Abstract
Head and neck squamous cell carcinomas (HNSCCs) develop through a series of precancerous stages from a pool of potentially malignant disorders (PMDs). Although we understand the genetic changes that lead to HNSCC, our understanding of the role of the stroma in the progression from precancer to cancer is limited. The stroma is the primary battleground between the forces that prevent and promote cancer growth. Targeting the stroma has yielded promising cancer therapies. However, the stroma at the precancerous stage of HNSCCs is poorly defined, and we may miss opportunities for chemopreventive interventions. PMDs already exhibit many features of the HNSCC stroma, such as inflammation, neovascularization, and immune suppression. Still, they do not induce cancer-associated fibroblasts or destroy the basal lamina, the stroma's initial structure. Our review aims to summarize the current understanding of the transition from precancer to cancer stroma and how this knowledge can reveal opportunities and limitations for diagnostic, prognostic, and therapeutic decisions to benefit patients. We will discuss what may be needed to fulfill the promise of the precancerous stroma as a target to prevent progression to cancer.