-
Clinical & Translational Oncology :... Oct 2021Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic...
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations.
Topics: Adrenal Gland Neoplasms; Aftercare; Algorithms; Biomarkers, Tumor; Catecholamines; Diagnostic Imaging; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Humans; Neoplasm Staging; Paraganglioma; Pheochromocytoma; Societies, Medical; Spain; Symptom Assessment
PubMed: 33959901
DOI: 10.1007/s12094-021-02622-9 -
Endocrine-related Cancer Apr 2023Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single... (Review)
Review
Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.
Topics: Humans; Pheochromocytoma; Paraganglioma; Mutation; Adrenal Gland Neoplasms
PubMed: 36748842
DOI: 10.1530/ERC-22-0373 -
Current Opinion in Pediatrics Aug 2021Great progress has been made in understanding the genetic and molecular basis of pheochromocytoma and paragangliomas (PPGLs). This review highlights the new standards in... (Review)
Review
PURPOSE OF REVIEW
Great progress has been made in understanding the genetic and molecular basis of pheochromocytoma and paragangliomas (PPGLs). This review highlights the new standards in the diagnosis and management of pediatric PPGLs.
RECENT FINDINGS
The vast majority of pediatric PPGLs have an associated germline mutation, making genetic studies imperative in the work up of these tumors. Somatostatin receptor-based imaging modalities such as 68Ga-DOTATATE and 64Cu-DOTATATE are shown to have the greatest sensitivity in pediatric PPGLs. Peptide receptor radionuclide therapies (PRRTs) such as 177Lu-DOTATATE are shown to have efficacy for treating PPGLs.
SUMMARY
Genetics play an important role in pediatric PPGLs. Advances in somatostatin receptor-based technology have led to use of 68Ga-DOTATATE and 64Cu-DOTATATE as preferred imaging modalities. While surgery remains the mainstay for management of PPGLs, PRRT is emerging as a treatment option for PPGLs.
Topics: Adrenal Gland Neoplasms; Child; Copper Radioisotopes; Humans; Paraganglioma; Pheochromocytoma
PubMed: 34039901
DOI: 10.1097/MOP.0000000000001029 -
Acta Biochimica Polonica Sep 2023Pheochromocytoma (PPC) and paraganglioma (PGL) are the tumors that rarely occur in the pediatric population (PPGL). Both originate from chromaffin cells,...
Pheochromocytoma (PPC) and paraganglioma (PGL) are the tumors that rarely occur in the pediatric population (PPGL). Both originate from chromaffin cells, pheochromocytoma is localized in the adrenal gland, whereas paragangliomas are regarded as the tumors present in other localizations, from head to the pelvis. The clinical image is characterized by the presence of the sustained hypertension, headaches, sweating, palpitations. The symptoms are caused by the catecholamine secretion or are related to tumor mass pressure on different organs. The catecholamines and their metabolites levels in urine collection or plasma are necessary for further evaluation of the diagnosis. In pediatric population the tumors occur in multiple familial syndromes such as Multiple Endocrine type 2, Neurofibromatosis type 1, Von Hippel-Lindau syndrome, Familial Paraganglioma syndrome are related to specific mutations (SDHx, RET, VHL, NF1) leading to the characteristic phenotype. The radiological and nuclear imaging are an important part of the examination. Although CT and MR are reported to have overall good sensitivity for the tumor detection, further analysis with nuclear imaging is recommended for the specified diagnosis. Right now 68GA-DOTATATE is regarded as the tracer of choice, leading to the complex evaluation of patients with different mutations and metastatic disease. The treatment of choice is the tumor excision. Also, lately new therapeutic approaches including genetically targeted therapies are under investigation for more complex treatment of tumors with underlying genetic cause or metastatic disease. Long term follow-up after treatment to avoid recurrence or to detect it in early stadium must be performed.
Topics: Child; Humans; Adolescent; Pheochromocytoma; Paraganglioma; Biological Transport; Catecholamines; Adrenal Gland Neoplasms
PubMed: 37717273
DOI: 10.18388/abp.2020_6955 -
Frontiers in Endocrinology 2023
Topics: Humans; Pheochromocytoma; Paraganglioma; Adrenal Gland Neoplasms
PubMed: 37383393
DOI: 10.3389/fendo.2023.1227543 -
Reviews in Endocrine & Metabolic... Feb 2023Diagnosis of pheochromocytoma or paraganglioma (PPGL) in pregnancy has been associated historically with high rates of materno-fetal morbidity and mortality. Recent... (Review)
Review
Diagnosis of pheochromocytoma or paraganglioma (PPGL) in pregnancy has been associated historically with high rates of materno-fetal morbidity and mortality. Recent evidence suggests outcomes are improved by recognition of PPGL before or during pregnancy and appropriate medical management with alpha-blockade. Whether antepartum surgery (before the third trimester) is required remains controversial and open to case-based merits. Women with PPGL in pregnancy are more commonly delivered by Caesarean section, although vaginal delivery appears to be safe in selected cases. At least some PPGLs express the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) which may explain their dramatic manifestation in pregnancy. PPGLs in pregnancy are often associated with heritable syndromes, and genetic counselling and testing should be offered routinely in this setting. Since optimal outcomes are only achieved by early recognition of PPGL in (or ideally before) pregnancy, it is incumbent for clinicians to be aware of this diagnosis in a pregnant woman with hypertension occurring before 20 weeks' gestation, and acute and/or refractory hypertension particularly if paroxysmal and accompanied by sweating, palpitations and/or headaches. All women with a past history of PPGL and/or heritable PPGL syndrome should be carefully assessed for the presence of residual or recurrent disease before considering pregnancy.
Topics: Pregnancy; Humans; Female; Pheochromocytoma; Cesarean Section; Paraganglioma; Adrenal Gland Neoplasms; Hypertension
PubMed: 36637675
DOI: 10.1007/s11154-022-09773-2 -
Frontiers in Endocrinology 2023Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively.... (Review)
Review
Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10-15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.
Topics: Humans; Pheochromocytoma; Tumor Microenvironment; Paraganglioma; Adrenal Gland Neoplasms; Succinates
PubMed: 37033265
DOI: 10.3389/fendo.2023.1137456 -
Endocrine Reviews May 2024Pheochromocytomas/paragangliomas are unique in their highly variable molecular landscape driven by genetic alterations, either germline or somatic. These mutations... (Review)
Review
Pheochromocytomas/paragangliomas are unique in their highly variable molecular landscape driven by genetic alterations, either germline or somatic. These mutations translate into different clusters with distinct tumor locations, biochemical/metabolomic features, tumor cell characteristics (eg, receptors, transporters), and disease course. Such tumor heterogeneity calls for different imaging strategies in order to provide proper diagnosis and follow-up. This also warrants selection of the most appropriate and locally available imaging modalities tailored to an individual patient based on consideration of many relevant factors including age, (anticipated) tumor location(s), size, and multifocality, underlying genotype, biochemical phenotype, chance of metastases, as well as the patient's personal preference and treatment goals. Anatomical imaging using computed tomography and magnetic resonance imaging and functional imaging using positron emission tomography and single photon emission computed tomography are currently a cornerstone in the evaluation of patients with pheochromocytomas/paragangliomas. In modern nuclear medicine practice, a multitude of radionuclides with relevance to diagnostic work-up and treatment planning (theranostics) is available, including radiolabeled metaiodobenzylguanidine, fluorodeoxyglucose, fluorodihydroxyphenylalanine, and somatostatin analogues. This review amalgamates up-to-date imaging guidelines, expert opinions, and recent discoveries. Based on the rich toolbox for anatomical and functional imaging that is currently available, we aim to define a customized approach in patients with (suspected) pheochromocytomas/paragangliomas from a practical clinical perspective. We provide imaging algorithms for different starting points for initial diagnostic work-up and course of the disease, including adrenal incidentaloma, established biochemical diagnosis, postsurgical follow-up, tumor screening in pathogenic variant carriers, staging and restaging of metastatic disease, theranostics, and response monitoring.
Topics: Humans; Pheochromocytoma; Adrenal Gland Neoplasms; Paraganglioma; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 38206185
DOI: 10.1210/endrev/bnae001 -
The Journal of Clinical Endocrinology... Sep 2023Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk....
CONTEXT
Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors.
OBJECTIVE
Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs.
METHODS
Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs.
RESULTS
Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx).
CONCLUSION
SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.
Topics: Humans; Adrenal Gland Neoplasms; Neoplasms, Second Primary; Paraganglioma; Pheochromocytoma; Receptors, Somatostatin; Retrospective Studies; Succinate Dehydrogenase
PubMed: 36946182
DOI: 10.1210/clinem/dgad166 -
Endocrine Sep 2019Takotsubo syndrome (TS), also known as neurogenic stunned myocardium or broken heart syndrome, is a recognized acute cardiac syndrome. In about 70% of cases, the... (Review)
Review
Takotsubo syndrome (TS), also known as neurogenic stunned myocardium or broken heart syndrome, is a recognized acute cardiac syndrome. In about 70% of cases, the syndrome is preceded by an emotional or a physical stressor. Among the innumerable physical trigger factors that may induce TS are pheochromocytomas and paragangliomas (PPGLs). PPGL-associated cardiovascular complications as "myocarditis", "myocardial infarction", "reversible cardiomyopathies", and "transient repolarization electrocardiographic changes" have been described since more than 70 years. During the last two decades, dozens of cases of PPGL-induced TS have been reported. PPGLs display increased catecholamine levels, sometimes massively elevated, which may trigger TS, most likely through hyperactivation of sympathetic nervous system including the cardiac sympathetic nerve terminal disruption with norepinephrine seethe and spillover. PPGL-induced TS is characterized by a dramatic clinical presentation with hemodynamic compromise and high complication rates. The prevalence of global and apical sparing pattern of TS in PPGL-induced TS is significantly higher than in other TS populations. In this report, the associations of PPGL-induced cardiovascular complications are analyzed, and clinical features, complications, outcome and treatment of PPGL-induced TS are reviewed.
Topics: Adrenal Gland Neoplasms; Humans; Paraganglioma; Pheochromocytoma; Takotsubo Cardiomyopathy
PubMed: 31399912
DOI: 10.1007/s12020-019-02035-3