A 53-year-old woman from Missouri (United States) with a 2-year history of kidney transplant presented to our dermatology department with multiple acneiform lesions on the face and numerous erythematous papules and nodules on both arms and legs. Biopsies revealed a very atypical florid pseudoepitheliomatous hyperplasia, at first interpreted, in light of the history of immunosuppression, as an invasive squamocellular carcinoma, associated with an unusual dense histiocytic infiltrate and nodular aggregates of foamy histiocytes. After the acute onset of fever, pancytopenia, and signs of ulcerative colitis, disseminated histoplasmosis was suspected. A biopsy taken from a rectal ulcer revealed numerous histiocytes with intracellular yeasts that were positive for periodic acid-Schiff and Grocott-Gomori methenamine silver fungal stains. Antifungal therapy with amphotericin B and itraconazole led to the healing of the skin lesions with scarring and postinflammatory hyperpigmentation. This case is an exceptional example that warns pathologists that (1) florid pseudoepitheliomatous hyperplasia can be undistinguishable from invasive squamocellular carcinoma, and complete excision of fast-growing lesions is always advised in case of doubt
(2) a dense infiltrate of foamy histiocytes may be the spy to a systemic infection, and a careful clinical and pathologic screening should be promptly initiated.