It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8⁺ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

Objectives: Prognoses for nasopharyngeal carcinoma (NPC) between categories T2 and T3 in the Eighth American Joint Committee on Cancer (AJCC) staging system were overlapped. We explored the value of skull base invasion (SBI) subclassification in prognostic stratification and use of induction chemotherapy (IC) to optimize T2/T3 categorization for NPC patients. Methods: We retrospectively reviewed 1752 NPC patients from two hospitals. Eight skull base bone structures were evaluated. Survival differences were compared between slight SBI (T3 patients with pterygoid process and/or base of the sphenoid bone invasion only) and severe SBI (T3 patients with other SBIs) with or without IC using random matched-pair analysis. We calculated the prognosis and Harrel concordance index (C-index) for the revised T category and compared IC outcomes for the revised tumor stages. Results: Compared to severe SBI, slight SBI showed better 5-year overall survival (OS) (81.5% vs. 92.3%, p = 0.001) and progression-free survival (PFS) (71.5% vs. 83.0%, p = 0.002). Additional IC therapy did not significantly improve OS and PFS in slight SBI. The proposed T category separated OS, PFS, and locoregional recurrence-free survival in T2 and T3 categories with statistical significance. An improved C-index for OS prediction was observed in the proposed T category with combined confounding factors, compared to the AJCC T staging system (0.725 vs. 0.713, p = 0.046). The survival benefits of IC were more obvious in the advanced stage. Conclusions: NPC patients with slight SBI were recommended to downstage to T2 category. The adjustment for T category enabled better prognostic stratification and guidance for IC use. Key Points: • For nasopharyngeal carcinoma (NPC) patients in T3 category, slight skull base invasion was a significant positive predictor for OS and PFS. • NPC patients with slight SBI might not gain significant survival benefits from induction chemotherapy. • Downstaging slight SBI NPC patients to T2 category would make a more accurate risk stratification, improve the predicting performance in OS, and have a better guidance in the use of IC for patients in advanced stage.

Distant metastasis is among the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. To identify patients with a high risk of distant metastasis is important to guide posttreatment surveillance, appropriate time treatments, and prolonging their long-term survival. In this study, we systematically examined the associations between a series of nodal-related characteristics and distant metastasis-free survival (DMFS) by detailed MRI reading and established a nomogram for DMFS in NPC patients. T-stage, age group, Epstein–Barr virus (EBV) level, central nodal necrosis, and nodal number were identified as independent risk factors for distant metastasis and were included into the final nomogram. The calibration plot showed a high agreement between the prediction by the nomogram and actual observations. Our established nomogram achieved a high C-index in predicting distant metastasis in both of the training cohort (0.737) and the validation cohort (0.718). This nomogram incorporated several readily available nodal features from the MR images, and it might be useful for guiding clinical decision and NPC patients' posttreatment surveillance. It also provides cues for how to redefine N-stage. Additional research is needed to confirm our conclusions.