Search Results (65)

Background: Pheochromocytomas and paragangliomas (PPGLs) can be metastatic in up to 30% of cases. To assess this risk, scoring systems like PASS and GAPP were developed, yet it is unclear whether these scores correlate with somatic genetic alterations. Methods: A retrospective pilot study. Twenty patients with sporadic pheochromocytoma, stratified into high- and low-risk groups based on GAPP and PASS scores. Somatic variant burden, derived from whole-exome sequencing, and clinical variables were compared between groups. Results: Six patients (30.0%) comprised the high-risk group; all had PASS scores >4 and GAPP scores indicating moderately differentiated PPGLs. Compared with the low-risk group, the high-risk group had larger tumors (4.7 vs. 3.4 cm, p = 0.03) and non-significant association with higher diastolic blood pressure (90 vs. 79 mmHg, p = 0.09), normetanephrine (8.5 vs. 2.3 X upper limit of normal [ULN], p = 0.08), and metanephrine (22.9 vs. 9.25 X ULN, p = 0.09) levels. The high-risk group also demonstrated a higher somatic variant burden, particularly for truncating variants (32 vs. 26, p = 0.04). As a continuous variable, only the GAPP score, not PASS score, showed a significant positive correlation with variant burden, observed for both non-missense (r = 0.57, p = 0.009) and frameshift (r = 0.47, p = 0.04) variants. Conclusions: Higher pathological severity scores are associated with increased rates of severe molecular somatic variants. The stronger link between GAPP score and genetic alteration rates suggests it may better reflect the genomic complexity of sporadic PPGLs. Full article

Background: Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms that may be sporadic or hereditary and may occur as isolated, multifocal, or syndromic disease within the pheochromocytoma-paraganglioma spectrum. Synchronous bilateral carotid body tumors (CBTs) and bilateral vagal paragangliomas (VPGLs) are exceptional, particularly when biochemical activity and metastatic nodal involvement coexist. Case Presentation: We report a 33-year-old man with a 2-year history of enlarging bilateral neck masses, positive family history, and markedly elevated noradrenaline (6430 pg/mL; reference range <750 pg/mL). Initial CT angiography suggested bilateral CBTs, and Metaiodobenzylguanidine (MIBG) scintigraphy did not demonstrate abnormal adrenal or distant uptake. After alpha- and beta-blockade, staged surgery was performed. Right CBT excision demonstrated metastatic PGL, with two of four lymph nodes positive. Subsequent MRI and operative reassessment revealed synchronous bilateral CBTs and bilateral VPGLs. Left-sided surgery required partial debulking of a vagal-adherent mass to preserve nerve continuity; pathology confirmed PGL with Ki-67 index approximately 2% and left neck nodes were negative. Postoperatively, profound bradycardia required temporary then permanent pacing, together with bilateral vocal cord paralysis. During follow-up, swallowing and voice improved, the pacemaker was removed, and late imaging showed stable residual cervical disease without visceral metastasis on chest/abdominal CT. Conclusions: This case highlights the diagnostic and therapeutic complexity of multicentric, biochemically active HNPGLs and supports individualized multidisciplinary management, genetic counseling, biochemical surveillance, and long-term follow-up. Full article

Radiomics may aid the noninvasive characterization of adrenal incidentalomas; however, reproducibility is limited by methodological heterogeneity. In this retrospective, single-center, exploratory study, we tested whether radiomic features from baseline non-enhanced computed tomography (NECT) discriminate benign from malignant/metastatic adrenal lesions and contextualized results with a PRISMA 2020 systematic review (PubMed/Scopus 2017–2025; PROSPERO CRD420251276627). Thirty-three patients (36 lesions: 12 lipid-rich adenomas, 9 lipid-poor adenomas, 6 pheochromocytomas, 7 malignant/metastatic lesions, 2 myelolipomas) were included; myelolipomas were excluded from primary comparisons. Two abdominal radiologists performed consensus 3D segmentation on NECT. Using LIFEx (v7.8.0) and IBSI definitions, 42 features were extracted and z-score standardized. LASSO selected four heterogeneity descriptors: First-order Entropy, gray-level co-occurrence matrix (GLCM) entropy, gray-level size zone matrix (GLSZM) non-uniformity, and neighboring gray tone difference matrix (NGTDM) busyness. Heterogeneity increased from lipid-rich adenomas to pheochromocytomas and malignant/metastatic lesions (Kruskal–Wallis, all p < 0.001. Pairwise separability, measured using the Vargha–Delaney A index (VDA) as a rank-based measure of separability, was highest for lipid-rich adenomas versus malignant/metastatic lesions (0.93), intermediate for lipid-poor adenomas versus pheochromocytomas (0.73), and lowest for lipid-rich versus lipid-poor adenomas (0.64). The review identified 18 eligible CT radiomics studies that consistently reported higher entropy/non-uniformity in pheochromocytomas and malignant lesions than in lipid-rich adenomas. Global heterogeneity metrics on NECT may complement conventional CT criteria in indeterminate lesions; external validation with robust reference standards is needed in larger, multicenter cohorts with harmonization. Full article

Hereditary predisposition substantially shapes prevention and management across urologic oncology. This narrative review synthesizes contemporary, practice-oriented guidance on whom to test, what to test, how to act on results, and how to implement care equitably for hereditary forms of prostate cancer, renal cell carcinoma (RCC), urothelial carcinoma, pheochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). We delineate between forms of indication-driven germline testing (e.g., universal testing in metastatic prostate cancer; early-onset, bilateral/multifocal, or syndromic RCC; reflex tumor mismatch repair (MMR)/microsatellite instability (MSI) screening in upper-tract urothelial carcinoma (UTUC); universal testing in PPGL; universal TP53 testing in ACC) and pair these strategies with minimum actionable gene sets and syndrome-specific surveillance frameworks. Key points include targeted prostate-specific antigen screening in BRCA2 carriers and the impact of BRCA/ATM variants on reclassification during active surveillance; major hereditary RCC syndromes with genotype-tailored surveillance and pathway-directed therapy (e.g., HIF-2α inhibition for von Hippel–Lindau disease); UTUC/bladder cancer in Lynch syndrome with tumor MMR/MSI screening, annual urinalysis (selective cytology), and immunotherapy opportunities in deficient MMR disease/MSI-H; PPGL management emphasizing universal germline testing, intensified surveillance for SDHB, cortical-sparing adrenalectomy, and emerging HIF-2α inhibition; and ACC care modified by Li–Fraumeni syndrome (minimization of radiation/genotoxic therapy with whole-body imaging surveillance). Testicular germ cell tumor remains largely polygenic, with no routine germline testing in typical presentations. Finally, we provide pre-/post-test genetic-counseling checklists and mainstreamed workflows with equity metrics to operationalize precision care and close real-world access gaps. Full article

Background: Large-scale data on the diagnostic performance of functional imaging in metastatic pheochromocytoma/paraganglioma (PPGL) are scarce. Objective: To analyze the diagnostic accuracy of functional imaging for the assessment of metastases during long-term follow-up (FU). Design: Retrospective cohort study, 1991–2025. Setting: Referral center. Outcomes: Sensitivity and specificity of ¹²³MIBG-, ¹⁸F-DOPA-, ⁶⁸GaDOTA-based and ¹⁸FDG PET/CT. Patients: Patients with metastatic PPGL and without PPGL, ≥1 functional imaging prior to first diagnosis and/or during FU and FU ≥ 3 months. Results: 59 ¹²³MIBG-, 101 ¹⁸F-DOPA-, 11 ¹⁸FDG- and 74 ⁶⁸GaDOTA-based PET/CT were performed in 57 patients with metastatic PPGL and 37 ¹²³MIBG-, 323 ¹⁸F-DOPA-, 259 ¹⁸FDG- and 641 ⁶⁸GaDOTA-based imaging in 527 patients without PPGL. FU was 11.6 ± 11.4 and 5.1 ± 4.7 years, respectively. Sensitivity for the detection of all metastases (total cohort) by patient-based analysis was comparable between ¹⁸F-DOPA (77%), both ⁶⁸GaDOTA-based tracers combined (67%) and ¹²³MIBG (72%); lesion-based analysis was better for ¹⁸F-DOPA (94%) than for ⁶⁸GaDOTA (85%) and ¹²³MIBG (67%). Specificity (patient- and lesion-based) of ¹⁸F-DOPA vs. ⁶⁸GaDOTA (96–99%) was comparable and better than ¹²³MIBG (73%) and ¹⁸FDG (75%). Conclusions: Sensitivity of ¹⁸F-DOPA was superior to ⁶⁸GaDOTA for the detection of all and bone metastases in the total cohort and in patients with PCC, that of ⁶⁸GaDOTA was better for bone metastases with PGL, specificity was comparable and for both was better than for ¹⁸FDG and ¹²³MIBG. Given the beneficial pharmaceutical properties and favorable diagnostic performance, ¹⁸F-DOPA may be a good alternative to ⁶⁸GaDOTA-based tracers for the functional imaging of metastatic PPGL. Full article

Metastatic or unresectable pheochromocytomas and paragangliomas (PPGLs) remain rare but clinically challenging neuroendocrine neoplasms with limited curative options. Traditionally managed with surgery, radionuclide therapy, or cytotoxic chemotherapy, systemic treatments have historically achieved disease stabilization, rather than durable remissions. In recent years, however, the therapeutic landscape has evolved substantially. Radiopharmaceuticals such as ¹³¹I-MIBG and ¹⁷⁷Lu-DOTATATE continue to play a pivotal role, achieving disease control in many patients. Cytotoxic regimens, particularly temozolomide, remain relevant, with some studies suggesting that SDHB-mutated PPGLs demonstrate a heightened sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression. Targeted agents are increasingly important: multi-kinase inhibitors such as sunitinib, anlotinib, and cabozantinib have shown meaningful activity. The landmark approval of belzutifan, a HIF-2α inhibitor, in 2025 represents the first oral targeted therapy for advanced/metastatic PPGL, which is particularly relevant for pseudohypoxic Cluster 1 tumors. Immunotherapy has yielded modest responses with checkpoint inhibitor monotherapy, but ongoing studies of dual checkpoint blockade and TKI–ICI combinations hold promise. Novel approaches, including PARP inhibition, metabolic targeting strategies, and cancer vaccines, are under investigation, especially for aggressive SDHB-related disease. Optimal sequencing of these therapies is emerging as a central challenge, with treatment strategies increasingly tailored to molecular genotype, tumor behavior, and functional imaging phenotype. This review summarizes current evidence and highlights ongoing clinical trials, underscoring a paradigm shift toward precision medicine and rational combination strategies. Collectively, these advances bring cautious optimism that metastatic PPGLs may soon become a more manageable chronic disease with improved survival and quality of life. Full article

Concurrent occurrence of two independent primary malignancies in a single dog is rare and presents diagnostic and surgical challenges. A 9-year-old neutered male Cocker Spaniel was diagnosed with adrenal pheochromocytoma and splenic diffuse large B-cell lymphoma. Abdominal imaging revealed two distinct masses. Surgical management included adrenalectomy, splenectomy, mesenteric lymphadenectomy, and excision of a small mass adherent to the portal vein adventitia. Histopathology confirmed two separate malignancies, with chromogranin A positivity supporting pheochromocytoma and CD20 positivity confirming B-cell lymphoma. No additional metastatic lesions were identified, and the portal vein-associated mass was considered an isolated lesion closely adherent to the vessel wall, with its exact pathogenesis remaining uncertain. To the authors’ knowledge, this represents the first veterinary report describing adrenal pheochromocytoma with portal vein involvement successfully managed by surgical removal. The patient recovered well and remained disease-free for three years without adjuvant therapy. This case emphasizes that, even in technically demanding situations, meticulous surgical planning and comprehensive oncologic assessment can achieve durable remission and inform future approaches to complex veterinary cancers. Full article

Pheochromocytomas and paragangliomas (PPGL) are classified as rare cancers but can be highly metastatic, particularly in individuals with inherited succinate dehydrogenase B (SDHB) mutations. As current therapies and the availability of SDHB-deficient animal models are both limited, we have previously constructed a nematode PPGL model, a transgenic worm carrying the R244H missense mutation equivalent to human R230H in the sdhb-1 gene. In this study, we show that R244H mutants display characteristics of PPGL tumors, such as pseudohypoxia activation and the accumulation of reactive oxygen species. The latter can be the result of compromised antioxidant machinery, as R244H mutants have reduced levels of cytosolic and mitochondrial superoxide dismutase enzymes. In addition, the expression of mitophagy markers pink-1 (PTEN-induced putative kinase) and pdr-1 (E3 ubiquitin-protein ligase parkin) were downregulated in R244H mutants, suggesting impaired mitophagy and reflecting the crucial role of mitochondrial health in PPGL pathology. Treatments by the SDH inhibitor fluopyram revealed that the SDH complex carrying the R244H mutation in subunit B displayed residual SDH activity, which was also confirmed by our structural analyses. We also observed a link between dopaminergic neuronal health and SDHB-1. Full article

Background and Clinical Significance: Zoledronic acid (ZA) is a widely used bisphosphonate for the prevention of skeletal-related events in patients with metastatic bone disease. While it is generally well tolerated, rare immune-mediated complications may be underrecognized. To date, myocarditis has not been reported in association with ZA. Case Presentation: A 35-year-old woman with metastatic pheochromocytoma developed acute, non-exertional chest pain approximately 36 h after receiving her first intravenous ZA infusion. Laboratory testing revealed elevated high-sensitivity troponin T, peaking at 1182 ng/L. Cardiac magnetic resonance imaging (CMR) demonstrated myocardial edema and subepicardial late gadolinium enhancement, consistent with acute myocarditis per the 2018 revised Lake Louise criteria. An extensive diagnostic workup excluded infectious, autoimmune, and ischemic causes. Symptoms and troponin levels improved following ZA discontinuation and supportive care. In the absence of alternative etiologies, and given the close temporal association with ZA administration, the diagnosis of presumed ZA-associated myocarditis was supported by clinical presentation, biochemical markers, and CMR findings, recognizing that histopathological confirmation is rarely pursued in clinically stable patients. Conclusions: To our knowledge, this is the first reported case of presumed zoledronic acid–associated myocarditis confirmed by cardiac MRI. This report highlights the diagnostic utility of CMR in suspected drug-related cardiac inflammation and the importance of considering myocarditis in patients presenting with unexplained chest pain following ZA infusion, particularly when other causes have been excluded. Full article

Gain-of-function gene alterations in rearranged during transfection (RET), a receptor tyrosine kinase, are observed in both sporadic and hereditary medullary thyroid cancers (MTCs) and pheochromocytomas and paragangliomas (PPGLs). Several tyrosine kinase inhibitors (TKIs) that target RET have been proven to be effective on MTCs and PCCs. Recently, TKIs, namely, sunitinib and selpercatinib, which were clinically used to target PPGLs, have been reported to decrease catecholamine levels without reducing tumor size. Our clinical case of metastatic medullary thyroid cancer, which is associated with RET mutations undergoing treatment with vandetanib, also suggests that vandetanib can decrease catecholamine levels. Therefore, we investigated the effect of vandetanib, a representative multi-targeted TKI for RET-related MTC, on cell proliferation and catecholamine synthesis in rat pheochromocytoma PC12 cells. Vandetanib reduced viable cells in a concentration-dependent manner. The dopamine and noradrenaline levels of the cell lysate were reduced in a concentration-dependent manner. They also decreased more prominently at lower concentrations of vandetanib compared to the inhibition of cell proliferation. The RNA knockdown study of Ret revealed that this inhibitory effect on catecholamine synthesis is mainly mediated by the suppression of RET signaling. Next, we focused on two signaling pathways downstream of RET, namely, ERK and AKT signaling. Treatment with vandetanib reduced both ERK and AKT phosphorylation in PC12 cells. Moreover, both an MEK inhibitor U0126 and a PI3K/AKT inhibitor LY294002 suppressed catecholamine synthesis without decreasing viable cells. This study in rat pheochromocytoma PC12 cells reveals the direct inhibitory effects of vandetanib on catecholamine synthesis via the suppression of RET-ERK and RET-AKT signaling. Full article

One of the main issues with paragangliomas and pheochromocytomas is that these tumors have up to a 20% rate of metastatic disease, which cannot be reliably predicted. While machine learning models hold great promise for enhancing predictive accuracy, their often opaque nature limits trust and adoption in critical fields such as healthcare. Understanding the factors driving predictions is essential not only for validating their reliability but also for enabling their integration into clinical decision-making. In this paper, we propose an architecture that combines data mining, machine learning, and explainability techniques to improve predictions of metastatic disease in these types of cancer and enhance trust in the models. A wide variety of algorithms have been applied for the development of predictive models, with a focus on interpreting their outputs to support clinical insights. Our methodology involves a comprehensive preprocessing phase to prepare the data, followed by the application of classification algorithms. Explainability techniques were integrated to provide insights into the key factors driving predictions. Additionally, a feature selection process was performed to identify the most influential variables and explore how their inclusion affects model performance. The best-performing algorithm, Random Forest, achieved an accuracy of 96.3%, precision of 96.5%, and AUC of 0.963, among other metrics, combining strong predictive capability with explainability that fosters trust in clinical applications. Full article

Background/Objectives: Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of neural crest origin that secrete varying levels of catecholamines. [¹⁸F]Fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valuable tool for the detection of metastases and the prediction of prognoses. However, varying FDG avidities in PPGLs raise concerns regarding cost-effectiveness and unnecessary radiation exposure. Catecholamine secretion patterns are associated with metastasis and clinical outcomes. This study aimed to explore the relationships among FDG avidity, catecholamine levels, and clinical factors in patients with PPGLs. Methods: This retrospective study included 25 patients with unresectable or metastatic PPGLs scheduled for [¹³¹I]metaiodobenzylguanidine therapy with FDG-PET data available within 40 days of urine catecholamine measurements. FDG avidity was assessed using semiquantitative parameters such as the maximum standardized uptake value (SUVmax), total metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Urine catecholamine levels were quantified. Logistic regression and Spearman’s correlation were performed to evaluate the relationship between FDG parameters and urinary catecholamine levels. Results: Urinary noradrenaline levels were significantly higher in patients with FDG-avid lesions than in those without (726.25 μg/day vs. 166.3 μg/day, p = 0.001). Noradrenaline levels showed significant positive correlations with SUVmax, MTV, and TLG (ρ = 0.527, 0.541, and 0.557, respectively; all p < 0.01). Urinary noradrenaline levels predicted FDG avidity with an AUC of 0.849; a cutoff value of 647.5 μg/day achieved 55.6% sensitivity and 100% specificity. Conclusions: Urinary noradrenaline levels were significantly associated with FDG avidity in PPGLs, suggesting their potential utility in predicting FDG-PET outcomes. Therefore, FDG-PET may be unnecessary in PPGL patients with low urinary noradrenaline levels. These findings may help optimize imaging strategies for patients with PPGLs. Full article

Pheochromocytomas and paragangliomas (PPGLs) are infrequent neuroendocrine hypervascular neoplasms arising within different sites of the paraganglion system. They are divided into sympathetic (including pheochromocytomas and extraadrenal paragangliomas) and parasympathetic extraadrenal tumors. These tumors are usually not malignant and grow slowly; about 90% of them are found in the adrenal paraganglia (pheochromocytomas). Extraadrenal tumors are most frequently located in the abdominal cavity (85%), followed by the thoracic cavity (12%), and head and neck (3%). About 25% of PPGLs are related to germline mutations, which are risk factors for multifocal and metastatic disease. In PPGL diagnostics, laboratory, biochemical, and imaging (anatomical and functional) examinations are used. Surgery is the standard management choice for locoregional disease. For patients who are not candidates for surgery and who have stable, not-growing, or slow-growing tumors, active observation or other less invasive techniques (i.e., stereotactic surgery, hypofractionated stereotactic radiotherapy) are considered. In metastatic disease, systemic therapies (tyrosine kinase inhibitors [TKIs], mTORC1 inhibitor everolimus, immunotherapy, cold somatostatin analogs [biotherapy], and radioligand therapy) are used. The prognosis for PPGLs is quite good, and the 5-year survival rate is >90%. The goal of this paper is to review knowledge on the etiopathogenesis, current diagnostics, and therapy for PPGL patients. Our paper is particularly focused on the current management of PPGLs. Full article

An adrenal mass discovered incidentally during imaging for unrelated clinical reasons is termed an “adrenal incidentaloma” (AI). AIs can be categorized as primary or metastatic, functioning or non-functioning, and benign or malignant. The primary goal of radiological evaluation is to exclude malignancy by differentiating between benign and malignant lesions. Most AIs are benign, with adenomas and macronodular bilateral adrenal hyperplasia being the most common types. Less common benign lesions include myelolipomas, pheochromocytomas, cysts, and hematomas. Malignant adrenal masses account for less than 10% of cases and often include metastases from other cancers or primary adrenal diseases, such as adrenocortical carcinoma and pheochromocytoma. Computed Tomography (CT) remains the gold standard for diagnosing adrenal incidentalomas, while Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) are utilized for indeterminate cases. Additionally, innovative imaging techniques such as texture analysis are gaining importance, as they can assess quantitative parameters that are not visible to the human eye. This review aims to provide an updated overview of malignant adrenal lesions on CT and MRI, emphasizing key imaging features suspicious for malignancy to aid in distinguishing between benign and malignant lesions. Furthermore, it highlights the growing role of radiomics as a supportive tool for radiologists. Full article

Background: Pheochromocytoma and paragangliomas (PPGLs) caused refractory hypertension in clinics. The sustained risk of local or metastatic recurrences or new tumor development prompted more research on diagnosis, prognosis prediction, and immunotherapy. Method: The tumor stemness is closely related to the heterogeneous growth of tumor, metastasis, and drug-resistance, and mRNA expression-based stemness indices (mRNAsi) could reflect tumor stemness. This was calculated based on OCLR machine learning algorithm and PPGLs patients’ TCGA RNAseq data. The relationship between clinical, molecular, and tumor microenvironment (TME) features and tumor stemness was analyzed through the hub genes that best captured the stem cell characteristics of PPGLs using weighted gene co-expression network analysis (WGCNA), Cox, and LASSO regression analysis. Results: Our study found that metastatic PPGLs had higher mRNAsi scores, suggesting the degree of tumor stemness could affect metastasis and progression. HRAS, CSDE1, NF1, RET, and VHL-mutant subtypes displayed significant difference in stemness expression. Patients were divided into stemness high-score and low-score subtypes. High-score PPGLs displayed the more unfavorable prognosis compared with low-score, associated with their immune-suppressive features, manifested as low macrophages M1 infiltration and downregulated expression of immune checkpoints. Furthermore, from the viewpoint of stemness features, we established a reliable prognostic for PPGLs, which has the highest AUC value (0.908) in the field so far. And this could stratify PPGLs patients into high-risk and low-risk subtypes, showing the significant differences in prognosis, underlying mechanisms correlated with specific molecular alterations, biological processes activation, and TME. Notably, high immune infiltration and tumor neoantigen in low-risk patients and further resulted in more responsive to immunotherapy. Conclusion: We indicated that tumor stemness could act as the potential biomarker for metastasis or prognosis of PPGLs, and integrated multi-data sources, analyzed valuable stemness-related genes, developed and verified a novel stemness scoring system to predict prognosis and guide the choice of treatment strategies. Full article