Calcifying cystic odontogenic tumors (CCOTs) are benign cystic tumors that form abnormally keratinized ghost cells. Mutations in CTNNB1, which encodes beta-catenin, have been implicated in the development of these tumors, but a causal relationship has not been definitively established. Thus, mutational hot spots in 50 cancer genes were examined by targeted next-generation sequencing in 11 samples of CCOT. Mutations in CTNNB1, but not in other genes, were observed in 10 of 11 cases. These mutations constitutively activate beta-catenin signaling by abolishing the phosphorylation sites Asp32, Ser33, or Ser37, and are similar to those reported in pilomatrixoma and adamantinomatous craniopharyngioma. In contrast, BRAF or NRAS mutations were observed in 12 and two control samples of ameloblastoma, respectively. In HEK293 cells, overexpression of mutated CTNNB1 also upregulated hair keratin, a marker of ghost cells. Furthermore, ghost cells were present in two cases of ameloblastoma with BRAF and CTNNB1 mutations, indicating that ghost cells form due to mutations in CTNNB1. The data suggest that mutations in CTNNB1 are the major driver mutations of CCOT, and that CCOT is the genetic analog of pilomatrixoma and adamantinomatous craniopharyngioma in odontogenic tissue.

Recent studies have shown that Notch signaling is involved in many types of cancers, including oral squamous cell carcinomas (OSCCs). However, the role of Notch signaling in the tumor microenvironment is not yet fully understood. In this study, we investigated the roles of NOTCH3 signaling in cancer associated fibroblasts (CAFs) in OSCCs. Immunohistochemical study of 93 human tongue OSCC cases indicated that about one third of OSCCs showed NOTCH3 expression in CAFs, and that this expression significantly correlated with tumor-size. In vitro study showed that OSCC cell lines, especially HO1-N-1 cells stimulated NOTCH3 expression in normal human dermal fibroblasts (NHDFs) through direct cell-to-cell contact. Immunohistochemical and morphometric analysis using human OSCC samples demonstrated that NOTCH3 expression in CAFs significantly correlated with micro-vessel density in cancer stroma. In vitro angiogenesis assays involving co-culture of NHDFs with HO1-N-1 and human umbilical endothelial cells (HUVECs), and NOTCH3 knockdown in NHDFs using siRNA, demonstrated that HO1-N-1 cells significantly promoted tube formation dependent on NOTCH3-expression in NHDFs. Moreover, NOTCH3 expression in CAFs was related to poor prognosis of the OSCC patients. This work provides a new insight into the role of Notch signaling in CAFs associated with tumor angiogenesis and the possibility of NOTCH3-targeted molecular therapy in OSCCs.

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Ghost cell odontogenic carcinoma (GCOC) is a rare malignant neoplasm characterized by the presence of ghost cells. It is considered to arise either de novo or from a preexisting benign precursor, calcifying odontogenic cyst (COC), or dentinogenic ghost cell tumor (DGCT). We report a case of a 44-year-old Japanese male with a left maxillary tumor. The patient received treatment to resect the left maxillary cyst 25 years prior; however, the details were uncertain. The tumor was resected with clear margins. Taken together with the results of histological and immunohistochemical examinations, the tumor was categorized between GCOC and DGCT, and we diagnosed the tumor as GCOC suggesting similarity to DGCT. Further, we focused on CTNNB1, which encodes β-catenin and is frequently mutated in COCs. In this tumor, we identified CTNNB1 Ser33Cys, one of the mutations typically found in COCs. This finding suggests that CTNNB1 is a common target for the pathogenesis of tumors accompanied by ghost cells.

Alpha‐L‐fucose is a component of glycans on the cell surface. Alpha‐L‐fucose is correlated with tumorigenesis and malignancy, and alpha‐L‐fucosidase‐1 (FUCA1), the enzyme that removes terminal α‐L‐fucose residues from glycoproteins, is downregulated in some high malignancy cancers. The expression profile of FUCA1 in head and neck tumors remains unknown, and we analyzed the expression profiles of FUCA1 and an upstream molecule p53 in mucoepidermoid carcinoma (MEC) and oral squamous cell carcinoma (OSCC). FUCA1 was expressed in most MECs irrespective of histopathological grading, whereas expression in OSCCs was low. High immunohistochemical intensity of p53 was detected in OSCCs at high frequency, but rarely detected in MECs. Genetic mutation analysis using next‐generation sequencing revealed no significant mutation of TP53 in MECs. We further analyzed the expression profiles of FUCA1 in normal major and minor salivary glands and found strong expression in the intercalated duct, moderate expression in mucous acinar cells and no expression in serous acinar cells. These contrasting immunohistochemical profiles and anatomical distribution in normal salivary glands suggest that FUCA1 is a useful marker to distinguish MEC from OSCC, and many MECs have similar immunohistochemical phenotypes to intercalated duct and mucous acinar cells.

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BackgroundA glomus tumor is a rare neoplasm usually found in the dermis or subcutaneous tissue of the extremities. It is rare for the glomus tumor to occur on the head and face. Only 26 glomus tumors of the oral region and affected bone have been reported in the English-language literature (Table 1). We report a case of a glomus tumor at the mandible. As a new point, the glomus tumor resorbed a bone and teeth roots when the tumor progressed into the mandible.Case presentationThe patient was a 44-year-old Japanese man who complained swelling of the right mandible. Radiographic examination showed a multilocular radiolucency area in the left mandible. Radiographic findings on our case resembled those of a common benign tumor. The lesion occupied to the premolar and molar area and revealed that the tumor resorbed the roots of the teeth. The lesion was removed surgically with the buccal cortical bone and buccal mucosa in contact with the mass of the tumor. The mass fully excised intraorally under general anesthesia, and the inferior alveolar nerve in contact with the mass was preserved.The specimen was pathologically diagnosed as a glomus tumor. Immunohistochemical staining was positive for vimentin, muscle-specific actin/HHF35, and calponin. A hairline-shaped area of positive staining for type IV collagen surrounding the tumor cells was also observed. In contrast, staining for alpha-SMA, cytokeratin (AE1/AE3), cytokeratin (CAM5.2), CK19, CD31, CD34, CD68, p63, S-100, Factor VIII, and desmin was all negative. The Ki-67 labeling index was almost 1%.A recurrent tumor was again detected in the site below the primary tumor at an 8-year follow-up, and it was surgically removed. The patient has had no symptoms of recurrence in 2 years after the second operation.ConclusionThe glomus tumor resorbed a bone and teeth roots when the tumor progressed into the mandible. The immunohistochemical features of the tumor were consistent with those described in previous reports. It is important to completely remove the Glomus tumor.

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