EGR1–BDNF–Linking Crosstalk Between Cancer Cells and Nerves for Perineural Invasion in Salivary Duct Carcinoma: Comparison of Salivary Duct Carcinoma De Novo and Ex Pleomorphic Adenoma

Salivary duct carcinoma (SDC) is primarily categorized as de novo (SDCDN) or ex pleomorphic adenoma (SDCXPA). The incidence of HMGA2 and PLAG1 fusion genes has been suggested to be higher in SDCXPA than in SDCDN. Surgical resection remains the main intervention due to limited guidance on new treatment strategies. However, frequent recurrence and challenging management of metastasis highlight the necessity for innovative treatments. This study aimed to investigate SDC characteristics, including perineural invasion (PNI), and elucidate its carcinogenic mechanisms and adverse prognostic factors. We analyzed 52 patients with SDC diagnosed in the National Cancer Center Hospital from 2014 to 2023. To compare gene expression profiles, we performed immunohistochemical staining, including Her2, adrenergic receptor, PLAG1, and HMGA2, followed by human epidermal growth factor receptor 2 (HER2) in situ hybridization and RNA sequencing of 30 cases. Differential analysis identified genes subjected to immunohistochemical staining and statistical analysis. Based on histologic classification using PLAG1 and HMGA2, 52 cases were classified as 26 cases (50%) SDCDN and 26 cases (50%) SDCXPA. Compared with SDCXPA, SDCDN showed higher perineural, venous, and lymphatic invasion rates (P = .0005, .0294, and .0044, respectively). Genetic expression profiling revealed clustering tendencies between these subtypes. Focusing on PNI, gene expression was decreased in early growth response 1 in tumor portions infiltrating perineural tissues, indicating a negative correlation (P < .0001). Additionally, RNA sequencing showed 3 new fusion genes. In conclusion, clinical disparities between SDCDN and SDCXPA based on molecular and pathological features were observed. We found early growth response 1-brain-derived neurotrophic factor–linking crosstalk between cancer cells and nerves for PNI in SDC, offering insights into future treatment and prognostic factors.