Ki-67 index of 55% distinguishes two groups of bronchopulmonary pure and composite large cell neuroendocrine carcinomas with distinct prognosis.

Little information is available concerning prognostic factors of bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical and molecular approach could be used for their prognostic evaluation.Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p-40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, MDM2) and genomic (TP53, RB1, ATM, JAK2, KRAS, STK11) findings were analyzed from BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). Ki-67 was expressed as a percentage of positive cells in hot spot as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNEC, Ki-67 was evaluated only in the LCNEC component.111 LCNECs were distinguished in: 70 pure LCNECs, 35 co-LCNECs [27 with adenocarcinoma (ADC); 8 with squamous cell carcinoma (SqCC) and 6 LCNECs with only napsin A immunoreactivity]. Ki-67 cut off at 55% evaluated in the NE component was the most powerful OS predictor (Log-rank P=0.0001) in all LCNECs: 34 LCNECs-A Ki-67 <55% and 77 LCNECs-B Ki-67 ≥55%; statistical differences in OS (Log-rank P=0.0001) were also observed between pure and co-LCNECs. A significant difference in OS was found between pure LCNEC-A and co-LCNEC-A (P<0.05) but not between pure LCNEC-B and Co-LCNEC-B. Co-LCNEC-ADC and LCNEC Napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (Log-rank P=0.0001). At multivariable analysis, tumor location, pure vs combined features and napsin A, but no single gene mutation, were significantly associated with OS, after adjustment for Ki-67 and study center (P<0.05).The Ki-67 proliferation index and the morphologic characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.