Keratocystoma: Molecular insights and diagnostic challenges in a rare salivary gland tumor

Keratosytoma is a rare, benign salivary gland tumor designated as a new entity by Nagao et al. in 2002. Recently, the discovery of RUNX2 gene rearrangement as a characteristic genetic alteration has established its classification as a distinct neoplasm, solidifying the inclusion of keratocystoma in the 5th edition of the WHO classification of Head and Neck Tumors. Clinically, keratocystoma occurs across a broad age range but is most prevalent among younger individuals, with no significant sex predilection. It typically presents as a slow-growing parotid mass. Histologically, the tumor is characterized by a multilocular cystic lesion lined by stratified squamous epithelium without atypia and lacks a granular cell layer. In addition to cyst formation, nests of squamous epithelium enclosed within fibrous stroma are also observed, sometimes along with salivary ducts with squamous metaplasia-like processes. Immunohistochemically, similar to normal squamous epithelium, tumor cells are positive for p63 and negative for myoepithelial markers, including SMA, calponin, and S-100. The Ki-67 labeling index is low, and p53 expression exhibits a wild-type pattern. The differential diagnosis encompasses a wide spectrum of conditions, ranging from non-neoplastic lesions to benign and malignant tumors composed of squamous epithelium. These include squamous cell carcinoma, mucoepidermoid carcinoma, metaplastic Warthin tumor, pleomorphic adenoma with squamous differentiation, dermoid cyst, epidermal cyst/cholesteatoma, and necrotizing sialometaplasia. Although a detailed histomorphological examination is essential for the diagnosis, testing for RUNX2 gene rearrangement is expected to play a pivotal role in the differential diagnosis of keratocystoma. More cases are necessary to better understand this rare salivary gland tumor.