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Endocrine Reviews Mar 2022Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With... (Review)
Review
Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
Topics: Adrenal Gland Neoplasms; Germ-Line Mutation; Humans; Mutation; Paraganglioma; Pheochromocytoma
PubMed: 34147030
DOI: 10.1210/endrev/bnab019 -
Journal of Nuclear Medicine : Official... Aug 2021Imaging plays a critical role in the management of pheochromocytomas and paragangliomas and often guides treatment. The discovery of susceptibility genes associated with...
Imaging plays a critical role in the management of pheochromocytomas and paragangliomas and often guides treatment. The discovery of susceptibility genes associated with these tumors has led to better understanding of clinical and imaging phenotypes. Functional imaging is of prime importance because of its sensitivity and specificity in subtypes of pheochromocytoma and paraganglioma. Several radiopharmaceuticals have been developed to target specific receptors and metabolic processes seen in pheochromocytomas and paragangliomas, including I/I-metaiodobenzylguanidine, 6-F-fluoro-l-3,4-dihydroxyphenylalanine, F-FDG, and Ga-DOTA-somatostatin analogs. Two of these have consequently been adapted for therapy. This educational review focuses on the current imaging approaches used in pheochromocytomas and paragangliomas, which vary among clinical and genotypic presentations.
Topics: Fluorodeoxyglucose F18; Humans; Paraganglioma; Pheochromocytoma; Positron Emission Tomography Computed Tomography
PubMed: 34330739
DOI: 10.2967/jnumed.120.259689 -
Endocrine Practice : Official Journal... Feb 2023To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas. (Review)
Review
OBJECTIVE
To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas.
METHODS
A literature review of english language papers with focus on most current literature.
RESULTS
Paragangliomas (PGLs) are a group of neuroendocrine tumors that arise in the parasympathetic or sympathetic ganglia. Head and neck PGLs (HNPGLs) comprise 65% to 70% of all PGLs and account for 0.6% of all head and neck cancers. The majority of HNPGLs are benign, and 6% to 19% of all HNPGLs develop metastasis outside the tumor site and significantly compromise survival. PGLs can have a familial etiology with germline sequence variations in different susceptibility genes, with the gene encoding succinate dehydrogenase being the most common sequence variation, or they can arise from somatic sequence variations or fusion genes. Workup includes biochemical testing to rule out secretory components, although it is rare in HNPGLs. In addition, imaging modalities, such as computed tomography and magnetic resonance imaging, help in monitoring in surgical planning. Functional imaging with DOTATATE-positron emission tomography, 18F-fluorodeoxyglucose, or 18F-fluorohydroxyphenylalanine may be necessary to rule out sites of metastases. The management of HNPGLs is complex depending on pathology, location, and aggressiveness of the tumor. Treatment ranges from observation to resection to systemic treatment. Similarly, the prognosis ranges from a normal life expectancy to a 5-year survival of 11.8% in patients with distant metastasis.
CONCLUSION
Our review is a comprehensive summary of the incidence, mortality, pathogenesis, presentation, workup and management of HNPGLs.
Topics: Humans; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Paraganglioma; Paraganglioma, Extra-Adrenal; Succinate Dehydrogenase; Tomography, X-Ray Computed
PubMed: 36252779
DOI: 10.1016/j.eprac.2022.10.002 -
The Journal of Clinical Endocrinology... Nov 2022Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but... (Review)
Review
Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat. This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines, and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized. Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (hypoxia-inducible factor 2 alpha [HIF2α] inhibitors, tumor vaccination together with checkpoint inhibitors, antiangiogenic therapies, kinase signaling inhibitors) are under evaluation in clinical trials. The HIF2α inhibitor belzutifan may prove to be particularly interesting for cluster 1B-/VHL/EPAS1-related PPGLs, whereas antiangiogenic therapies seem to be primarily effective in cluster 1A-/SDHx-related PPGLs. Some combination therapies currently being evaluated in clinical trials, such as temozolomide/olaparib, temozolomide/talazoparib, or cabozantinib/atezolizumab, will provide data for novel therapy for metastatic PPGLs. It is likely that advances in such molecular targeted therapies will play an essential role in the future treatment of these tumors, with more personalized therapy options paving the way towards improved therapeutic outcomes.
Topics: Humans; Pheochromocytoma; Sunitinib; Temozolomide; Paraganglioma; Adrenal Gland Neoplasms; Randomized Controlled Trials as Topic
PubMed: 35973976
DOI: 10.1210/clinem/dgac471 -
Journal of Hypertension Aug 2020: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes... (Review)
Review
Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension.
: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.
Topics: Adrenal Gland Neoplasms; Biomedical Research; Consensus; Europe; Humans; Hypertension; Paraganglioma; Pheochromocytoma
PubMed: 32412940
DOI: 10.1097/HJH.0000000000002438 -
The Journal of Clinical Endocrinology... Apr 2021Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas... (Review)
Review
CONTEXT
Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas will exhibit metastatic behavior.
EVIDENCE ACQUISITION
Extensive searches in the PubMed database with various combinations of the key words pheochromocytoma, paraganglioma, metastatic, malignant, diagnosis, pathology, genetic, and treatment were the basis for the present review.
DATA SYNTHESIS
To pinpoint metastatic potential in PPGLs is difficult, but nevertheless crucial for the individual patient to receive tailor-made follow-up and adjuvant treatment following primary surgery. A combination of histological workup and molecular predictive markers can possibly aid the clinicians in this aspect. Most patients with PPGLs have localized disease and may be cured by surgery. Plasma metanephrines are the main biochemical tests. Genetic testing is important, both for counseling and prognostic estimation. Apart from computed tomography and magnetic resonance imaging, molecular imaging using 68Ga-DOTATOC/DOTATATE should be performed. 123I-MIBG scintigraphy may be performed to determine whether 131I-MIBG therapy is a possible option. As first-line treatment in patients with metastatic disease, 177Lu-DOTATATE or 131I-MIBG is recommended, depending on which shows best expression. In patients with very low proliferative activity, watch-and-wait or primary treatment with long-acting somatostatin analogues may be considered. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect.
CONCLUSIONS
Metastatic PPGLs need individualized management and should always be discussed in specialized and interdisciplinary tumor boards. Further studies and newer treatment modalities are urgently needed.
Topics: Abdominal Neoplasms; Adrenal Gland Neoplasms; Animals; Humans; Paraganglioma; Pheochromocytoma
PubMed: 33462603
DOI: 10.1210/clinem/dgaa982 -
Head and Neck Pathology Mar 2022This review article provides a brief overview of the new WHO classification by adopting a question-answer model to highlight the spectrum of head and neck neuroendocrine... (Review)
Review
Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms.
This review article provides a brief overview of the new WHO classification by adopting a question-answer model to highlight the spectrum of head and neck neuroendocrine neoplasms which includes epithelial neuroendocrine neoplasms (neuroendocrine tumors and neuroendocrine carcinomas) arising from upper aerodigestive tract and salivary glands, and special neuroendocrine neoplasms including middle ear neuroendocrine tumors (MeNET), ectopic or invasive pituitary neuroendocrine tumors (PitNET; formerly known as pituitary adenoma) and Merkel cell carcinoma as well as non-epithelial neuroendocrine neoplasms (paragangliomas). The new WHO classification follows the IARC/WHO nomenclature framework and restricts the diagnostic term of neuroendocrine carcinoma to poorly differentiated epithelial neuroendocrine neoplasms. In this classification, well-differentiated epithelial neuroendocrine neoplasms are termed as neuroendocrine tumors (NET), and are graded as G1 NET (no necrosis and < 2 mitoses per 2 mm; Ki67 < 20%), G2 NET (necrosis or 2-10 mitoses per 2 mm, and Ki67 < 20%) and G3 NET (> 10 mitoses per 2 mm or Ki67 > 20%, and absence of poorly differentiated cytomorphology). Neuroendocrine carcinomas (> 10 mitoses per 2 mm, Ki67 > 20%, and often associated with a Ki67 > 55%) are further subtyped based on cytomorphological characteristics as small cell and large cell neuroendocrine carcinomas. Unlike neuroendocrine carcinomas, head and neck NETs typically show no aberrant p53 expression or loss of RB reactivity. Ectopic or invasive PitNETs are subtyped using pituitary transcription factors (PIT1, TPIT, SF1, GATA3, ER-alpha), hormones and keratins (e.g., CAM5.2). The new classification emphasizes a strict correlation of morphology and immunohistochemical findings in the accurate diagnosis of neuroendocrine neoplasms. A particular emphasis on the role of biomarkers in the confirmation of the neuroendocrine nature of a neoplasm and in the distinction of various neuroendocrine neoplasms is provided by reviewing ancillary tools that are available to pathologists in the diagnostic workup of head and neck neuroendocrine neoplasms. Furthermore, the role of molecular immunohistochemistry in the diagnostic workup of head and neck paragangliomas is discussed. The unmet needs in the field of head and neck neuroendocrine neoplasms are also discussed in this article. The new WHO classification is an important step forward to ensure accurate diagnosis that will also form the basis of ongoing research in this field.
Topics: Carcinoma, Neuroendocrine; Head and Neck Neoplasms; Humans; Ki-67 Antigen; Neuroendocrine Tumors; Paraganglioma; Pituitary Neoplasms; World Health Organization
PubMed: 35312985
DOI: 10.1007/s12105-022-01435-8 -
The Lancet. Diabetes & Endocrinology May 2023Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck... (Review)
Review
Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.
Topics: Humans; Adrenal Gland Neoplasms; Germ-Line Mutation; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase; Practice Guidelines as Topic
PubMed: 37011647
DOI: 10.1016/S2213-8587(23)00038-4 -
Nature Communications Feb 2023The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we...
The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
Topics: Humans; Adrenal Gland Neoplasms; Genomics; Neoplasms, Second Primary; Paraganglioma; Pheochromocytoma; Tumor Microenvironment
PubMed: 36854674
DOI: 10.1038/s41467-023-36769-6 -
Journal of Biomedical Science Nov 2022Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of... (Review)
Review
Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
Topics: Humans; Neovascularization, Pathologic; Paraganglioma; Succinates; Succinic Acid; Vascular Endothelial Growth Factor A; Neoplasms; Neoplasm Metastasis; Extracellular Space
PubMed: 36344992
DOI: 10.1186/s12929-022-00878-z