Pathological subtype dictates survival and failure pattern in laryngeal neuroendocrine neoplasms: a 15-year single-institution experience

BACKGROUND: Laryngeal neuroendocrine neoplasms (LNENs) comprise < 1% of laryngeal malignancies, and evidence-based treatment guidelines remain lacking. We sought to delineate clinicopathological features, therapeutic strategies, and survival determinants in a single-institution cohort of consecutive patients with primary LNEN. METHODS: We retrospectively identified 31 consecutive patients with primary LNEN treated between 2010 and 2024. Histology was centrally reviewed by two head-and-neck pathologists and categorized as well-differentiated neuroendocrine tumor (NET, G1-G3) or poorly differentiated neuroendocrine carcinoma (NEC, small-cell/large-cell). All cases underwent immunohistochemistry (Syn, CgA, Ki-67) and multidisciplinary therapy. Survival analyses were performed with Kaplan-Meier and Cox proportional-hazards models. RESULTS: Median age was 60 years, 90.3% were male, and 80.6% had a smoking history. NEC accounted for 71% (22/31) and NET for 29% (9/31). NEC exhibited higher Ki-67 index (85% vs. 10%, P < 0.001), more advanced stage (63.6% vs. 33.3%, P = 0.013), and a predilection for distant metastasis (85.7% vs. 25.0%, P = 0.002). Median overall survival (OS) was 27.0 months for NEC vs. not reached for NET (P < 0.001); 5-year OS was 0% vs. 44.4%. Median disease-free survival (DFS) was 19.0 vs. not reached (P < 0.001). Multivariate analysis identified NEC subtype (HR = 4.23, 95% CI 1.39-12.90), T3-4 stage (HR = 2.61, 95% CI 1.02-6.66), and lymph nodal positivity (HR = 3.12, 95% CI 1.20-8.10) as independent predictors of poor OS; NEC subtype (HR = 3.67, 95% CI 1.15-11.70) and N+ (HR = 3.51, 95% CI 1.22-10.10) predicted inferior DFS. Distant metastasis was the first mode of failure in 68.9% of curative-intent cases. CONCLUSIONS: Pathologic subtype (NEC vs. NET) emerges as the dominant independent predictor of survival in this cohort. NEC demonstrates a systemic biological phenotype characterized by early distant metastasis. These findings support the hypothesis that intensified perioperative systemic therapy, rather than locoregional escalation, warrants prospective investigation. Multi-center, molecularly stratified trials are needed to establish a precision-medicine paradigm for this rare disease.