Diagnostic criteria and evolving molecular characterisation of pulmonary neuroendocrine carcinomas

Neuroendocrine carcinomas of the lung are currently classified into two categories: small-cell lung carcinoma and large-cell neuroendocrine carcinoma. Diagnostic criteria for small-cell and large-cell neuroendocrine carcinoma are based solely on tumour morphology; however, overlap in histologic and immunophenotypic features between the two types of carcinomas can potentially make their classification challenging. Accurate diagnosis of pulmonary neuroendocrine carcinomas is paramount for patient management, as clinical course and treatment differ between small-cell and large-cell neuroendocrine carcinoma. Molecular-genetic, transcriptomic, and proteomic data published over the past decade suggest that small-cell and large-cell neuroendocrine carcinomas are not homogeneous categories but rather comprise multiple groups of distinctive malignancies. Nuances in the susceptibility of small-cell lung carcinoma subtypes to different chemotherapeutic regimens and the discovery of targetable mutations in large-cell neuroendocrine carcinoma suggest that classification and treatment of neuroendocrine carcinomas may be informed by ancillary molecular and protein expression testing going forward. This review summarizes the current diagnostic criteria, prognostic and predictive correlates of classification, and evidence of previously unrecognised subtypes of small-cell and large-cell neuroendocrine carcinoma.