The Sinus Is the Victim, Pepsin Is the Perpetrator: Posterior Sinonasal Syndrome as the Etiological Precursor to Chronic Rhinosinusitis, Field Carcinogen of the Upper Aerodigestive Tract, and the Biological Imperative for Mucosal-Preserving Surgery

Objective: To propose Posterior Sinonasal Syndrome (PSS) as the etiological precursor to a defined subset of chronic rhinosinusitis (CRS), establish pepsin as a field carcinogen across the upper aerodigestive mucosal surface, and define the biological imperative for mucosal-preserving surgery in PSS-CRS patients. Methods: Synthesis of peer-reviewed evidence across four domains: pepsin endocytosis mechanisms in upper airway epithelium; pepsin detection in sinonasal, nasopharyngeal, and middle ear tissue; epidemiological trends in pediatric upper airway disease; and clinical outcomes in refractory CRS. Evidence is stratified as established, strongly inferred, or proposed requiring confirmatory study. Results: Pepsin, delivered via laryngopharyngeal reflux along a defined anatomical concentration gradient, produces receptor-mediated intracellular injury in posterior nasal epithelium — a mechanism established in laryngeal cells and strongly inferred in nasal cells. This injury lowers the posterior nasal mucosal inflammatory threshold, creating PSS as a priming state preceding clinical CRS. Pepsin has been detected within malignant tissue at two anatomically distinct sites: laryngeal and hypopharyngeal carcinoma, and nasopharyngeal carcinoma in 85.7% of cases versus 17.2% of controls — the two-site molecular fingerprint of a field carcinogen across the full upper aerodigestive surface. Pepsin detection in 83% of pediatric middle ear effusions and its correlation with adenoid hypertrophy grade establish that this process begins in childhood. PSS represents a third inflammatory driver of CRS, independent of allergy and anatomy, unrecognized by the 2025 AAO-HNS guideline. Five confirmatory studies and a nasal lavage pepsin assay validation pathway are defined. Conclusion: PSS is the etiological precursor to a misidentified subset of treatment-resistant CRS. Pepsin is both the primary driver of posterior nasal mucosal priming and a field carcinogen across the upper aerodigestive surface. Aggressive tissue-resecting FESS in this population is biologically counterproductive. The confirmatory studies are named, the clinical tools are within reach, and the patients are in rhinology practices now.