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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 -
Current Opinion in Endocrinology,... Jun 2021This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing... (Review)
Review
PURPOSE OF REVIEW
This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing knowledge gaps, and discusses future research directions.
RECENT FINDINGS
Germline pathogenic variants (PVs) are found in up to 40% of those with PCC/PGL. Tumors with germline PVs are broadly categorized as Cluster 1 (pseudohypoxia), including those with SDH, VHL, FH, and EPAS1 PVs, or Cluster 2 (kinase signaling) including those with NF1, RET, TMEM127, and MAX PVs. Somatic driver mutations exist in some of the same genes (RET, VHL, NF1, EPAS1) as well as in additional genes including HRAS, CSDE1 and genes involved in cell immortalization (ATRX and TERT). Other somatic driver events include recurrent fusion genes involving MAML3.
SUMMARY
PCC/PGL have the highest association with germline PVs of all human solid tumors. Expanding our understanding of the molecular pathogenesis of PCC/PGL is essential to advancements in diagnosis and surveillance and the development of novel therapies for these unique tumors.
Topics: Adrenal Gland Neoplasms; Genetic Predisposition to Disease; Humans; Mutation; Paraganglioma; Pheochromocytoma; Signal Transduction
PubMed: 33764930
DOI: 10.1097/MED.0000000000000634 -
Current Hypertension Reports Jan 2018Pheochromocytomas and paragangliomas (PPGLs) are uncommon catecholamine-producing neuroendocrine neoplasms that usually present with secondary hypertension. This review... (Review)
Review
PURPOSE OF REVIEW
Pheochromocytomas and paragangliomas (PPGLs) are uncommon catecholamine-producing neuroendocrine neoplasms that usually present with secondary hypertension. This review is to update the current knowledge about these neoplasms, the pathophysiology, genetic aspects and diagnostic and therapeutic algorithms based on scientific literature mostly within the past 3 years.
RECENT FINDINGS
Eighty to eighty-five percent of PPGLs arise from the adrenal medulla (pheochromocytomas; PCCs) and the remainder from the autonomic neural ganglia (paragangliomas; PGLs). Catecholamine excess causes chronic or paroxysmal hypertension associated with sweating, headaches and palpitations, the presenting features of PPGLs, and increases the cardiovascular morbidity and mortality. Genetic testing should be considered in all cases as mutations are reported in 35-40% of cases; 10-15% of PCCs and 20-50% of PGLs can be malignant. Measurements of plasma-free metanephrines or 24-h urine-fractionated metanephrines help biochemical diagnosis with high sensitivity and specificity. Initial anatomical localization after biochemical confirmation is usually with computed tomography (CT) or magnetic resonance imaging (MRI). Iodine metaiodobenzylguanidine (I-MIBG) scintigraphy, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) is often performed for functional imaging and prognostication prior to curative or palliative surgery. Clinical and biochemical follow-up is recommended at least annually after complete tumour excision. Children, pregnant women and older people have higher morbidity and mortality risk. De-bulking surgery, chemotherapy, radiotherapy, radionuclide agents and ablation procedures are useful in the palliation of incurable disease. PPGLs are unique neuroendocrine tumours that form an important cause for endocrine hypertension. The diagnostic and therapeutic algorithms are updated in this comprehensive article.
Topics: Adrenal Gland Neoplasms; Algorithms; Genetic Testing; Humans; Hypertension; Paraganglioma; Pheochromocytoma
PubMed: 29356966
DOI: 10.1007/s11906-018-0804-z -
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 -
Problemy Endokrinologii Oct 2023Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic» and... (Review)
Review
Currently, all pheochromocytoma/paraganglioma (PPGLs) are considered malignant due to metastatic potential. Consequently, PPGLs are divided into «metastatic» and «non-metastatic». Metastatic PPGLs can be with synchronous metastasis (metastases appear simultaneously with the identified primary tumor) or metachronous (metastases develop after removal of the primary tumor). The term metastatic PPGLs is not used in the presence of tumor invasion into surrounding organs and tissues, without the presence of distant metastases of lymphogenic or hematogenic origin. It is generally believed that about 10% of pheochromocytomas and about 40% of sympathetic paragangliomas have metastatic potential. On average, the prevalence of PPGLs with the presence of metastases is 15-20%. Risk factors for metastatic PPGLs are widely discussed in the literature, the most significant of which are groups of clinical, morphological and genetic characteristics. The review presents a discussion of such risk factors for metastatic PPGLs as age, localization and type of hormonal secretion of the tumor, the size and growth pattern of the adrenal lesion, the presence of necrosis and invasion into the vessels, the tumor capsule surrounding adipose tissue, high cellular and mitotic activity, Ki-67 index, expression of chromogranin B and S100 protein, the presence of genetic mutations of three main clusters (pseudohypoxia, kinase signaling and Wnt signaling).Over the past two decades, a number of authors have proposed various predictor factors and scales for assessing a probability of metastatic PPGLs. The review contains detailed description and comparison of sensitivity and specificity of such predictor scales as PASS, GAPP, M-GAPP, ASES and COPPS.
Topics: Humans; Pheochromocytoma; Adrenal Gland Neoplasms; Risk Factors; Paraganglioma; Neoplasm Metastasis
PubMed: 38796759
DOI: 10.14341/probl13331 -
Current Treatment Options in Oncology Oct 2023Temporal bone paragangliomas (TBPs) are indolent, classically benign and highly vascular neoplasms of the temporal bone. There are two types of TBPs, tympanomastoid... (Review)
Review
Temporal bone paragangliomas (TBPs) are indolent, classically benign and highly vascular neoplasms of the temporal bone. There are two types of TBPs, tympanomastoid paragangliomas (TMPs) and tympanojugular paragangliomas (TJPs). The most common symptoms are hearing loss and pulsatile tinnitus. Diagnostic workup, besides conventional physical and laboratory examinations, includes biochemical testing of catecholamine and genetic testing of SDHx gene mutations as well as radiological examination. Although surgery is traditionally the mainstay of treatment, it is challenging due to the close proximity of tumor to critical neurovascular structures and thus the high risk of complications, especially in patients with advanced lesions. Radiotherapy and active surveillance have been increasingly recommended for selected patients. Decision on treatment should be made comprehensively. Curative effect depends on various factors. Long-term follow-up with clinical, laboratory, and radiological examinations is essential for all patients.
Topics: Humans; Paraganglioma; Temporal Bone; Mutation; Genetic Testing; Retrospective Studies; Head and Neck Neoplasms
PubMed: 37556048
DOI: 10.1007/s11864-023-01127-7 -
Trends in Cancer Jan 2018Recent comprehensive molecular analysis allowed the identification of unique molecular signatures in pheochromocytomas (PHEOs) and paragangliomas (PGLs). Here we... (Review)
Review
Recent comprehensive molecular analysis allowed the identification of unique molecular signatures in pheochromocytomas (PHEOs) and paragangliomas (PGLs). Here we summarize the main pathway clusters activated by PHEO- and PGL-susceptibility genes: pseudohypoxic, kinase, and Wnt signaling. Molecular characterization and clustering of PHEOs and PGLs may help in the application of principles of personalized medicine and in decision making for targeted therapy of these tumors.
Topics: Adrenal Gland Neoplasms; Genomics; Humans; Molecular Targeted Therapy; Mutation; Paraganglioma; Pheochromocytoma; Precision Medicine; Signal Transduction; Wnt Proteins
PubMed: 29413423
DOI: 10.1016/j.trecan.2017.11.001 -
Hormone and Metabolic Research =... Jul 2019Carney-Stratakis Syndrome (CSS) comprises of paragangliomas (PGLs) and gastrointestinal stromal tumors (GISTs). Several of its features overlap with Carney Triad (CT) -... (Review)
Review
Carney-Stratakis Syndrome (CSS) comprises of paragangliomas (PGLs) and gastrointestinal stromal tumors (GISTs). Several of its features overlap with Carney Triad (CT) - PGLs, GISTs, and pulmonary chondromas. CSS has autosomal dominant inheritance, incomplete penetrance, and greater relative frequency of PGL over GISTs. The PGLs in CSS are multicentric and GISTs are multifocal in all the patients, suggesting an inherited susceptibility and associating the two manifestations. In this review, we highlight the clinical, pathological, and molecular characteristics of CSS, along with its diagnostic and therapeutic implications.
Topics: Adult; Chondroma; Female; Gastrointestinal Stromal Tumors; Germ-Line Mutation; Humans; Leiomyosarcoma; Lung Neoplasms; Male; Paraganglioma; Paraganglioma, Extra-Adrenal; Stomach Neoplasms
PubMed: 31174229
DOI: 10.1055/a-0918-8340 -
Khirurgiia 2022Neck paragangliomas are orphan diseases with incidence 1:30 000-1:100 000. Life expectancy is poor in patients with distant metastasis (5-year overall survival 11.8%),... (Review)
Review
Neck paragangliomas are orphan diseases with incidence 1:30 000-1:100 000. Life expectancy is poor in patients with distant metastasis (5-year overall survival 11.8%), whereas 5-year overall survival in patients with regional metastasis is 76.8-82.4%. Meanwhile, there is still no any reliable tool for prediction of malignant potential of paraganglioma. Above-mentioned data indicate an importance of early diagnosis and timely treatment of neck paragangliomas. Total resection of tumor in ablastic conditions is a gold standard of treatment. However, surgery is associated with a high risk of neurovascular complications and requires multidisciplinary approach. Nevertheless, new knowledge dedicated to different aspects of pathogenesis of neck paraganglioma, diagnosis and treatment arise every year. This review is devoted to modern data on neck paragangliomas.
Topics: Head and Neck Neoplasms; Humans; Paraganglioma
PubMed: 35775846
DOI: 10.17116/hirurgia202207164