Sunitinib for the treatment of patients with advanced pheochromocytomas or paragangliomas: The phase 2 non-randomized SUTNET clinical trial.

BACKGROUND: Metastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option. METHODS: We conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011-002632-99. RESULTS: Fifty patients were included. At a median follow-up of 71.7 months (IQR 35.4-100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1-69.3) and median PFS was 14.1 months (95 % CI 8.9-25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy. CONCLUSION: Sunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile.

Acute onset of hypertensive encephalopathy in a dog with right adrenal pheochromocytoma and neoplastic invasion of the caudal vena cava: Case report and review of the literature.

Background: Canine pheochromocytomas (PCCs) are rare tumors of the adrenal medulla. Clinical signs are often vague, resulting in intermittent catecholamine over secretion or neoplastic invasion of adjacent structures. Case Description: A 12-year-old Epagneul Breton dog with a 1-year history of chronic kidney disease, was examined for acute onset of severe neurological signs. Based on clinical and instrumental data, hypertensive encephalopathy was suspected. Cardiac and abdominal ultrasound were performed. Severe hypertensive cardiopathy and a right adrenal gland mass with invasion of the caudal vena cava were diagnosed. Computed tomography imaging confirmed the suspect of invasive malignant neoplasia. Emergency pharmacological therapy was started to reduce systemic pressure, improve clinical signs, and stabilize the dog in view of surgical resolution. After initial improvement, patient conditions abruptly worsened, and euthanasia was elected. Histology examination confirmed a right adrenal PCC, with caval invasion. Conclusion: To the authors' conclusions, acute hypertensive encephalopathy is a peculiar manifestation of PCCs. Ultrasound is a useful, and rapid test to suspect PCC as it can detect adrenal alterations, caval invasion, metastasis, and cardiac sequelae consistent with the condition. PCC can mimic multiple affections, and be misinterpreted, especially when a concurrent disease has already been diagnosed. Veterinarians need to be aware that comorbidities could mask clinical signs and delay diagnosis. Furthermore, this clinical case reminds us to include PCC also in the differential diagnosis of dogs with an acute onset of severe neurological signs.

[The relationship between clinical characteristics and pathological features in patients with pheochromocytomas/paragangliomas].

Objective: To explore the correlation between clinical characteristics and pathological features in patients with pheochromocytoma/paraganglioma (PPGLs). Methods: A case series study. A retrospective analysis was conducted on patients with single and primary PPGLs after postoperative pathological diagnosis who were admitted to Peking Union Medical College Hospital between January 2019 and December 2022. The patients were divided into the Ki-67<3% group and the Ki-67≥3% group with Ki-67 proliferation index of 3% as the threshold. The relationship between clinical and pathological characteristics of PPGLs was analyzed. Results: A total of 399 PPGLs patients were included, with 177 males and 222 females, aged [M(Q1, Q3)] 45.0(35.5, 53.0) years. Among them, 226 (56.6%) cases originated from the adrenal gland, while 104 cases (26.1%) from the retroperitoneum. 20.9% (27/129) of the patients were found to harbor germline mutations of susceptibility genes, with SDHB mutations being the most common (10.1%, 13/129). The Ki-67 staining was performed on 302 cases, with a Ki-67 proliferation index [M(Q1, Q3)] of 2.0% (1.0%, 3.0%). There were 194 cases in Ki-67<3% group and 108 cases in Ki-67≥3% group. Compared with the patients in Ki-67<3% group, the age of onset in Ki-67≥3% group was younger (P=0.029). Compared with the patients with paragangliomas without SDHB or Cluster 1A-related gene mutations, positive 131I-meta-iodobenzylguanidine (131I-MIBG) imaging or negative O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry staining, those with SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging or positive MGMT immunohistochemistry staining had a higher Ki-67 index (all P<0.05). Compared with adrenal pheochromocytoma, retroperitoneal paragangliomas had a higher proportion of SDHB mutations and a higher proportion of normetanephrine (NMN) secretory types (all P<0.05). Compared with adrenal pheochromocytoma, the maximum diameter of head and neck paraganglioma tumors was smaller [3.0 (1.9, 3.8) cm vs 4.7 (3.4, 6.4) cm, P<0.001] and the proportion of Ki-67≥3% was higher (61.3% vs 33.8%, P=0.007). Conclusions: PPGLs patients with earlier onset age, SDHB or Cluster 1A-related gene mutations, negative 131I-MIBG imaging, or positive MGMT immunohistochemistry staining tend to have a higher Ki-67 index. Head and neck tumors, though smaller, exhibit a higher proliferation potential.

Characterisation of an Adult Zebrafish Model for SDHB-Associated Phaeochromocytomas and Paragangliomas.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from chromaffin cells. Pathogenic variants in the gene succinate dehydrogenase subunit B (SDHB) are associated with malignancy and poor prognosis. When metastases arise, limited treatment options are available. The pathomechanism of SDHB-associated PPGL remains largely unknown, and the lack of suitable models hinders therapy development. Germline heterozygous SDHB pathogenic variants predispose to developing PPGLs with a life-long penetrance of around 50%. To mimic the human disease phenotype, we characterised adult heterozygous sdhb mutant zebrafish as a potential model to study SDHB-related PPGLs. Adult sdhb mutant zebrafish did not develop an obvious tumour phenotype and were anatomically and histologically like their wild-type siblings. However, sdhb mutants showed significantly increased succinate levels, a major hallmark of SDHB-related PPGLs. While basal activity was increased during day periods in mutants, mitochondrial complex activity and catecholamine metabolite levels were not significantly different. In conclusion, we characterised an adult in vivo zebrafish model, genetically resembling human carriers. Adult heterozygous sdhb mutants mimicked their human counterparts, showing systemic elevation of succinate levels despite the absence of a tumour phenotype. This model forms a promising basis for developing a full tumour phenotype and gaining knowledge of the pathomechanism behind SDHB-related PPGLs.

Genetic and Molecular Biomarkers in Aggressive Pheochromocytomas and Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms producing catecholamines that occur as hereditary syndromes in 25-40% of cases. To date, PPGLs are no longer classified as benign and malignant tumors since any lesion could theoretically metastasize, even if it occurs only in a minority of cases (approximately 10-30%). Over the last decades, several attempts were made to develop a scoring system able to predict the risk of aggressive behavior at diagnosis, including the risk of metastases and disease recurrence; unfortunately, none of the available scores is able to accurately predict the risk of aggressive behavior, even including clinical, biochemical, and histopathological features. Thus, life-long follow-up is required in PPGL patients. Some recent studies focusing on genetic and molecular markers (involved in hypoxia regulation, gene transcription, cellular growth, differentiation, signaling pathways, and apoptosis) seem to indicate they are promising prognostic factors, even though their clinical significance needs to be further evaluated. The most involved pathways in PPGLs with aggressive behavior are represented by Krebs cycle alterations caused by succinate dehydrogenase subunits (SDHx), especially when caused by SDHB mutations, and by fumarate hydratase mutations that lead to the activation of hypoxia pathways and DNA hypermethylation, suggesting a common pathway in tumorigenesis. Conversely, PPGLs showing mutations in the kinase cascade (cluster 2) tend to display less aggressive behavior. Finally, establishing pathways of tumorigenesis is also fundamental to developing new drugs targeted to specific pathways and improving the survival of patients with metastatic disease. Unfortunately, the rarity of these tumors and the scarce number of cases enrolled in the available studies represents an obstacle to validating the role of molecular markers as reliable predictors of aggressiveness.

The effect of mass functionality on laparoscopic adrenalectomy outcomes.

PURPOSE: This study aimed to determine the effect of adrenal mass functionality and different hormone subtypes synthesized by the adrenal masses on laparoscopic adrenalectomy (LA) outcomes. MATERIALS AND METHODS: The study included 298 patients, 154 of whom were diagnosed with nonfunctional masses. In the functional group, 33, 62, and 59 patients had Conn syndrome, Cushing's syndrome, and pheochromocytoma, respectively. The variables were analyzed between the functional and nonfunctional groups and then compared among functional masses through subgroup analysis. RESULTS: The incidence of diabetes mellitus, hypertension, and obesity, blood loss, and length of hospital stay (LOH) were significantly higher in the functional group than in the nonfunctional group. In the subgroup analysis, patients with pheochromocytoma had significantly lower body mass index but significantly higher mass size, blood loss, and LOH than the other two groups. A positive correlation was found between mass size and blood loss in patients with pheochromocytoma (p ≤ 0.001, r = 0.761). However, no significant difference in complications was found among the groups. CONCLUSIONS: In this study, patients with functional adrenal masses had higher comorbidity rates and American Society of Anesthesiologists scores. Moreover, blood loss and LOH were longer on patients with functional adrenal masses who underwent LA. Mass size, blood loss, and LOH in patients with pheochromocytoma were significantly longer than those in patients with other functional adrenal masses. Thus, mass functionality did not increase the complications.

Management of metastatic pheochromocytomas and paragangliomas: when and what.

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers.

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

Evaluating the diagnostic efficacy of whole-body MRI versus 123I-mIBG/131I-mIBG imaging in metastatic pheochromocytoma and paraganglioma.

This study aimed to compare tumor lesion detectability and diagnostic accuracy of whole-body magnetic resonance imaging (WB-MRI) and radioiodine-labeled meta-iodo-benzylguanidine (mIBG) imaging techniques in patients with metastatic pheochromocytoma and paraganglioma (PPGL). This retrospective study included 13 patients had pheochromocytoma and 5 had paraganglioma, who were all suspected of having metastatic tumors. Each patient underwent WB-MRI and 123I-mIBG as a pretreatment screening for 131I-mIBG therapy. Two expert reviewers evaluated WB-MRI, 123I-mIBG images, and post-therapy 131I-mIBG images for the presence of metastatic lesions in the lungs, bones, liver, lymph nodes, and other organs. Diagnostic measures for detecting metastatic lesions, including sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristics (ROC)-area under the curve (AUC), were calculated for each imaging technique. We analyzed WB-MRI images for detecting metastatic lesions, which demonstrated sensitivity, specificity, accuracy, PPV, NPV, and AUC of 82%, 97%, 90%, 96%, 86%, and 0.92, respectively. These values were 83%, 95%, 89%, 94%, 86%, and 0.90 in 123I-mIBG images and 85%, 92%, 89%, 91%, 87%, and 0.91 in post-therapy 131I-mIBG images, respectively. Our results reveal the comparable diagnostic accuracy of WB-MRI to one of the mIBG images.

Sibutramine-induced pheochromocytoma crisis: A rare and lethal occurrence.

Pheochromocytoma is a neuroendocrine tumor that secretes catecholamines; excessive catecholamine secretion can lead to pheochromocytoma crisis (PCC), a rare and life-threatening condition. Sibutramine, a serotonin and norepinephrine reuptake inhibitor, was previously used for obesity treatment but is now banned due to its cardiovascular side effects. Although fatalities related to PCC and adverse events associated with sibutramine have been frequently reported individually, there is no documented literature addressing PCC-induced by sibutramine. Here we report a rare case of fatal sibutramine-induced PCC in a previously asymptomatic young female with undiagnosed pheochromocytoma. The 25-year-old patient took a weight-loss pill containing sibutramine for the first time and subsequently experienced nausea, vomiting, chest tightness, and other symptoms. She went to hospital about 6 hours after taking the pill but died approximately 4 hours later despite the resuscitation efforts. An autopsy revealed a pheochromocytoma in the right adrenal gland. The cause of death was attributed to sibutramine-induced PCC. To our knowledge, this is the first report to document the occurrence of sibutramine-induced PCC.

Inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Inflammatory rhabdomyoblastic tumors are relatively recently recognized soft tissue tumors with a low malignant potential. Here, we present a case of concurrent inflammatory rhabdomyoblastic tumor (IRMT), adrenal pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1 (NF1). To our knowledge, this is the first time that this constellation of tumors has been described in the literature. CASE PRESENTATION: A female patient in her late 20s with known NF1 was diagnosed with an inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a short succession. IRMT was found to harbor a near-haploid genome and displayed a typical immunohistochemical profile as well as a focal aberrant p53 expression pattern. CONCLUSIONS: This case report strengthens the theory that defects in the tumor suppressor NF1 play a central role in the pathogenesis of inflammatory rhabdomyoblastic tumors and that IRMT may be part of the spectrum of neurofibromatosis type 1 related tumors.

Seventy years of pheochromocytomas and paragangliomas in Argentina. The FRENAR database.

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors characterized by the excessive production of catecholamines. This study aims to describe the clinical characteristics of PPGL cases in Argentina over recent decades. A multicenter retrospective cross-sectional analysis was carried out using a database comprising both pediatric and adult patients with confirmed PPGL diagnoses based on pathological reports. A cohort of 486 patients with PPGL was recruited. Women represent 58.4% of the patients, with a mean age of 38.3 years old at the time of diagnosis and 15.2% of the patients were under the age of 18. Hypertension, as well as classic signs and symptoms, were present in 80.9% of the patients. The adrenal incidentaloma, as a mode of presentation, increased in the last two decades rising from 3.9% (1953-2000) to 21.8% (2001-2022), p<0.001. Most tumors were located within the adrenal glands, accounting 83.0% of the cases, with bilateral occurrences noted in 20.0%. The median tumor size was 4.8cm. Local recurrence and metastases were observed in 10.9% and 12.2%. Out of 412 patients, 87.0% exhibited urinary excretion elevation of catecholamines and/or their metabolites. Furthermore, 148 patients, representing 30.4% of the study population, displayed a distinct genetic profile indicative of hereditary syndromes. The distribution of hereditary syndromes revealed that MEN2, VHL, and PGL4 constituted the most prevalent syndromes. This population-based study, spanning seven decades, offers valuable insights into the demographic and clinical characteristics of PPGL patients in Argentina.

A Comparison of Near-Infrared Autofluorescence Findings in Benign Versus Malignant Adrenal Tumors.

BACKGROUND: Many adrenal tumors are deemed radiologically indeterminate and surgically removed. Adrenal tissue, like parathyroid glands, exhibits near-infrared autofluorescence (NIRAF) properties. This study was designed to investigate the potential of NIRAF to differentiate benign versus malignant adrenal tumors. METHODS: Patients undergoing adrenalectomy between October 2021 and May 2023 were prospectively studied. Adrenalectomy specimens were inspected with NIRAF imaging. Specimen autofluorescence (AF) characteristics were recorded. Comparisons were made between different tumor types and a logistic regression model was constructed to differentiate benign versus malignant tumors. A receiver operating characteristic curve was used to identify an optimal AF threshold differentiating benign versus malignant tumors. RESULTS: A total of 108 adrenal specimens were examined: adrenocortical adenomas/other benign lesions (n = 72), pheochromocytomas (n = 18), adrenocortical neoplasms of uncertain behavior (n = 4), and malignant tumors (n = 14). A significant difference in normalized AF intensity was identified when comparing adrenocortical adenomas (3.08 times background) with pheochromocytomas (1.95, p = 0.001) and malignant tumors (1.11, p < 0.0001). The Area Under the Curve differentiating benign vs malignant tumors was 0.87, with an optimal normalized AF threshold at 1.93. CONCLUSIONS: Different adrenal pathologies exhibit diverse AF properties. These findings suggest a potential intraoperative utility of NIRAF in predicting benign versus malignant nature for radiologically indeterminate adrenal tumors.

Safety and surgical outcomes of robotic adrenalectomy from a 15-year experience at a single institution.

Robotic adrenalectomy (RA) has gained significant popularity in the management of adrenal gland diseases. We report our experience at a single tertiary institution and evaluate the safety and surgical outcomes of RA. The data of 122 consecutive patients who underwent RA from October 2009 to December 2022 at Korea University Anam Hospital (Seoul, Korea) were reviewed. There were no perioperative complications. Clinicopathological features and surgical outcomes were retrospectively analyzed through complete chart reviews. Noteworthy findings include the influence of sex, tumor size, and body mass index on operation time, with the female and small tumor groups exhibiting shorter operation times (P = 0.018 and P = 0.009, respectively). Pheochromocytoma was identified as a significant independent risk factor for a longer operation time in the multivariate analysis [odds ratio (OR), 3.709; 95% confidence interval (CI), 1.127-12.205; P = 0.031]. A temporal analysis revealed a decreasing trend in mean operation times across consecutive groups, reflecting a learning curve associated with RA adoption. RA is a safe and effective operative technique alternative to laparoscopic adrenalectomy that has favorable surgical outcomes and enhances the convenience of the operation.

A comparative analysis of surgically excised hereditary and sporadic pheochromocytomas: Insights from a single-center experience.

Pheochromocytoma is a tumor that usually originating from adrenal medullary chromaffin cells and producing one or more catecholamines, can manifest as hereditary or sporadic. While the majority pheochromocytomas are sporadic, hereditary forms are often associated with genetic syndromes such as von Hippel-Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. This study aims to analyze data from our series of surgically excited pheochromocytoma patients and compare the characteristics between hereditary and sporadic cases. We retrospectively evaluated 33 diagnosed pheochromocytoma patients, documenting clinical features, surgical complications, and tumor characteristics in both hereditary and sporadic cases. Among the patients, 21% (7 individuals) had hereditary pheochromocytoma, while 79% (26 individuals) had sporadic cases. During diagnosis, hereditary pheochromocytoma patients exhibited a significantly lower mean age compared to the sporadic group (26.4 ± 9.9 years vs. 50.4 ± 14.0 years; p < 0.001). The maximum tumor size was also lower in hereditary cases compared to sporadic cases (p = 0.004). Adrenal tumor localization analysis showed that 63.6% were right-sided, 24.2% were left-sided, and 12.1% were bilateral. Laboratory analysis revealed significantly higher urinary norepinephrine levels in hereditary pheochromocytoma patients (p = 0.021). Our findings suggest that hereditary pheochromocytoma cases are characterized by a younger age at diagnosis, smaller tumor size, and a higher prevalence of multiple bilateral adrenal adenomas. We recommend genetic testing for all pheochromocytoma patients, particularly those with early-onset disease and bilateral adrenal tumors.

Validation and Evaluation of 5 Scoring Systems for Predicting Metastatic Risk in Pheochromocytoma and Paraganglioma.

Currently, 5 scoring systems have been proposed in the literature for predicting metastatic risk in pheochromocytoma and paraganglioma (PPGL): Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), Composite Pheochromocytoma/paraganglioma Prognostic Score (COPPS), Age, Size, Extra-adrenal location, Secretion type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) model. To validate and evaluate these 5 scoring systems, we conducted a retrospective review of cases diagnosed as PPGL at the Department of Pathology, West China Hospital of Sichuan University, between January 2012 and December 2019. A total of 185 PPGL cases were included, comprising 35 cases with metastasis and 150 cases remained metastasis-free for over 8 years after surgery. The criteria of the 5 scoring systems were used for scoring and risk classification. The predictive performance of the 5 scoring systems was validated, compared, and evaluated using concordance index (C-index) and decision curve analysis (DCA). The C-indices for PASS, GAPP, and SGAP were 0.600, 0.547, and 0.547, respectively, indicating low discriminative ability. In contrast, COPPS and ASES had C-indices of 0.740 and 0.706, respectively, indicating better discriminative performance. DCA also showed that the predictive capability of COPPS was superior to that of ASES, with both outperformed PASS, while PASS had better predictive ability than GAPP and SGAP. Our analysis indicated that pathology-based scoring systems cannot accurately predict metastatic risk of PPGL. Establishing a precise prediction system requires integrating clinical, pathologic, and molecular information, using a scientific methodology for predictive factor selection and weight assessment.

EPAS1-related pheochromocytoma/paraganglioma.

In 2012, somatic EPAS1 pathogenic variants were found to cause a triad of pheochromocytoma/paragangliomas (PPGLs), polycythemia, and somatostatinoma. Since then, a limited number of studies on this subject have been reported, and data on the long-term outcome of metastatic disease are not available on this rare syndrome. We comprehensively reviewed EPAS1-related PPGL and describe an unusual patient who has been living with an EPAS1-related metastatic PPGL for 47 years. The results of this work show that EPAS1 pathogenic variants are rare, more in females and patients without pathogenic variants in other PPGL susceptibility genes. PPGLs are the most common manifestation followed by polycythemia and somatostatinoma. The EPAS1 pathogenic variants are often postzygotic, and the timing of their acquirement during embryonic development seems to correlate with the number and timing of development of the disease manifestations. Although recurrent and multifocal disease is common in EPAS1-related PPGL, distant metastases are uncommon and usually indolent. This is illustrated by a case of a man who was diagnosed at the age of 9 years and is currently 56 years old, alive, and well for 47 years with these metastases. He was found to have a somatic EPAS1 pathogenic variant (c.1592C>A, p.Pro531His) in bilateral pheochomocytoma and a pancreatic NET (somatostatinoma) but not in genomic DNA isolated from peripheral leukocytes. This and previous reports suggest that distant metastases are uncommon and less aggressive in EPAS1-related PPGLs compared to those found in other hereditary PPGLs.

Adolescent- and adult-onset neuroblastic tumor: A retrospective multicenter observational study of patients diagnosed in France between 2000 and 2020.

BACKGROUND: Adult- and adolescent-onset neuroblastomas are rare, with no established therapy. In addition, rare pheochromocytomas may harbor neuroblastic components. This study was designed to collect epidemiological, diagnostic and therapeutic data in order to better define the characteristics of malignant peripheral neuroblastic tumors (MPNT) and composite pheochromocytomas (CP) with MPNT. PROCEDURE: Fifty-nine adults and adolescents (aged over 15 years) diagnosed with a peripheral or composite neuroblastic tumor, who were treated in one of 17 institutions between 2000 and 2020, were retrospectively studied. RESULTS: Eighteen patients with neuroblastoma (NB) or ganglioneuroblastoma (GNB) had locoregional disease, and 28 patients had metastatic stage 4 NB. Among the 13 patients with CP, 12 had locoregional disease. Fifty-eight percent of the population were adolescents and young adults under 24 years of age. The probability of 5-year event-free survival (EFS) was 40% (confidence interval: 27%-53%). CONCLUSIONS: Outcomes were better for patients with localized tumor than for patients with metastases. For patients with localized tumor, in terms of survival, surgical treatment was the best therapeutic option. Multimodal treatment with chemotherapy, surgery, radiotherapy, and immunotherapy-based maintenance allowed long-term survival for some patients. Adolescent- and adult-onset neuroblastoma appeared to have specific characteristics associated with poorer outcomes compared to pediatric neuroblastoma. Nevertheless, complete disease control improved survival. The presence of a neuroblastic component in pheochromocytoma should be considered when making therapeutic management decisions. The development of specific tools/resources (Tumor Referral Board, Registry, biology, and trials with new agents or strategies) may help to improve outcomes for patients.

Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.

BACKGROUND: Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells. METHODS: We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life. TRIALS REGISTRATION: jRCT2021220012 registered on 17 June 2022.

Preoperative prediction of metastatic pheochromocytoma and paraganglioma using clinical, genetic, and biochemical markers: A cohort study.

BACKGROUND: The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%-20%. Although there are indicators to assess metastatic risks, none of them predict metastasis reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL. METHODS: In the cross-sectional cohort (n = 180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra-adrenal location, and secretory type (ASES) score in the longitudinal cohort (n = 114). RESULTS: In the cross-sectional cohort, pseudohypoxia group-related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16 nmol/L, and tumor size >6.0 cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval [CI]: 0.738-0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567-0.814, p = 0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio = 25.07, 95% CI: 5.65-111.20). A GMS score ≥2 (p < 0.001), but not ASES score ≥2 (p = 0.090), was associated with shorter progression-free survival. CONCLUSION: The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL.