Grade 3 Lung Carcinoids/NETs: The IASLC Pathology Committee Study with Proposal of a New Diagnostic Category

Lung carcinoids are well-differentiated neuroendocrine tumors (NETs), designated in the current thoracic WHO classification as typical carcinoids (grade 1) and atypical carcinoids (grade 2), whereas rare tumors with carcinoid/NET morphology and >10 mitoses/2mm² are designated as large cell neuroendocrine carcinoma (LCNEC). This approach, however, has been a matter of growing debate.

Lung resections of tumors with carcinoid/NET morphology and >10 mitoses/2 mm² were contributed by the members of IASLC Pathology Committee. Digitized slides and detailed clinicopathologic, immunohistochemical, and molecular data were collected and analyzed.

In total, 28 cases meeting the study criteria were collected from 9 institutions in 6 countries. Tumors exhibited mean mitotic counts of 15/2mm² (range, 11-30/2mm²) and mean hot-spot Ki-67 rate of 32% (range 13-54%). In all cases, Ki-67 was heterogeneous, containing cold-spot zones with Ki-67 of <1%-15%. In all cases, Rb and p53 showed wild-type pattern by immunohistochemistry. Next-generation sequencing (n=9) revealed wild-type RB1 and TP53, low TMB (1.3-3.3 mutations/Mb), and genomic alterations characteristic of lung carcinoids. The study cohort exhibited significantly worse OS and RFS than control groups of 117 typical and 52 atypical carcinoids (P<0.0001 for all comparisons).

In this international multi-institutional study, we address a major unresolved issue for WHO classification. By assembling the largest cohort to-date of the study cases, we propose that they should be classified as grade 3 carcinoids/NETs rather than LCNEC to enable clinical management more aligned with their biology. The concurrent IASLC proposal to include Ki-67 as additional criterion for grade 3 carcinoids should further enhance this approach.