Metastatic Pheochromocytomas And Paragangliomas Research Articles

The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues or extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing on PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.

Outcomes of systemic treatment according to germline mutational status in patients with metastatic pheochromocytoma and paraganglioma

IntroductionMetastatic disease affects approximately 15% to 17% of patients with pheochromocytomas and paragangliomas (PPGLs). Unfortunately, treatment options for metastatic PPGLs are limited and rely on small, nonrandomized clinical trials. The impact of germline mutation status on systemic treatment outcomes remains unclear. To address these gaps, we retrospectively evaluated treatment outcomes in patients with PPGL. Patients and MethodsBetween December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. ResultsThe median age of the patients was 49. Germline mutations were revealed in nine patients (39.1%) out of 23 who underwent germline testing, with SDHB mutation being the most frequent in 5 patients. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy was administered to 18 patients, with an objective response rate (ORR) of 22% and a disease control rate (DCR) of 67%. The median progression-free survival (PFS) was 7.9 and the median overall survival (OS) was 36.2 months. Sunitinib was given to 6 patients, which had an ORR of 33%, a DCR of 83%, and a median PFS of 14.6 months. Notably, patients with SDHB/SDHD mutation (4 patients and one patient, respectively) who received CVD treatment had a significantly better OS than those without (median OS 94.0 months vs. 13.7 months, P = .01). ConclusionOur study reveals that CVD and sunitinib are effective treatments for metastatic PPGLs. The results are consistent with previous studies and patients with SDHB and SDHD mutations may benefit most from CVD treatment.

SAT305 Clinical Characteristics And Outcomes Of Patient With Metastatic Pheochromocytoma/Paraganglioma (PPGL) And Extreme Elevated Biochemistry

Abstract Disclosure: T. Prodanov: None. A. Jha: None. S. Talvacchio: None. M. Nazari, MD: None. K. Pacak, MD, PhD: None. Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrinetumors arising from chromaffin cells in adrenal or extra-adrenal locations,respectively. PPGLs are characterized by an excessive production ofcatecholamines and/or metanephrines. Most of the symptoms of PPGLs, likehypertension, headaches, palpitation, sweating, and anxiety are an effect ofoverproduction of catecholamines and/or metanephrines. Metastatic PPGLs mayoccur in as many as 35% of patients, with higher metastatic potential observed in succinatedehydrogenase subunit B (SDHB)-related tumors (up to 90%). ClinicalCase: A retrospective analysis of 422patients with metastatic PPGL diagnosed and treated from 2000 to 2023 at theNational Institutes of Health, in Bethesda, Maryland, was conducted. We found42 patients with extremely elevated free plasma normetanephrine levels.Extremely elevated level was defined if the value was 100 times or more higherthan the upper reference limit. Free plasma normetanephrine and metanephrinewere measured. Therelated descriptive analyses of this cohort are as follows: 18 (42.8%) werefemales, 24 (57.2%) were males. The average age of patients at the time of theprimary tumor diagnosis was 39.3 ± 44 years. At theirinitial presentation, there were 29 (69.1%) patients with solitary tumors; and13 (30.9%) with metastatic tumors. In 20 (47.6%) patients, primary tumor waslocated in the adrenal gland, 19 (45.3%) had extra-adrenal PGL and head andneck PGL was seen in 3 (7.1%) patients. The average time interval to metastaticdisease was 5.7 ± 20 years. Thirteen(30.9%) patients had metastatic disease at the initial presentation. Theelevated plasma normetanephrine values ranged from 11407 to 69697 pg/mL (normalrange 18-112 pg/mL). The highest level was 622 times above upper referencelimit. None of the patients were found with elevated metanephrine 100 timesthat of upper reference limit.Genetictesting showed pathogenic variants in SDHB in 22 (52.4%), SDHA in2 (4.7%), NF1 in 2 (4.7%), VHL in 1 (2.3%), IDH1 in 1 (2.3%),and apparently sporadic disease in 12 (28.6%) patients, respectively. Overallsurvival, defined as time from diagnosis until last follow up/death was 11.47 ± 22.5 years.Twentypatients received CVD therapy, 13 patients received 131I-MIBGtherapy, 4 patients received 177Lu-DOTATATE therapy, 9 receivedlocalized radiation therapy. Thirty-nine out of 42 (92.8%) patients died due tometastatic PPGL most likely related to cardiovascular complications. Conclusion:Patients presented with extremely elevatednormetanephrine levels were found to have poorer prognosis as 92.8% (39/42) ofpatients died due to complications associated with their disease. Patients whopresent with extremely elevated plasma metanephrines should be carefullymonitored and managed. Presentation: Saturday, June 17, 2023

Predictive Factors of Early 18F-Fluorodeoxyglucose-Positron Emission Tomography Response to [131I] Metaiodobenzylguanidine Treatment for Unresectable or Metastatic Pheochromocytomas and Paragangliomas

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that produce catecholamines. [¹³¹I] metaiodobenzylguanidine (MIBG)-avid unresectable or metastatic PPGLs are treated with [¹³¹I] MIBG radionuclide therapy. A high metabolic tumour volume (MTV) and total lesion glycolysis (TLG) can be poor prognostic factors. Therefore, we evaluated the metabolic responses to [¹³¹I] MIBG therapy with respect to other clinical factors. Methods: A retrospective study was performed on a series of 20 patients who underwent FDG-PET before and after [¹³¹I] MIBG therapy. We administered a single dose comprising 5.5 GBq of [¹³¹I] MIBG (usually three times; for some cases, the number was increased or decreased considering treatment efficacy and side effects). Semi-quantitative parameters (SUVmax, MTV, and TLG) were calculated using the liver SUV (mean + 3 × standard deviation) as a threshold on Metavol software. The semi-quantitative FDG-PET parameters for determining response were complete response (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). We divided our study participants into the PD and non-PD groups (i.e., SD + PR + CR) and compared the overall survival (OS) between the two groups. Subsequently, we evaluated the relationships between metabolic response and age, sex, tumour type, metastatic site, chemotherapy or external radiation history, and 24-h urine catecholamine levels by univariate logistic regression analyses. Results: Both MTV-based and TLG-based criteria for PD versus non-PD were significant prognostic factors (p = 0.014). However, treatment response as evaluated based on the SUVmax was not a significant predictor. Higher urinary dopamine levels were associated with poor metabolic response as assessed by MTV and TLG (OR 1.002, p = 0.029). The other clinical parameters were non-significant. Conclusion: Poor metabolic response (measured with MTV and TLG) to [¹³¹I] MIBG therapy in unresectable or metastatic PPGLs was related to shorter OS. The poor metabolic response can be predicted using the urinary dopamine level.

Outcomes of systemic treatment in patients with metastatic pheochromocytoma and paraganglioma: A single center retrospective analysis.

2 Background: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. Although 15-17% of patients develop metastatic disease, there are very limited systemic treatment options. In this study, we aimed to evaluate the treatment landscape and outcome in PPGL patients retrospectively. Methods: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. Metastatic PPGLs included a locally advanced unresectable disease, initially metastatic disease, and recurrent disease. Systemic treatment involves cytotoxic chemotherapy and targeted agents, and efficacy analysis included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: The median age at diagnosis was 49 years (range, 15–74), 17 patients were male (52%), and 22 patients were pheochromocytomas (67%). Disease status was recurrent (73%), initially metastatic (21%), and locally advanced (6%). Of 23 patients who underwent germline tests, 14 (61%) were identified with germline mutations, and the most frequent mutation was SDHB germline mutation (n=8, 57%). Of the 33 patients, 18 received chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD). The ORR was 22% (4/18; all PR), and the disease control rate (DCR) was 67% (n=12). The median PFS was 7.9 months [95% confidence interval (CI), 1.6-not available (NA)], and the median OS was 36.2 months (95% CI, 5.7-NA). Six patients were treated with sunitinib, and the ORR was 33% (2/6; all PR), and the DCR was 83% (n=5). The median PFS was 14.6 months (95% CI, 3.6-NA), and the median OS was 14.6 months (95% CI, 3.6-NA). In CVD treatment, patients with SDHB/SDHD mutation (either germline or somatic) were significantly associated with superior OS & PFS compared with the non-SDHB/SDHD mutation group, with a median OS of 94.0 months vs. 5.7 months (P = 0.01) and a median PFS of 20.1 months vs. 1.6 months (P = 0.03), respectively. In the SDHB/SDHD mutation group, the ORR was 50% (3/6, all PR), and the DCR was 100% (n=6), but in a non-SDHB/SDHD mutation group, the ORR was 11% (1/9, PR) and the DCR was 44% (n=4). Conclusions: Systemic treatment with CVD and sunitinib provided meaningful disease control, and outcomes were comparable with previous data. Especially, CVD treatment was effective in patients with SDHB/SDHD mutation, and further validation is needed in future studies.

PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors associated with poor prognosis and limited therapeutic options. Recent advances in oncology-related immunotherapy, specifically in targeting of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathways, have identified a new treatment potential in a variety of tumors, including advanced and rare tumors. Only a fraction of patients being treated by immune checkpoint inhibitors have shown to benefit from it, displaying a need for strategies which identify patients who may most likely show a favorable response. Building on recent, promising outcomes in a clinical study of metastatic PPGL using pembrolizumab, a humanized IgG4κ monoclonal antibody targeting the PD-1/PD-L1 pathway, we examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in our PPGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy. We evaluated RNA expression in the NIH cohort of 48 patients with known genetic predisposition (sporadic; pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: RET, NF1) and 6 normal medulla samples (NAM). For comparison, 72 PPGL samples from The Cancer Genome Atlas (TCGA) were used for analysis of gene expression based on the variant status (pseudohypoxia: SDHB, VHL, EPAS1, EGLN1; kinase signaling: NF1, RET). Expression of PD-L1 was elevated in the PPGL cohort compared to normal adrenal medulla, aligning with the TCGA analysis, whereas PD-L2 was not elevated. However, expression of PD-L1 was lower in the pseudohypoxia cluster compared to the sporadic and the kinase signaling subtype cluster, suggesting that sporadic and kinase signaling cluster PPGLs could benefit from PD-1/PD-L1 therapy more than the pseudohypoxia cluster. Within the pseudohypoxia cluster, expression of PD-L1 was significantly lower in both SDHB- and non-SDHB-mutated tumors compared to sporadic tumors. PD-L1 and PD-L2 expression was not affected by the metastatic status. We conclude that PD-L1 and PD-L2 expression in our cohort of PPGL tumors was not linked to metastatic behavior, however, the presence of PPGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with PPGL.

Effects of Wnt-β-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells.

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures.

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n = 10) and kinase signaling-associated cluster 2-related (n = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

Metastatic pheochromocytomas and paragangliomas: where are we?

Pheochromocytomas and paragangliomas (PPGLs) can metastasize in approximately 15-20% of cases. This review discusses the available evidence on the biology and treatment of metastatic PPGLs. Chemotherapy is the first-line treatment option for this evolving and symptomatic disease. In patients with high MIBG uptake and positive PETGa-68, radiometabolic treatment may be considered. The efficacy of sunitinib has been shown in observational studies, and pembrolizumab has been evaluated in phase II clinical studies, while other agents investigated in this setting are anti-angiogenic drugs cabozantinib, dovitinib, axitinib and lenvatinib. As these agents' efficacy and safety data, alone or in combination, are scant and based on few treated patients, enrollment in clinical trials is mandatory. Future therapeutic options may be represented by DNA repair system inhibitors (such as olaparib), HIF2 inhibitors and immunotherapy.

Integrated PET/MRI With 68Ga-DOTATATE and 18F-FDG in Pheochromocytomas and Paragangliomas: An Initial Study.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with metastatic potential. Both 68Ga-DOTATATE and 18F-FDG PET/CT scans have been demonstrated to have important roles in imaging PPGLs, but less is known about the performance of PET/MRI for PPGLs. The study is aimed to investigate whether diffusion-weighted imaging-MRI (DWI-MRI) has an added value to PET imaging in the identification of PPGL lesions by means of integrated PET/MRI. Eleven patients who underwent both 18F-FDG and 68Ga-DOTATATE PET/MRI within 2 weeks were retrospectively included in the study. A total of 56 PPGL lesions were analyzed, and lesion-based detection rates of 68Ga-DOTATATE PET, 18F-FDG PET, DWI-MRI, and PET/MRI were calculated and compared, respectively. 68Ga-DOTATATE PET was superior to 18F-FDG PET and DWI-MRI in imaging PPGLs with a lesion-based detection rate of 96.4% (54/56) (95% confidence interval [CI], 87.7%-99.6%), 85.7% (48/56) (95% CI, 76.3%-95.2%), and 89.3% (50/56) (95% CI, 80.9%-97.6%), respectively. PET/MRI with DWI could improve the detection rate of 68Ga-DOTATATE and 18F-FDG PET alone up to 100% in metastatic PPGLs. Lesions of PPGL demonstrated markedly higher tracer uptake in 68Ga-DOTATATE PET than in 18F-FDG PET (P = 0.009 for primary lesion, P = 0.033 for metastases). 68Ga-DOTATATE PET showed a higher detection rate than 18F-FDG for PPGLs. In integrated PET/MRI, MRI had an added value to 18F-FDG PET but not much to 68Ga-DOTATATAE PET in identifying PPGL lesions.

Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia, respectively. PPGLs have the highest degree of heritability among endocrine tumors. Currently, ~40% of individuals with PPGLs have a genetic germline and there are at least 12 different genetic syndromes related to these tumors. Metastatic PPGLs are defined by the presence of distant metastases at sites where chromaffin cells are physiologically absent. Approximately 10% of pheochromocytomas and ~40% of sympathetic paragangliomas are linked to metastases, explaining why complete surgical resection is the first-choice treatment for all PPGL patients. The surgical approach is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise. In this review, we summarize and discuss the most relevant aspects of perioperative management in patients with pheochromocytomas and sympathetic paragangliomas.

Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

Germline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6-6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

High-specific-activity 131iodine-metaiodobenzylguanidine for therapy of unresectable pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPG) are rare cancers arising from the adrenal medulla (pheochromocytoma) or autonomic ganglia (paraganglioma). They have highly variable biological behavior. Most PPG express high-affinity norepinephrine transporters, allowing active uptake of the norepinephrine analog, 131iodine-metaiodobenzylguanidine (131I-MIBG). Low-specific-activity forms of 131I-MIBG have been used since 1983 for therapy of PPG. High-specific-activity131I-MIBG therapy improves hypertension management, induces partial radiological response or stable disease, decreases biochemical markers of disease activityand is well tolerated by patients. This drug, approved in the USA in July 2018, is the first approved agent for patients with unresectable, locally advanced or metastatic PPG and imaging evidence of metaiodobenzylguanidine uptake, who require systemic anticancer therapy.

The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

Phase II Clinical Trial of Pembrolizumab in Patients with Progressive Metastatic Pheochromocytomas and Paragangliomas.

Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients’ hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor.

Management and outcome of metastatic pheochromocytomas/paragangliomas: an overview.

Metastatic pheochromocytomas and paragangliomas (PPGLs) occur in about 5-26% of cases and are characterized by a heterogeneous prognosis. Metastases can be synchronous at the initial diagnosis, but they can occur also many years after surgery for the primary tumor. To date, the treatment of patients affected by metastatic PPGLs represents a clinical challenge because of the lack of guidelines. The aim of this article is to review the available management options and their impact on the outcomes of patients with metastatic PPGLs. Generally, treatments are not curative. Surgery, when possible, can be used to reduce hormonal symptoms and cardiovascular morbidity. Chemotherapy plays a role in patients with high burden tumor and rapid disease progression. Tyrosine kinases inhibitors (TKIs) might be considered for their ability to block the angiogenesis and cell growth. Radiation therapy and interventional radiology techniques can help in the management of local metastases to control symptoms and avoid tumor progression. On the other hand, peptide receptor radionuclide therapy (PRRT), using 90Y or 177Lu-DOTATATE, could be a promising therapy. In addition, high specific 131I-MIBG was approved by the Food and Drug Administration (FDA) in the US for the treatment of patients affected by metastatic and unresectable 131I-MIBG positive PPGLs. Considering the different pathways involved in the pathogenesis of PPGLs, several target therapies have been proposed and are under evaluation in clinical trials. The choice of the appropriate treatment should be based on multidisciplinary and personalized approach taking into account the rarity and the variability of these tumors.

Epidemiology and Prognosis of Pheochromocytoma/Paraganglioma in Korea: A Nationwide Study Based on the National Health Insurance Service.

BackgroundPheochromocytomas and paragangliomas (PPGLs) are rare endocrine tumors originating from chromaffin cells. PPGLs are associated with a high mortality rate and several complications. To date, no epidemiological studies have been conducted on PPGLs in Asia. This study aimed to investigate the epidemiology and prognosis of PPGLs in Korea using nationwide data.MethodsUsing the National Health Insurance Service Database, subjects with a principal diagnosis of PPGLs on two or more occasions between 2003 and 2014 who satisfied the operational definition of PPGLs were included. Incidence, prevalence, complications, metastasis, and mortality were investigated.ResultsIn total, 1048 subjects with a mean age of 47.6±16.1 years were included. There was no sex preponderance. The overall prevalence of PPGLs was 2.13 per 100,000 persons, and the overall age-standardized incidence rate was 0.18 per 100,000 person-years. Malignant PPGLs accounted for 17.7% (185 of 1,048) of cases, and 94 subjects exhibited metastasis at the time of diagnosis. Among initially non-metastatic PPGLs, 9.5% (nine of 954) eventually metastasized after a mean duration of 78.1±41.4 months. The 5-year survival rates for non-metastatic and metastatic PPGLs at diagnosis were 97% and 84%, respectively. Multivariable Cox regression models adjusted for covariates showed that metastatic PPGLs were associated with a 2.40-fold higher risk of mortality than non-metastatic PPGLs (95% confidence interval, 1.38 to 4.17; P=0.002).ConclusionPPGLs are rare in Korea, and the prognosis of these endocrine tumors varies depending on whether they are benign or malignant. This epidemiological study paves the way for further research on PPGLs.

Metastatic pheochromocytoma and paraganglioma: recent advances in prognosis and management

Metastatic pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with variable prognosis. This review highlights recent studies on outcomes and management of patients with metastatic PPGL. Latest advances were made in identifying predictors of favorable outcomes of patients with metastatic PPGL. Recent studies evaluated the efficacy of tyrosine kinase inhibitors, high-specific-activity radiopharmaceuticals, and peptide receptors radionuclide therapy in treatment of metastatic disease. Moreover, ongoing studies are assessing the effects of hypoxia-inducible factor 2αα and heat shock protein 90 inhibitors as potential therapies. Several active studies are evaluating the efficacy of systemic chemo, immuno, radiopharmaceutical, and peptide receptor radionuclide therapies to relieve local and adrenergic symptoms and provide survival benefit for patients with symptomatic and/or progressive advanced metastatic PPGL. Owing to rarity and wide-outcome variability, multidisciplinary team effort and personalized approach are central in caring for patients with metastatic PPGL.

Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with SDHB- and FH-mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression.Experimental Design: Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of TERT comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and ATRX mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes. Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in SDHB-mutated paragangliomas (P = 2.42e-09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group (P = 0.169), yet ATRX mutations were found preferentially in SDHB/FH-mutated metastatic tumors (P = 0.0014). Telomerase activation and ATRX mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; P = 6.50E-07 and 1.90E-07, respectively); OS (hazard ratio, 97.4 and 44.1; P = 4.30E-03 and 2.00E-03, respectively) and were associated with worse MFS and OS (log-rank tests P < 0.0001). Assessment of telomerase activation and ATRX mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma.

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features.Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro.Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression.Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.