Staging System for Neuroendocrine Tumors of the Lung Needs to Incorporate Histologic Grade

Neuroendocrine tumors of the lung are staged with the American Joint Committee on Cancer (AJCC) TNM system for non-small cell lung cancer. However neuroendocrine tumors have a distinct clinical behavior with grade providing critical prognostic information. We aim to determine components of a tumor-specific staging system.

We identified 12,415 of 58,736 neuroendocrine patients with complete 8th edition AJCC staging information in the National Cancer Database from 2004 to 2014. Data were randomized into training (n = 8324) and validation (n = 4091) sets and analyzed separately. Recursive partitioning followed by Cox regression was performed to classify by grade (G1, typical carcinoid; G2, atypical carcinoid; G3, large cell neuroendocrine), T category, and nodal status. Overall survival according to individual grade and an integrated grade-specific staging was compared by Kaplan-Meier analysis.

Overall 7524 G1, 1211 G2, and 3680 G3 tumors were analyzed with no differences between sets. Each grade was separately classified by the AJCC TNM system with poor separation of the curves and clustered survival. Recursive partitioning identified grade as the most significant factor driving overall survival. Subsequent partitions identified nodal status and then T category as additional important factors, consistent with results from the Cox regression analysis (G2 hazard ratio, 3.05 [95% confidence interval, 2.65-3.5]; G3 hazard ratio, 9.03 [95% confidence interval, 8.22-9.92]). When grade was integrated with nodal status and T category to approximate a tumor-specific staging system, distinct overall survival stratification occurred at each proposed stage.

Grade was the dominant driver of prognosis in patients with neuroendocrine tumors of the lung. Incorporation of grade with traditional TNM parameters better discriminates between stage categories compared with current AJCC staging. Future staging systems for neuroendocrine tumors of the lung should include histologic grade.