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Cancer Medicine Jul 2023Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla. When these tumors have an extra-adrenal location, they... (Review)
Review
Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla. When these tumors have an extra-adrenal location, they are called paragangliomas (PGLs) and arise from sympathetic and parasympathetic ganglia, particularly of the para-aortic location. Up to 25% of PCCs/PGLs are associated with inherited genetic disorders. The majority of PCCs/PGLs exhibit indolent behavior. However, according to their affiliation to molecular clusters based on underlying genetic aberrations, their tumorigenesis, location, clinical symptomatology, and potential to metastasize are heterogenous. Thus, PCCs/PGLs are often associated with diagnostic difficulties. In recent years, extensive research revealed a broad genetic background and multiple signaling pathways leading to tumor development. Along with this, the diagnostic and therapeutic options were also expanded. In this review, we focus on the current knowledge and recent advancements in the diagnosis and treatment of PCCs/PGLs with respect to the underlying gene alterations while also discussing future perspectives in this field.
Topics: Humans; Pheochromocytoma; Paraganglioma; Carcinogenesis; Cell Transformation, Neoplastic; Adrenal Gland Neoplasms
PubMed: 37145019
DOI: 10.1002/cam4.6010 -
Endocrine Practice : Official Journal... Apr 2015Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are neural crest cell tumors associated with catecholamine production and assessed by a metanephrine/methoxytyramine... (Review)
Review
OBJECTIVE
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are neural crest cell tumors associated with catecholamine production and assessed by a metanephrine/methoxytyramine measurement. This review summarizes the genetics of these tumors.
METHODS
Case presentation, review of the relevant literature, and bullet point conclusions.
RESULTS
Genetic research over the past 10 years has led to a better understanding of the pathogenesis of these tumors, currently associated with 20 susceptibility genes (both somatic and germ-line mutations). Although most of these genes can be divided into two clusters (clusters 1 and 2), recent data suggest that all mutations converge on the hypoxia-inducible factor signaling pathway. Most of the susceptibility genes are well characterized and associated with specific clinical presentations, including biochemical phenotype, tumor location and behavior, as well as neoplasms or similar characteristics. Correct and early detection of hereditary PHEO/PGL is paramount, as early diagnosis leads to improved and focused treatment, along with better outcomes. However, missed or delayed diagnosis of hereditary PHEO/PGL forestalls proper treatment and results in multiple, recurrent, or metastatic tumors and avoidable complications in some patients.
CONCLUSION
Early diagnosis allows prompt screening for potentially lethal cancers associated with specific gene mutations and makes genetic testing more readily available to first-degree and other relatives of an index patient. Thus, understanding the genetics of these tumors is an essential part of endocrinology.
Topics: Adrenal Gland Neoplasms; Adult; Female; Humans; Mutation; Paraganglioma; Pheochromocytoma
PubMed: 25716634
DOI: 10.4158/EP14481.RA -
Hematology/oncology Clinics of North... Feb 2016Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare but unique neuroendocrine tumors. The hypersecretion of catecholamines from the tumors can be associated with... (Review)
Review
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare but unique neuroendocrine tumors. The hypersecretion of catecholamines from the tumors can be associated with high morbidity and mortality, even when tumors are benign. Up to 40% of PCCs/PGLs are associated with germline mutations in susceptibility genes. About one-quarter are malignant, defined by the presence of distant metastases. Treatment options for unresectable metastatic disease, including chemotherapy, (131)I-MIBG, and radiation, can offer limited tumor and hormone control, although none are curative. This article reviews the inherited genetics, diagnosis, and treatment of PCCs and PGLs.
Topics: Catecholamines; Drug Therapy; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Mutation; Paraganglioma; Pheochromocytoma; Radiotherapy; Tumor Burden
PubMed: 26614373
DOI: 10.1016/j.hoc.2015.09.006 -
Surgical Oncology Clinics of North... Jan 2016This article highlights the epidemiology and pathophysiology of pheochromocytomas and paragangliomas. The current management of pheochromocytoma and paragangliomas,... (Review)
Review
This article highlights the epidemiology and pathophysiology of pheochromocytomas and paragangliomas. The current management of pheochromocytoma and paragangliomas, including utilization and interpretation of biochemical testing, preoperative imaging, and genetic screening are discussed. Furthermore, perioperative surgical management, outcomes, and recommended follow-up are reviewed.
Topics: Humans; Paraganglioma; Pheochromocytoma
PubMed: 26610778
DOI: 10.1016/j.soc.2015.08.006 -
Tumori Dec 2022Pheochromocytomas and paragangliomas (PPGLs) can metastasize in approximately 15-20% of cases. This review discusses the available evidence on the biology and treatment... (Review)
Review
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.
Topics: Humans; Pheochromocytoma; Paraganglioma; Adrenal Gland Neoplasms; Peripheral Nervous System Neoplasms; Neoplasms, Second Primary
PubMed: 35593402
DOI: 10.1177/03008916221078621 -
Turk Patoloji Dergisi 2015Genomic studies in the recent decades lead to the identification of new genetic mutations that have been shown to play detrimental roles in the formation of... (Review)
Review
Genomic studies in the recent decades lead to the identification of new genetic mutations that have been shown to play detrimental roles in the formation of pheochromocytoma or paraganglioma. The majority of these genetic mutations detected affect two major cellular pathways - pseudo hypoxic pathway and kinase signalling pathway. Genetic mutations also resulted in syndromes related to paraganglioma/pheochromocytoma. The classical syndromes comprise - neurofibromatosis, multiple neuroendocrine neoplasia (MEN) (II and III) syndromes and von Hippel-Lindau syndrome. Also, mutations in succinate dehydrogenase genes contribute to the understanding of hereditary paragangliomapheochromocytoma syndromes, Carney's triad and Carney- Stratakis syndrome. Lesions newly known to be associated with the genetic mutations in pheochromocytoma/ paraganglioma include gastrointestinal stromal tumour and renal cell carcinoma. Pathological features, proliferative index, genetic and biochemical parameters could help to predict the malignant potential of paraganglioma and pheochromocytoma. Different predictive systems have been proposed and with the help of immunochemical studies. Pathologist should be aware of the advances in knowledge and contribute to the validation of the pathological features and markers for prediction of malignant potential of this group of tumours.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Biopsy; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Molecular Diagnostic Techniques; Paraganglioma, Extra-Adrenal; Phenotype; Pheochromocytoma; Predictive Value of Tests; Prognosis
PubMed: 26177321
DOI: 10.5146/tjpath.2015.01318 -
Abdominal Radiology (New York) Apr 2022Bladder paragangliomas (bPGL) are rare neuroendocrine tumors arising from the sympathetic paraganglia present in the bladder wall. Bladder PGLs are typically submucosal... (Review)
Review
Bladder paragangliomas (bPGL) are rare neuroendocrine tumors arising from the sympathetic paraganglia present in the bladder wall. Bladder PGLs are typically submucosal or intramural but when subserosal may not be readily visible at cystoscopy. The average size at presentation is 3.9 cm (range 1.0-9.1 cm). When small, bPGL are usually spherical, well-marginated and homogeneous. Larger bPGL are typically more complex with peri- and intra-tumoral neovascularity and central necrosis. On ultrasound, increased color Doppler signal is typical. The increased soft tissue resolution of MRI enables localization of bPGL within the bladder wall more accurately than CT. Restricted diffusion and avid contrast enhancement help differentiate small bPGLs from leiomyomas, which have similar appearances on ultrasound and CT. Nuclear medicine techniques identify bPGLs and their metastases with high specificity, Ga-DOTATATE PET/CT having largely replaced I-mIBG SPECT/CT as the first line functional investigation. Imaging is essential to aid surgical planning, as endoscopic resection is often not possible or incomplete due to tumor location. For patients with advanced disease, Ga-DOTATATE PET/CT and I-mIBG SPECT/CT assess suitability for peptide receptor radionuclide therapy. Up to 63% of bPGL patients have a germline mutation, most commonly in the SDHB subunit gene, increasing their risk of developing pheochromocytomas and further paragangliomas; lifelong annual biochemical and periodic imaging screening from skull base to pelvis is therefore recommended.
Topics: Adrenal Gland Neoplasms; Humans; Organometallic Compounds; Paraganglioma; Pheochromocytoma; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radionuclide Imaging; Urinary Bladder
PubMed: 35157102
DOI: 10.1007/s00261-022-03443-2 -
Endocrine-related Cancer Jul 2020Metastatic pheochromocytomas and paragangliomas are rare, highly vascular tumors that spread primarily to the lymph nodes, skeletal tissue, lungs, and liver. Tumor... (Review)
Review
Metastatic pheochromocytomas and paragangliomas are rare, highly vascular tumors that spread primarily to the lymph nodes, skeletal tissue, lungs, and liver. Tumor morbidity is related to their size, location, hormonal activity, vascular nature, and rate of progression. Systemic therapies for this indication are limited. Only high-specific-activity iodine-131 metaiodobenzylguanidine is approved in the Unites States for treatment of these patients, and not all patients are candidates for this radiopharmaceutical. Antiangiogenic medications are currently being evaluated in prospective clinical trials for patients with metastatic pheochromocytomas and paragangliomas, and preliminary results have been encouraging. Antiangiogenic medications frequently offer antineoplastic effects with sometimes durable responses. However, cardiovascular toxicity and the development of tumor resistance may limit their efficacy. Experience derived from clinical trials is being used to identify mechanisms to effectively improve drug toxicity and possibly prevent the emergence of resistance. Therefore, antiangiogenic medications represent a therapeutic option for patients with metastatic pheochromocytomas and paragangliomas. Furthermore, in the world of oncology, there is strong scientific interest in the development of clinical trials that combine antiangiogenic medications with other modalities such as immunotherapy, radiopharmaceuticals, and hypoxia inhibitors since these combinations may substantially enhance clinical outcomes, including survivorship. In this review, we examine the progress made to date on antiangiogenic treatments for patients with metastatic pheochromocytomas and paragangliomas.
Topics: Adrenal Gland Neoplasms; Angiogenesis Inhibitors; Humans; Paraganglioma; Pheochromocytoma
PubMed: 32369773
DOI: 10.1530/ERC-20-0043 -
Advances and Technical Standards in... 2024Paragangliomas are the most common tumors at jugular foramen and pose a great surgical challenge. Careful clinical history and physical examination must be performed to...
Paragangliomas are the most common tumors at jugular foramen and pose a great surgical challenge. Careful clinical history and physical examination must be performed to adequately evaluate neurological deficits and its chronologic evolution, also to delineate an overview of the patient performance status. Complete imaging evaluation including MRI and CT scans should be performed, and angiography is a must to depict tumor blood supply and sigmoid sinus/internal jugular vein patency. Screening for multifocal paragangliomas is advisable, with a whole-body imaging. Laboratory investigation of endocrine function of the tumor is necessary, and adrenergic tumors may be associated with synchronous lesions. Preoperative prepare with alpha-blockage is advisable in norepinephrine/epinephrine-secreting tumors; however, it is not advisable in exclusively dopamine-secreting neoplasms. Best surgical candidates are young otherwise healthy patients with smaller lesions; however, treatment should be individualized each case. Variations of infratemporal fossa approach are employed depending on extensions of the mass. Regarding facial nerve management, we avoid to expose or reroute it if there is preoperative function preservation and prefer to work around facial canal in way of a fallopian bridge technique. If there is preoperative facial nerve compromise, the mastoid segment of the nerve is exposed, and it may be grafted if invaded or just decompressed. A key point is to preserve the anteromedial wall of internal jugular vein if there is preoperative preservation of lower cranial nerves. Careful multilayer closure is essential to avoid at most cerebrospinal fluid leakage. Residual tumors may be reoperated if growing and presenting mass effect or be candidate for adjuvant stereotactic radiosurgery.
Topics: Humans; Jugular Foramina; Neurosurgical Procedures; Paraganglioma; Skull Base Neoplasms
PubMed: 38700686
DOI: 10.1007/978-3-031-42398-7_10 -
European Journal of Clinical... Sep 2015Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background. (Review)
Review
BACKGROUND
Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background.
DESIGN
We searched the PubMed database through February 2015 to identify studies characterizing metastatic PCs/PGLs as well as currently established and evolving therapies.
RESULTS
Large size tumours (> 5 cm), PASS score > 6 and Ki-67 labelling index > 3% are the most robust indices of metastatic PCs/PGLs albeit with great variability. Germline succinate dehydrogenase complex, subunit B (SDHB) mutation constitutes the main reliable molecular predictor of malignancy. Plasma and urinary methoxytyramine are the biochemical markers characterizing metastatic PCs/PGLs along with evolving molecular markers such as miRNAs and SNAIL. Conventional imaging is used for tumour localization, whereas (18)F-FDG-PET for staging of metastatic PCs/PGLs especially those related to SDHB gene mutations. In addition, (68)Ga-DOTATATE PET/CT is emerging as a highly sensitive alternative. Surgery remains the gold standard treatment in reducing tumour bulk and/or controlling the clinical syndrome. Treatment with (131)I-MIBG or radiolabelled somatostatin analogues is considered for unresectable disease. Conventional chemotherapy is reserved for more advanced and refractory to other therapies disease although new schemes are currently evolving. Recent genetic studies have highlighted a number of pathways involved in PCs/PGLs pathogenesis directing towards the use of targeted therapies which have still to be validated in clinical practice.
CONCLUSIONS
Metastatic PCs/PGLs remain an orphan disease that is only curable by surgery. However, advances in genomic analyses have improved the pathogenesis of these tumours and may lead to effective and more personalized treatments in the near future.
Topics: 3-Iodobenzylguanidine; Adrenal Gland Neoplasms; Fluorodeoxyglucose F18; Humans; Multimodal Imaging; Mutation; Paraganglioma; Pheochromocytoma; Positron-Emission Tomography; Radiopharmaceuticals; Succinate Dehydrogenase; Tomography, X-Ray Computed
PubMed: 26183460
DOI: 10.1111/eci.12495