Phe ochromocytomas and paragangliomas (PPGLs) are rare neural crest-derived tumors with malignant potential and a highly variable natural history, where some patients achieve a cure through surgical resection, while others experience an aggressive and protracted disease course characterized by recurrence and metastasis. While currently no definitive curative treatment exists for metastatic PPGLs, ongoing trials and advances in biology of the disease present a beacon of hope. We present a case that illustrates a 15-year treatment journey, illustrating the complexity of metastatic PPGL treatment with different modalities, each with distinct efficacy and toxicity profiles. The choice of treatment is often an art, as much as it is based on evidence, as the clinician must balance among several factors, including tumor-related (pace of progression, tumor burden) and patient-related (functional status, symptoms, general health) ones. Through a stepwise approach, this discussion aims to provide insights into the evolving landscape of metastatic PPGL management.

• Klíčová slova
• Lutathera, catecholamines and metanephrines, chemotherapy, fumarate hydratase, genetics, metastatic disease, neuroendocrine tumors, peptide receptor radionuclide therapy, pheochromocytoma and paraganglioma, tyrosine kinase inhibitor,
• MeSH
• feochromocytom * diagnóza   patologie   sekundární   terapie   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory nadledvin * diagnóza   patologie   terapie   MeSH
• paragangliom * diagnóza   patologie   sekundární   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

• MeSH
• dítě MeSH
• dospělí MeSH
• feochromocytom * genetika   terapie   diagnóza   MeSH
• lidé MeSH
• nádory nadledvin * genetika   terapie   diagnóza   MeSH
• paragangliom * genetika   terapie   MeSH
• sukcinátdehydrogenasa genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• přehledy MeSH
• Názvy látek
• SDHB protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH

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.

• Klíčová slova
• biomarkers, chemotherapy, molecular biology, prognostic factor, surgery, target therapy,
• MeSH
• feochromocytom * diagnóza   genetika   terapie   MeSH
• karcinogeneze MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• nádory nadledvin * diagnóza   genetika   terapie   MeSH
• paragangliom * diagnóza   genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

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.

• MeSH
• feochromocytom * diagnóza   genetika   terapie   MeSH
• lidé MeSH
• nádory nadledvin * diagnóza   genetika   terapie   MeSH
• paragangliom * diagnóza   genetika   terapie   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• sukcinátdehydrogenasa genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• SDHD protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human paraganglioma (PGL) samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1800 integral membrane proteins (IMPs). We found 45 "tumor enriched" proteins, i.e., proteins identified in all five PGLs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well-established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well-characterized human PPGL samples. Compared to control chromaffin tissue, PSMA was markedly overexpressed in high-risk PPGLs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including SDHB, VHL, and EPAS1 mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA overexpression in PPGLs which could translate to therapeutic and diagnostic applications of anti-PSMA radio-conjugates in high-risk PPGLs.

• Klíčová slova
• PSMA, Pitchfork, integral membrane proteins, mass spectrometry, membrane proteomics, neuroendocrine cancer, paraganglioma, pheochromocytoma, theranostics,
• MeSH
• antigeny povrchové genetika   MeSH
• feochromocytom diagnóza   genetika   MeSH
• glutamátkarboxypeptidasa II genetika   MeSH
• lidé MeSH
• nádory nadledvin diagnóza   genetika   MeSH
• paragangliom diagnóza   genetika   MeSH
• proteom genetika   MeSH
• teranostická nanomedicína MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny povrchové MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II MeSH
• proteom MeSH

: 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.

• MeSH
• biomedicínský výzkum MeSH
• feochromocytom * diagnóza   genetika   terapie   MeSH
• hypertenze * MeSH
• konsensus MeSH
• lidé MeSH
• nádory nadledvin * diagnóza   genetika   terapie   MeSH
• paragangliom * diagnóza   genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH
• Geografické názvy
• Evropa MeSH