Morphologic variants in PanNETs: clinicopathologic and prognostic associations

Background Pancreatic neuroendocrine tumors (PanNETs) exhibit morphologic heterogeneity, including uncommon variant patterns that create diagnostic challenges and whose clinicopathologic significance remains incompletely defined. Methods We retrospectively analyzed 82 resected, well-differentiated PanNETs to identify non-classical morphologic variants and evaluate their clinicopathologic and survival associations. Morphologic variants were classified using literature-based criteria. Overall survival and recurrence-free survival were assessed using Kaplan-Meier and Cox models. Results Morphologic variants were identified in 20 tumors (24%), including eosinophilic (oncocytic-hepatoid), dyscohesive/plasmacytoid-rhabdoid, lipid-rich, peliotic/angiomatoid, paraganglioid, and pseudoglandular patterns. Variants previously classified as aggressive (n = 14) were significantly associated with higher Ki-67 indices ( p = 0.044) and higher WHO grades ( p = 0.007). No significant associations were observed between variant status and pathologic stage, nodal status, or metastatic disease at diagnosis. Aggressive variants showed a trend toward shorter overall survival, although this did not reach statistical significance ( p = 0.086). In multivariable Cox models for recurrence-free survival, nodal involvement remained independently associated with recurrence risk. The Ki-67 index showed a trend toward increased recurrence risk, although this did not reach statistical significance, whereas morphologic variant status did not show an independent prognostic impact. Conclusion Morphologic variants constitute an important component of the histologic spectrum of PanNETs and are associated with adverse histopathologic features. Recognition of these patterns is important in diagnostic practice, especially in limited biopsy or metastatic settings where they may mimic other neoplasms. Given the limited number of variant cases and survival events in this single-institution cohort, their independent prognostic significance remains unproven, and non-classical morphologies should be interpreted cautiously alongside established parameters, such as nodal status and proliferation index.