Concordance of Genetic Alterations in Poorly Differentiated Colorectal Neuroendocrine Carcinomas and Associated Adenocarcinomas

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Abstract
Background: The histopathologic spectrum of colorectal neuroendocrine tumors ranges from benign to highly malignant. In this spectrum, poorly differentiated neuroendocrine carcinoma (PDNC) is the most aggressive type, characterized by early dissemination and a rapidly fatal course. Since it is unclear whether PDNC originates from neoplastic transformation of preexisting neuroectodermal cells, pluripotent epithelial stem cells, or adenocarcinoma precursor cells, we investigated the histogenesis of this type of cancer by performing genetic analyses on a series of colorectal tumors. Methods: Archived histologic sections of colorectal PDNC from nine patients were analyzed; gastrointestinal carcinoid tumor specimens from four patients were used as controls. The specimens were deparaffinized, microdissected, and analyzed genetically. After DNA extraction, polymerase chain reaction amplification was performed to investigate alteration (i.e., loss of heterozygosity [LOH]) of the APC (adenomatous polyposis coli), DCC (deleted in colorectal carcinoma), and p53 (also known as TP53) genes. Results: LOH of the APC, DCC, or p53 genes was observed in six of eight informative PDNC tumors; no LOH was detected in the carcinoid control specimens. Four of five informative PDNC tumors had associated adenocarcinoma; LOH of the APC and p53 genes in these tumors involved the same allele in both tissue components. Four of the five tumors with associated adenocarcinoma showed LOH of the DCC gene; in three of these four tumors, the PDNC and adenomatous components showed LOH of the same allele. Conclusions: PDNC and associated adenocarcinoma appear to be derived from the same cell of origin, which is most likely either a pluripotent epithelial stem cell or an adenocarcinoma precursor cell.