Lung cancer (Amsterdam, Netherlands) · 2026
Clinicopathological and prognostic validation of pulmonary carcinoid/NET G3: evidence for a distinct subgroup of well-differentiated neuroendocrine neoplasms.
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Kirmann Jules, Riffet Marc, Bazille Céline, Quintyn Marie-Laure, Planchard Gaëtane, Dubois Fatemeh, Jean-Jacques Bastien
Аннотация
BACKGROUND: Pulmonary neuroendocrine neoplasms (NENs) comprise a biological spectrum ranging from well-differentiated carcinoid tumors to poorly differentiated neuroendocrine carcinomas. In 2026, the International Association for the Study of Lung Cancer (IASLC) proposed an updated classification introducing pulmonary carcinoid/NET G3 as a distinct category of well-differentiated tumors with increased proliferative activity, incorporating Ki-67 into the diagnostic framework and aligning pulmonary NENs with other organ systems. However, the clinicopathological characteristics and prognostic significance of this newly proposed entity remain incompletely defined.
METHODS: We conducted a retrospective single-center study of pulmonary neuroendocrine neoplasms diagnosed between 2007 and 2024. Clinical, histopathological, immunohistochemical, and survival data were collected. Tumors with well-differentiated morphology and increased proliferative activity were identified using predefined study criteria (mitotic count > 10/2 mm2 and/or Ki-67 > 20 %). Following publication of the 2026 IASLC proposal, these tumors are referred to as carcinoid/NET G3 throughout the revised manuscript. RB1 and p53 immunohistochemistry was performed, and survival was analyzed using Kaplan-Meier estimates and Cox regression.
RESULTS: Among 155 pulmonary neuroendocrine neoplasms, eight (5.2 %) fulfilled criteria for carcinoid/NET G3. These tumors exhibited well-differentiated morphology despite elevated proliferative activity, retained RB1 expression, and a wild-type p53 immunophenotype, distinguishing them from LCNEC. Clinically, carcinoid/NET G3 showed an intermediate prognosis between conventional carcinoids and LCNEC. Mitotic count and Ki-67 demonstrated only moderate correlation, and Ki-67 identified additional biologically relevant tumors with relatively low mitotic activity.
CONCLUSIONS: Our findings provide independent clinicopathological validation of the recently proposed IASLC carcinoid/NET G3 concept. Integration of morphology, Ki-67, RB1 and p53 may improve diagnostic classification and prognostic stratification of pulmonary neuroendocrine neoplasms while supporting implementation of the emerging pulmonary carcinoid/NET G1-G3 framework.
METHODS: We conducted a retrospective single-center study of pulmonary neuroendocrine neoplasms diagnosed between 2007 and 2024. Clinical, histopathological, immunohistochemical, and survival data were collected. Tumors with well-differentiated morphology and increased proliferative activity were identified using predefined study criteria (mitotic count > 10/2 mm2 and/or Ki-67 > 20 %). Following publication of the 2026 IASLC proposal, these tumors are referred to as carcinoid/NET G3 throughout the revised manuscript. RB1 and p53 immunohistochemistry was performed, and survival was analyzed using Kaplan-Meier estimates and Cox regression.
RESULTS: Among 155 pulmonary neuroendocrine neoplasms, eight (5.2 %) fulfilled criteria for carcinoid/NET G3. These tumors exhibited well-differentiated morphology despite elevated proliferative activity, retained RB1 expression, and a wild-type p53 immunophenotype, distinguishing them from LCNEC. Clinically, carcinoid/NET G3 showed an intermediate prognosis between conventional carcinoids and LCNEC. Mitotic count and Ki-67 demonstrated only moderate correlation, and Ki-67 identified additional biologically relevant tumors with relatively low mitotic activity.
CONCLUSIONS: Our findings provide independent clinicopathological validation of the recently proposed IASLC carcinoid/NET G3 concept. Integration of morphology, Ki-67, RB1 and p53 may improve diagnostic classification and prognostic stratification of pulmonary neuroendocrine neoplasms while supporting implementation of the emerging pulmonary carcinoid/NET G1-G3 framework.