Spontaneous Transformation from Lung Adenocarcinoma to <i>MYC</i>‐amplified Large Cell Neuroendocrine Carcinoma

Recent studies suggest that lung adenocarcinoma cells are closely associated with the tumorigenesis of large-cell neuroendocrine carcinoma via cellular transformation. However, morphological evidence, along with genetic abnormalities before, during, and after transformation, is quite limited. We present here a case of combined large-cell neuroendocrine carcinoma and adenocarcinoma exhibiting acinar and solid patterns. Adenocarcinoma cells with abundant mucin, exhibiting positivity for both napsin-A and neuroendocrine markers, were partially found in the acinar adenocarcinoma component and extensively observed in the solid adenocarcinoma component. Next-generation sequencing using extracted genomic DNA from the three components revealed homozygous TP53 (missense) and STK11 (nonsense) mutations in all three components, suggesting monoclonal origin. Furthermore, MYC gene amplification, recently presumed to be a pivotal driver in neuroendocrine transformation, was observed in both the solid adenocarcinoma and large-cell neuroendocrine carcinoma components. These genetic findings corresponded to pre- and post-transformation morphology, providing compelling evidence that some kinds of adenocarcinomas may serve as a precursor of large-cell neuroendocrine carcinoma.