Extramammary Paget disease (EMPD) is a locally aggressive cutaneous
malignancy that usually arises in anogenital or axillary skin.
Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its
ligand (PD-L1) are approved for the treatment of several types of
cancer, and response to these generally correlates with increased PD-L1 expression by
tumor cells. The expression of PD-L1 and composition and density of the
tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to
immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the
tumor-associated immune infiltrate in EMPD and evaluated associations between
biomarker expression and clinicopathologic parameters. Twenty-one EMPD
tumors were evaluated for
tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the
tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of
mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by
tumor cells (3/21; 14%) and the
tumor-associated immune infiltrate (15/21; 71%), and PD-1 was expressed by the
tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD
tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the
tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the
tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2; range, 543-2115;) than in those who died (median, 611 cells/mm2; range, 481-908; p = 0.049). In all MPD cases, PD-L1 was absent in
tumor cells but present in the
tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.