Clarifying the Diagnostic Boundaries in High-Grade Neuroendocrine Neoplasms: A Commentary on Histopathologic and Genetic Distinctions

• Abha E. John

  Assistant Professor, Christian Medical College, Ludhiana, India

  Author

Background: High-grade neuroendocrine neoplasms (NENs) encompass well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs), which differ significantly in morphology, genetics, prognosis, and therapeutic response. The article reviewed by Sun et al. (Am J Clin Pathol. 2025;163(6):804–814) provides a synthesis of histopathologic, immunohistochemical, and genomic criteria to aid in distinguishing these entities. Objective: To critically appraise the review by Sun et al., highlighting its strengths, identifying areas needing further clarity, and suggesting directions for future research to refine diagnostic and therapeutic strategies. Methods: A narrative critical appraisal was undertaken, examining the review’s discussion of morphology, immunohistochemistry, genetic profiling, proliferation indices, imaging modalities, and treatment implications, with reference to current literature and practice guidelines. Key Appraisal Points: Strengths: Comprehensive synthesis of morphologic patterns, genetic alterations (ATRX, DAXX, MEN1 in G3 NETs; TP53, RB1 in NECs), and proliferation indices. Useful incorporation of WHO classification updates and proposed diagnostic algorithms. Clear delineation of functional imaging differences (somatostatin receptor imaging for G3 NETs vs FDG PET for NECs). Limitations: Absence of a defined systematic review methodology (search strategy, selection criteria, quality assessment). Limited discussion on handling borderline Ki-67 indexes cases and mixed morphologic features in small biopsies. Small sample sizes in genomic profiling studies; organ-specific mutation patterns not explored. Undefined immunohistochemistry interpretation criteria for p53 and ATRX mutation status. Clinical Relevance: Highlights the importance of integrating histology, proliferation rate, immunohistochemistry, genetics, and imaging in diagnosis. Emphasizes differing prognoses and treatment responsiveness—PRRT, temozolomide, and somatostatin analogues for G3 NETs vs platinum-based chemotherapy and emerging immunotherapy for NECs. Conclusions: The review by Sun et al. makes a valuable contribution to refining diagnostic boundaries between G3 NETs and NECs. Greater methodological transparency, standardized biomarker interpretation, and larger multicentre genomic studies are needed to strengthen evidence and guide practice. Integrating proliferative indices with multimodal diagnostic algorithms holds promise for improving accuracy and patient outcomes.

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