Thymic Neuroendocrine Tumors: Evolving Insights and Innovative Approaches

TL;DR

This review discusses treatment strategies for rare thymic neuroendocrine tumors, emphasizing the need for personalized and prospective studies to improve outcomes.

Contribution

The paper provides an updated overview of treatment approaches and highlights the need for prospective studies and molecular refinement in managing thymic neuroendocrine tumors.

Findings

Surgical resection is the primary treatment for TNENs when feasible.

Peptide receptor radionuclide therapy shows promise for somatostatin receptor–positive tumors.

Multidisciplinary and individualized treatment approaches are essential due to tumor heterogeneity.

Abstract

Thymic neuroendocrine tumors (TNENs) are exceptionally rare and a clinically heterogeneous malignancy, often diagnosed at an advanced stage and lacking standardized treatment algorithms. Due to the scarcity of dedicated evidence, most therapeutic strategies are extrapolated from other neuroendocrine neoplasms.

This narrative review provides an updated overview of current and emerging treatment approaches for TNENs, focusing on histology-driven strategies and the evolving role of targeted and radionuclide therapies. A comprehensive literature search was conducted through PubMed/MEDLINE and Embase from January 1, 2000, up to May 31, 2025, integrating retrospective series, real-world data, and ongoing clinical trials.

Surgical resection remains the cornerstone of treatment whenever feasible. The benefit of adjuvant therapy in well-differentiated tumors is unclear, whereas thymic neuroendocrine carcinomas often require multimodal approaches, including platinum–etoposide chemotherapy and radiotherapy. Retrospective evidence suggests that even well-differentiated, high-grade tumors may respond to cytotoxic agents. Somatostatin analogues are widely used in indolent or peptide receptor-positive tumors, whereas everolimus and, more recently, cabozantinib represent options for progressive disease. Peptide receptor radionuclide therapy has demonstrated encouraging results in somatostatin receptor–positive tumors and is currently under further investigation in prospective trials involving thymic primaries. However, the 5-year overall survival rate varies significantly (approximately 28%–80%), underlining an urgent need for prospective, subtype-specific studies.

The management of TNENs requires a multidisciplinary and individualized approach based on histologic subtype, somatostatin receptor status, and disease aggressiveness. Despite promising therapeutic options, robust prospective data remain limited. The integration of TNENs into basket trials, the molecular refinement of prognostic subgroups (e.g., NET G3), and the conduct of dedicated multicenter prospective studies are urgently needed to define optimal treatment algorithms and improve clinical outcomes in these rare entities.

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