Primary duodenal adenocarcinoma accounts for less than 0.5% of all gastrointestinal cancers. We report a case of duodenal adenocarcinoma with highly divergent growth patterns consisting of poorly differentiated adenocarcinoma and neuroendocrine carcinoma proven to arise as a single neoplasm of monoclonal origin, as demonstrated by microdissection-based mutational profiling. Multicomponent growth patterns, as seen in this case, can occasionally be encountered in gastrointestinal malignancies and have led to speculation about the pathogenesis. The methods used to clearly establish monoclonal origin based on the unique profiling of mutational damage can address fundamental issues related to tumor development and progression, while providing cogent clinical information. Our findings confirm the great potential for intestinal epithelial cells to differentiate along different histogenetic lines during tumor progression.