We aimed to identify and compare key molecular alterations underlying adrenocorticotropin (ACTH)-producing neuroendocrine tumors (NETs) in Cushing's disease and ectopic ACTH syndrome. Whole-exome sequencing was performed on 34 pituitary ACTH-secreting NETs (corticotroph tumors: 30 microadenomas and 4 macroadenomas) and 8 ectopic ACTH-producing NETs of lung, pancreatic, and renal origin. Somatic point mutations, copy-number alterations, and loss of heterozygosity (LOH) were compared between corticotroph and ectopic ACTH-producing NETs. Corticotroph tumors demonstrated significantly more gene deletions and LOH events compared with ectopic ACTH-producing NETs (median 1687 and 2573.5 affected genes in corticotroph tumors, respectively). In corticotroph tumors recurrent subtelomeric deletions and LOH on chromosome 19 affecting FAM98C, RASGRP4, RYR1, MAP4K1, and EIF3K were observed. Notably, TERT deletion was detected in 94% of corticotroph tumors versus only 12.5% ectopic ACTH-producing NETs. In contrast, ectopic ACTH-producing NETs frequently exhibited chromosomal duplications on chromosomes 17 and 21, enriched for keratin-associated protein gene clusters. Recurrent somatic point mutations were identified in BRAF, CACNA1I, KLHL20, MCCC2, LRP1, TCP11X2, USP8, and USP48 genes, explaining the molecular basis of disease in 20 of 34 corticotroph tumors and 2 of 6 lung ACTH-producing NETs (LRP1 R1497Q and CACNA1I S639T). These findings indicate that corticotroph tumors predominantly demonstrated deletions and LOH involving subtelomeric genes, whereas ectopic ACTH-producing tumors more commonly exhibited chromosomal duplications. Potentially relevant somatic mutations were detected in 59% of corticotroph tumors and in 33% of lung ACTH-producing NETs. In conclusion, ACTH-producing NETs of pituitary versus other localizations demonstrate significantly different genetic alterations despite similar clinical and secretory phenotypes.

Differentiated thyroid cancer (DTC) is characterized by retention of thyroid-specific functions, particularly iodide uptake mediated by the sodium-iodide symporter (NIS), which underlies the effectiveness of radioiodine (RAI) imaging and therapy. Loss of iodine avidity reflects tumor dedifferentiation and is a defining feature of aggressive, RAI-refractory disease. The Thyroid Differentiation Score (TDS), introduced by The Cancer Genome Atlas (TCGA) program, provides a quantitative transcriptomic measure of thyroid lineage identity based on coordinated expression of genes involved in thyroid hormone biosynthesis and transport. This comprehensive narrative review synthesizes current evidence supporting TDS as a unifying framework linking oncogenic drivers, signaling pathways, tumor microenvironment, metabolic reprogramming, and clinical behavior across thyroid cancer subtypes, including papillary, follicular, poorly differentiated, anaplastic, and pediatric tumors. MAPK pathway activation, particularly via BRAFV600E, is associated with suppression of thyroid differentiation programs, whereas RAS-like and fusion-driven tumors tend to retain higher differentiation states. Emerging data connect TDS with tumor aggressiveness, recurrence risk, immune and inflammatory signaling, and resistance to RAI therapy. The role of TDS in guiding redifferentiation strategies using targeted tyrosine kinase inhibitors is also discussed, highlighting its potential as a biomarker for patient selection in RAI re-sensitization approaches. TDS is a well-established biological measure of thyroid-lineage differentiation and has shown prognostic associations in retrospective studies. However, its value as an individual predictive or theranostic biomarker remains investigational. Future work should focus on developing a personalized theranostic TDS that integrates matched normal tissue, molecular profiling, functional imaging, and machine learning to potentially better predict iodine-handling capacity and optimize precision management in thyroid cancer.

The recent development of new medical therapies has transformed Cushing's disease and acromegaly management, offering patients more individualized and effective treatment strategies beyond surgery and also addressing unmet clinical needs for persistent disease. In Cushing's disease, newer steroidogenesis inhibitors, pituitary-directed therapies, and glucocorticoid receptor antagonists coupled with increasing recognition of disease heterogeneity have highlighted the importance of individualized therapy selection based on corticotroph adenoma characteristics, severity of hypercortisolism, comorbidities, and patient-specific priorities. Management strategies increasingly focus on normalization of biochemical markers and on improvement in quality of life and metabolic outcomes, cardiovascular risk reduction, and prolongation of long-term remission. In acromegaly, the medical treatment landscape has expanded beyond monthly injectable and/or oral somatostatin receptor ligands and pegvisomant to include newer octreotide formulations, selective oral somatostatin receptor agonists, combination approaches, and a highly targeted growth hormone receptor antagonist. These developments have enabled improved biochemical control, patient convenience, and long-term disease management. Nevertheless, unmet challenges in enabling optimal management include delayed diagnosis, treatment resistance, adverse drug effects, adenoma recurrence, and the burden of chronic disease monitoring. For both disorders, ongoing clinical trials and emerging precision medicine approaches are refining therapeutic algorithms and offer optimism for further improved patient outcomes. This review focuses on newly approved and investigational medical treatments for acromegaly and Cushing's disease and their evolving role within pituitary care.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms with an exceptionally high genetic contribution, often driven by single high-penetrance mutations. Approximately one third of patients harbor germline mutations and another third carry somatic driver mutations, allowing stratification into three molecular clusters: pseudohypoxia-related (cluster 1), kinase signaling-related (cluster 2) and Wnt-signaling-related (cluster 3). These clusters differ in catecholamine secretion, malignancy, and metastatic behavior. Although PPGLs have long been viewed as immunologically 'cold' due to their low neoantigen load and limited T cell infiltration, recent studies show a more complex immune landscape, with differences observed between indolent and metastatic tumors, and between genomic clusters. The interaction between the tumor and immune system is, in general, closely associated with tumorigenesis and disease prognosis, with both the innate and adaptive immune system playing pivotal roles. This review summarizes how tumor-derived catecholamines and cluster-specific genetic drivers and metabolic programs are able to orchestrate immune modulation in PPGL. Within clusters of PPGL, distinct metabolic and signaling alterations such as pseudohypoxia, tricarboxylic acid cycle oncometabolites, and aberrant kinase and B-catenin signaling shape both the tumor microenvironment and systemic immune response. We highlight therapeutic opportunities together with approaches that harness or reprogram innate immune memory. Recognizing PPGL as metabolically and immunologically stratified tumors may enable rational, personalized combination therapies for patients with inoperable, recurrent or metastatic disease, and might explain the heterogeneous response to immunotherapy currently observed.

Therapeutic options for metastatic pheochromocytomas and paragangliomas (mPPGLs) remain limited. Recent studies indicate that tyrosine kinase inhibitors (TKIs) offer a promising treatment approach. This study aims to evaluate the efficacy and safety of TKIs for mPPGLs based on available evidence. A systematic search for studies investigating the treatment of mPPGLs with TKIs was conducted across PubMed, Embase, and Web of Science from database inception to February 2026. Data were synthesized using fixed- or random-effects meta-analysis model. Subgroup analysis was conducted based on the status of the SDHB gene and subtypes of TKIs. A total of 11 studies, comprising 4 observational and 7 interventional studies, with 246 patients involved. The stable disease rate, objective response rate (ORR), and disease control rate (DCR) were 51.8% (95% CI: 44.6-59.1%), 27.7% (95% CI: 21.6-34.3%), and 84.2% (95% CI: 74.8-91.9%), respectively. The proportion of discontinuation due to adverse events was 11.3% (95% CI: 5.4-18.7%). The combined median progression-free survival and overall survival were 13.4 (95% CI: 7.9-14.7) and 26.7 (95% CI: 24.9-49.4) months. Pooled ORR (36.8% (95% CI: 21.1-53.8%) vs 20.1% (95% CI: 10.8-31.0%), P = 0.06) and DCR (92.2% (95% CI: 79.6-99.7%) vs 78.5% (95% CI: 57.3-94.5%); P = 0.269) were higher in patients with SDHB-related mPPGL than in those with non-SDHB mPPGL, although the differences were not statistically significant. Notably, sunitinib showed no therapeutic superiority over other TKI subtypes, with lower pooled ORR (21.2% (95% CI: 14.0-29.4%) vs 36.9% (95% CI: 26.9-47.4%); P = 0.04) and DCR (72.6% (95% CI: 63.9-80.6%) vs 94.5% (95% CI: 87.2-99.3%); P = 0.001). Consequently, TKIs show promising efficacy and manageable adverse event rates in mPPGL, supporting TKIs as components of the systematic treatment.

Multiple endocrine neoplasia type 1 (MEN1) is the most common genetic syndrome causing neuroendocrine tumours (NETs) with metastatic duodenopancreatic NETs (dpNETs) forming the predominant cause of MEN1-related mortality. Peptide receptor radionuclide therapy with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-DOTATATE) is an established treatment for advanced dpNETs. As MEN1 loss of function has been associated with potential radiosensitizing effects, this retrospective study evaluated outcomes of patients with germline MEN1-associated NET after treatment with 177Lu-DOTATATE. This is a retrospective cohort study in patients with MEN1 and metastatic NETs treated with 177Lu-DOTATATE compared with a control group of patients with advanced sporadic pancreatic NETs (panNETs). Survival outcomes, response rates and adverse events after the initiation of 177Lu-DOTATATE were evaluated. A total of nineteen MEN1 patients with dpNETs and fifty-seven sporadic panNET controls were included. No significant difference in median progression-free survival with 39.6 months (95% CI: 13.7-65.5) in the MEN1 group versus 45.0 months (95% CI: 35.7-54.3) in the control group was seen, with a hazard ratio of 1.086 (95% CI: 0.60-1.98). Overall survival was similar between groups with 97.8 months (95% CI: 36.3-159.3) and 89.3 months (95% CI: 54.6-123.9), respectively, and a hazard ratio of 0.883 (95% CI: 0.43-1.82). There were no significant differences in objective radiological response (44.4% in the MEN1 group versus 35.2% in the control group) or in grade ≥ 3 toxicity. MEN1 patients with advanced dpNETs benefit equally from 177Lu-DOTATATE treatment as those with sporadic panNETs in terms of survival and response. These findings support the use of PRRT in MEN1-associated dpNETs similar to sporadic cases.

Historically, the study of cellular metabolism and the cellular proteome have largely focused on specific proteins and metabolites in certain cellular pathways. With the advent of new 'omics' technologies, researchers have been able to probe disruptions and alterations in cellular homeostasis on a near proteome-wide and metabolome-wide basis. Yet, the truly interconnected and interdependent nature of the cellular metabolome and proteome has only become more evident with the discovery of proteome-wide protein post-translational modifications (PTMs), such as lysine acylation by acetyl-CoA or succinyl-CoA. Such PTMs link proteome function to fluctuating concentrations of tricarboxylic acid (TCA) cycle metabolites. Tumorigenesis in TCA cycle-defective tumors that upregulate acylating agents, such as succinyl-CoA and acetyl-CoA, provides a relevant context for understanding the breadth of protein acylation in disease. In particular, succinate dehydrogenase (SDH)-loss chromaffin cells can be transformed into the neuroendocrine tumors pheochromocytomas and paragangliomas (PPGLs), but sensitive diagnostic and effective therapeutic options for metastatic disease remain limited. Interrogating cell models of SDH-loss PPGLs provides a unique opportunity to capture the effects of SDH loss on cellular metabolism and protein acylation while exploring new avenues for improved diagnostics and novel therapeutic targets in these rare diseases.

Papillary thyroid carcinoma (PTC), the most common endocrine malignancy, frequently exhibits invasive behaviors, including tumor invasion and cervical lymph node metastasis, which serve as major determinants of prognosis. However, reliable predictive biomarkers for these aggressive features remain elusive. This study systematically elucidates the tumor-suppressive role of MIB E3 ubiquitin protein ligase 2 (MIB2) in PTC and delineates its underlying molecular mechanism. Integrated bioinformatics analysis and validation in clinical specimens demonstrated significant downregulation of MIB2 in PTC tissues relative to normal thyroid counterparts, with reduced MIB2 expression strongly inversely correlated with aggressive clinicopathological parameters, including lymph node metastasis and extrathyroidal extension. Functional assays revealed that ectopic MIB2 expression markedly attenuated PTC cell proliferation, migration, and invasion in vitro and tumorigenicity in vivo, whereas MIB2 knockdown exacerbated these malignant phenotypes. Mechanistically, MIB2 directly interacted with hexokinase 2 (HK2) via its RING domain, thereby promoting K48-linked polyubiquitination and subsequent proteasomal degradation of HK2. This led to substantial suppression of HK2 protein levels, impairment of glycolytic flux, and consequent restriction of PTC cell aggressiveness. To our knowledge, this is the first demonstration that MIB2 functions as a key negative regulator of PTC invasiveness by targeting HK2 for K48-linked ubiquitination-dependent degradation, thereby modulating glycolytic metabolism. These findings establish MIB2 as a critical suppressor in PTC progression and highlight its potential as a diagnostic biomarker and therapeutic target for aggressive PTC, providing a foundation for the development of precision intervention strategies.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) in papillary thyroid carcinoma (PTC) and play a critical role in disease progression. We previously reported that interleukin-6 (IL-6) promotes PTC progression through activation of MAPK signaling. However, whether CAFs serve as a major source of IL-6 and the underlying regulatory mechanisms remain incompletely understood. By integrating single-cell RNA-seq data from patients with PTC, we identified fibroblasts as the predominant cellular source of IL-6, with IL-6 expression positively correlated with the CAF marker ACTA2. Primary CAFs isolated from PTC tissues exhibited enhanced proliferation, migration, glycolysis, and IL-6 secretion compared with normal fibroblasts (NFs), and these phenotypes were further potentiated by hypoxia. Mechanistically, hypoxia-induced reactive oxygen species (ROS) accumulation in CAFs, which activated NF-κB signaling to drive IL-6 production. Blocking NF-κB with JSH-23 or scavenging ROS with NAC or MitoQ abrogated hypoxia-induced IL-6 expression. In non-contact co-cultures, CAF-derived IL-6 promoted PTC cell proliferation and MAPK pathway activation under hypoxia, whereas IL-6 knockdown reversed these effects. In vivo, co-injection of CAFs with PTC cells enhanced tumor growth, which was significantly suppressed by the IL-6 receptor blocker tocilizumab. Collectively, these findings reveal that hypoxia activates a ROS/NF-κB/IL-6 axis in CAFs, which in turn drives PTC progression through paracrine IL-6 signaling. Targeting this pathway may represent a potential therapeutic strategy for aggressive PTC.

A high proportion of patients with pheochromocytomas and paragangliomas (PPGLs) show glycemic dysregulation. However, studies on the effects of antidiabetic drugs on PPGL tumor growth are still lacking. We evaluated the effects of glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide, metformin, and insulin on fresh patient-derived PPGL primary cultures (n = 54), including 8 cluster 1 tumors and 18 cluster 2/3 tumors (n = 4 tumors with RET pathogenic variants (PVs)). We correlated the primary culture data with clinical data from 67 patients enrolled in the prospective clinical trial PROSPHEO (NCT03344016). We found cluster-dependent effects of semaglutide in patient primary cultures, with significant antitumor effects in cluster 1 PPGLs. Interestingly, we found tumor-promoting effects of high-dose semaglutide in three PPGLs with germline RET PVs (MEN2 syndrome), but not in a PPGL with a somatic RET PV. Metformin displayed overall antitumor effects, whereas insulin showed individual tumor-promoting effects in the patient primary cultures. Consistently, clinical data confirmed larger median tumor sizes in PPGL patients receiving insulin therapy compared with those receiving metformin/GLP-1RA therapy or those without antidiabetic therapy. Overall, we provide novel data on the effects of antidiabetic drugs on PPGL tumor growth, including significant antitumor effects of the GLP-1RA semaglutide in cluster 1 PPGLs and tumor-promoting effects in patients with MEN2 syndrome. Further confirmation of our data in prospective clinical studies is required.

Papillary thyroid carcinoma (PTC) usually has a good prognosis, but lacks effective molecular biomarkers and therapeutic targets. However, a subset of patients develops lymph node metastasis, radioiodine resistance, and recurrence. Cathepsin S (CTSS), a lysosomal cysteine protease, has been implicated in several malignancies, yet its role and regulation in PTC remain unclear. We integrated GEO and TCGA-THCA datasets with eQTL-based genetic instrument analyses to screen PTC-related genes and evaluate their association with clinicopathological features and DFS. CTSS expression was examined in clinical tissues and cell lines by immunohistochemistry, RT-qPCR, and western blotting. Gain- and loss-of-function models were used to assess the effects of CTSS on PTC cell proliferation, colony formation, migration, apoptosis, and nude-mouse tumor growth. RNA-seq and TCGA pathway-score correlation analysis were used to explore downstream pathways, and transcriptional regulation was investigated by in silico prediction, ChIP-qPCR, and dual-luciferase assays. CTSS emerged as a candidate gene associated with PTC occurrence, lymph node metastasis, and shorter DFS. CTSS was markedly upregulated in PTC tissues and cell lines. Functionally, CTSS knockdown suppressed proliferation and migration/invasion and promoted apoptosis, whereas CTSS overexpression enhanced malignant phenotypes in the examined PTC cell models. CTSS expression was associated with activation of the PI3K/AKT/mTOR pathway, and CTSS inhibition attenuated pathway activation and tumor growth. TCF4 bound the CTSS promoter, increased CTSS transcription, and TCF4 knockdown reduced CTSS expression and PI3K/AKT/mTOR pathway activity. These findings suggest that CTSS promotes malignant phenotypes in PTC and is associated with PI3K/AKT/mTOR activation, while TCF4 may contribute to CTSS transcriptional regulation.

Subsequent thyroid carcinomas (STCs) are common after childhood cancer treatment and have well-described risk factors, whereas information on subsequent thyroid adenomas (STAs) remains limited. This study compared treatment-related risk factors for STCs and STAs, assessed their associations with other subsequent neoplasms, and evaluated the incidence of STCs relative to that in the age-matched national general population. The study cohort included 4,348 childhood cancer survivors treated between 1975 and 2020; 48% were female, 23% had lymphomas, and 77% had solid tumors. STCs occurred in 44 survivors (59% female), and STAs occurred in 23 (65% female). Compared with the national general population, the risk of STCs was 7.6-fold higher in females and 23.6-fold higher in males. The median age at diagnosis was lower for STCs (25.8 vs 29.8 years). Hodgkin lymphoma was the most frequent primary cancer in both groups (48% vs 57%). The median age at first cancer diagnosis was similar between the groups (9.8 vs 9.4 years). Neck radiotherapy was a major risk factor in both groups (59% vs 83%). Additional subsequent malignant neoplasms occurred in 14% of patients with STCs and 13% of patients with STAs, whereas subsequent benign neoplasms occurred in 20% and 26%, respectively. The incidence of subsequent benign neoplasms was higher in patients with STCs than in patients with other first subsequent malignant neoplasms (P < 0.05). STCs predominated over STAs (66%). Shared risk factors included neck radiotherapy and Hodgkin lymphoma. STCs were diagnosed at a younger age. The frequent occurrence of additional subsequent neoplasms highlights the need for long-term surveillance.

Paragangliomas and phaeochromocytomas, recently reclassified to unify the disease as extra-adrenal and intra-adrenal paragangliomas, are rare neuroendocrine tumours. These tumours have an exceptionally strong hereditary component, with up to 40% of cases being driven by germline mutations in susceptibility genes; therefore, a cornerstone of modern PPGL care is the genotype-first approach, which heavily dictates initial assessment, surgical strategy, and follow-up. In recent years, the clinical landscape has evolved rapidly, leading to the publication of more than ten new consensus statements since 2022. This review article highlights some of these major paradigm shifts including i) a transition towards genotype-tailored clinical management, ii) specialized paediatric diagnostic and management protocols, iii) updated histopathological criteria, iv) the use of advanced targeted therapeutics, and v) the integration of novel predictive tools.

Neuroendocrine neoplasms (NENs) are a diverse group of rare cancers with high heritability and limited treatment options for metastatic disease. Genomic testing guidelines for patients with NENs are limited to germline testing in high-risk individuals and tumour mutational burden (TMB) in a subset of patients. Here, we assess the prevalence of clinically actionable somatic variants using gene panel testing in the AACR GENIE database, and our real-world experience using additional genomic testing methodologies such as whole genome sequencing (WGS) and circulating tumour DNA sequencing for patients with NENs. The AACR GENIE database contained large panel data for 2,838 samples representing 26 different NEN subtypes. Of the samples, 19.1% had an OncoKB-defined actionable variant; however, only 1.6% were Level 1. TMB ≥ 10 mut/Mb was found in 21% of the assessable AACR GENIE cohort, mostly in NEC subtypes. Our institutional cohort of 30 patients was analysed using tumour-normal WGS in 24/33 testing episodes. Eight of thirty patients (27%) had variant-based clinical trial recommendations made. Seven of twenty-four WGS cases (29%) had clinically reportable germline variants identified. Circulating tumour DNA testing (n = 5/33) was used to sequence patients with uncontrolled hormone syndromes and when adequate tissue was not available. In selected patients with certain metastatic NET subtypes or NECs, our data support consideration of comprehensive tumour-normal genomic testing.