Pathogenesis of necrotizing sialometaplasia: Insights from histopathological examination and disease model analysis

Necrotizing sialometaplasia (NSM) is a benign, self-limiting salivary gland lesion that closely mimics malignancy. Beyond its diagnostic relevance, NSM provides a valuable model for investigating how salivary epithelial cells and stromal fibroblasts respond to acute microenvironmental stress.

Advances in histopathology, together with the development of salivary gland-derived organoids and formalin-fixed paraffin-embedded (FFPE) organoid protocols, provide a robust platform for studying epithelial-stromal interactions in the oral cavity. Salivary gland organoids recapitulate the key architectural and functional features of native tissue, enabling controlled exposure to inflammatory cytokines and hypoxia. The subsequent development of an FFPE-compatible organoid protocols permits routine hematoxylin and eosin and immunohistochemical staining of three-dimensional cultures, facilitating direct comparison with human specimens. Using these approaches, recent studies have demonstrated that fibroblast-derived transforming growth factor-β3 (TGF-β3) suppresses salivary epithelial proliferation and induces squamous metaplasia. Meanwhile, hypoxic stress preferentially injures acinar cells while sparing myoepithelial and basal cells, which subsequently become sources of TGF-β3 in early NSM-like lesions. Collectively, these findings connect established etiological concepts, such as ischemia and trauma, to defined molecular and cellular mechanisms.

This review summarizes salivary gland organoid technology and FFPE-based analytical methods and integrates organoid-derived evidence with histopathological observations to propose a stepwise model of NSM pathogenesis driven by hypoxia-induced acinar injury and TGF-β3-mediated epithelial metaplasia.