Molecular alterations in high-grade neuroendocrine tumors of the small intestine
Agathe Hercent1,2,3, Julien Masliah-Planchon4, David Cohen3
1Department of Pathology, FHU MOSAIC, Beaujon-Bichat Hospitals, AP-HP, Université Paris-Cité, Paris, France.
Abstract:
High-grade neuroendocrine tumors of the small intestine are separated into two groups: well-differentiated neuroendocrine tumors (NETs, high-grade) and poorly differentiated neuroendocrine carcinomas (NECs). They represent very rare entities, with few molecular data available, and are very challenging to treat. In this study we aimed to describe the molecular profile of these tumors and their spatial and temporal heterogeneity. We collected a national multicenter cohort of high-grade NETs (14 patients) and NECs (11 patients). DNA and RNA were extracted and somatic point mutations, copy number variations, and gene expression levels were studied using high-throughput sequencing of a panel of 571 genes and RNA sequencing, respectively. Additional samples to study spatial or temporal heterogeneity were available for 12 patients, leading to a total of 42 samples analyzed. Differential diagnostic markers were confirmed by immunohistochemistry. NECs resemble their counterparts in other organs, with a relatively high tumor mutational burden (TMB) and frequent alteration of TP53 and RB1, together with organ-specific alterations such as APC. In contrast, high-grade NETs resemble low-grade NETs, with a low TMB but frequent chromosomic alterations. Transcriptomic analysis confirmed that high-grade NETs and NECs are two distinct entities, with specific drivers. Serotonin pathway markers were the most efficient to discriminate high-grade ileal NETs from NECs. Despite variations in the proliferation index, NETs showed little spatial and temporal heterogeneity, suggesting that epigenetic mechanisms play a crucial role in tumor progression. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Insights
High-grade neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) of the small intestine are distinct. Molecular profiling reveals NECs have high tumor mutational burden and TP53/RB1 alterations, while NETs show chromosomal changes.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- High-grade neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) of the small intestine are rare, challenging to treat, and poorly understood molecularly.
- Limited molecular data exists for these aggressive gastrointestinal malignancies.
Purpose of the Study:
- To elucidate the molecular profiles and heterogeneity of high-grade small intestine NETs and NECs.
- To identify distinct molecular drivers and diagnostic markers for these tumor types.
Main Methods:
- A national multicenter cohort of 25 patients (14 high-grade NETs, 11 NECs) was analyzed.
- High-throughput sequencing (571-gene panel, RNA-seq) and immunohistochemistry were employed.
- Spatial and temporal heterogeneity was assessed in 12 patients with additional samples.
Main Results:
- NECs exhibited high tumor mutational burden (TMB) with frequent TP53, RB1, and APC alterations, similar to other organ NECs.
- High-grade NETs displayed low TMB but frequent chromosomal alterations, resembling low-grade NETs.
- Transcriptomic analysis confirmed NETs and NECs as distinct entities; serotonin pathway markers differentiated ileal NETs from NECs.
- NETs showed limited spatial/temporal heterogeneity, suggesting epigenetic roles in progression.
Conclusions:
- High-grade small intestine NETs and NECs are molecularly distinct entities.
- Molecular profiling and specific markers like those in the serotonin pathway can aid in differential diagnosis.
- Epigenetic mechanisms likely drive NET progression with minimal heterogeneity.
