Nodular syphilis with a granulomatous inflammatory histopathologic pattern is an uncommon cutaneous presentation of secondary syphilis which could pose a diagnostic challenge for clinicians and pathologists alike.

A 33-year-old male diagnosed with HIV presented with a 5-week history of asymptomatic generalized erythematous papules and nodules with overlying scales, with involvement of the palms and soles. Histopathologic examination of a nodule from the forearm revealed non-caseating granulomas in a background of a mixed cell inflammatory infiltrate composed of lymphocytes, epithelioid and foamy histiocytes, plasma cells, neutrophils, and multinucleated giant cells. Warthin-Starry Stain revealed spirochetal organisms, while Fite-Faraco and Periodic Acid-Schiff stains were negative for acid-fast bacilli and fungal elements, respectively. Rapid plasma reagin (RPR) was reactive (1:256). Patient was given a single dose of benzathine penicillin G 2.4 million units intramuscularly, with noted complete resolution of skin lesions as well as an 8-fold decrease in RPR titers.

Nodular lesions are an uncommon cutaneous manifestation of secondary syphilis, and the associated histopathologic finding of granulomatous inflammatory pattern is also unusual, posing a diagnostic challenge. With the increasing prevalence of syphilis, especially among HIV patients, dermatologists, dermatopathologists, internists, and infectious disease specialists should be aware of such presentations of syphilis.