Unravelling mesenteric fibrosis in small intestinal neuroendocrine tumours and implications for clinical management.

Mesenteric fibrosis (MF) is an extensive fibrotic reaction common in small intestine neuroendocrine tumours (SI-NETs) and develops around mesenteric metastasis. While primary SI-NETs can remain asymptomatic for years, mesenteric metastasis (MM) and the resulting MF frequently leads to serious complications. Despite its clear impact on quality of life, MF pathophysiology remains poorly understood and treatment options are currently limited to surgical interventions. This review summarizes the literature on MF in SI-NET patients, emphasizing gaps in knowledge and potential research directions. Clinical research confirms that MF is a frequent complication, often causing severe morbidity, including mesenteric ischaemia and obstruction. Addressing these issues requires further research into MF pathogenesis and contributory factors, such as elastic vascular sclerosis (EVS), which are currently underexplored. Advancing this field will necessitate collaboration, supported by clear definitions and standardized diagnostic and grading systems for MF linked to clinical data, which are presently lacking. While MF-directed translational research remains scarce, recent studies focusing on tumour microenvironment have begun to uncover possible pathways involved in MF. Serotonin, pro-fibrotic growth factors and cytokines may play a role in activating cancer-associated fibroblasts and immune cells within the tumour microenvironment, aggravating extracellular matrix protein deposition and possibly creating positive feedback loops that promote fibrosis. Recently classified as an organ, the mesentery may harbour unique properties for stimulating the establishment of MF. Emerging research is paving the way for new MF treatment options that are urgently needed.