Mutations of nicastrin and proline–serine–threonine phosphatase-interacting protein 1 genes, upregulation of proinflammatory cytokines (including tumor necrosis factor (TNF), interleukin (IL)-17, and IL-23), altered microbiome, and physiological and environmental factors, such as obesity and smoking, are the four key factors that contribute to the pathogenesis of HS [12]. Here, TNF is linked to histiocytic sarcoma.