma that usually originates in the anogenital area and axillae outside the mammary glands. EMPD mostly progresses slowly and is often diagnosed as carcinoma in situ; however, upon becoming invasive, it promptly and frequently metastasizes to regional lymph nodes, leading to subsequent distant metastasis. To date, several chemotherapy regimens have been used to treat metastatic EMPD; however, they present limited effect and patients with distant metastasis exhibit a poor prognosis. Recently, basic and translational investigative research has elucidated factors and molecular mechanisms underlying the promotion of metastasis, which can lead to targeted therapy-based emerging treatment strategies. Here, we aim to discuss current therapies and their limitations; advancements in illustrating mechanisms promoting invasion, migration, and proliferation of EMPD tumor cells; and future therapeutic approaches for metastatic EMPD that may enhance clinical outcomes.

Keywords: CD163+M2 macrophage; CXCR4–stromal cell-derived factor-1 axis; HER2–PI3K/ERK signaling; anti-PD-1 antibody; lymphangiogenesis; metastatic extramammary Paget’s disease; mismatch-repair deficient; receptor activator of nuclear factor kappa-B ligand–RANK signaling.

Figure 1

Signaling pathways involved in the progression of extramammary Paget’s disease. (A) The aberrant activation of HER2, molecules involved in the RAS–RAF–MEK–ERK signaling or PI3K–AKT–mTOR signaling promote the proliferation and survival of Paget cells. Likewise, the androgen–androgen receptor (AR) signaling can induce the proliferation and survival of Paget cells. Red, Food and Drug Administration-approved drugs for other cancers that target aspects of this pathway. (B) The interaction of Paget cells with lymphatic endothelial cells (LECs) through the CXCR4–stromal cell-derived factor-1 (SDF-1) signaling or with CD163⁺Arg1⁺ M2 macrophages through the receptor activator of nuclear factor kappa-B ligand (RANKL)–RANK signaling facilitates metastasis of Paget cells.