Nodular Secondary Syphilis: Systematic Review of an Underrecognized Clinical Phenotype

Secondary syphilis presents with a highly polymorphic spectrum of cutaneous lesions that frequently mimic inflammatory, infectious, or neoplastic diseases. Nodular presentations pose a substantial diagnostic challenge, as they clinically resemble unrelated conditions ranging from cutaneous lymphomas to deep fungal infections and granulomatous dermatoses. Nodulo-ulcerative necrotic lesions associated with systemic symptoms and human immunodeficiency virus (HIV) infection, or other causes of immunosuppression, have usually been classified in a severe subset known as malignant syphilis. It is currently debated whether all clinically nodular presentations of secondary syphilis belong to this malignant variant, considering that nodular lesions alone do not automatically categorize the disease as malignant and that cases with nodules have been reported in immunocompetent patients. A systematic review was performed to identify reports of secondary syphilis with nodular cutaneous manifestations with the goal to provide a clear nosological framework and clinical description of nodular secondary syphilis. We searched PubMed and Embase via Elsevier using a combination of controlled vocabulary and free-text terms and collected 144 published cases of nodular syphilis. Our results highlighted that nodular variants of secondary syphilis can occur even in the absence of advanced immunosuppression and should not be regarded as manifestations exclusive to immunocompromised individuals or those living with HIV. Additionally, our data do not support a clear benefit of extended regimens in the absence of documented late-stage disease or neurosyphilis, although the striking presentation of nodular and ulcerative forms may prompt more aggressive or prolonged treatments empirically. Effective management relies on timely recognition and appropriate antibiotic therapy, which appears highly effective regardless of HIV status or clinical severity.