Papillary thyroid carcinoma (PTC) is less aggressive when associated with lymphocytic thyroiditis (LT), even in the presence of oncogenic BRAF, including smaller tumours, less lymph node involvement, and reduced extrathyroidal extension (1). To investigate possible immune mechanisms underlying this association, we compared the tumour microenvironment of PTC-BRAF with and without LT using single-cell RNA sequencing (scRNA-seq). Single-cell libraries were generated from fresh and fixed tumour samples with post-dissociation viability >70% using the 10x Genomics Chromium platform and sequenced on an Illumina NovaSeq 6000. We analysed scRNA-seq data from 11 PTC-BRAF tumours, including four with LT (one publicly available sample) and seven without LT. Downstream analyses included quality control, batch correction, dimensionality reduction, and differential gene expression analysis. We found neutrophils were the predominant myeloid cell type in PTCs without LT. Thyrocytes without LT showed significant expression of the neutrophil recruitment chemokine ECRG4. In the absence of LT, neutrophils expressed oncogenic genes with poor clinical outcomes. In contrast, thyrocytes from tumours with LT showed increased expression of MHC-II antigen presentation, consistent with effective immune surveillance. Thyrocytes and macrophages in the presence of LT showed enrichment of interferon gamma response pathways. Our data suggests LT in thyroid cancer is associated with enhanced antigen presentation and fewer features of pro-tumorigenic innate immune activity. These results identify previously under recognized innate immune cell population and associated transcriptomic features which suggests new mechanisms to target immune treatments in PTC refractory to other therapies.

Peptide receptor radionuclide therapy (PRRT) is an emerging and promising targeted treatment for aggressive pituitary neuroendocrine tumours (PitNETs) and pituitary carcinomas refractory to conventional therapies. Its use is supported by the frequent expression of somatostatin receptors (SSTR), predominantly SSTR2, in pituitary tumour cells, enabling selective delivery of β-emitting radionuclides such as 177Lu-DOTATATE and 90Y-DOTATOC, resulting in targeted antitumour and antisecretory effect. This narrative review summarizes current scanty evidence on PRRT efficacy and safety in aggressive pituitary tumours. Successful outcomes were reported in some cases, in terms of tumour growth and/or hormonal reduction, or relief of mass-effect-related symptoms. PRRT related adverse events are mostly mild and transient, predominantly hematologic, with clinically significant renal toxicity uncommon when amino-acid nephroprotection is used. Preserved pituitary function and no clinically significant PRRT-induced hypopituitarism have been reported. Overall, PRRT represents a biologically rational and potentially effective option for selected patients with SSTR-positive aggressive PitNETs after failure of previous therapies.

Clinically inapparent node metastases, requiring neck dissection in addition to thyroidectomy, pose a diagnostic challenge in patients with medullary thyroid cancer (MTC). Although desmoplasia negativity has emerged as a powerful marker of node negative disease, its clinical utility in hereditary MTC remains ill-defined. This cross-sectional investigation employed multivariable logistic regression on, and stratification of clinical variables by, nodal status of 124 RET carriers with MTC who underwent initial total thyroidectomy with at least central neck dissection between 2000 and 2025 at a tertiary center. Unlike tumor size, grade, laterality, index status, and sex, only desmoplasia (>10% vs. ≤5%), basal serum calcitonin (>500 pg/ml >> 101-500 pg/ml vs. ≤100 pg/ml), and RET category (highest [p.Met918Thr] vs. any other) were independently associated with node metastases. In unilateral MTC, desmoplasia ≤5% was always associated with freedom from node metastases (0 of 15 patients), whereas tumor size ≤5 mm and basal serum calcitonin ≤100 pg/ml were associated with node metastases in 4 (18%) of 22 patients and 4 (15%) of 26 patients, respectively. In bilateral MTC, none of the above thresholds were sufficiently discriminatory, suggesting cross-contamination by the contralateral MTC. In unilateral MTC with desmoplasia ≤5%, node metastases were always absent, regardless of whether basal calcitonin levels were ≤100 (based on 13 patients) or >100 pg/ml (based on 2 patients). This comprehensive proof-of-concept study demonstrates that RET carriers with desmoplasia negative unilateral MTC may forgo node dissection at specialist centers, similarly to what has been proposed for patients with desmoplasia negative sporadic MTC.

Incidentally discovered pathogenic germline genetic variants refer to the finding of a pathogenic variant in a gene that is unrelated to the reason for the initial test and is not actively sought. Our clinical understanding of the risk of developing a particular medical condition and the required clinical action for a specific pathogenic gene variant is predominately based on knowledge and information acquired from cases ascertained through a 'phenotype-first approach' rather than in clinically unselected individuals. Therefore, a modified approach is required for incidentally discovered gene variants. Data from large UK and US population-based cohorts have demonstrated that RET variants classified as moderate-risk RET variants as per the American Thyroid Association (ATA) classification, have a low penetrance for medullary thyroid cancer and other RET related conditions (e.g. phaeochromocytoma) and are not associated with excess mortality when identified incidentally in clinically unselected adult individuals. Here, we provide guidance based on multidisciplinary expert consensus opinion for the reporting and subsequent clinical surveillance and management of patients with incidentally discovered RET gene variants in the UK.

Endocrine therapies initially enforce lineage identity in hormone-driven cancers, yet sustained hormonal suppression often triggers a coordinated systems-level rewiring through lineage plasticity. Previously, lineage plasticity has been characterized as a discrete bypass mechanism, which lacks fluidic identity changes. Here, we describe the process as a progressive, adaptive trajectory of endocrine escape. We describe how the disruption of hormone receptor-anchored identity programs creates permissive conditions for transitions into HR-indifferent or neuroendocrine- or basal-like states. Next, we summarize historical methodologies for investigating lineage plasticity, such patient-derived organoids, genetically engineered mouse models (GEMMS), lineage tracing, and single-cell multi-omics, and discuss novel systems biology approaches to enable the early detection and modeling of these unstable intermediate states. Lastly, we present promising and potential uses for artificial intelligence and machine learning for dissecting therapy-induced identity shifts and resistance mechanisms. Intercepting these trajectories before lineage commitment offers a critical window for precision oncology interventions.

Aggressive and metastatic pituitary neuroendocrine tumors constitute a rare yet biologically distinct group of lesions, marked by rapid growth, therapeutic resistance, and unpredictable clinical behavior. Despite their rarity, they contribute disproportionately to morbidity due to the absence of reliable prognostic and therapeutic frameworks. Recent evidence has reframed aggressiveness as a multidimensional process shaped by somatic variants, chromosomal instability, and epigenetic remodeling. Recurrent alterations in ATRX, TP53, and SF3B1, widespread copy number losses, and lineage-specific methylation and transcriptomic profiles help delineate tumors with early malignant potential. Single-cell and immune profiling studies reveal proliferative, migratory, and immunoevasive subpopulations that may underpin variable clinical trajectories and treatment responses. Clinically, temozolomide remains the only systemic therapy with consistent benefit, while immune checkpoint inhibitors, anti-VEGF agents, and peptide receptor radionuclide therapy show emerging efficacy in selected settings. Progress will rely on harmonizing diagnostic criteria, integrating molecular and imaging biomarkers, and embedding translational endpoints into clinical trials. Together, these advances define a path toward more precise recognition and management of aggressive pituitary tumors.

The molecular characterization of Pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of the different PitNET types, and allowing better understanding of their biology. The most frequent recurring somatic driver alterations were recognized in corticotroph PitNETs (USP8, USP48, BRAF) and somatotroph PitNETs (GNAS), and, much less frequently, in lactotroph PitNETs (SF3B1). Additional well-characterized somatic driver alterations, including TP53, ATRX, and DAXX, are enriched in aggressive corticotroph tumors. Identification of new molecular markers and delineation of their clinical phenotypes are enabling further subclassification of PitNETs based on tumor molecular profiles, with earlier recognition of more aggressive variants. These molecular markers also provide an opportunity for new targeted therapies. Beyond single-gene alterations, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA dysregulation, are emerging as important contributors to PitNET pathogenesis and potential therapeutic targets. Multi-omics approaches encompassing genomics, transcriptomics, epigenomics, and proteomics are transforming PitNET classification. In this review, we provide a comprehensive, data-driven update on somatic driver alterations, epigenetic alterations, converging signaling pathways, and the related emerging therapeutic targets in PitNETs, integrating pooled analyses from published cohorts.

This narrative review examines the literature on parathyroid disease in the context of ageing, focusing on parathyroid adenoma and parathyroid carcinoma. Parathyroid disease incidence increases with age. We reviewed the available literature on age-related changes in parathyroid physiology and the differences in clinical approach and outcomes in older adults. Available evidence suggests that mechanisms associated with parathyroid adenoma development include structural remodelling of the parathyroid gland, age-related renal function decline and somatic mutations. The evidence for these mechanisms comes from small-scale studies and would benefit from further research. The evidence available suggests that there are some clinical and biochemical differences in parathyroid adenoma presentation in older adults. It also suggests that older adults may be undertreated, with concerns around suitability for surgery driving this. Parathyroid carcinoma has very limited literature available for both its underlying pathophysiology and clinical outcomes. Parathyroid adenoma rarely transforms to parathyroid carcinoma. This literature review shows that ageing does have an impact on the development of parathyroid disease but that there is a lack of large-scale studies around this. We hope this review will help guide further research in this area and, thus, improve care of older adults.

Artificial intelligence (AI) is rapidly moving from conceptual innovation to high-performing algorithms across the pituitary patient pathway, promising benefits to patients, endocrinologists and surgeons alike. Pre-operatively, machine learning applied to facial imaging and natural language processing of electronic health records show potential for earlier identification of pituitary adenomas and timelier referral from primary providers to a specialist endocrinologist. Intraoperatively, computer vision systems have already augmented surgical training but have the potential to become integrated real-time decision support systems. Post-operatively, predictive models may help to forecast complications and longer-term remission, endocrinological outcomes or recurrence. Across these domains, the emergence of large, multimodal datasets, which integrate clinical text, endocrinological investigations, radiological imaging, and intraoperative video, promises further AI improvements, yet the impact of AI on real-world clinical decision-making is less clear and depends as much on implementation processes and clinicians themselves. This review provides an overview of AI technologies for pituitary patients and explores some of the challenges translating them to clinical practice.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with poor survival and limited treatment options. To comprehensively characterize its molecular landscape and identify clinically relevant subtypes, we performed an integrated genomic analysis - including whole-exome sequencing, RNA sequencing, and copy number variation profiling - on 61 Chinese patients with ACC. We identified recurrent mutations in TP53 (25%), CTNNB1 (15%), ZNRF3 (10%), and MEN1 (8%). Unsupervised clustering of transcriptomic data revealed four distinct molecular subtypes: cortisol-driven (CD, 14%), immune-suppressed (IS, 40%), cell cycle-altered (CCA, 22%), and immunomodulatory (IM, 24%). The CD subtype exhibited steroidogenic pathway activation; the IS subtype showed T cell receptor downregulation and the worst disease-free survival; the CCA subtype was marked by chromosomal instability and cell cycle gene overexpression; and the IM subtype displayed enriched immune signaling and favorable outcomes. Copy number analysis further uncovered focal amplifications (e.g. TERT, CDK4) and HLA-II deletions. This study establishes a novel molecular classification of ACC, providing a framework for subtype-specific therapeutic strategies, such as CDK4/6 inhibition for CCA and immunotherapy for IM tumors, while highlighting the clinical challenges of immune-cold IS tumors.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.