Laryngeal Histoplasmosis in a Non-Endemic Region: A Diagnostic Challenge

<i>Histoplasma capsulatum</i> is a dimorphic fungus endemic to the Ohio and Mississippi River valleys. Although pulmonary involvement is most common, rare extrapulmonary manifestations such as laryngeal histoplasmosis can mimic malignancy and pose diagnostic challenges, particularly in immunosuppressed individuals residing outside endemic areas. We describe a 40-year-old immunosuppressed male on tumor necrosis factor-alpha (TNF-α) inhibitor therapy who presented with progressive dysphagia, hoarseness, and weight loss. Laryngoscopy revealed verrucous supraglottic lesions concerning for malignancy. Imaging further raised suspicion for neoplastic or granulomatous disease. However, biopsy revealed <i>H. capsulatum</i> and confirmed with fungal staining. The patient failed initial treatment with oral itraconazole and required escalation to intravenous amphotericin B, followed by long-term oral antifungal therapy. Discontinuation of infliximab and close multidisciplinary follow-up led to full clinical resolution. This case highlights the importance of considering histoplasmosis in the differential diagnosis of laryngeal lesions, even in non-endemic regions and HIV-negative patients. Immunomodulatory therapies such as TNF-α inhibitors increase susceptibility to disseminated fungal infections. Early biopsy, appropriate fungal staining, and prompt antifungal therapy are critical for accurate diagnosis and successful treatment of this rare but serious presentation.