Abstract
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.
Highlights
Extramammary Paget disease (EMPD) is an uncommon cutaneous adenocarcinoma most often arising in older patients and in the anogenital area or axilla [1,2,3,4]
Demographic and clinical-pathologic characteristics for the 21 patients with EMPD are summarized in Tables 1 and 2
Twenty specimens were from available primary tumors, and one was from a metastatic lymph node since the primary tumor tissue was not available for further study
Summary
Extramammary Paget disease (EMPD) is an uncommon cutaneous adenocarcinoma most often arising in older patients (approximately 95% of patients were >50 years old) and in the anogenital area (approximately 90% of cases) or axilla (approximately 7% of cases) [1,2,3,4]. The tumor cells are most often confined to the epithelium (Figure 1A) but occasionally invade the underlying dermis or submucosa. Treatment of EMPD generally includes aggressive surgical extirpation, but this can be associated with high patient morbidity [5,6]. Even with aggressive surgical excision, EMPD exhibits a high rate of local recurrence (44 of 174 cases (25%) in a Mayo Clinic study [7]) owing to multifocality and subclinical extension; rarely, nodal and systemic metastases develop (10 of 261 cases (3.8%) in the Mayo Clinic study [7]). Effective systemic therapies for metastatic or locally advanced disease are lacking. Lymphocytes (100×) in the tumor-associated immune infiltrate. Lymphocytes (100×) in the tumor-associated immune infiltrate. (F) Weak and predominantly partial membranous expression of PD-L1 in EMPD tumor cells (200×), shown for comparison (1–2+ intensity).
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