Endocrine Pathology最新文献

Epstein-Barr virus (EBV)-positive neuroendocrine carcinoma (NEC) of the nasopharynx is a rare malignancy with poor prognosis and lacks squamous markers, rendering it biologically distinct from nasopharyngeal carcinoma (NPC) of squamous epithelial origin. However, its molecular features remain largely undefined, and the entity has not been formally recognized as a nasopharyngeal carcinoma subtype, substantially limiting advances in its diagnosis and treatment. In this study, we performed whole-exome sequencing on seven EBV-positive nasopharyngeal NECs. These tumors exhibited a high tumor mutational burden and recurrent mutations in TP53, APC, and PROK2, with enrichment of alterations in the TP53/WNT, NOTCH, and RTK/RAS/PI3K pathways-mimicking the genomic landscape of NECs at other anatomical sites but clearly diverging from that of NPC. In addition, we identified potentially actionable alterations involving TP53 and KMT2A, suggesting avenues for targeted therapeutic exploration. Collectively, our findings provide molecular evidence supporting EBV-positive NEC of the nasopharynx as a distinct clinicopathologic entity, and offer valuable insights into its oncogenesis and potential therapeutic vulnerabilities.

Although defects in the mismatch repair (MMR) system have been occasionally reported in aggressive/metastatic pituitary neuroendocrine tumors (PitNETs), the potential role of MMR dysregulation in pituitary tumorigenesis is largely unknown. This study aimed to evaluate the expression of the four key MMR components in a large series of PitNETs. MMR gene expression was studied by RT-qPCR in 127 tumors (54 PIT1, 51 SF1, 22 TPIT), and semi-quantitative immunohistochemistry (score 0-12) in selected cases (n=46). MSH2/6 and MLH1 promoters methylation was studied in 96 tumors. Except for MLH1, tumor lineage of origin was the most significant factor influencing MMR transcripts (P=0.005, <0.001 and 0.039 for MSH2/6 and PMS2, respectively), the highest levels being observed in SF1 tumors. Within subgroups, MMR transcripts were significantly lower in large/invasive PIT1 and in functioning TPIT tumors. MSH2 promoter methylation was occasionally associated with reduced MSH2 expression. Global loss of MSH6 (score 0), defining MMR deficiency, was observed in a single silent lactotroph PitNET, unrelated to the Lynch's syndrome. Near global loss involving MSH6, MSH2 or PMS2 (score 1) was observed in 5 tumors (1 lactotroph, 1 SF1, 3 TPIT). MMR mutations were excluded in 4/5 cases but 2 had LOH at MSH2/MSH6 loci. Heterogeneous immunostaining for any MMR (score 2-4) was also observed in 15 cases. In conclusion, MMR deficiency was rarely observed (2.2%) but reduced MMR expression could be found, especially in functioning corticotroph and invasive lactotroph tumors. The molecular mechanisms and prognostic significance of such findings would deserve further investigation.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy accounting for 1-2% of thyroid carcinomas. As a neuroendocrine neoplasm, it shares molecular features with other aggressive neuroendocrine carcinomas, including alterations in the Myc and Notch pathways. Delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch pathway and a validated therapeutic target in small cell lung carcinoma, has attracted interest as a biomarker and potential target in other neuroendocrine tumors; however, its relevance in MTC remains poorly characterized. We performed a multicenter retrospective study of 119 MTC cases resected between 2000 and 2024 across five European institutions. DLL3 immunohistochemistry was assessed on whole sections using the Ventana SP347 antibody, with expression categorized as null (< 1%), low (1-49%), or high (≥ 50%). Interobserver agreement between two endocrine pathologists was substantial (weighted kappa = 0.80). DLL3 positivity (≥ 1%) was observed in 89.1% of cases; 53.8% showed low and 35.3% high expression. DLL3-high expression correlated with adverse histopathological features, including larger tumor size, high-grade histology, desmoplasia, positive surgical margins, and lymph node metastases. In survival analyses, DLL3-high expression was associated with significantly shorter disease-free survival (HR 7.96, p = 0.05) and overall survival (HR 11.6, p = 0.01). Our findings indicate that DLL3 is frequently expressed in MTC and its high expression identifies tumors with aggressive pathological characteristics and poor clinical outcomes. These results support DLL3 as a potential prognostic biomarker and therapeutic target in MTC, highlighting the need for further validation and integration into clinical trials of DLL3-directed therapies.