[Rudolf-Virchow Prize 1999. Genetics of respiratory tract carcinomas: correlation of genotype and phenotype].

In contrast to carcinomas of the upper respiratory tract lung cancer shows a considerable variety of histological differentiations and is particularly known for its morphological heterogeneity. Of clinical relevance, however, is only the distinction between small cell carcinomas (SCLC) and non-small cell lung cancer (NSCLC). We meanwhile investigated a tumor collective of several hundred respiratory tract carcinomas by Comparative Genomic Hybridization (CGH) and developed computer software for the statistical comparison of tumor groups. The analysis revealed recurrent patterns of chromosomal imbalances which are associated with morphological histotypes and biological phenotypes, e.g. there are chromosomal imbalances predominantly found in SCLC compared to NSCLC but also a considerable overlap between both entities. Specifically, the pattern of metastasizing lung squamous cell carcinomas (SCC) approaches that of SCLC. In addition, the analysis of a metastasizing combined SCLC after microdissection showed a clonal relationship between the SCC component of the primary tumor and the SCLC metastasis. These findings have direct consequences for the pathogenesis and classification of lung cancer. First, SCLC should be differentiated into primary and secondary carcinomas. Whereas primary SCLC as the predominant tumor type evolve directly from a precursor cell of probably epithelial origin, secondary SCLC develop via a NSCLC intermediate. Second, neuroendocrine differentiation in lung carcinomas should be used as a marker for dedifferentiation, worse prognosis and rapid tumor progression rather than an indicator of a putative tumor stem cell. The primary data is available at our online tumor database at http://amba.charite.de/cgh/.