Abstract IA10: Pathology of lung neuroendocrine tumors: In search of evidence for classification

Abstract

Abstract Neuroendocrine (NE) tumors comprise approximately 25% of all tumors in human lung. As a group they continue to provide challenges at biological, molecular and pathological level for uniform classification. The prototype of NE tumors is the highly aggressive small cell lung cancer (SCLC) that accounts 15% of human lung cancers. For years lung cancers were clinically classified mainly into SCLCs and non-SCLCs (NSCLCs) while it has become evident that lung NE tumors actually form a complex spectrum from SCLC to carcinoid with shifting boundaries. The current WHO classification recognizes SCLC, its variant form combined SCLC, typical and atypical carcinoids as well as large cell NE carcinoma (LCNEC) and its variant form combined large cell carcinoma, the last two cancers under the main NSCLC category of large cell carcinoma. With the exception of the LCNEC, it is expected that the diagnoses will be rendered by routine hematoxylin-eosin stain according the established criteria. Benign entities include diffuse idiopathic pulmonary NE cell hyperplasia which is described in the chapter of preinvasive lesions. Over time there have been several efforts to place lung NE tumors into two to four-tier categories according to their malignant potential (high versus low grade) or degree of differentiation often leaving behind confusing terminology that is later misused. Unlike surgically resected NSCLCs, most NE tumors are frequently diagnosed from biopsies which remains a seldom recognized fact that may create its own biases. The diagnosis that experts most often agree with is SCLC, while distinctions between atypical carcinoid and LCNEC that are in the middle of the spectrum are often disputed. Many molecular studies have also “correctly” classified the endpoints of the NE spectrum while grouping in the middle of it has produced varied results. Moreover, several studies have suggested that NSCLCs with NE features (NSCLC-NEs) is a distinct carcinoma type with worse prognosis than ordinary non-NE NSCLC, while others disagree. Biologically this category is very interesting as NSCLCs and SCLCs are ultimately thought to be derived from the same cell. The regulation of NE differentiation is poorly understood. The proneural achaete-scute homolog 1 (ASCL1), a lineage-dependent oncogene may be a key factor for NE differentiation. On the other hand, it was recently shown that the deletion of the tumor suppressor genes Rb1 and p53 specifically in NE cells, a subpopulation of cells in normal airways, or in alveolar non-NE type2 pneumocytes of mice resulted in SCLCs closely mimicking human disease. These results provide experimental evidence for the close relationship of NE and non-NE epithelial cells in carcinogenesis.