Abstract
BACKGROUND: Adenoid cystic carcinoma (ACC) of the head and neck is a rare malignancy with suboptimal outcomes despite multimodal therapy. High recurrence rates and chemoradiation resistance underscore the unmet need for molecularly guided strategies. The aim of this study was to explore the influence of clinical characteristics and molecular stratification on prognosis. METHODS: This investigation employs integrated molecular profiling of 182 ACC specimens to delineate clinically actionable genetic alterations. Inclusion required: (I) histologically confirmed ACC; (II) surgery and adjuvant radiotherapy; and (III) ≥36-month follow-up with quarterly imaging. MYB fusions and NOTCH activation were assessed via next-generation sequencing (NGS). Multivariate Cox models adjusted for tumor stage (T stage), histology, and metastasis evaluated recurrence and survival. RESULTS: Patients (median age: 45.24 years; T4: 37.4%) exhibited: MYB alterations (59.90%), isolated NOTCH activation (6.00%), and co-alterations (7.10%). After covariate adjustment, MYB/NOTCH co-alterations predicted the poorest outcomes: 76.9% recurrence rate [adjusted hazard ratio (HR) =5.945; 95% confidence interval (CI): 2.318-15.162; P<0.001]and 69.2% mortality (HR =7.856; 95% CI: 3.024-20.406; P<0.001), significantly surpassing isolated MYB (33.9% recurrence, P=0.04) or NOTCH (63.6% recurrence, P=0.02) subgroups. The all-cause mortality rate was 30.22% (55/182). The median survival time for the co-alterations group was 51 months, for the MYB group was 108 months, for the NOTCH group was 80 months, and for the wild gene type was 187 months. CONCLUSIONS: Concurrent MYB and NOTCH alterations define a molecularly aggressive ACC subset requiring intensified surveillance. These findings advocate for routine molecular stratification to guide adjuvant therapy selection. While other clinical factors (e.g., T stage) contribute to prognosis, these alterations identify patients who may benefit from dual-pathway inhibitors. Prospective validation is needed to confirm clinical utility.