Seronegative secondary syphilis in a patient with hematologic malignancy on anti-CD20 therapy: case report and review of serologic responses to spirochetal infection in patients receiving B-cell-depleting therapies

ABSTRACT Background The expanding use of B-cell-depleting anti-CD20 monoclonal antibodies has introduced diagnostic challenges for infections that are traditionally confirmed through serologic testing. Seronegative secondary syphilis is exceptionally rare and has historically been described only in profoundly immunocompromised patients with advanced HIV/AIDS. This case represents a novel clinical scenario in the era of targeted immunologic therapy. Case Summary We report the case of a 44-year-old man with marginal zone lymphoma receiving maintenance obinutuzumab, who presented with a symmetric, pruritic, palmoplantar predominant papulosquamous eruption accompanied by fatigue and elevated inflammatory markers. Extensive serologic testing for syphilis, including repeated treponemal (TP-PA, treponemal IgG) and nontreponemal (RPR) assays, remained completely nonreactive on multiple occasions. However, a skin punch biopsy demonstrated epidermal hyperplasia with a dense plasma cell-rich lymphohistiocytic infiltrate. Immunohistochemical staining for Treponema pallidum revealed numerous spirochetes in the epidermis and superficial dermis, confirming the diagnosis of secondary syphilis. The patient received three weekly intramuscular doses of benzathine penicillin G (2.4 million units per dose) with complete clinical resolution and no adverse effects. Serologic tests remained nonreactive on follow-up evaluation. Conclusion This case is the first documented report of persistent seronegative secondary syphilis in a patient receiving obinutuzumab therapy. It underscores the critical importance of maintaining a high index of clinical suspicion and pursuing tissue-based diagnostics when serologic tests fail to explain compelling clinical findings in patients with profound B-cell depletion. Clinicians managing patients on anti-CD20 therapies must recognize the limitations of serologic diagnosis for infections that typically depend on antibody detection.