Discussion

The oncocytic variant of pancreatic neuroendocrine tumors (O-NETs) is a distinct and rare subtype, representing approximately 5% to 7.2% of well-differentiated pancreatic neuroendocrine tumors (WDNETs). A strategic priority in modern pancreatobiliary oncology is the recognition of morphological variants that deviate from classical presentations. 

A unifying provisional category proposed by Xue et al. (2020) is the category "Metabolic Cell Phenotype" that shares the traits of abundant cytoplasm and nucleolar prominence—markers of high metabolic activity, including;

• Oncocytic (Oxyphilic): Mitochondria-rich cells with granular eosinophilic cytoplasm. Low N/C ratio (< 1/4)

• Hepatoid: Mimicking the polygonal architecture and central nuclei of hepatocytes. High N/C ratio (> 1/2)

• Lipid-rich: Characterized by abundant foamy or microvesicular cytoplasm.

• Discohesive/Plasmacytoid: Featuring sheets of cells lacking cellular adhesion.

Microscopic findings

Instead of the “organoid” pattern (small nests/trabecular with delicate fibrovascular septa) of the classic NET, the oncocytic net frequently exhibits a diffuse or solid growth pattern, appearing as broad bands and solid sheets. Using EM, approximately 60% of the oncocyte’s cytoplasm is packed with globose or oval mitochondria. These organelles are not only numerous but structurally aberrant, featuring altered cristae that appear in lamelliform, tubular, or flat stacks. 

Immunohistochemical (IHC) Profiling and Diagnostic Pitfalls

O-NETs generally retain positivity for standard neuroendocrine markers (synaptophysin, chromogranin, INSM-1, CD56). However, the most important pitfall is its aberrant expression of Arginase-1 and HepPar-1 (50% of these cases), which might lead to misdiagnosis of metastatic hepatocellular carcinoma (HCC). O-NETs do not have distinct mutations from WDNETs 

Clinical outcome

Data from stepwise logistic regression (Xue et al., 2020) indicates that aggressive morphology (the metabolic phenotype) was an independent determinant of adverse outcome (more aggressive behavior, metastatic risk, vascular invasion, higher rate of recurrence, and typically larger at the time of diagnosis), regardless of the proliferation index.

References

1. Di Carlo S, et al. (2015). Oncocytic Neuroendocrine Tumour of the Pancreas and Duodenum: Two Case Reports with Review of the Literature. Journal of Pancreas, 16(4): 380–383.

2. Hsiao WY, et al. (2025). Oncocytic subtype of well differentiated neuroendocrine tumor: clinicopathologic and molecular associations of a cohort diagnosed on fine needle aspiration (FNA). Journal of the American Society of Cytopathology, 14(4): 209–221.

3. Shetty D, et al. (2024). Pancreatic neuroendocrine tumor with abundant mitochondria. Indian Journal of Cancer, 61(2): 415–417.

4. Xue Y, et al. (2020). Morphologic Variants of Pancreatic Neuroendocrine Tumors: Clinicopathologic Analysis and Prognostic Stratification. Endocrine Pathology, 31: 239–253.