Classification and prognostic stratification of bronchopulmonary neuroendocrine neoplasms

: The accuracy and reproducibility of the WHO 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO2019), and to analyse its accuracy and prognostic impact. Two BP-NEN cohorts from Japan and Germany, 393 tumors (88% surgically resected), were reviewed and the clinicopathological data of the resected tumors (n=301) were correlated to patients´ disease free survival (DFS). The PanNEN-WHO2017 classification stratified the 350 tumors into 91 (26%) NET G1, 52 (15%) NET G2, 15 (4%) NET G3 and 192 (55%) neuroendocrine carcinomas (NEC). NECs, but not NETs, were immunohistochemically characterized by abnormal p53 (100%) and Rb1 (83%) expression. The Ki67 index, which was on average 4 times higher than mitotic count (p<0.0001), was prognostically more accurate than the mitotic count. NET G3 patients had a worse outcome than NET G1 (p<0.01) and NET G2 patients (p=0.02), respectively. No prognostic difference was detected between NET G3 and NEC patients after 5 year DFS. It is concluded that stratifying BP-NEN patients according to the DiS-NEN-WHO2019 classification results in three prognostically well-defined NET groups, if grading is solely based on Ki67 index. Mitotic count alone may underestimate malignant potential of low-grade NETs.