Low-grade neuroendocrine tumors arising in intestinal adenomas: evidence for alterations in the adenomatous polyposis coli/β-catenin pathway.

Low-grade neuroendocrine tumors (NETs) arising in intestinal adenomas are rare. They are occasionally observed in patients with familial adenomatous polyposis (FAP), suggesting a role for the adenomatous polyposis coli/β-catenin pathway. We identified 25 composite adenoma/low-grade NETs from colorectum (21) and duodenum (4) and evaluated their clinicopathological features, survival, and nuclear β-catenin expression by immunohistochemistry. β-catenin staining was scored as % positivity × intensity (weak, 1; moderate, 2; and strong, 3), for a total possible score of 300. Control groups included 1781 adenomas without NET, 63 composite adenoma/high-grade neuroendocrine carcinomas (NECs), and 32 sporadic NETs. Among 25 adenoma/low-grade NETs, 4 (16%) occurred in patients with FAP. Size of the NET component ranged from 0.01 to 0.9 cm (mean, 0.32 cm). Most (84%) arose in "advanced" adenomas (size >1 cm, villous architecture [72%], or high-grade dysplasia [56%]). In contrast, villous architecture and high-grade dysplasia were present in only 14% (P < .001) and 7% (P < .001), respectively, of adenomas without NET. Overall survival with adenoma/low-grade NET was significantly higher than adenoma/high-grade NEC but significantly lower than sporadic NET (P < .001). Higher β-catenin expression was seen in adenoma/low-grade NETs (mean score, 231) compared with sporadic NETs (mean score, 48; P < .0001) and adenoma/high-grade NEC (mean score, 173; P = .04). In summary, composite adenoma/low-grade NETs most commonly occur with advanced polyps, but the NET component itself is generally small and indolent. In contrast to sporadic NETs, the occurrence of these lesions in FAP and their high levels of nuclear β-catenin expression support a pathogenic role for the adenomatous polyposis coli/β-catenin pathway.