BACKGROUND: Poorly differentiated large cell neuroendocrine carcinomas (LCNEC) comprise a rare and still scarcely known subgroup of neuroendocrine tumors. The objective of this study was to investigate the epidemiology, clinical presentation, prognostic factors, and molecular pathways of patients with poorly differentiated LCNEC. METHODS: Forty-one patients who had a confirmed diagnosis of poorly differentiated LCNEC according to the criteria of the most recent World Health Organization classification of neuroendocrine tumors of the lung entered the study. The clinicopathologic features of patients with poorly differentiated LCNEC were reviewed, prognostic parameters for their survival were studied, and the prognostic roles of the proteins involved in cell cycle regulation were investigated with tissue array analysis in a subset of patients with LCNEC. RESULTS: Twenty-four men and 17 women with a median age of 63 years (age range, 26-81 years) who had LCNEC were studied. LCNEC developed after therapy for a first cancer in 14% of patients. Neither a personal or familial history of endocrine tumors nor a primary association that was compatible with an inherited syndrome was observed. The increase of at least 1 serum biologic marker was observed in 93% of patients. A primary tumor was identified in only 63% patients. Thirty-one patients had distant metastases, and 10 patients had only lymph node metastases at the time of the diagnosis. The 5-year survival rate was 24%. High mitotic count, low expression of neuroendocrine markers, and a Bcl-2/Bax ratio > 1 were unfavorable prognostic factors for survival (P < .01). All patients who had isolated peripheral lymph node LCNEC achieved a cure. CONCLUSIONS: The results from this study highlighted distinctive clinical features and prognostic indicators of poorly differentiated LCNEC. Peripheral isolated lymph node clinical presentation is proposed as a new clinical entity.