Metastatic disease and major adverse cardiovascular events preceding diagnosis are the main determinants of disease-specific survival of pheochromocytoma/paraganglioma: long-term follow-up of 303 patients.

Purpose: The natural history in unselected cohorts of patients with pheochromocytoma/ paraganglioma (PPGL) followed for a period >10 years remains limited. We aimed to describe baseline characteristics and outcome of a large cohort and to identify predictors of shorter survival. Methods: This retrospective single-center study included 303 patients with newly diagnosed PPGL from 1968 to December 31, 2023, in 199 prospectively supplemented since July 2020. Mean follow-up was 11.4 (range 0.3-50) years, germline genetic analyses were available in 92.1%. The main outcome measures were overall (OAS), disease-specific (DSS), recurrence-free (RFS) survival and predictors of shorter survival evaluated in patients with metastases at first diagnosis (n=12), metastatic (n=24) and nonmetastatic (n=33) recurrences and without evidence of PPGL after first surgery (n=234). Results: Age at study begin was 49.4 ± 16.3 years. There were 72 (23.8%) deaths, 15 (5.0%), 29 (9.6%) and 28 (9.2%) due to PPGL, cardiovascular disease (CVD) and malignant or other diseases, respectively. Median OAS, DSS1 (tumor-related) and DSS2 (DSS1 and death caused by CVD) were 4.8, 5.9 and 5.2 years (patients with metastases at first diagnosis), 21.2, 21.2 and 19.9 years, and 38.0, undefined and 38.0 years (patients with metastatic and with nonmetastatic recurrences, respectively). Major adverse cardiovascular events (MACE) preceded the first diagnosis in 15% (n=44). Shorter DSS2 correlated with older age (P ≤ 0.001), male sex (P ≤ 0.02), MACE (P ≤ 0.01) and primary metastases (P<0.0001, also for DSS1). Conclusion: The clinical course of unselected patients with PPGL is rather benign. Survival rates remain high for decades, unless there are MACE before diagnosis or metastatic disease.

Whole-lesion CT histogram analysis as an advanced technique in the portal venous phase: differentiating lipid poor adrenal adenomas from pheochromocytomas.

PURPOSE: Adrenal computed tomography (CT) has limitation due to imaging overlaps inthe washout characteristics of pheochromocytomas and adenomas (especially lipid-poor). The aim of this study was to investigate the distinguishability of lipid-poor adrenal adenomas and pheochromocytomas using whole-lesion CT histogram analysis. MATERIALS AND METHODS: Histopathologically proven 24 lipid-poor adenomas and 29 pheochromocytomas (total 53 lesions in 53 patients) were included in this retrospective study. Data obtained from standard and volumetric examinations of the lesions by dedicated adrenal CT were compared between the two groups using univariate analysis. Parameters that showed differences were further evaluated using multivariate logistic regression analysis. RESULTS: Univariate analysis revealed significant differences between the two groups in terms of lesion size, lesion volume, percentage of relative wash out, peak HU values and the percentage of voxels with attenuation ≥ 100 HU, ≥ 110 HU and ≥ 120 HU (p = 0.0001, P = 0.0001, P = 0.01, P = 0.008, p = 0.04, p = 0.02, p = 0.02, respectively). Multivariate analysis revealed lesion size ≥ 22.05 mm (OR: 22; p < 0.0001), the percentage of voxels with attenuation ≥ 120 HU being ≥ 9% (OR: 3.27; p = 0.04), peak HU value ≥ 161.5 HU (OR: 4.40; p = 0.01) as risk factors for pheochromocytomas. CONCLUSIONS: Whole lesion CT histogram analysis can be used to differentiate pheochromocytomas from lipid-poor adenomas. Lesion volume, the percentage of voxels with attenuation ≥ 120 HU and peak HU values are independent parameters that can assist in this differentiation. These findings may help avoid unnecessary biopsies and surgeries for lipid-poor adenomas, while identifying pheochromocytoma risk may improve perioperative patient management. Our results should be validated by future prospective studies.

Genotype and clinical phenotype characteristics of MAX germline mutation-associated pheochromocytoma/paraganglioma syndrome.

Objective: The aim of this study was to investigate the genotypic and clinical phenotypic characteristics of MAX germline mutation-associated pheochromocytoma (PCC) and paraganglioma (PGL). Methods: We retrospectively analyzed the family investigation data and clinical genetic characteristics of six individuals from three independent families with PCC carrying MAX germline mutations from December 2005 to March 2024. A literature review was then conducted of the six carriers and another 103 carriers from the other 84 families with MAX germline mutations reported previously. Results: There were 109 patients in 87 families with all five exons and 53 types of MAX germline mutations. p.R33* (c.97C>T; 21.1%), p.R75* (c.223C>T; 13.8%), and p.A67D (c.200C>A; 7.3%), which accounted for 42.2% of mutations detected, were the most common mutations. Moreover, 101 (92.7%) patients developed PCCs, including 59 bilateral PCCs and 42 unilateral PCCs, and 19 (18.8%) patients showed metastasis. The mean age at diagnosis was 32.8 ± 12.6 (13-80) years. The male-to-female ratio was 1.3:1. In 11 (10.9%) patients, the PCC was accompanied by chest or abdominal PGL, and one other patient had sole head and neck PGL. Nine (8.3%) patients also had functional pituitary adenomas, 11 (10.9%) developed other neuroendocrine tumors (NETs), and 7 (6.4%) presented with concomitant non-NET. Meanwhile, MAX-p.Q82Tfs*89 and p.E158A mutations are reported for the first time in this study. Conclusion: MAX germline mutations may cause new types of multiple endocrine neoplasia. A comprehensive baseline assessment of neural crest cell-derived diseases is recommended for all individuals with MAX germline mutations. The risk of bilateral and metastatic PCCs should also be considered.

The heterobivalent (SSTR2/albumin) radioligand [67Cu]Cu-NODAGA-cLAB4-TATE enables efficient somatostatin receptor radionuclide theranostics.

Somatostatin type 2 receptor (SSTR2) radionuclide therapy using ß- particle-emitting radioligands has entered clinical practice for the treatment of neuroendocrine neoplasms (NENs). Despite the initial success of [177Lu]Lu­DOTA-TATE, theranostic SSTR2 radioligands require improved pharmacokinetics and enhanced compatibility with alternative radionuclides. Consequently, this study evaluates the pharmacokinetic effects of the albumin-binding domain cLAB4 on theranostic performance of copper­67-labeled NODAGA-TATE variants in an SSTR2-positive mouse pheochromocytoma (MPC) model. Methods: Binding, uptake, and release of radioligands as well as growth-inhibiting effects were characterized in cells grown as monolayers and spheroids. Tissue pharmacokinetics, absorbed tumor doses, and projected human organ doses were determined from quantitative SPECT imaging in a subcutaneous tumor allograft mouse model. Treatment effects on tumor growth, leukocyte numbers, and renal albumin excretion were assessed. Results: Both copper­64- and copper­67-labeled versions of NODAGA-TATE and NODAGA-cLAB4­TATE showed similar SSTR2 binding affinity, but faster release from tumor cells compared to the clinical reference [177Lu]Lu­DOTA-TATE. The bifunctional SSTR2/albumin-binding radioligand [67Cu]Cu­NODAGA-cLAB4­TATE showed both an improved uptake and prolonged residence time in tumors resulting in equivalent treatment efficacy to [177Lu]Lu­DOTA-TATE. Absorbed doses were well tolerated in terms of leukocyte counts and kidney function. Conclusion: This preclinical study demonstrates therapeutic efficacy of [67Cu]Cu­NODAGA-cLAB4­TATE in SSTR2-positive tumors. As an intrinsic radionuclide theranostic agent, the radioligand provides stable radiocopper complexes and high sensitivity in SPECT imaging for prospective determination and monitoring of therapeutic doses in vivo. Beyond that, copper­64- and copper­61-labeled versions offer possibilities for pre- and post-therapeutic PET. Therefore, NODAGA-cLAB4-TATE has the potential to advance clinical use of radiocopper in SSTR2-targeted cancer theranostics.

Hereditary Pheochromocytoma as a Main Manifestation of von Hippel Lindau Disease (vHL) in Childhood - A Long-term Follow-up of 5 Patients with vHL from One Family.

Von Hippel-Lindau disease (vHL) is a hereditary, autosomal dominant syndrome manifested by a predisposition to the occurrence of benign and malignant neoplasms. The spectrum of vHL-related neoplasms includes: pheochromocytoma (PHEO), central nervous system and retinal hemangioblastomas, renal clear cell carcinoma, epididymal cystadenomas, pancreatic neuroendocrine tumors as well as visceral (renal and pancreatic) cysts. We report the family (5 patients) with genetically confirmed vHL in which every member had PHEO diagnosed during pediatric care. The presented family had a missense variant in the VHL gene (ex1 g.A451G gene, p. S80G) which is connected with an increased risk of PHEO. Performing screening laboratory and imaging tests in patients with genetically confirmed vHL disease can help to avoid the occurrence of disease symptoms and to perform an elective surgery in safe conditions. Due to the risk of coexisting pathologies and the complexity of the disease, patients with vHL require long-term care.

Total loss of VHL gene function impairs neuroendocrine cancer cell fitness due to excessive HIF2α activity.

Loss-of-function germline von Hippel-Lindau (VHL) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain-of-function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2-dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma.

Diagnostic performance of [18 F]FDOPA PET/CT and other tracers in pheochromocytoma: A meta-analysis.

RATIONALE AND OBJECTIVES: PET-CT is extensively used in the diagnosis of pheochromocytoma (PHEO). However, various PET-CT tracers are recommended for the diagnosis of PHEO. Therefore, this study evaluated the diagnostic performance of all tracers currently used in the PET-CT detection of PHEO. METHODS: Studies were retrieved from PubMed, Web of Science, Embase, and Cochrane Library from inception to Feb. 7, 2024. The studies were screened according to the eligibility criteria and the data were extracted. Quality of the included studies was evaluated by the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic (sROC) curve (AUC) were pooled in Stata 15, and diagnostic accuracy was pooled in R 4.3.3. RESULTS: Sixteen studies were included in the meta-analysis. The sensitivity and specificity of [18 F]FDOPA PET/CT for initial PHEO diagnosis were 97% (95% CI: 91%-99%, I2 = 46.14%, p > 0.01) and 94% (95% CI: 86%-98%, I2 = 87.90%, p < 0.01), respectively. The AUC was 0.99 (95% CI: 0.98-1.00). The diagnostic accuracy of [18 F]FDOPA PET/CT was 98.9% (95% CI: 95%-100%) for PHEO patients and 89.7% (95% CI: 85.4%-92.8%) for PHEO lesions. [68Ga]DOTATATE PET/CT had a diagnostic accuracy of 86.9% (95% CI: 78.2%-93.9%) for PHEO and 87.5% (95% CI: 70.3%-95.4%) for PHEO lesions. FDG PET/CT had a diagnostic accuracy of 85.2% (95% CI: 73.6%-94.1%) for PHEO and 86.8% (95% CI: 73%-94.2%) for PHEO lesions. [68Ga]DOTANOC PET/CT had a diagnostic accuracy of 79.3% (95% CI: 49.2%-98.3%) for PHEO. CONCLUSIONS: In general, PET/CT demonstrates superior performance in the diagnosis of PHEO. In addition, [18 F]FDOPA PET/CT has the best diagnostic performance in PHEO compared with other tracers. Given the limited research on other PET/CT tracers and the potential constraints on their widespread use, additional multicenter and multiregional studies are warranted to further evaluate their diagnostic performance and provide recommendations for clinical use.

Robotic and Laparoscopic Adrenalectomy for Pheochromocytoma: An International Multicenter Study.

BACKGROUND AND OBJECTIVE: Robotic adrenalectomy (RA) has attracted interest as an alternative to laparoscopic adrenalectomy (LA) for patients with pheochromocytoma, although its beneficial effects are uncertain. Our aim was to compare RA and LA outcomes for these patients. METHODS: Data for patients who underwent RA or LA for pheochromocytoma in 46 international centers between 2012 and 2022 were reviewed. We analyzed baseline characteristics and postoperative complications at discharge, 90 d, and 1 yr. We conducted propensity score matching (PSM; 1:1 ratio) and multivariable analyses to evaluate outcomes and risk factors for the occurrence of complications and higher Comprehensive Complication Index (CCI). KEY FINDINGS AND LIMITATIONS: Of 1755 patients, 1613 (91.9%) underwent LA and 142 (8.1%) underwent RA. Estimated blood loss, conversion rate, complication rate, and CCI at discharge, 90 d, and 1 yr were similar between the groups. However, RA was associated with a longer operative time in comparison to LA (100 vs 123 min; p < 0.001), but not after PSM (p = 0.120). Multivariable analysis revealed that Charlson comorbidity index (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.07-1.29; p = 0.001), and tumor size per 1-cm increment (OR 1.13, 95% CI 1.07-1.21; p < 0.001) were independently associated with the incidence of complications, but there was no significant difference in complication rates between the LA and RA groups (OR 1.09, 95% CI 0.63-1.87; p = 0.767). After PSM, RA was associated with a lower rate of severe (grade ≥3a) complications in comparison to LA (p = 0.023). CONCLUSIONS AND CLINICAL IMPLICATIONS: RA is a safe alternative to LA and yields similar outcomes for patients with pheochromocytoma. RA may be associated with a lower likelihood of severe complications. Further studies are warranted to determine the role of robotic surgery in pheochromocytoma. PATIENT SUMMARY: Pheochromocytoma is a rare tumor in the adrenal gland and the gold-standard treatment is surgical removal. We assessed patient outcomes after robot-assisted surgery compared with laparoscopic surgery and found that outcomes are similar, but the rate of severe complications may be lower if a surgical robot is used.

Role of B cells in intratumoral MBTA immunotherapy of murine pheochromocytoma model.

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

Catecholamine-Induced Cardiomyopathy Secondary to Pheochromocytoma Rescued With Percutaneous Left Ventricular Assist Device: Novel Application of the Impella CP in a Pediatric Patient.

Background: Catecholamine-induced cardiomyopathy is an uncommon complication of pheochromocytoma. Pheochromocytoma is a rare tumor that predominantly occurs in adults, making catecholamine-induced cardiomyopathy secondary to pheochromocytoma in children an exceedingly rare presentation. Treatment typically consists of medical management followed by surgical resection. Mechanical support, typically salvage therapy with extracorporeal membrane oxygenation, has been used in adult patients with cardiogenic shock and after cardiac arrest, but to our knowledge, the use of mechanical support has not been described in pediatric patients. Case Report: A 16-year-old female presented with cardiogenic shock resulting from catecholamine-induced cardiomyopathy secondary to pheochromocytoma. She was treated with a percutaneous left ventricular assist device to allow myocardial recovery while medical therapy was optimized. Given the early initiation, the patient's myocardial recovery was prompt, and only 3 days of device support were required. She was discharged in good condition and subsequently underwent uncomplicated laparoscopic resection of the tumor a few weeks later. Conclusion: In pediatric patients with catecholamine-induced cardiomyopathy secondary to pheochromocytoma, aggressive measures of support-including mechanical support and infrequently used options such as percutaneous left ventricular assist devices-should be considered early in treatment to maintain adequate cardiac output, avoid cardiac arrest, and allow for prompt myocardial recovery.

Differentiation of pheochromocytoma and adrenal lipoid adenoma by radiomics: are enhanced CT scanning images necessary?

Purpose: To establish various radiomics models based on conventional CT scan images and enhanced CT images, explore their value in the classification of pheochromocytoma (PHEO) and lipid-poor adrenal adenoma (LPA) and screen the most parsimonious and efficient model. Methods: The clinical and imaging data of 332 patients (352 lesions) with PHEO or LPA confirmed by surgical pathology in the Affiliated Hospital of Qingdao University were retrospectively analyzed. The region of interest (ROI) on conventional and enhanced CT images was delineated using ITK-SNAP software. Different radiomics signatures were constructed from the radiomics features extracted from conventional and enhanced CT images, and a radiomics score (Rad score) was calculated. A clinical model was established using demographic features and CT findings, while radiomics nomograms were established using multiple logistic regression analysis.The predictive efficiency of different models was evaluated using the area under curve (AUC) and receiver operating characteristic (ROC) curve. The Delong test was used to evaluate whether there were statistical differences in predictive efficiency between different models. Results: The radiomics signature based on conventional CT images showed AUCs of 0.97 (training cohort, 95% CI: 0.95∼1.00) and 0.97 (validation cohort, 95% CI: 0.92∼1.00). The AUCs of the nomogram model based on conventional scan CT images and enhanced CT images in the training cohort and the validation cohort were 0.97 (95% CI: 0.95∼1.00) and 0.97 (95% CI: 0.94~1.00) and 0.98 (95% CI: 0.97∼1.00) and 0.97 (95% CI: 0.94∼1.00), respectively. The prediction efficiency of models based on enhanced CT images was slightly higher than that of models based on conventional CT images, but these differences were statistically insignificant(P>0.05). Conclusions: CT-based radiomics signatures and radiomics nomograms can be used to predict and identify PHEO and LPA. The model established based on conventional CT images has great identification and prediction efficiency, and it can also enable patients to avoid harm from radiation and contrast agents caused by the need for further enhancement scanning in traditional image examinations.

Adrenal Oncocytic Pheochromocytoma: Insights From a Challenging Diagnostic Journey.

Pheochromocytomas are rare adrenal medulla tumors originating from chromaffin cells, accounting for 10% of primary adrenal neoplasms. Oncocytic variants of pheochromocytomas are rare and have been reported in only 150 cases. This report describes the case of a 60-year-old female who arrived with a non-functional adrenal tumor. This case report emphasizes the importance of a comprehensive histological and immunohistochemical study for diagnosing this rare diagnostic entity and its potential diagnostic pitfalls.

Usefulness of the Primary Tumor Standardized Uptake Value of Iodine-123 Metaiodobenzylguanidine for Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma.

PURPOSE: To examine the usefulness of semi-quantitative analysis using the standardized uptake value (SUV) of iodine-123 metaiodobenzylguanidine ([123I]-MIBG) for predicting metastatic potential in patients with pheochromocytoma (PHEO) and paraganglioma (PGL). PROCEDURES: This study included 18 PHEO and 2 PGL patients. [123I]-MIBG visibility and SUV-related parameters (SUVmax, SUVmean, tumor volume of [123I]-MIBG uptake [TV_MIBG], and total lesion [123I]-MIBG uptake) were compared with the pathological grading obtained using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), which are used to predict metastatic potential. The PASS scores were categorized as < 4 and ≥ 4. Based on the GAPP scores, PHEOs/PGLs were categorized as follows: well, moderately, and poorly differentiated tumors. The Mann-Whitney U test or Spearman's rank correlation was used to assess differences or associations between two quantitative variables. RESULTS: All PHEOs/PGLs were visualized on [123I]-MIBG scintigraphy. There were 16 PASS < 4 and 4 PASS ≥ 4 tumors. Moreover, 11 and 9 tumors were well and moderately differentiated, respectively. The uptake scores and SUV-related parameters significantly differed between tumors with a PASS score of < 4 and those with a PASS score of ≥ 4 (each, p > 0.05). Moderately differentiated tumors had significantly higher uptake scores and SUV-related parameters except TV_MIBG than well-differentiated tumors (each, p < 0.05). The GAPP score was positively correlated with the uptake scores and SUV-related parameters (each, p < 0.05) except TV_MIBG. CONCLUSIONS: The primary tumor [123I]-MIBG uptake assessed using SUV-related parameters can be an imaging tool for predicting metastatic potential in patients with PHEO/PGL.

Screening and treatment of endocrine hypertension focusing on adrenal gland disorders: a narrative review.

Most cases of high blood pressure have no identifiable cause, termed essential hypertension; however, in approximately 15% of cases, hypertension occurs due to secondary causes. Primary aldosteronism (PA) and pheochromocytoma and paraganglioma (PPGL) are representative endocrine hypertensive diseases. The differentiation of endocrine hypertension provides an opportunity to cure and prevent target organ damage. PA is the most common cause of secondary hypertension, which significantly increases the risk of cardiovascular disease compared to essential hypertension; thus, patients with clinical manifestations suggestive of secondary hypertension should be screened for PA. PPGL are rare but can be fatal when misdiagnosed. PPGL are the most common hereditary endocrine tumors; therefore, genetic testing using next-generation sequencing panels is recommended. Herein, we aimed to summarize the characteristic clinical symptoms of PA and PPGL and when and how diagnostic tests and treatment strategies should be performed.

Malignant pheochromocytoma invading the ureteral wall muscle layer: A case report.

Pheochromocytoma is a neuroendocrine tumor for which surgical resection is the main treatment.Malignant pheochromocytoma is very rare. Here,we present a case of adrenal pheochromocytoma invading the ureteral wall muscle layer, which resulted in left adrenal and left nephrectomy.

The current and upcoming era of radiomics in phaeochromocytoma and paraganglioma.

The topic of the diagnosis of phaeochromocytomas remains highly relevant because of advances in laboratory diagnostics, genetics, and therapeutic options and also the development of imaging methods. Computed tomography still represents an essential tool in clinical practice, especially in incidentally discovered adrenal masses; it allows morphological evaluation, including size, shape, necrosis, and unenhanced attenuation. More advanced post-processing tools to analyse digital images, such as texture analysis and radiomics, are currently being studied. Radiomic features utilise digital image pixels to calculate parameters and relations undetectable by the human eye. On the other hand, the amount of radiomic data requires massive computer capacity. Radiomics, together with machine learning and artificial intelligence in general, has the potential to improve not only the differential diagnosis but also the prediction of complications and therapy outcomes of phaeochromocytomas in the future. Currently, the potential of radiomics and machine learning does not match expectations and awaits its fulfilment.

Prevention and management of hypertensive crises in children with pheochromocytoma and paraganglioma.

Hypertensive crises in pediatric patients are rare conditions. However, determining their precise prevalence is more challenging than in adults due to the heterogeneity in the definition itself. These crises frequently occur without a prior diagnosis of hypertension and may indicate an underlying cause of secondary hypertension, including pheochromocytoma/paraganglioma (PPGL). The mechanisms of hypertensive crises in the pediatric population with PPGL are directly related to different types of catecholamine excess. Noradrenergic tumors typically present with sustained hypertension due to their predominant action on α1-adrenoceptors in the vasculature. Conversely, adrenergic tumors, through epinephrine binding to ß2-adrenoceptors in addition to stimulation of α1- and α2-adrenoceptors, more frequently cause paroxysmal hypertension. Furthermore, the biochemical phenotype also reflects the tumor localization and the presence of a genetic mutation. Recent evidence suggests that more than 80% of PPGL in pediatric cases have a hereditary background. PPGL susceptibility mutations are categorized into three clusters; mutations in cluster 1 are more frequently associated with a noradrenergic phenotype, whereas those in cluster 2 are associated with an adrenergic phenotype. Consequently, the treatment of hypertensive crises in pediatric patients with PPGL, reflecting the underlying pathophysiology, requires first-line therapy with alpha-blockers, potentially in combination with beta-blockers only in the case of tachyarrhythmia after adequate alpha-blockade. The route of administration for treatment depends on the context, such as intraoperative or pre-surgical settings, and whether it presents as a hypertensive emergency (elevated blood pressure with acute target organ damage), where intravenous administration of antihypertensive drugs is mandatory. Conversely, in cases of hypertensive urgency, if children can tolerate oral therapy, intravenous administration may initially be avoided. However, managing these cases is complex and requires careful consideration of the selection and timing of therapy administration, particularly in pediatric patients. Therefore, facing these conditions in tertiary care centers through interdisciplinary collaboration is advisable to optimize therapeutic outcomes.

MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

Ruptured triple hormone-secreting adrenal cortical carcinoma with hyperaldosteronism, hypercortisolism, and elevated normetanephrine: a case report.

We report a case of a ruptured triple hormone-secreting adrenal mass with hyperaldosteronism, hypercortisolism, and elevated normetanephrine levels, diagnosed as adrenal cortical carcinoma (ACC) by histology. A 53-year-old male patient who initially presented with abdominal pain was referred to our hospital for angiocoagulation of an adrenal mass rupture. Abdominal computed tomography revealed a heterogeneous 19×11×15 cm right adrenal mass with invasion into the right lobe of the liver, inferior vena cava, retrocaval lymph nodes, and aortocaval lymph nodes. Angiocoagulation was performed. Laboratory evaluation revealed excess cortisol via a positive 1-mg overnight dexamethasone suppression test, primary hyperaldosteronism via a positive saline infusion test, and plasma normetanephrine levels three times higher than normal. An adrenal mass biopsy was performed for pathological confirmation to commence palliative chemotherapy because surgical management was not deemed appropriate considering the extent of the tumor. Pathological examination revealed stage T4N1M1 ACC. The patient started the first cycle of adjuvant mitotane therapy along with adjuvant treatment with doxorubicin, cisplatin, and etoposide, and was discharged. Clinical cases of dual cortisol- and aldosterone-secreting ACCs or ACCs presenting as pheochromocytomas have occasionally been reported; however, both are rare. Moreover, to the best of our knowledge, a triple hormone-secreting ACC has not yet been reported. Here, we report a rare case and its management. This case report underscores the necessity of performing comprehensive clinical and biochemical hormone evaluations in patients with adrenal masses because ACC can present with multiple hormone elevations.