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Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models

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Grade Progression and High-Grade Transformation in Neuroendocrine Neoplasms.

Udhayvir S Grewal¹, Matthew Gosse², Seth J Concors³

¹Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University , Atlanta, GA, United States.

Endocrine-Related Cancer

|July 13, 2026

Summary

Neuroendocrine neoplasms (NENs) can transform from well-differentiated tumors (NETs) to poorly differentiated carcinomas (NECs). This review explores the molecular, morphologic, and clinical aspects of this grade progression in gastroenteropancreatic NENs.

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Area of Science:

Oncology
Gastroenterology
Pathology

Background:

Epithelial neuroendocrine neoplasms (NENs) are diverse malignancies with varying differentiation and behavior.
Current classifications differentiate well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs).

Purpose of the Study:

To review the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation.
To highlight the roles of clonal evolution and treatment pressure in NENs.
To discuss implications for diagnosis and treatment strategies.

Main Methods:

Literature review synthesizing recent evidence on NEN grade progression.
Analysis of molecular, morphologic, and clinical data.
Discussion of diagnostic and therapeutic challenges.

Main Results:

A subset of NETs can evolve to NEC-like tumors, exhibiting increased Ki-67, atypia, and genomic alterations (e.g., TP53, RB1 inactivation).
This grade progression creates diagnostic and therapeutic ambiguity.
Clonal evolution and treatment selection pressure contribute to tumor transformation.

Conclusions:

Understanding NEN grade progression is crucial for accurate diagnosis and effective therapy.
Further research is needed to refine diagnostic criteria and treatment approaches for evolving NENs.
Implications for imaging, biopsy, molecular profiling, and therapy selection are discussed.