Morphology and Ki-67 Proliferative Index Drive Prognosis in Combined Large Cell Neuroendocrine Carcinomas of the Lung

Background: While little information is available concerning the molecular landscape and prognostic factors of pulmonary large cell neuroendocrine carcinomas (LCNECs) even less is known about combined LCNECs (co-LCNECs). These are LCNECs in which a part of the whole tumor (any extent) is composed of a non-neuroendocrine component, most often adenocarcinoma (ADK) or squamous cell carcinoma (SqCC). Revision of a large multicenter series of LCNECs enabled us to extrapolate co-LCNECs and describe their clinical- pathological and prognostic features. Design: Surgical specimens of 148 LCNECs were centrally reviewed with combined features identified. Morphology, immunohistochemical (Ki-67, Napsin A, p-40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, Rb1, MDM2) and genomic (TP53, RB1, ATM, JAK2, KRAS, STK11) findings were studied and correlated with Overall Survival (OS). Results: LCNEC diagnosis was confirmed in 123 patients (Table1): 75 pure LCNECs, 48 co-LCNECs (37 combined with ADK; 8 with SqCC) and 3 LCNECs showing only Napsin A positivity but no morphologic evidence of ADK. Applying Ki-67 labeling index cut off at 55% for the NE component, lesions were subdivided into two subgroups: co-LCNECs-A Ki-67 <55% (15 combined with ADK and 3 with SCC) and co-LCNECs-B Ki-67 ≥55% (25 combined with ADK and 5 with SqCC). Napsin A and Alcian blue expression were statistically more frequent in LCNECs-A (P=0.01; P=0.004) compared to LCNECs-B. Median OS for all LCNECs was 1.4 years; statistical differences in OS (HR 1.96, 95% CI 1.30-2.95, P <0.001) were observed between pure (median OS 1.3 years) and co-LCNECs (median OS 1.8 years). This difference in OS was maintained between pure LCNEC-A and co-LCNEC-A (P <0.05) but disappeared for LCNEC-B. At univariate analysis variables associated (P <0.05) with poor OS were p40 expression and absence of combined features, while variables associated with longer OS were tumor peripheral location, Napsin A and Alcian blue staining. At multivariable analysis, only tumor location and Napsin A remained significantly associated with OS, after adjustment for Ki-67 and study center. With regards to molecular analyses, 26 cases (54,2 %) of the co-LCNEC group were studied (see Table 1). No single next-generation sequencing marker was statistically associated with OS. Conclusions: The identification and morphologic characterization of combined features in LCNECs as well as the application of Ki-67 cut off at 55% contribute in predicting clinical outcome of pure-LCNEC and co-LNEC patients.