Systemic therapy for stage IV primary extramammary Paget disease: A systematic review of reported clinical outcomes.

Abstract

e21564 Background: Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma with limited evidence guiding systemic therapy in advanced or metastatic disease. We conducted a systematic review to characterize patient demographics, metastatic patterns, systemic treatments, and reported outcomes in stage IV primary EMPD. Methods: We performed a systematic review of PubMed/MEDLINE and the Cochrane Database, along with major conference proceedings, from inception through November 2025. Eligible cases included stage IV (M1) disease. Secondary EMPD arising from an underlying malignancy was excluded. Data were extracted at the case level, including metastatic patterns, systemic treatment regimens, and outcomes. The primary outcome was treatment response, categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The objective response rate (ORR; CR + PR) was calculated among cases with reported response data. Analyses were primarily descriptive, with exploratory comparisons performed where feasible, in accordance with PRISMA guidelines. Results: Seventy-five patients with distant metastatic primary EMPD were identified. Median age was 66 years (range, 47–88); 60% were male. Primary tumor sites were most commonly scrotal/penoscrotal (52.0%), followed by vulvar (14.7%) and perianal/perineal (12.0%). Metastatic involvement included bone metastases in 41.3%, visceral metastases in 36.0%, lymph node (LN)-only disease in 25.3%, and skin/scalp metastases in 4.0%. Among cases with reported response data (n = 42), ORR was 64.3%, including CR in 26.2% and PR in 38.1%. Progressive disease occurred in 31.0% of reported cases. Progressive disease rates were higher in patients with visceral metastases compared with those without visceral involvement. Platinum- and taxane-based chemotherapy were the most frequently used regimens, commonly in combination. HER2-targeted therapy was reported in 9.3% of cases and was almost always combined with chemotherapy. No statistically significant association between HER2-targeted therapy and ORR was observed (OR 0.81; p = 1.00), though this analysis was markedly underpowered. Biomarker and safety reporting were inconsistent, with occasional grade ≥3 toxicities and rare treatment-related deaths described. Conclusions: Systemic therapy for stage IV primary EMPD is associated with objective responses in a substantial proportion of reported cases, particularly with platinum- and taxane-based chemotherapy. However, outcomes appear poorer in patients with visceral metastatic disease. Evidence supporting HER2-targeted therapy remains limited by small sample size and reporting bias. Prospective, multi-institutional studies and standardized reporting of biomarkers and outcomes are imperative to define optimal systemic treatment strategies for this rare malignancy.