Non-L-cell immunophenotype and large tumor size in rectal neuroendocrine tumors are associated with aggressive clinical behavior and worse prognosis.

According to the 2010 World Health Organization classification, all gastrointestinal neuroendocrine tumors (NETs) are classified as malignant except for L-cell-type (glucagon-like peptide [GLP] and peptide YY [PYY]-producing) NETs. However, L-cell immunophenotype in rectal NETs has not been widely studied previously. Immunohistochemical labeling of L-cell markers with GLP1 and PYY was performed in 208 surgically or endoscopically resected rectal NET cases with tissue microarrays and was compared with clinicopathologic features and patient survival. Rectal NETs with non-L-cell immunophenotype and large tumor size (>1 cm) were associated with increased tumor grading, advanced T category, lymphovascular and perineural invasions, and lymph node and distant metastases (P<0.001, each). Rectal NET patients with non-L-cell phenotype and measuring >1 cm had significantly worse survival outcome than other groups by univariate (P<0.001) and multivariate (P<0.001) analyses. In summary, non-L-cell immunophenotype and large tumor size are associated with increased tumor grading and staging, concurrently indicating that they are independently poor prognostic indicators in rectal NET patients. Therefore, combining L-cell phenotype and tumor size can demonstrate the clinical behavior of rectal NETs more precisely than use of L-cell immunophenotype alone.