Small cell lung cancers express neuroendocrine (NE) cell features, while most non-SCLC tumors lack these features. We studied the cytogenetic and genetic alterations in cell lines derived from three unusual subtypes of lung cancer: including carcinoids, non-small cell lung cancers expressing NE properties (NSCLC-NE) and extrapulmonary small cell cancers (ExPuSC) and compared them with those of SCLC and NSCLC lines. Our studies included: cytogenetic studies, restriction fragment length polymorphism (RFLP) analyses with 8 probes spanning commonly deleted loci on chromosomes 3p, 13q and 17p, retinoblastoma gene product (RB) expression, and mutations in the ras and p53 genes. We also summarize previously published data on in vitro chemosensitivity patterns and MDRl gene expression. Our studies demonstrate that all three of the NE cell subtypes have their own distinctive genotypes and phenotypes, each having some similarities and dissimilarities with SCLC and NSCLC.