Histopathologic and genetic distinction of well-differentiated grade 3 neuroendocrine tumor versus poorly-differentiated neuroendocrine carcinoma in high-grade neuroendocrine neoplasms

Objectives: The classification of neuroendocrine neoplasms has evolved significantly. In the current World Health Organization (WHO) classification, well-differentiated grade 3 neuroendocrine tumors (G3-NETs) are distinguished from poorly-differentiated neuroendocrine carcinomas (NECs) based on morphology despite using the same proliferation indices, which poses diagnostic challenges. This review aims to assist pathologists in making an accurate diagnosis, which is crucial for patient management as G3-NETs and NECs have different prognoses and chemotherapy responses. Methods: A literature review and meta-analyses were conducted to summarize current knowledge of G3-NETs and NECs, focusing on histopathologic and genetic characteristics. Results: Grade 3 neuroendocrine tumors and NECs are distinct entities with differences in histopathology, genetics, and clinical presentations. Grade 3 neuroendocrine tumors have a lower Ki-67 proliferation index and tumor mutational burden compared to NECs. Distinct gene mutations and pathways have been identified in G3-NETs and NECs, offering potential for developing a diagnostic gene panel. The 2022 WHO classification recognizes the use of immunohistochemistry for somatostatin receptors 2/5, TP53, Rb, Menin, P27, ATRX, and DAXX to distinguish G3-NETs and NECs. In particular, TP53 and ATRX immunohistochemistry may be useful in routine diagnostics. Conclusions: Specific immunohistochemistry and genetic tests should be developed and incorporated into the classification to reliably distinguish G3-NETs from NECs.