Thymic neuroendocrine tumours: molecular landscape, immune microenvironment and therapeutic perspectives

Thymic neuroendocrine tumours (T-NETs) are rare, aggressive malignancies with distinct biology and poor outcomes. Current management is extrapolated from other neuroendocrine tumours (NETs), highlighting a critical need for a synthesised understanding of their unique molecular and immune landscape.

We conducted a comprehensive narrative review (2000-2026) of T-NETs, interrogating PubMed, Embase, Web of Science and Scopus. Focus was placed on clinicopathology, molecular alterations, tumour immune microenvironment and therapeutic outcomes.

T-NETs encompass a spectrum from well-differentiated carcinoids to high-grade carcinomas. Their molecular drivers are grade-specific, featuring TP53 (tumour protein p53)/RB1 (retinoblastoma 1) loss and chromosomal instability in high-grade tumours, alongside prevalent chromatin remodelling and PI3K (phosphatidylinositol 3-kinase)-mTOR (mechanistic target of rapamycin) dysregulation. The immune microenvironment is predominantly "inflamed", with heterogeneous PD-L1 (programmed death-ligand 1)/VISTA (V-domain Ig suppressor of T-cell activation) expression and T-cell infiltration that is often restrained by a myeloid-rich stroma. For clinical management, surgical resection is curative for localised disease. In advanced stages, therapy is extrapolated from other NETs and includes somatostatin analogues (for somatostatin receptor-positive tumours), everolimus, temozolomide-based regimens and, in selected cases, peptide receptor radionuclide therapy. Immunotherapy and novel combinations represent emerging investigational avenues.

T-NETs are biologically distinct thymic malignancies. Improved care will require thymus-specific molecular and immune profiling, standardised diagnostic criteria, and prospective collaborative studies to move beyond extrapolated treatment paradigms.