Dupilumab-associated lymphoproliferative disorders: a comprehensive review on clinicohistopathologic features and...

Dupilumab, a monoclonal antibody targeting interleukin 4 receptor, has shown significant efficacy in treating atopic dermatitis (AD). However, emerging case reports indicate that it may unmask or cause cutaneous T cell lymphoma (CTCL). This review analyzes 29 studies involving 124 patients who developed lymphoproliferative disorders after dupilumab, including 13 cases of lymphoproliferative reactions not meeting lymphoma criteria. The median time from dupilumab initiation to biopsy-confirmed lymphoproliferative disorders was 5 months, with 39.05% of cases in advanced stages. Histopathological examination of dupilumab-induced CTCL reveals epidermotropism with spongiosis and increased superficial lymphoid infiltration. Notably, early lymphoproliferative reaction shows subtle lymphoma features, characterized by perivascular infiltration with sprinkled intraepidermal lymphocytes, CD30 expression, and absence of clonal TCR rearrangement and T-cell markers loss. Adult-onset AD patients, particularly those with atypical skin lesions, short-term exacerbation, or no atopy history, should be closely monitored during dupilumab treatment, and skin biopsy is essential if no clinical improvement occurs. Discontinuation is recommended when lymphoid infiltration increases, even without typical lymphoma features. The mechanisms underlying dupilumab-associated lymphoma remain speculative. Current hypotheses include upregulation of IL13RA2 signaling pathway, prolonged persistence of immune cell populations, and varying responses of different tumor cell subclusters. Additionally, the effects of dupilumab on various cell types are complex and multifaceted. Consequently, the distribution of type 2 inflammatory cytokine receptors and the patterns of cellular infiltration within the microenvironment may impact disease progression following dupilumab treatment. Further research is needed to clarify the mechanisms linking dupilumab to CTCL for better defining dupilumab's safety profile.