Distinct Histopathological and Transcriptomic Signatures of Central Compartment Atopic Disease

Central compartment atopic disease (CCAD) is a distinct phenotype of chronic rhinosinusitis (CRS) characterized by central polypoid changes and a strong association with allergy. While its clinical presentation is established, its specific histopathological features and transcriptomic profile remain poorly characterized. This study aimed to comprehensively evaluate the pathological and molecular profiles of CCAD in comparison to other CRS subtypes.

In this multicenter retrospective study, 221 eligible CRS patients were stratified into four phenotypes: CCAD (n = 48), sinonasal polyps with concomitant central compartment disease (CC, n = 40), and CRSwNP not otherwise specified (NOS). The NOS cohort was further subdivided based on the dominance of maxillary (M) versus ethmoid (E) sinus opacification (Lund-Mackay scores) into NOS M≤E (n = 90) and NOS M>E (n = 43) subgroups. We comprehensively analyzed demographics, symptom scores, computed tomography metrics, and structured histopathological features. Furthermore, RNA sequencing was performed on representative nasal tissues (n = 5 per group) to elucidate distinct transcriptomic signatures and underlying biological pathways.

Clinically, CCAD patients exhibited a significantly higher prevalence of allergic rhinitis (79.2%) compared to other groups, despite having lower overall radiological opacification scores. Histopathologically, CCAD was defined by an eosinophil-rich, stromal-dominant remodeling pattern, featuring prominent basement membrane thickening, fibrosis, and seromucinous gland hyperplasia. This contrasted sharply with the epithelial-centric remodeling (e.g., squamous metaplasia) observed in non-eosinophilic subtypes. Transcriptomic analysis revealed that CCAD shares a type 2 inflammatory signature with the CC subtype, showing high molecular similarity (only 19 differentially expressed genes). However, gene set enrichment analysis (GSEA) highlighted unique features in CCAD, including mast cell activation and macrophage cytokine production pathways.

CCAD represents a specialized type 2 CRS endotype characterized by central anatomical obstruction, allergic burden, and specific stromal remodeling. While its molecular proximity to diffuse CC suggests a shared pathogenic origin, unique mechanisms involving mast cell activation and macrophage cytokine production distinguish its local pathophysiology. Longitudinal studies are needed to define its relationship with diffuse disease.