Epithelial neuroendocrine neoplasms (NENs) comprise a biologically diverse group of malignancies that span a wide spectrum of differentiation, proliferative activity, and clinical behavior. Contemporary classifications distinguish well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs). However, growing longitudinal data indicate a subset of NETs may undergo temporal evolution characterized by rising Ki-67, increasing morphologic atypia, and acquisition of genomic alterations classically associated with NEC, particularly TP53 and, less commonly, RB1 inactivation. These phenomena, referred to as grade progression and high-grade transformation, can result in tumors with NEC-like behavior despite retention of a NET molecular backbone, creating diagnostic and therapeutic ambiguity. In this review, we synthesize recent evidence on the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation, highlight the role of clonal evolution and treatment-associated selection pressure, and discuss implications for imaging, biopsy strategy, molecular profiling, and therapy selection.

Colorectal neuroendocrine carcinoma (NEC) is a rare and aggressive cancer, and in a subset of patients associated with an adenocarcinoma (AC) component. When both components exceed 30% of the tumour, it is classified as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), although there is an ongoing debate wether any presence of two distinct components should be sufficient for a MiNEN diagnosis. This study aimed to investigate the origin and subsequent genetic changes of these two components. Ten colorectal cases suitable for sampling of an AC and a poorly differentiated NEC component were identified from the NORDIC NEC Registry and sequenced across a 360-cancer gene panel. Mock phylogenetic trees were constructed from the molecular profiles of each sample within a patient. All 10 cases revealed a common trunk of shared somatic mutations, including well-known colorectal cancer driver mutations such as BRAF, KRAS, APC, and TP53. In all cases, a single branching point separated the AC and NEC components. Private AC and NEC mutations generally had low variant allele frequencies, indicating that most AC and NEC cells were genetically similar. NEC compared to AC samples demonstrated higher frequency of private mutations (p=0.009), indicating higher mutation rate, and greater ploidy (p=0.012), suggesting an association between genomic duplication and AC-to-NEC transition. Shared mutations indicate a common clonal origin, underscoring the role of established colorectal driver mutations in the early development of these tumours, while the mechanisms underlying NEC differentiation remain poorly understood and may involve non-genetic factors.

Hepatic arterial embolization reduces liver tumor burden and hormonal secretion in neuroendocrine tumors, but its safety in patients with carcinoid heart disease is underexplored, and current guidelines suggest managing the cardiac disease first. We assessed the safety and efficacy of hepatic arterial embolization in patients with neuroendocrine tumors and concomitant carcinoid heart disease in a single-center retrospective study including patients with liver metastases and carcinoid heart disease confirmed on expert transthoracic echocardiography between 2001 and 2025. The primary endpoint was procedural safety; secondary endpoints were symptom control, biochemical response, and overall survival. Twenty-seven patients (median age 58.6 years) underwent 69 embolization procedures using bland, conventional, and drug-eluting bead techniques. Severe carcinoid heart disease was present in 52% of patients, and right-sided valvular disease was found in 96%, with tricuspid regurgitation predominating. No procedure-related or cardiovascular death occurred. Two cardiac complications (7%) arose, both in patients with severe pre-existing valvular disease, together with four extra-cardiac complications. Carcinoid syndrome symptoms and urinary 5-hydroxyindoleacetic acid levels decreased significantly after treatment, whereas cardiac symptoms remained stable. Median overall survival was 6.25 years, with a five-year survival of 60%. Hepatic arterial embolization appears feasible with an acceptable safety profile in patients with neuroendocrine tumors and concomitant carcinoid heart disease when performed in expert centers with multidisciplinary management, and may contribute to carcinoid syndrome control. Prospective multicenter studies are warranted to confirm these findings and to define the optimal sequencing of hepatic arterial embolization and cardiac valve surgery.

The B7 family exerts complex and diverse immunomodulatory effects on the occurrence and development of thyroid diseases. The abnormal expression and polymorphisms of B7 family molecules in autoimmune thyroid diseases results in disruption of immune tolerance, activation of autoreactive T cells, and thyroid tissue damage. The dysfunction of B7 family is also closely related to the progression of thyroid cancer (TC) through remodeling tumor microenvironment and mediating immune evasion. Of note, targeting B7 family has become promising strategies for TC treatment. In addition, B7 family signaling linking to immune cell subsets, tertiary lymphoid structure formation, and therapeutic response are also discussed. With the emerging findings of B7 family members in thyroid diseases, understanding the comprehensive roles and mechanisms of B7 molecules would facilitate the clinical translation of B7-based immunotherapy.

Pituitary neuroendocrine tumors (PitNETs) exhibit diverse biological behaviors, yet the metabolic determinants underlying lineage-specific characteristics remain poorly understood. This study characterized intratumoral steroid metabolite profiles in relation to transcription factor (TF)-defined lineages and radiological tumor features in 69 PitNET specimens obtained during transsphenoidal surgery between 2021 and 2023. Tumors were classified according to WHO 2022 TF-based criteria (SF-1, PIT-1, TPIT). Tissue concentrations of 14 steroid metabolites were quantified via liquid chromatography-tandem mass spectrometry, with associations evaluated using multivariable regression and partial least squares discriminant analysis (PLS-DA). Gonadotroph tumors (n=34) exhibited marked pregnenolone (PREG) elevation compared to other lineages (median 104.6 vs 1.2 ng/g, p<0.001, ε2=0.38). Corticotroph tumors (n=9) showed enrichment of glucocorticoid metabolites, particularly 11-deoxycortisol (adjusted p=0.002, ε2=0.30), while PIT-1 tumors (n=23) displayed intermediate levels. PLS-DA corroborated these patterns, with 11-deoxycortisol and pregnenolone emerging as the primary discriminators (68% total variance). Multivariable analysis confirmed SF-1 lineage as independently associated with PREG levels after adjusting for clinical and radiological covariates (adjusted R2=0.56, p<0.001). Inverse associations were observed between deoxycorticosterone/11-deoxycortisol and tumor expansion (r=-0.7 and r=-0.4, both p<0.001), and PREG correlated with cavernous sinus invasion within gonadotroph tumors (p=0.03). During follow-up (median 32-38 months), steroid profiles showed no association with clinical outcomes. TF-defined PitNET lineages exhibit distinct intratumoral steroid profiles reflecting intrinsic metabolic properties of lineage-specific cell populations, revealing a novel metabolic dimension to PitNET biology.

Somatic mutations in the gene encoding splicing factor 3B subunit 1 (SF3B1), a key component of the splicing machinery, have been described in patients with PRL-secreting pituitary neuroendocrine tumors (PRL-PitNET) and associated with aggressiveness and resistance to pharmacological therapy with dopamine agonists (DAs). Dopamine receptor type 2 (DRD2) represents the main target for PRL-PitNETs treatment with DAs, even if about 10% of patients is resistant. Aims of the study were to: 1) test the effects of SF3B1 inhibitor pladienolide B in tumoral lactotroph cells expressing wild-type or mutated SF3B1R625H; 2) investigate SF3B1 impact on tumoral cells responsiveness to DRD2 agonist cabergoline. Pladienolide B treatment reduced cell proliferation (-45.1(15.3)%,p<0.001), PRL secretion (-19.25(35.1)%,p<0.05) and increased apoptosis (+2.4(2.5)-fold,p<0.05) in rat tumoral MMQ cells. Pladienolide B antimitotic, proapoptotic and antisecretory effects were maintained in primary cultured cells from both resistant and responsive PRL-PitNETs. SF3B1R625H overexpression increased tumoral lactotrophs proliferation and migration. Moreover, the antimitotic efficacy of pladienolide B, but not of cabergoline, was maintained in MMQ cells transfected with SF3B1R625H. Cabergoline effects on cell proliferation, AKT activation, cyclin D3 and p27 were abolished in MMQ cells silenced for SF3B1. Accordingly, SF3B1R625H overexpression and SF3B1 silencing reduced DRD2 expression at both protein and transcript level, an effect reverted by nonsense-mediated decay inhibitor NMDI14. In conclusion, we demonstrated a relevant role of SF3B1 in PRL-PitNET. Indeed, SF3B1 inhibitor pladienolide B exerted antitumoral actions in PRL-PitNET cells bearing wild-type or mutated SF3B1. Moreover, both SF3B1R625H overexpression and SF3B1 genetic silencing reduced DRD2 expression and signaling.

Hereditary endocrine neoplastic syndromes require structured, lifelong surveillance owing to their multisystem involvement, variable penetrance, and high risk of multifocal and metastatic disease. Functional imaging (FI) is now integral to their management, providing molecular characterisation that complements conventional anatomical modalities and frequently enables earlier or more specific lesion detection. This review summarises current FI approaches across major hereditary syndromes, including Multiple Endocrine Neoplasia types 1-4, von Hippel-Lindau disease and hereditary phaeochromocytoma-paraganglioma syndromes with emphasis on radiotracer selection, genotype-phenotype correlations and implications for clinical practice. The performance and biological rationale for established radiotracers including 18F-FDG, 68Ga-DOTATATE, 18F-DOPA and choline-based PET agents and emerging probes is described. Increasing evidence supports genotype-directed imaging algorithms, particularly in HPPS, where molecular subtype predicts tracer avidity and guides theranostic strategies. The expanding theranostic framework, anchored in somatostatin receptors and norepinephrine transporter-directed radiopharmaceuticals has reshaped treatment pathways for advanced and metastatic disease. Implementation challenges persist, including variable global access, high costs, workforce limitations and concerns regarding cumulative radiation exposure during decades of surveillance. Technical constraints related to spatial resolution, partial-volume effects, and motion artefact continue to limit the sensitivity of small-lesion detection. Emerging approaches incorporating radiomics and artificial intelligence offer opportunities to enhance lesion characterisation, infer genetic subtype, and improve prognostication. Advancing FI in hereditary endocrine neoplasia will require genetically informed surveillance protocols, harmonised imaging standards, and equitable access to specialised modalities. Collectively, these developments have the potential to refine risk stratification, improve treatment selection, and optimise long-term outcomes for individuals with hereditary endocrine malignancies.

Small bowel neuroendocrine tumors represent a rare malignancy, and most patients present with metastatic disease at diagnosis. While current guidelines from the North American Neuroendocrine Tumor Society and the European Neuroendocrine Tumor Society agree that resection is indicated for symptomatic tumors causing obstruction, ischemia, or bleeding, the role of primary tumor resection in otherwise asymptomatic patients with unresectable metastatic disease remains controversial. This article reviews the existing evidence and highlights the role of primary tumor resection in the setting of metastatic disease. Retrospective studies support mixed findings: some boast a survival advantage for patients undergoing resection of the primary tumor, while others caution that other prognostic factors, including those related to tumor biology, are the true drivers of this benefit. However, it is known that many patients are not truly asymptomatic if a thorough history and physical is performed, and symptom burden can become significant over time. Upfront resection of the primary small bowel tumor prevents development of local complications, such as bowel obstruction or mesenteric vascular compromise, which may require emergency surgery. It has been shown that patients who underwent surgery in the emergent setting (as opposed to elective) had worse survival outcomes and tended to have more incomplete tumor resection and a significantly smaller lymph node yield. Nonetheless, the absence of prospective or randomized controlled studies leaves the value of primary tumor resection unproven, underscoring the critical need for well-designed trials incorporating quality-of-life metrics and obstruction-free survival as key patient-centered outcomes.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody-drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher's exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.

Ectopic hormone secretion from neuroendocrine neoplasms in the lung (lung-NENs) is rare and poorly explored. Emerging evidence indicates that hormone-secreting NENs carry a worse prognosis. We hypothesised that ectopic hormone production and secretion in lung-NENs is a negative prognostic marker. A retrospective cohort of 167 patients with lung-NENs (121 females, median age: 68 (min-max: 15-85) years), excluding small cell lung cancer, was analysed for clinical and biochemical data and outcome. Tumour tissue was evaluated for serotonin and calcitonin expression. Among 127 patients with hormone measurements, 52 had increased levels, with 5-hydroxyindoleacetic acid (5-HIAA) predominating (n = 38), followed by calcitonin (n = 20). There was no correlation between serotonin expression in tumour tissue and elevated levels of 5-HIAA, while high calcitonin levels were strongly correlated with calcitonin expression in tumour samples (OR: 21.86, P = 0.002). Furthermore, diffuse calcitonin staining was associated with a shorter overall survival (OS) (P = 0.036). Hormone-secreting tumours had a significantly shorter OS than non-secreting tumours (62 vs 124 months, P = 0.024), and multiple hormone secretion further worsened survival (33 vs 69 vs 124 months, P = 0.002). In multivariate analysis, multiple hormone secretion remained an independent negative prognostic factor (P = 0.042). In conclusion, hormone secretion in lung-NENs is associated with a shorter OS, particularly in patients with multiple hormone secretion. Diffuse calcitonin expression in tumour tissue is an additional negative prognostic marker. We recommend routine hormone testing at baseline and at disease progression in metastatic lung-NEN patients and suggest a more intensified therapeutic strategy in cases with detectable hormone secretion.

Pituitary tumours are intracranial neoplasms that pose significant clinical challenges due to their potential for recurrence, therapeutic resistance and resultant endocrine dysfunction and mass effects. In the normal anterior pituitary, resident pituitary stem cells (PSCs) contribute to tissue homeostasis and cellular turnover. The extent to which PSCs contribute to tumourigenesis is not known, but an increasing number of studies have been aiming to address this. In this review, we summarise current evidence implicating PSCs and tumour stem-like populations in pituitary tumour biology, including potential roles in tumour initiation, maintenance and progression. We outline practical criteria for defining tumour stem cells and evaluate findings from functional studies of human tumours, emerging single-cell and spatial transcriptomic datasets and murine lineage-tracing models. We also provide a curated overview of published single-cell RNA sequencing studies of pituitary tumours, highlighting reported stem/progenitor populations and transcriptional signatures across tumour subtypes and propose a framework for future genomic analyses. Finally, we discuss the translational implications of these findings, including the potential for targeting stem-like populations and their associated signalling pathways.

The androgen receptor (AR) is a key transcription factor in prostate cancer (PCa), whose enhanced and altered functions are known drivers of cancer progression. A key aspect of this is reprogramming of the AR cistrome, which consists of genome-wide enhancer-binding sites through which AR regulates gene expression. The magnitude and biological impact of the AR cistrome are impacted by the AR itself, including the responses to ligand, as well as the organization of the associated DNA response elements, and availability of pioneer factors, cofactors, and noncoding RNAs, all of which contribute to a functional transcription complex. In this review, we will examine, in the context of PCa progression, the factors that affect the binding of AR and its interacting partners at enhancers, with a focus on AR cistrome reprogramming. We also discuss the clinical utility of targeting the AR-enhancer nucleoprotein complex and the potential of using the AR cistrome as a prognostic tool.

Thyroid cancer exhibits pronounced cellular heterogeneity, yet the mechanisms underlying epithelial-mesenchymal transition (EMT) and tumor microenvironment (TME) remodeling remain incompletely understood. In this study, single-cell RNA sequencing of 92,849 cells from 20 thyroid tissue samples derived from underage and adult patients was performed to systematically characterize immune and epithelial heterogeneity through cell type annotation, subclustering, and functional enrichment analyses. A total of 26 distinct cell clusters were identified, encompassing immune and stromal compartments, with notable age- and stage-specific differences in T cell, epithelial, and macrophage subsets. EMT-high tumors were characterized by stromal enrichment, immune suppression, and transcriptional activation of canonical EMT drivers, including TGFB1, SNAI1/2, TWIST1/2, and ZEB1/2. Functional validation demonstrated that shRNA-mediated knockdown of PHTF2 or SNAI1 in TPC-1 and KTC-1 cell lines significantly inhibited proliferation and clonogenic capacity, accompanied by upregulation of CDH1 and downregulation of multiple EMT-associated genes. Furthermore, EMT-high tumors exhibited distinct drug sensitivity profiles, including reduced responsiveness to conventional chemotherapeutics and increased sensitivity to agents such as camptothecin and dabrafenib. Collectively, these findings identify PHTF2 and SNAI1 as key regulators of EMT and tumor cell proliferation in thyroid cancer, and suggest that EMT-driven TME remodeling contributes to immune evasion and therapeutic resistance, thereby revealing EMT-associated vulnerabilities as potential targets for precision therapy.