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BMC Medical Genomics Sep 2020Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk,...
BACKGROUND
Carotid and vagal paragangliomas (CPGLs and VPGLs) are rare neoplasms that arise from the paraganglia located at the bifurcation of carotid arteries and vagal trunk, respectively. Both tumors can occur jointly as multiple paragangliomas accounting for approximately 10 to 20% of all head and neck paragangliomas. However, molecular and genetic mechanisms underlying the pathogenesis of multiple paragangliomas remain elusive.
CASE PRESENTATION
We report a case of multiple paragangliomas in a patient, manifesting as bilateral CPGL and unilateral VPGL. Tumors were revealed via computed tomography and ultrasound study and were resected in two subsequent surgeries. Both CPGLs and VPGL were subjected to immunostaining for succinate dehydrogenase (SDH) subunits and exome analysis. A likely pathogenic germline variant in the SDHD gene was indicated, while likely pathogenic somatic variants differed among the tumors.
CONCLUSIONS
The identified germline variant in the SDHD gene seems to be a driver in the development of multiple paragangliomas. However, different spectra of somatic variants identified in each tumor indicate individual molecular mechanisms underlying their pathogenesis.
Topics: Carotid Artery Diseases; Cranial Nerve Neoplasms; Female; Humans; Middle Aged; Neoplasms, Multiple Primary; Paraganglioma; Succinate Dehydrogenase; Vagus Nerve Diseases; Vascular Neoplasms
PubMed: 32948182
DOI: 10.1186/s12920-020-00789-8 -
Endocrine Pathology Mar 2021Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus,... (Review)
Review
Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pan-genomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype-phenotype correlations for PPGLs. The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype-phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.
Topics: Adrenal Gland Neoplasms; Genetic Predisposition to Disease; Genomics; Genotype; Humans; Paraganglioma; Pheochromocytoma
PubMed: 33433885
DOI: 10.1007/s12022-020-09658-7 -
Current Opinion in Oncology Jan 2021Pheochromocytomas and paragangliomas are rare tumors arising, respectively, from the adrenal medulla and extra-adrenal sympathetic or parasympathetic paraganglia. The... (Review)
Review
PURPOSE OF REVIEW
Pheochromocytomas and paragangliomas are rare tumors arising, respectively, from the adrenal medulla and extra-adrenal sympathetic or parasympathetic paraganglia. The main therapeutic objectives in case of metastatic disease are the reduction of tumor burden and the control of symptoms resulting from excessive catecholamine secretion. Treatment choices constitute not only a wait and see attitude, locoregional approaches, chemotherapy regiments but also radiopharmaceutical agents, and they should be discussed in a specialized multidisciplinary board. This review will briefly discuss the radiopharmaceutical modalities in patients with pheochromocytomas and paragangliomas (I-MIBG and PRRT).
RECENT FINDINGS
I-MIBG (Azedra) has received FDA approval for patients with iobenguane-scan-positive, unresectable, locally advanced or metastatic pheochromocytomas and paragangliomas who require systemic anticancer therapy, whereas peptide receptor radionuclide therapy using radiolabelled somatostatin analogues is currently performed in compassionate use, with very promising results. No prospective head-to-head comparison between the modalities has been conducted to date.
SUMMARY
Promising results have been reported for both radiopharmaceutical agents, mostly in the setting of retrospective series. No prospective head-to-head comparison between the modalities is yet available.
Topics: 3-Iodobenzylguanidine; Adrenal Gland Neoplasms; Humans; Iodine Radioisotopes; Paraganglioma; Pheochromocytoma; Radiopharmaceuticals; Receptors, Peptide
PubMed: 33093336
DOI: 10.1097/CCO.0000000000000691 -
Diagnostics (Basel, Switzerland) Jul 2022Paragangliomas are rare, non-epithelial neuroendocrine neoplasms originating in paraganglia, for instance the adrenal medulla, or at extra-adrenal locations. The aim of... (Review)
Review
Paragangliomas are rare, non-epithelial neuroendocrine neoplasms originating in paraganglia, for instance the adrenal medulla, or at extra-adrenal locations. The aim of this study was to review the literature regarding abdominal extra-adrenal paragangliomas diagnosed pre-operatively with fine-needle biopsy (FNA and/or FNB). The PubMed database was searched to identify such cases, using a specific algorithm and inclusion/exclusion criteria. An unpublished case from our practice was also added to the rest of the data, resulting in a total of 36 cases for analysis. Overall, 24 (67%) lesions were found in females, whereas 12 (33%) in males. Most (21/36; 58.33%) were identified around and/or within the pancreatic parenchyma. FNA and/or FNB reached or suggested a paraganglioma diagnosis in 17/36 cases (47.22%). Of the preoperative misdiagnoses, the most common was an epithelial neuroendocrine tumor (NET). Regarding follow-up, most patients were alive with no reported recurrence; however, 5/36 patients exhibited a recurrence or a widespread disease, whereas one patient died 48 months following her diagnosis. In two patients, transient hypertension was reported during the EUS-FNA procedure. In conclusion, this study showed that the preoperative diagnosis of these lesions is feasible and, while diagnostic pitfalls exist, they could significantly be avoided with the application of immunochemistry.
PubMed: 36010170
DOI: 10.3390/diagnostics12081819 -
Radiology. Imaging Cancer May 2022Paragangliomas are neuroendocrine tumors that derive from paraganglia of the autonomic nervous system, with the majority of parasympathetic paragangliomas arising in the... (Review)
Review
Paragangliomas are neuroendocrine tumors that derive from paraganglia of the autonomic nervous system, with the majority of parasympathetic paragangliomas arising in the head and neck. More than one-third of all paragangliomas are hereditary, reflecting the strong genetic predisposition of these tumors. The molecular basis of paragangliomas has been investigated extensively in the past couple of decades, leading to the discovery of several molecular clusters and more than 20 well-characterized driver genes (somatic and hereditary), which are more than are known for any other endocrine tumor. Head and neck paragangliomas are largely related to the pseudohypoxia cluster and have been previously excluded from most molecular profiling studies. This review article introduces the molecular classification of paragangliomas, with a focus on head and neck paragangliomas, and discusses its impact on the management of these tumors. Genetic testing is now recommended for all patients with paragangliomas to provide screening and surveillance recommendations for patients and relatives. While CT and MRI provide excellent anatomic characterization of paragangliomas, gallium 68 tetraazacyclododecane tetraacetic acid-octreotate (ie, Ga-DOTATATE) has superior sensitivity and is recommended as first-line imaging in patients with head and neck paragangliomas with concern for multifocal and metastatic disease, patients with known multifocal and metastatic disease, and in candidates for targeted peptide-receptor therapy. Molecular Imaging, MR Perfusion, MR Spectroscopy, Neuro-Oncology, PET/CT, SPECT/CT, Head/Neck, Genetic Defects © RSNA, 2022.
Topics: Head and Neck Neoplasms; Humans; Magnetic Resonance Imaging; Paraganglioma; Paraganglioma, Extra-Adrenal; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radionuclide Imaging
PubMed: 35549357
DOI: 10.1148/rycan.210088 -
The Journal of Pathology May 2024Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and...
Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83-1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PubMed: 38795318
DOI: 10.1002/path.6291 -
Frontiers in Veterinary Science 2023Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia,...
Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. Given the current lack of effective medical treatment, there is a need for novel therapeutic strategies. To identify druggable pathways driving PPGL development, we performed RNA sequencing on PPGLs ( = 19) and normal adrenal medullas (NAMs; = 10) of dogs. Principal component analysis (PCA) revealed that PPGLs clearly clustered apart from NAMs. In total, 4,218 genes were differentially expressed between PPGLs and NAMs. Of these, 232 had a log fold change of >3 or < -3, of which 149 were upregulated in PPGLs, and 83 were downregulated. Compared with NAMs, PPGLs had increased expression of genes related to the cell cycle, tumor development, progression and metastasis, hypoxia and angiogenesis, and the Wnt signaling pathway, and decreased expression of genes related to adrenal steroidogenesis. Our data revealed several overexpressed genes that could provide targets for novel therapeutics, such as Ret Proto-Oncogene (), Dopamine Receptor D2 (), and Secreted Frizzled Related Protein 2 (). Based on the PCA, PPGLs were classified into 2 groups, of which group 1 had significantly higher Ki67 scores ( = 0.035) and shorter survival times ( = 0.04) than group 2. Increased expression of 1 of the differentially expressed genes between group 1 and 2, pleiotrophin (), appeared to correlate with a more aggressive tumor phenotype. This study has shed light on the transcriptomic profile of canine PPGL, yielding new insights into the pathogenesis of these tumors in dogs, and revealed potential novel targets for therapy. In addition, we identified 2 transcriptionally distinct groups of PPGLs that had significantly different survival times.
PubMed: 37691636
DOI: 10.3389/fvets.2023.1155804 -
Endocrine Reviews Feb 2024Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues or extra-adrenal...
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues or extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing on PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.
PubMed: 38377172
DOI: 10.1210/endrev/bnae005 -
Journal of Cardiothoracic Surgery May 2020Paragangliomas are rare endocrine tumors that arise from the extra-adrenal autonomic paraganglia and sympathetic paragangliomas usually secret catecholamines and are...
INTRODUCTION
Paragangliomas are rare endocrine tumors that arise from the extra-adrenal autonomic paraganglia and sympathetic paragangliomas usually secret catecholamines and are located in the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. In contrast, most parasympathetic paragangliomas are nonfunctional and located along the glossopharyngeal and vagal nerves in the neck and at the base of the skull. Such neoplasms, although rare, are clinically important because they may recur after surgical resection and 10% of them give rise to metastases causing death with the lymphatic nodes, bones, liver, and lungs being the most common locations.
CASE PRESENTATION
We present a case of a 26-year-old male patient that was diagnosed with paraganglioma of the right-frontal lobe infiltrating the falx and frontal bone which was diagnosed after suffering from a headache and abnormal vision. On initial work-up he was found to have right pulmonary nodules that increased in size after follow up and other nodules appeared in the contralateral lung. He underwent subtotal resection of the brain tumor and complete resection of the bilateral pulmonary nodules.
CONCLUSION
To our knowledge, paraganglioma is considered to be a rare entity in the central nervous system with very few cases being reported in the supratentorial region and no cases were reported of metastatic such paraganglioma to the lung.
Topics: Adult; Brain; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Multiple Pulmonary Nodules; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paraganglioma; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 32393294
DOI: 10.1186/s13019-020-01113-2 -
Clinical Endocrinology Jul 2021Phaeochromocytomas and paragangliomas (PPGLs) are rare tumours that arise from the adrenal medulla or extra-adrenal sympathetic or parasympathetic paraganglia. Recent... (Review)
Review
Phaeochromocytomas and paragangliomas (PPGLs) are rare tumours that arise from the adrenal medulla or extra-adrenal sympathetic or parasympathetic paraganglia. Recent advances in genetics have greatly enhanced understanding of the pathogenesis and molecular physiology of PPGL. Concomitantly, advances in molecular imaging mean four techniques are now available for use in PPGLs: [ I]-MIBG coupled with SPECT/CT; [ F]- FDG, [ Ga]-DOTATATE and [ F]-FDOPA coupled with PET/CT. Each modality relies on unique cellular uptake mechanisms that are contingent upon the tumour's molecular behaviour-which, in turn, is determined by the tumour's genetic profile. This genotype-phenotype correlation means the appropriate choice of radiotracer may depend on the known (or suspected) underlying genetic mutation, in addition to the clinical indication for the scan-whether confirming diagnosis, staging disease, surveillance or determining eligibility for radionuclide therapy. Given these rapid recent changes in genetic understanding and molecular imaging options, many clinicians find it challenging to choose the most appropriate scan for an individual with PPGL. To this end, recent guidelines published by the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging (EANM/SNMMI) have detailed the preferred radiotracer choices for individuals with PPGL based on their genotype and/or clinical presentation, providing timely clarity in this rapidly moving field. The current review summarizes the implications of the genotype-phenotype relationship of PPGL, specifically relating this to the performance of molecular imaging modalities, to inform and enable practising endocrinologists to provide tailored, personalized care for individuals with PPGL.
Topics: Adrenal Gland Neoplasms; Genomics; Humans; Molecular Imaging; Paraganglioma; Pheochromocytoma; Positron Emission Tomography Computed Tomography
PubMed: 33296100
DOI: 10.1111/cen.14375