Ten-Year Single-Center Experience in the Surgical Treatment of Carotid Body Tumors.

The hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome, caused by germline mutations in succinate dehydrogenase (SDHx) genes, predisposes individuals to pheochromocytomas (Pheo), paragangliomas (PGLs), renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). Notably, tumors with succinate dehydrogenase subunit B (SDHB) deficiency demonstrate an increased metastatic risk and current systemic treatments remain only palliative. Hence, discovering novel therapeutic avenues to improve SDHB cancer prognosis is an urgent need. Here, we leveraged human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT) to discover SDH-dependent mitochondria-directed cytotoxic agents. Given the reduced ATP-generating capacity of SDHB-KO cells, we hypothesized that they would be uniquely sensitive to futile cycle induction with mitochondrial ionophores. Indeed, ionophores exhibited preferential cytotoxicity toward SDHB-KO cells. However, the mitochondria-directed chemotherapeutic compound Ym155 demonstrated more potent and dramatic preferential cytotoxicity toward SDHB-KO cells. Importantly, SDH-dependent cytotoxicity of Ym155 was validated in multiple cell models, including primary human pheochromocytoma cells, a mouse pheochromocytoma (MPC) cell line and primary SDHB-deficient mouse kidney cells. Notably, genetic evidence of Ym155 synthetic lethality with SDHB deficiency was buttressed in additional cell models using two chemical inhibitors of SDH enzyme activity. Mechanistically, SDH deficiency sensitized cells to Ym155-induced DNA damage. Strikingly, SDH-dependent Ym155 sensitivity was recapitulated by inhibition of the histone demethylase KDM4, a downstream consequence of SDH deficiency. In summary, accumulation of succinate in SDH-deficient tumors inhibited KDM4 activity, impaired DNA repair and yielded enhanced susceptibility to Ym155-induced reactive oxygen species (ROS) generation. The identified intrinsic susceptibilities of SDHB-deficient cancers have the potential to be therapeutically leveraged.

Background/Objectives: The co-occurrence of a carotid body tumor (CBT) and papillary thyroid carcinoma (PTC) is a rare clinical event. The frequency of this dual pathology in recent reports has sparked a debate on whether it represents a true pathophysiological association or an artifact of increased diagnostic surveillance. This study aims to report the prevalence, clinicopathological characteristics, management, and outcomes of concurrent CBT and PTC in a contemporary cohort. Methods: We conducted a retrospective review of patients who underwent CBT resection at two tertiary centers between 2014 and 2024. Data on patient demographics, tumor characteristics, preoperative imaging, surgical management (single stage vs. staged), final histopathology, and clinical outcomes were collected and analyzed. Results: Overall, 32 patients with surgically resected CBTs were included. Eleven patients (34.4%) had thyroid nodules identified on preoperative imaging. The mean age of the participants was 57.2 ± 16.3 years. Females represented the majority of the population (n = 27, 84.4%). Nine patients underwent thyroid surgery with subsequent pathological confirmation. Management involved resection at two different time intervals in five cases (55.6%) and a single-stage operation in four (44.4%). On final pathology, PTC was confirmed in eight patients (25.0%). During the follow-up period, no recurrences of either tumor type were observed. Conclusions: The prevalence of concurrent PTC in patients with CBTs is significantly higher than previously reported, reaching 25% in our cohort. This incidental finding raises the possibility of surveillance bias or underlying genetic mechanisms. Management with either a single-stage or staged surgical approach was not associated with major complications. The prognosis for patients with this dual pathology is excellent and appears to be dictated by the independent characteristics of each tumor.

Rare and Unusual Complications Following Embolization for Carotid Body Tumors

Baroreflex Failure After Surgical Resection of Bilateral Carotid Body Tumors: A Systemic Review

Carotid body tumors (CBTs) are rare paragangliomas arising at the carotid bifurcation, with Shamblin III lesions posing substantial operative risk due to circumferential arterial encasement. When arterial resection and reconstruction are required, reliable confirmation of carotid perfusion is essential. This is the case of a 24-year-old male patient with a right-sided Shamblin III CBT managed with preoperative embolization, segmental internal fluorescence-guided carotid artery resection, and end-to-end reconstruction. Intraoperative indocyanine green fluorescence angiography (ICG-FA) demonstrated immediate, homogeneous perfusion across the reconstructed segment, with no delay or focal hypofluorescence. The postoperative course was uneventful, with no neurologic or vascular complications. This case illustrates the potential role of intraoperative ICG-FA as a real-time adjunct to confirm carotid patency and perfusion following complex vascular tumor resection.

Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs), collectively known as PPGLs, are rare neuroendocrine tumors that produce catecholamines. The majority of PPGL cases are caused by germline and/or somatic mutations in over 20 different genes. A study of post-surgical PCC patients revealed a high risk of new tumor recurrence in both hereditary and apparently sporadic cases, suggesting that some germline mutations remain undetected. Since transcript levels can indicate gene dysfunction, our study focuses on the transcriptional profiling of PCC-associated genes in post-surgical patients. Methods: RT-PCR was performed on blood samples from patients and a control group. The t-SNE algorithm was applied to the transcriptional data. Sanger sequencing was used to identify mutations in the coding sequences of the VHL, SDHB, RET, and NF1 genes. Results: We obtained transcriptional profiles for 11 genes involved in the Krebs cycle and for 21 genes involved in the hypoxia, PI3K/AKT/mTOR, and RAS/RAF/ERK signaling pathways. We identified a minimal set of 16 genes with stable transcription levels that can be used to differentiate PCC patients from controls. Germline mutations in the VHL, SDHB, RET and NF1 genes, which correlated with an altered transcriptional profile, were detected in three patients. Conclusions: Our pilot data suggest that transcript levels of the genes involved in Krebs cycle, hypoxia, PI3K/AKT/mTOR, and RAS/RAF/ERK signaling pathways indicate their potential suitability as a candidate diagnostic marker. The results from this pilot study form the basis for a larger project to investigate gene transcription in an expanded cohort of patients who have undergone surgery for PCC.

Incidentally vs nonincidentally diagnosed paragangliomas: Experience of a tertiary referral center.

Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and ganglia of the autonomic nervous system. Approximately one-third are causatively associated with pathogenic germline variants. Metastatic disease develops in up to 25% of patients with PCC/PGL, for whom therapeutic options are limited, and no targeted treatments exist. Tumor evolution in metastatic PCC/PGL has not been well delineated. We performed whole-exome sequencing of paired specimens from 27 patients with metastatic PCC/PGL to better understand cancer progression. Tumors demonstrate high rates of loss-of-function variants in chromatin remodeling and DNA damage repair genes, suggesting potential therapeutic targets. Low rates of shared somatic variants were observed between primary tumors and metastases, with evidence of independent monoclonal pathogenic variants in metastatic tumors. These findings suggest that PCC/PGL metastases develop via monoclonal seeding and parallel progression.

Carotid tumors are rare, hyper-vascular structures arising from the chemoreceptors of the carotid body. In this study, we will discuss the classification and diagnosis of carotid body tumors, as well as surgical resection, which is the definitive treatment for these lesions. We will highlight important preoperative considerations to minimize the risk of bleeding, cranial nerve injury, and stroke with surgical resection.

Pheochromocytomas (PCCs) and paragangliomas (PGLs), collectively PPGLs, are rare tumors with significant molecular heterogeneity, which complicates prognosis and treatment. This study analyzed publicly available datasets (TCGA-PPGLs, GSE19422, GSE60459) to identify differentially expressed genes (DEGs) related to mitochondrial autophagy and ferroptosis in PPGLs. We identified 6,286 DEGs, including 31 mitochondrial ferroptosis-related DEGs (MFRDEGs). A prognostic model based on four genes (AMBRA1, EIF2S1, SRC, PHGDH) demonstrated high predictive accuracy (AUC > 0.9). Functional enrichment analysis highlighted key pathways, including mitophagy and Fc epsilon receptor I (FcεRI) signaling. Protein-protein interaction (PPI) and ceRNA network analyses revealed potential regulatory mechanisms. Calibration and decision curve analyses confirmed the model's clinical utility. These findings offer insights into PPGL molecular mechanisms, suggest prognostic biomarkers, and propose candidate therapeutic targets to improve risk stratification and personalized treatment. However, experimental validation is required to confirm their biological relevance before clinical application.

IntroductionParagangliomas (PGLs) are rare neuroendocrine tumors. Atypical manifestations such as skin lesions mimicking vasculitis secondary to catecholamine-induced vasoconstriction are extremely rare. Both hypoxia observed in cyanotic congenital heart disease, like tetralogy of Fallot (TOF), and succinate dehydrogenase B (SDHB) germline mutations can activate hypoxia-inducible factor (HIF) pathways, leading to tumor proliferation.Clinical CaseA 34-year-old female patient, with a history of TOF repair, hypothyroidism, hypertension, carotid body tumor surgery, and autoamputation of two toes in the right foot, presented with necrotic, ulcerative lesions on her extremities. The patient was treated with steroids and methotrexate for 3 months. Examination revealed blood pressure of 100/70 mmHg, a diastolic murmur in the pulmonary area, pretibial edema, right third toe gangrene, and multiple skin lesions (Figure 1). Rheumatologic tests for vasculitis were negative, and the skin biopsy was inconclusive. Abdominopelvic CT performed for vascular imaging and detected a retroperitoneal mass (80x46 mm) in the posterior of the pancreas. 18F-FDG PET/CT showed intense uptake. Significant increase in urinary normetanephrine (10-fold) and norepinephrine (18-fold) levels was detected. 68Ga Dotatate PET/CT revealed intense somatostatin receptor activity. Focal uptake was seen on the MIBG scan. The tumor was inoperable due to involvement of the superior mesenteric and celiac arteries. Genetic analysis identified a pathogenic heterozygous SDHB gene variant (c.262A>C; p.Thr88Pro).Given the ineffectiveness of vasculitis treatment, it was discontinued. The gangrenous toe was amputated, and the patient was managed with hyperbaric oxygen therapy along with alpha blockade therapy. The treatment resulted in the healing of necrotic lesions. 177Lu-Dotatate therapy resulted in partial tumor regression and biochemical response, but it was discontinued due to pancytopenia. Therapy was resumed with thrombopoietin receptor agonist support but later discontinued due to recurrent cytopenia.131I-MIBG therapy was administered. However, despite these interventions, the patient developed progressive cardio-renal complications and died due to sudden arrhythmia.ConclusionThis case highlights the rare hypoxia-related PGL phenotype in a patient with TOF and SDHB mutation. Although SDHB mutations are sufficient to initiate PGL development via pseudohypoxia, the accompanying chronic systemic hypoxia due to TOF may have exerted a synergistic effect by further stabilizing HIF signaling, thereby accelerating tumorigenesis and contributing to the unusual clinical presentation. Cutaneous lesions mimicking vasculitis may be attributed to catecholamine-induced vasoconstriction and ischemia. Recognition of atypical findings may allow for early diagnosis and intervention. Multidisciplinary management is essential in inoperable cases with complex comorbidities.Figure 1:Necrotic cutaneous lesions of the patient’s lower extremity

Artificial intelligence (AI) and machine learning (ML) are reshaping cancer research and care. In pediatric oncology, early evidence-most robust in imaging-suggests value for diagnosis, risk stratification, and assessment of treatment response. Pediatric endocrine tumors are rare and heterogeneous, including intra- and extra-adrenal paraganglioma (PGL), adrenocortical tumors (ACT), differentiated and medullary thyroid carcinoma (DTC/MTC), and gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Here, we provide a pediatric-first, entity-structured synthesis of AI/ML applications in endocrine tumors, paired with a methods-for-clinicians primer and a pediatric endocrine tumor guardrails checklist mapped to contemporary reporting/evaluation standards. We also outline a realistic EU-anchored roadmap for translation that leverages existing infrastructures (EXPeRT, ERN PaedCan). We find promising-yet preliminary-signals for early non-remission/recurrence modeling in pediatric DTC and interpretable survival prediction in pediatric ACT. For PGL and GEP-NEN, evidence remains adult-led (biochemical ML screening scores; CT/PET radiomics for metastatic risk or peptide receptor radionuclide therapy response) and serves primarily as methodological scaffolding for pediatrics. Cross-cutting insights include the centrality of calibration and validation hierarchy and the current limits of explainability (radiomics texture semantics; saliency ≠ mechanism). Translation is constrained by small datasets, domain shift across age groups and sites, limited external validation, and evolving regulatory expectations. We close with pragmatic, clinically anchored steps-benchmarks, multi-site pediatric validation, genotype-aware evaluation, and equity monitoring-to accelerate safe, equitable adoption in pediatric endocrine oncology.

Accurate preoperative assessment of internal carotid artery (ICA) invasion is crucial in managing glomus jugulare tumors. This study evaluated the efficacy of contrast-enhanced 3D BRAin VOlume (BRAVO) imaging compared to enhanced fast spin-echo (FSE) T1-weighted imaging and enhanced computed tomography (CT). Retrospective analysis was performed on imaging data from surgically confirmed glomus jugulare tumors, including temporal bone enhanced BRAVO, enhanced T1-weighted FSE, and temporal bone enhanced CT sequences. ICA encasement and stenosis by tumor were graded and compared based on intraoperative assessment. According to Fisch criteria, the preoperative image C-type based on BRAVO, FSE and CT were separately and compared with surgical C-type (gold standard). Among 21 patients, For image Fisch C-type, BRAVO showed excellent agreement with surgical C-type (κ = 1.000, P < 0.001), outperforming enhanced FSE (κ = 0.561) and CT (κ = 0.702). For ICA encasement, BRAVO had moderate agreement (κ = 0.513), slightly better than enhanced FSE (κ = 0.431) but inferior to enhanced CT (κ = 0.648). For ICA stenosis, BRAVO (κ = 0.588) surpassed enhanced FSE (κ = 0.339) but was less accurate than enhanced CT (κ = 0.716). Enhanced BRAVO and temporal bone enhanced CT are complementary for assessing ICA involvement in glomus jugulare tumors, offering superior accuracy over conventional FSE imaging.

Abstract Pheochromocytomas and paragangliomas are relatively rare tumors, with an incidence of approximately 0.6 cases per 100,000 person-years. Moreover, the co-occurrence of these tumors is extremely rare and is often associated with pheochromocytomas/paragangliomas-related pathogenic mutations. We present the case of a 33-year-old female diagnosed with bilateral carotid body paragangliomas and a concurrently detected pheochromocytoma, with metastases to the abdominal lymph nodes and lung. DNA analysis revealed a mutation in the succinate dehydrogenase subunit D gene. The tumors displayed high-grade SSTR expression (Krenning grade 4 uptake) on Gallium-68 [⁶⁸Ga]-DOTA-(Tyr3)-octreotate Positron Emission Tomography/Computed Tomography, with no significant tracer concentration on the I-131 MIBG scan. Another notable feature in this case was the visually evident intra- and inter-tumoral metabolic heterogeneity on 18F-fluorodeoxyglucose positron emission tomography/computed tomography, especially within the multiple carotid paragangliomas. With the adoption of a multimodality diagnostic approach (MRI, FDG PET/CT, SSTR PET/CT, and I-131 MIBG scintigraphy), a holistic theranostic approach was employed with the most rational therapeutic option offered to the patient.

Hereditary paragangliomas (PGLs) caused by germline SDHD pathogenic variants (PVs) exhibit a parent-of-origin effect, with tumors arising almost exclusively when the PV is inherited from the paternal allele. The Hensen model proposes that a cluster of maternally expressed tumor suppressor genes (TSGs) on chromosome 11p15.5 may play a crucial role in SDHD-related PGL tumorigenesis, wherein somatic loss of maternal 11p and wild-type SDHD allele, in conjunction with a paternally inherited SDHD PV, triggers tumor development. To systematically localize and identify the most crucial maternal-expressed TSGs within 11p15.5, we developed a novel single nucleotide variant (SNV)-oriented, capture-based targeted enrichment approach followed by next-generation sequencing (NGS) to enable high-resolution loss-of-heterozygosity (LOH) analysis. Among 13 SDHD-related PGLs and 23 non-SDHD-related PGLs, a somatic loss of 11p15.5-15.4 was detected in 92% and 47%, respectively, a significant difference (p = 0.0035). Parental genotype analysis confirmed that the lost chromosome was of maternal origin. In our studies, 12/13 SDHD-related tumors demonstrated complete loss of the maternal 11p15.5-15.4 region, preventing localization of a specific driver TSG. Only one exceptional SDHD-related tumor retained this region, warranting further investigation into the mechanism underlying parent-of-origin tumorigenesis.

Radiation Therapy for Benign Diseases and Premalignant Conditions.

Quality of life among patients with carotid body tumors in a retrospective matched-pair observational study

We present a very rare case of a carotid body tumor accompanied by a large nonfunctioning epiaortic paraganglioma requiring ascending aorta replacement. Even though multiple paragangliomas in different locations in a single patient are highly uncommon, preoperative discovery of an extrathoracic neuroendocrine tumor should prompt full screening for the presence of multiple tumors.

BackgroundTo classify CBT patients using machine learning-based clustering analysis to identify subgroups with different risks of complications and outcomes.Methods: This retrospective, dual-center study included 127 patients who underwent CBT resection between 2003 and 2019. Clinical data were collected. Clustering analysis was performed using the Gower distance and silhouette coefficient to determine the optimal number of clusters. Clinical characteristics and outcomes were compared between phenotypes.ResultsPhenotype 1 (n = 29) consisted of patients who received preoperative embolization therapy, with a Shamblin III classification in 55.2% of cases and the shortest operative time (110 min). Phenotype 2 (n = 46) included patients with high-grade Shamblin classification without embolization therapy, characterized by longer operative times (240 min) and higher rates of vascular reconstruction (58.7%). Phenotype 3 (n = 52) comprised mainly female patients (80.8%) with Shamblin I tumors (51.9%) and the smallest tumor diameter (3 mm). Phenotype 2 had significantly higher estimated blood loss, postoperative stay, and cranial nerve injury rates compared to other phenotypes.ConclusionsPatients in Phenotype 2, with large tumors and high Shamblin classifications, had higher complication rates. Preoperative embolization combined with surgical resection was associated with lower surgical risks in these high-risk patients. This approach may provide a more precise method for identifying high-risk patients and could guide clinical decision-making.