CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Analysis of colorectal neuroendocrine carcinomas with glandular components
Neuroendocrine carcinomas are relatively infrequent in the colorectum and are characterized by neuroendocrine morphology and expression of neuroendocrine markers, such as synaptophysin, chromogranin A, and CD56. They appear to be biologically distinct from the less aggressive neuroendocrine tumors and more biologically related to adenocarcinoma. Furthermore, neuroendocrine carcinomas are often spatially proximate to conventional adenocarcinoma components and can sometimes be classified as mixed adenoneuroendocrine carcinomas if they meet the requisite criteria. The authors conducted a study in which they identified a series of 15 cases of colorectal neuroendocrine carcinomas with glandular components, 10 of which were classified as mixed adenoneuroendocrine carcinomas. After identifying the pure glandular and pure neuroendocrine components by morphologic and immunohistochemical examination, the separate components were microdissected for genetic analysis. In all cases, an abrupt morphologic transition from glandular to neuroendocrine components occurred. KRAS gene mutation analysis revealed identical mutational status in the glandular and neuroendocrine components of all cases, suggesting a common clonal origin. Ten cases were examined by a next-generation sequencing panel of 50 cancer-related genes. In the tumors analyzed, 130 mutations were identified, 55 of which were seen in pure glandular components and 75 in neuroendocrine components. Of these mutations, 32.6 percent were shared among the two components, 40.7 percent were exclusive to the neuroendocrine components, and 26.7 percent were exclusive to the glandular components. The most frequent mutations were seen in TP53, KRAS, and APC, with 62 percent of these shared among the two components. Also seen were PIK3CA mutations, occurring more often in the glandular components, and RB1 and MET mutations, more often seen in the neuroendocrine components, although these differences were not significant. Mutations identified in TP53, KRAS, APC, RB1, MET, BRAF, ERBB4, and PTPN11 could be classified as founding clone mutations, as determined by identifying mutations seen in nearly 100 percent of tumor cells. However, mutations in other genes, including PIK3CA, had lower allele fractions and were, therefore, determined to be a later event that defined some subclones. The founding mutations were more likely to be shared between the neuroendocrine and glandular components. Whole exome sequencing performed on three cases identified shared mutations in all of them, but the shared mutations were only nine percent of all mutations seen, while 44.4 percent were exclusive to the glandular components and 46.6 percent exclusive to the neuroendocrine components. While histologic examination showed an abrupt transition, the genetic findings in this study appear to demonstrate a common clonal progenitor due to identical KRAS mutational status and additional shared mutations identified by next-generation panel and exome sequencing. However, the findings of mutations exclusive to glandular or neuroendocrine components show divergent evolution likely early in tumor development. In addition, this study demonstrates that the genetic basis of neuroendocrine carcinomas is distinct from that of neuroendocrine tumors or carcinoids.
Woischke C, Schaaf CW, Yang HM, et al. In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components [published online ahead of print September 2, 2016]. Mod Pathol. doi:10.1038/modpathol.2016.150.
Correspondence: Dr. D. Horst at david.horst@med.uni-muenchen.de