Paradoxical development of reactive squamous atypia and aggressive, invasive squamous cell carcinoma following 5-fluorouracil for field cancerization with concurrent immunomodulation

5-fluorouracil (5-FU) is a widely prescribed therapy for field cancerization. However, the emergence of cutaneous squamous cell carcinoma (cSCC) after 5-FU treatment is poorly described. We report five patients treated for field cancerization at four university hospitals between March 2019 and May 2021 who had eruptive cSCCs of varying severity following 5-FU. We examined the indications for treatment, immunosuppression status, onset of cSCCs, staging and outcomes. The patients (three female, two male; median age 74 years) were treated with 5-FU for field cancerization. Four, including two solid-organ-transplant recipients, were on immunomodulating therapy. Eruptive cSCCs developed within 3 weeks to 3 months of 5-FU treatment, mostly within the treated area. Staging revealed a spectrum of BWH T2b in two patients and BWH T1 in three. Eruptive cSCCs are a poorly characterized adverse event of topical 5-FU treatment. High-risk T-stage cSCCs, not yet reported and distinct from eruptive squamous atypia, may also develop despite low-grade background disease. Inflammation and immunomodulation could contribute to pathogenesis.