THADA::IGF2BP3 fusion results in IGF2BP3 (IMP3) overexpression, driving a subset of RAS-like indolent thyroid tumors, typically noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) or minimally invasive encapsulated follicular variant of papillary thyroid carcinoma (miEFVPTC). These also have distinct morphologic features that have yet to be characterized. We assessed 51 cases of surgically resected thyroid nodules with IMP3 positivity or IGF2BP3 overexpression (IMP3+) and compared them to 113 pathologically similar cases without IMP3 positivity (IMP3–) within the same time frame (2014–2025). IMP3+ cases were diagnosed as miEFVPTC (n=36), NIFTP (n=14), with only one follicular adenoma. On comparative morphologic analysis, key features selectively noted in IMP3+ tumors included: low power “pale blue” optical clarity, condensation of cellularity at the nodule periphery, microfollicles interspersed between macrofollicles, perifollicular sclerosis, clear cytoplasm, perinuclear indentation by cytoplasmic vacuoles, “squared-off” nuclei, prominent single nuclear grooves, grade 3 nuclei, and background chronic lymphocytic thyroiditis. Oncocytic cytoplasm and solid/trabecular/insular growth were exclusive to the IMP3– group. Only one of 34 (2.9
It has been recently demonstrated that papillary thyroid carcinomas (PTCs) that develop distant metastases are characterized by three genetic alterations: Chr1qamp, TERT_locusamp, TERT_promotermut. This signature, named THYT1, holds the potential as an early prognostic predictor to identify patients at risk for disease progression. To implement the use of this signature in clinical practice we first developed a droplet digital PCR approach for a faster and cost-effective detection of the THYT1 in PTCs, then we validated its performance in a retrospective monocentric case–control training cohort (N = 90) of PTCs and in a separated multicentric validation cohort (N = 143) of PTCs. We also investigated THYT1 feasibility in cytological pre-surgical thyroid smears. In the training set, THYT1 evaluation by ddPCR showed 93
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.
Ampullary somatostatin-producing D-cell neuroendocrine tumors are rare neoplasms that may be associated with type 1 neurofibromatosis. The molecular features of sporadic ampullary somatostatin-producing D-cell neuroendocrine tumors (SAMSOM-NETs) remain poorly characterized. We performed an integrated morphological, immunohistochemical, and genomic analysis of a multicenter series of SAMSOM-NETs. Eleven cases were included (73
