Radioiodine therapy of differentiated thyroid cancer is effective and possibly curative in patients with metastatic lesions that retain iodine avidity. However, in clinical practice, iodine avidity in any metastatic site is usually unknown at the point of initial treatment. Avidity prediction could enable more tailored initial radioiodine treatment. This work aimed to establish the best predictive factors for iodine avidity and subsequent treatment response. Thirty-one patients with metastatic or recurrent thyroid cancer sites in which iodine avidity could be assessed by image-based analysis were included. In tissue specimens from primary surgery, immunohistochemical expression of thyroglobulin (Tg), thyroid peroxidase (TPO), sodium-iodide symporter (NIS) and Ki67, and mutational status of BRAF, RAS and the TERT promoter was analyzed. Biochemical and structural response were assessed by serum Tg response and radiological evaluation. High-risk histology (widely invasive follicular, tall cell subtype papillary, differentiated high-grade or poorly differentiated thyroid carcinoma) combined with expression of TPO, Tg and cytoplasmic NIS performed well in predicting treatment response and iodine avidity. Approximately half of the variation between patients was explained by those variables, outperforming pT stage and mutational status. TPO and Tg expression were the largest contributors in prediction modelling. Radioiodine treatment response and iodine avidity in thyroid cancer can be predicted from histopathological analysis of the primary tumor. High-risk histology and expression of TPO, Tg and NIS were robust and informative predictors. This may be used to adapt treatment strategy in adjuvant and metastatic therapy settings.
Thyroid cancer, the most frequent endocrine tumor, has a good prognosis. However, the survival rate of patients with recurrent or metastatic forms that become resistant to conventional treatments, drops to less than 20% at 10 years, with a mean life expectancy of 3-5 years. The molecular mechanisms that drive the advancement of these forms are still largely unknown, and, therefore, the identification of disease progression biomarkers is of great clinical relevance. Dickkopf-1 (DKK1) is a regulator of the Wnt signaling cascade that controls several biological processes including cell proliferation, differentiation and migration. DKK1 has been associated with progression and poor prognosis in different types of tumors; however, its role in thyroid cancer is still not well defined, and a better characterization is needed. The present study investigated the role of DKK1 in the growth of papillary and follicular thyroid cancers, in in vitro and in vivo models. In vitro, DKK1 silencing, through siRNA, and deletion, via CRISPR/Cas9 editing, were performed in different papillary and follicular thyroid cancer cell lines. Both silencing and deletion reduced cell growth and migration, with the involvement of β-catenin-dependent Wnt and PI3K/mTOR pathways. In vivo xenograft tumor models, DKK1 deletion reduced tumor growth. In conclusion, our findings support the key role of DKK1 in the growth of differentiated thyroid cancers both in vitro and in vivo.
Although uncommon, thyroid nodules (TN) in pediatric and young adult patients carry higher malignancy risk and often present with a high burden of metastatic disease than adults. The molecular features underlying this distinct clinical behavior remain unclear. We analyzed Afirma Genomic Sequencing Classifier (GSC) data from 283,621 TN, comparing patients <21 and ≥21 years. Cytology (Bethesda), GSC benign (B) vs suspicious (S) calls, and Afirma Xpression Atlas (XA) variant/fusion profiles were evaluated in GSC-S and Bethesda V/VI samples. Genome-wide expression was used to derive pathway signatures and thyroid cancer-related scores: BRAF-RAS score (BRS), ERK, follicular and epithelial-to-mesenchymal transition (FMT, EMT) and thyroid differentiation scores (TDS). Among 2,397 patients <21 (median age 18.9; 81.4% female) and 281,224 adults ≥21 (median age 59.8; 77.1% female), <21 samples showed more Bethesda V/VI cytology (14.5% vs 5.0%; p<0.0001) and a lower GSC-B rate (43.5% vs 68.8%; p<0.0001). In GSC-S samples, total variant detection was higher in <21 (45.3% vs 37.4%), with enriched BRAF p.V600E, TSHR, and DICER1 variants, while HRAS variants were more common in adults (all p<0.01). Gene fusions involving RET, NTRK3 and ALK were enriched in <21 (14.5% vs 5.5%; p<0.0001). TERT promoter mutations were absent in <21 yrs GSC-S and Bethesda V/VI samples (vs 4.2% and 9.3% in adults). GSC-S <21 showed cell-cycle pathway enrichment. RET/NTRK/ALK-positive <21 demonstrated enrichment of angiogenesis and EMT pathways, higher ERK/EMT/FMT scores, and lower BRS/TDS scores vs genotyped-matched adults. These molecular differences provide mechanistic insight into the more invasive phenotype in pediatric and young adult TN.
Arginine vasopressin (AVP) deficiency, previously termed central diabetes insipidus, arises from impaired AVP synthesis or secretion by the hypothalamus and/or the posterior pituitary gland and presents with hypotonic polyuria and polydipsia. To differentiate AVP deficiency from AVP resistance and primary polydipsia, a stepwise diagnostic work-up is required. In recent years, copeptin, as a reliable surrogate marker of AVP secretion, has been incorporated into diagnostic algorithms, and copeptin-based stimulation tests have substantially improved diagnostic accuracy. Once AVP deficiency has been established, identification of the underlying cause is essential. A wide range of etiologies, including neurosurgical and traumatic injuries, granulomatous, inflammatory and autoimmune diseases, vascular events, infections, and genetic defects, require a diagnostic approach tailored to the suspected diagnosis. Evaluation should include a careful assessment of the patient's personal and family history, clinical examination, laboratory studies, imaging and, when indicated, tissue biopsy. In patients with apparently idiopathic AVP deficiency, a careful longitudinal follow-up is warranted, since it may represent the first manifestation of an underlying pathology. Treatment of AVP deficiency consists of desmopressin replacement combined with etiology-specific management.
Succinate dehydrogenase (SDH) is an enzyme complex that plays a major role in cellular metabolism, as it sits at the interface between carbon metabolism in the Krebs cycle and oxidative phosphorylation for energy production. The precursor and product of the enzymatic reaction, succinate and fumarate, respectively, are regulators of various cellular and biological processes, such as epigenetic status, hypoxia responses and angiogenesis, metabolic reprogramming, tumourigenesis, and immune responses. Succinate is considered an oncometabolite, and SDHx genes are tumour suppressor genes. Carriers of germline pathogenic variants (PVs) in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) carry a life-long risk of developing tumours, predominantly phaeochromocytomas and paragangliomas (PPGLs). Research has focused mainly on the disease state in which, in accordance with the Knudson two-hit model, the second allele is inactivated in tumour cells; the biological consequences are massive intracellular accumulation of succinate and/or reactive oxygen species (ROS), which in turn leads to tumourigenesis. Little is known about the haploinsufficient state, in which the wild-type SDHx copy at least partially sustains SDH function and keeps intracellular succinate and ROS levels in ranges that are, if not normal, then at least non-tumourigenic. This review will consolidate the literature regarding genotype differences between SDHx PV carriers, the phenotype of non-tumoural cells in healthy individuals, and the role of environmental factors in influencing tumour development, potentially via tipping succinate (or ROS) levels above a tumourigenic threshold.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. Over the past two decades, the genomic characterization of PPGLs has profoundly transformed their diagnosis, classification, risk stratification, and therapeutic management. Up to 40% of PPGLs harbor germline pathogenic variants, the highest proportion among human neoplasms, and somatic driver events are identified in a substantial fraction of the remaining cases. Integrative multi-omic studies have established three main molecular clusters: a pseudohypoxic cluster driven by Krebs-cycle alterations (SDHx, FH, MDH2, DLST) and HIF-2α pathway alterations (VHL, EPAS1, EGLN1/2); a kinase-signaling cluster driven by activation of RAS/MAPK and PI3K/AKT pathways (RET, NF1, HRAS, TMEM127, MAX); and a Wnt-signaling cluster characterized primarily by MAML3 fusions. This review summarizes progress in PPGL genomics, highlighting geographic and sex-related particularities. Using EPAS1/HIF-2α and RET as paradigmatic examples, we illustrate how diverse germline, somatic, mosaic, and fusion events converge on common core signaling hubs that can be therapeutically exploited with FDA-approved selective inhibitors for relevant targets (e.g. belzutifan for HIF-2α; selpercatinib and pralsetinib for RET). We further review the genomic determinants of metastatic risk (SDHB, ATRX, TERT, and MAML3 fusions), the immune microenvironment of metastatic disease, and emerging radionuclide theranostics, liquid biopsy biomarkers, and integrative multi-omic approaches that are reshaping precision medicine for PPGLs.
Papillary thyroid cancer (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. To investigate possible immune mechanisms underlying this association, we compared the tumour microenvironment of PTC-BRAF with LT and that 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: 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 that 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 suggest that LT in thyroid cancer is associated with enhanced antigen presentation and fewer features of pro-tumourigenic innate immune activity. These results identify previously under-recognised innate immune cell population and associated transcriptomic features, which suggest 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 (SSTRs), 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 effects. This narrative review summarises current limited evidence on PRRT efficacy and safety in aggressive pituitary tumours. Successful outcomes have been reported in some cases in terms of tumour growth reduction and/or hormonal reduction or relief of mass-effect-related symptoms. PRRT-related adverse events are mostly mild and transient, predominantly haematological, 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.
Neuroendocrine prostate cancer (NEPC) is a rare and aggressive variant of prostate cancer (PC) that can be de novo (d-NEPC) or transform from prior prostate adenocarcinoma (PCa) as treatment-emergent NEPC (t-NEPC). This study aimed to study the clinical characteristics and overall survival (OS) of NEPC using data from the SEER and NCRAS registries and to compare OS of d-NEPC and t-NEPC. A total of 1,465 patients with NEPC were extracted from SEER (n = 990, 2010-2022) and NCRAS (n = 475, 2010-2021). Patients were classified as t-NEPC if preceded by a documented PCa. The primary outcome was OS measured from the date of NEPC diagnosis. Kaplan-Meier analysis, the log-rank test, and Cox regression were performed for SEER, NCRAS, and pooled cohorts. t-NEPC represented 9.9% in NCRAS and 15.2% in SEER. Small cell carcinoma was the most common subtype (80.2% NCRAS, 74.7% SEER). Median time to transformation was 4.63 years in NCRAS and 5 years in SEER. In the pooled cohort, median OS was 9 months for d-NEPC and 7 months for t-NEPC (log-rank P < 0.001). The 60-month OS was 7.9% for d-NEPC and 4.0% for t-NEPC. In the pooled multivariable Cox regression, t-NEPC was independently associated with worse OS (aHR: 1.30, 95% CI: 1.11-1.53, P = 0.001). Data source was not associated with OS (aHR: 1.08, P = 0.206), indicating comparable OS between the USA and England. In this bi-national, population-based study, t-NEPC was associated with worse OS than d-NEPC. OS for NEPC was comparable between the USA and England. These findings support distinguishing d-NEPC from t-NEPC.
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 metastatic 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.
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 as 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. Finally, 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.
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 predominantly 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.
The SDHC c.397C>T (p.Arg133Ter) germline pathogenic variant is present in over 40% of mutation-positive paragangliomas in French-Canadian patients, supporting a founder effect. We aimed to characterize pheochromocytomas and paragangliomas (PPGLs) associated with this variant in a large international cohort of European descent. We conducted an international case series of adults with PPGLs carrying the SDHC c.397C>T germline pathogenic variant, treated between 2010 and 2024 at four university hospitals: two in the province of Québec (Canada), one in the Northeastern United States, and one in France. Among the 45 patients confirmed with PPGLs harboring the SDHC c.397C>T pathogenic variant, 46.7% were women, and the mean age at diagnosis was 49.7 years. Forty-four patients (97.8%) had paragangliomas, and one (2.2%) had a pheochromocytoma. The most common paraganglioma sites were the head and neck (26/44, 59.1%), followed by the thoracic (including mediastinal) region (12/44, 27.3%; half located in or near cardiac structures), and finally the abdominal region (6/44, 13.6%). Multiple tumors were present in 15.6% (7/45) of cases, and metastatic disease was identified in 11.1% (5/45). Following surgical resection, four patients (15.4%) experienced recurrence during a mean follow-up of 7.9 years. Loss of SDHB protein expression was confirmed in all available immunohistochemistry samples. The SDHC c.397C>T founder pathogenic variant, likely originating from France, is common in the province of Québec, with probable migration to New England (USA), and appears enriched for thoracic (including mediastinal) paragangliomas. Although based on a limited series, affected patients remain at risk of recurrence and metastasis and should be followed up closely.
The molecular characterization of pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of different PitNET types and allowing a 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 noncoding 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.
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.
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.
