Genetic alterations in combined neuroendocrine neoplasms of the lung.

Large-cell neuroendocrine and small-cell lung carcinomas are highly aggressive neuroendocrine tumors that can be associated in a variant of 'small-cell lung carcinoma combined with large-cell neuroendocrine carcinoma'. Little is known about this rare tumor type with biphenotypic neuroendocrine differentiation. The aim of the present study was to genetically characterize each component of a series of combined small-cell/large-cell neuroendocrine carcinomas, to gain information on their histogenesis and to compare the alterations observed with those found in their respective pure forms. To this end, 22 formalin-fixed, paraffin-embedded lung neuroendocrine tumors obtained from surgical resections were investigated: six combined small-cell/large-cell carcinomas, eight pure large-cell carcinomas and eight pure small-cell carcinomas. For the combined neuroendocrine neoplasms, DNA was extracted separately from each of the two cytologically different populations. Allelic imbalance was investigated by PCR amplification of 30 highly polymorphic microsatellite markers located at 11 different chromosomal regions. A common background of genetic alterations, similar in both components of the combined neoplasms, was demonstrated at 17p13.1, 3p14.2-3p21.2, 4q12-4q24, 5q21 and 9p21. In fact, the two components appeared to be more similar to each other than to their respective pure forms. In addition, allelic imbalances preferentially involving one of the two components were found. These alterations often appeared to be specific for this histological variant, as compared with those observed in pure forms or in the literature. In conclusion, this is the first report in which a molecular characterization of the variant of small-cell lung carcinoma combined with large-cell neuroendocrine carcinoma was performed. The finding of common alterations in the two phenotypically different neuroendocrine cell components suggests a close genetic relationship and supports the hypothesis of a monoclonal origin from a common ancestor. The genetic differences observed provide the basis for the divergent differentiation and parallel the morphological differences in the two components of these combined neuroendocrine neoplasms.