In this review article, we focus on the diversity of the origin of oral squamous cell carcinoma(OSCC), and discuss cancer stem cells(CSCs)as a key player to explain the malignancy of OSCC. CSCs are a subset of cancer cells that have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer autonomously grow and develop into cancer. We hypothesize that OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs.

It is widely known that human malignancies are caused by genomic and epigenomic alterations. In oral squamous cell carcinoma（OSCC）, numerous gene alterations have also been reported. However, in clinical practice, these findings are not utilized at all. Therefore, we have attempted to identify gene alterations that would be useful in the diagnosis and treatment of OSCC. First, we extracted genomic DNA and total RNA from the primary tumor and adjacent normal tissues, respectively. Subsequently, targeted ultradeep sequencing by a next-generation sequencer with the use of a custom panel specialized for OSCC was performed to detect gene mutations. Gene mutations detected only in tumor derived genomic DNA were defined as tumor-specific gene mutations. Furthermore, comprehensive gene expression analysis by microarray was conducted, and the gene expression profiles from tumor and normal tissues were compared for detecting gene expression alterations. In the mutation analysis using 48 OSCC cases, tumor-specific gene mutations were observed in TP53 90%, NOTCH1 38%, CDKN2A 29%, PIK3CA 13%, and HRAS 8% of cases. Some genetic mutation was detected in all except for one case. On the other hand, in the expression analysis using 150 OSCC cases, 143 genes showing significant expression changes of 5-fold or more in tumor tissues were observed. Subsequently, when we examined the relationship between these gene alterations and cervical lymph node metastasis, we found 29 genes that showed a significant correlation with lymph node metastasis. These results revealed the somatic mutations and aberrant expression of specific genes in OSCC. Detection of these gene alterations is useful for prediction of latent cervical lymph node metastasis and detection of minimal residual disease by liquid biopsy.

Cowden syndrome is an autosomal-dominant inherited disorder caused by a germline mutation in the PTEN gene. This condition is characterized by multiple hamartoma-like lesions in the skin, mucosa, breasts, thyroid, endometrium, and gastrointestinal tract and is associated with a high risk of concomitant malignancies such as breast, thyroid, endometrial, and c olorectal cancers. Oral mucosal lesions in Cowden syndrome typically present as papillary masses that involve the gingiva, lips, and the tongue, producing a cobblestone appearance. We report a case of Cowden syndrome in a 53-year-old woman who presented with multiple masses in the oral cavity. Following evaluation, we suspected Cowden syndrome based on findings of acrokeratosis of the extremities, multiple papillary masses in the oral cavity, and a past medical history of breast and thyroid carcinomas. We performed a detailed examination to confirm our diagnosis. She met the diagnostic criteria of the National Comprehensive Cancer Network and was diagnosed with Cowden syndrome after a PTEN pathogenic variant was detected by cancer gene multi-panel testing.

Oncocytoma is a benign salivary gland tumor composed predominantly of oncocyte, which are large epithelial cells with eosinophilic granular cytoplasm resulting from an accumulation of mitochondria. Oncocytoma is uncommon; most cases occur in the parotid gland. We encountered a rare case of oncocytoma of the submandibular gland.
　An 80-year-old man with a gradually-growing mass in the left submandibular region came to our clinic. The tumor was elastic soft and mobile, with a clear margin. He did not complain of pain. Contrast-enhanced computed tomography（CT） showed a homogenous submandibular mass of approximately 50 mm in diameter, and magnetic resonance images（MRI） indicated a high-intensity mass on T1 weighted imaging in the left submandibular region. The patient underwent surgery under general anesthesia. Pathological examination showed that the tumor cells were large with eosinophilic granular cytoplasm, and on the basis of these findings we diagnosed the tumor as an oncocytoma.
　No recurrence has been detected as of nine years after the operation.

Solitary fibrous tumor（SFT） is a rare tumor in the oral region, and NAB2-STAT6 gene fusions are pathognomonic for SFT. Recently, various NAB2-STAT6 genotypes have been confirmed. This paper describes a case of a histologically rare metastasis of SFT with intermediate malignant potential that occurred in the maxillary gingiva. A 96-year-old woman visited our hospital because of swelling of the upper gingiva. Intra-oral examination revealed a well-defined elastic hard mass measuring 20×15×15 mm in the maxillary tuberosity. After several imaging examinations, a clinical diagnosis of benign tumor in the upper jaw was suggested. The lesion was surgically excised. Histological examination showed randomly arranged short spindle-shaped cells with indistinct, pale eosinophilic cytoplasm within a variably collagenous stroma, nuclear atypia, and five mitoses in ten high power fields. Immunohistochemical examination showed positive for STAT6, CD34, and CD99, and Ki-67 labeling index was 15%. The patient was considered to be at intermediate risk according to the 3-variable model for the prediction of metastatic risk. Genetic analysis showed NAB2 exon6-STAT6 exon 17 fusion gene. The histological diagnosis was SFT indicating intermediate malignant potential, but with intermediate risk of metastasis. No recurrence or metastasis have been observed in the five years following surgery.