Distinct Molecular Pathways Driving Thymic and Pulmonary Neuroendocrine Neoplasms: Organ of Origin Defines Molecular Identity and Yields CD44 as a Marker of Pulmonary Neuroendocrine Tumors

Abstract Thymic and pulmonary neuroendocrine neoplasms (NEN) are morphologically similar but arise from different embryonic tissues. Whether this similarity extends to shared molecular programs is unclear. We compared 45 thymic and 37 pulmonary NEN by immunohistochemistry, targeted and exome sequencing, NanoString RNA profiling and mass spectrometry-based proteomics. The RNA and proteomic profiles of pulmonary and thymic neuroendocrine tumors (LuNET and TNET) were clearly different, while the profiles of neuroendocrine carcinomas of both organs (LuNEC and TNEC) were largely overlapping. A subgroup of TNET corresponding to NET G3 clustered with lower-grade thymic NET rather than NEC. NET of both organs showed a low mutational burden and were proliferatively quiescent but diverged metabolically: LuNET showed broad metabolic and stress signaling and TNET a quiescent phenotype with PI3K/AKT/mTOR as the only enriched pathway. NEC of both organs converged on cell cycle activation and metabolic depletion with frequent TP53 and RB1 co-inactivation, but diverged immunologically: LuNEC were immune-hot, whereas TNEC showed epithelial–mesenchymal transition and a markedly lower mutational burden. CD44 stood out in both the transcriptomic and the proteomic analysis and was therefore immunohistochemically validated in an independent, larger cohort that included also gastrointestinal and pancreatic tumors. CD44 was high in pulmonary NET and low in every other subgroup ( p = 2.1 × 10⁻¹³), identifying it as a new complementary marker of pulmonary origin. In summary, thoracic NEN segregate by anatomical origin as well as by differentiation grade. Wether these differences require treatments adapted to the organ of origin remains to be established.