P53 +/- Rb1 - ASCL1 low Phenotype Predicts Better Prognosis after Surgical Resection in Large Cell Neuroendocrine Carcinoma: A Molecular Characteristic and Clinical-Pathological Investigation of Lung Neuroendocrine Tumors

Background: Based on morphology, necrosis degree, and proliferation status, lung neuroendocrine tumors (NETs) are commonly divided into four subtypes: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). However, cases difficult to classify still exist in diagnosis. Methods: We immunohistochemically investigated the molecular phenotypes in lung NETs and assessed their prognostic value. Results: After morphological re-analysis of 179 NETs, 19 cases were classified as undefined, which included 3 cases showing carcinoid morphology with high proliferation (Ki67>20% or mitotic count>10/2mm 2 ), and 16 cases showing intermediate differentiated morphology with Ki67 among 20% to 60%. Furthermore, molecular phenotypes were determined by expression of p53, Rb1, ASCL1, STK11, and gene mutation status of KRAS. Interestingly, p53 wt Rb1 + distinguished an unique subcategory from undefined lung NET cases which differ from SCLC or LCNEC in prognosis, indicating WD-NET G3 existed in lung NETs. Additionally, in LCNEC, high ASCL1 expression was only relevant to lymph node metastasis rather than overall survival. However, in p53 +/- Rb1 - LCNEC phenotype, low ASCL1 predicted better outcomes, along with less risk of lymph node metastasis. Conclusion: This study provided evidence for existence of WD-NET G3 in NETs and revealed promising prognosis of p53 +/- Rb1 - ASCL1 low subcategory in LCNEC, which could be beneficial to the evaluation of patient status in future clinic practice.