Low Grade Neuroendocrine Tumors Arising in Intestinal Adenomas: Evidence for Alterations in the Beta-Catenin/APC Pathway
Jeannelyn S Estrella, Melissa W Taggart, Asif Rashid, Susan C Abraham. U.T. M.D. Anderson Cancer Center, Houston, TX
Background: Although high grade/small cell neuroendocrine tumors (NETs) arising from intestinal adenomas are well-described, intestinal adenomas rarely give rise to low grade NETs; the largest series to date includes only 4 cases. Such lesions have occasionally been reported in patients with familial adenomatous polyposis (FAP), suggesting a role for the APC/beta-catenin pathway in composite adenoma/low grade NET.
Design: We identified 18 cases of composite adenoma/low grade NET arising in the colorectum (15) and duodenum (3). These cases were evaluated for size, depth of invasion, presence of other invasive elements (adenocarcinoma, squamous carcinoma), lymphovascular invasion, survival, and nuclear beta-catenin expression by immunohistochemistry. Beta-catenin staining was scored as % nuclear positivity multiplied by intensity (weak=1, moderate=2, strong=3), for a total possible score of 300. Control groups included 63 adenoma/high grade NET and 32 sporadic intestinal NET.
Results: Adenoma/low grade NETs ranged from 0.01-0.9 cm. NET alone comprised the invasive component in thirteen (72%) cases, whereas the other 5 also contained adeno- or squamous carcinoma. The NET component was confined to lamina propria in 5 (28%), muscularis mucosae in 5 (28%), and submucosa in 8 (44%). Only one showed lymphovascular invasion by NET, and all were alive without evidence of disease at last follow-up. Four (22%) patients had FAP. In comparison to sporadic low grade NET, adenoma/low grade NET had significantly higher beta-catenin expression (mean score of 231 vs 48, p>0.001). High levels of nuclear beta-catenin expression were also found in adenoma/high grade NET (mean score, 173) but were not significantly different from adenoma/low grade NET.
|Adenoma/low grade NET (n=18)||Adenoma/high grade NET (n=63)||p|
|Age||63y (20-84y)||58y (30-88y)||NS|
|Gender (male)||11 (61%)||31 (49%)||NS|
|Size||0.4 cm (0.01-0.9 cm)||4.3 cm (0.2-18 cm)||0.004|
|NET only||13 (72%)||45 (71%)||NS|
|+ACA||3 (17%)||12 (19%)||NS|
|+SCC||1 (6%)||5 (8%)||NS|
|+ACA and SCC||1 (6%)||1 (2%)||NS|
|Lymphatic invasion||1 of 16 (6%)||36 of 38 (95%)||0.001|
|Lymph node metastasis||0 of 5 (0%)||28 of 34 (82%)||0.001|
|Distant metastasis||0 (0%)||54 of 59 (92%)||0.001|