Improvement of pathological staging system for neuroendocrine tumors of the lung

BACKGROUND: Currently, the tumor, node, and metastasis (TNM) staging system has a limited value in prognostic stratification for neuroendocrine tumors of the lung (NETL). A specific pathological staging system was therefore explored. METHODS: Two cohorts were assessed: the training cohort was composed of surgically treated patients from the Surveillance, Epidemiologic, and End Results (SEER) database [2004–2015]; the Shanghai cohort included Shanghai resident patients treated at Shanghai Pulmonary Hospital [2009–2018]. Multivariable Cox regression analysis was performed to identify factors associated with overall survival. A new staging system was proposed based on survival tree, and was further compared with the 8(th) edition of the TNM staging system. RESULTS: In the training set (n=3,204), multivariate Cox analysis showed that tumor histotype and nodal status were independently associated with survival, but not T stage. Therefore, by incorporating NETL histotype (G1, low-grade typical pulmonary carcinoids; G2, intermediate-grade atypical pulmonary carcinoids; G3, high-grade large-cell neuroendocrine carcinomas) and N stage, a new staging system was developed: IA, G1N0; IB, G1N1 or G2N0; II, G1N2, G2N1-2, or G3N0; III, G3N1-2. Five-year survival rates were 91.2%, 81.3%, 50.2% and 27.6% for the new stages IA to III in the validation set (n=3,204), respectively (P<0.001). Additionally, the new staging system had significantly better predictive ability than the TNM staging system, in both the SEER [C-index, 0.75 vs. 0.62; net reclassification improvement (NRI), 0.62; integrated discrimination improvement (IDI), 20%] and Shanghai (IDI, 8%) cohorts. Based on the new staging system, adjuvant chemotherapy conferred a significantly better survival in stage-III NETL cases (HR =0.34, 95% CI, 0.25–0.45). CONCLUSIONS: The new pathological staging system can better predict NETL prognosis than the 8(th) edition of the TNM staging system, with the potential to guide postoperative treatment.