Keratocystoma is a rare benign tumor of the salivary glands, histologically characterized by a multicystic structure lined with keratinizing stratified squamous epithelium.1 The lesion was first reported by Seifert et al. in 1999 as an unusual choristoma of an 8-year-old girl, resembling a cutaneous trichoadenoma.2 In 2002, Nagao et al. described two additional cases with identical histological features where the tumor cells were apparently transformed from the salivary gland duct epithelium through a squamous metaplasia–like process and introduced the term keratocystoma.3 The squamous tumor nests showed no lobular arrangements, and the epithelial lining of the cysts showed budding to form solid squamous cell islands. Keratinized squamous epithelium without a granular layer is a characteristic feature of keratocystomas. Based on these findings, keratocystoma was considered a true neoplasm rather than a choristoma. Furthermore, the absence of cellular atypia, necrosis, or vascular invasion, coupled with the lack of clinical malignant features, such as recurrence or metastasis, supported its classification as a benign tumor.

Subsequent reports of keratocystoma have been sporadic,4, 5, 6, 7, 8, 9, 10, 11, 12 and owing to its rarity, clinical, pathological, and molecular insights have remained limited. In 2024, Bishop et al. conducted the largest series of molecular studies on this tumor to date, identifying a characteristic genetic alteration: RUNX2 gene rearrangement, which has reinforced keratocystomas as a distinct neoplasm.13 The tumor has also been newly included in the 5th edition of the WHO Classification as a benign salivary gland neoplasm,1 garnering significant attention.

This article reviews the clinical, histopathological, and molecular characteristics of keratocystoma, a rare but diagnostically challenging salivary gland tumor. The differential diagnoses are also discussed.