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Endocrine-related Cancer Nov 2019In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and... (Review)
Review
In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT's antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high-specific-activity 131I-MIBG for inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies.
Topics: Adrenal Gland Neoplasms; Animals; Genomics; Humans; Molecular Imaging; Paraganglioma; Pheochromocytoma; Prognosis; Radiopharmaceuticals; Somatostatin
PubMed: 31561209
DOI: 10.1530/ERC-19-0165 -
Current Opinion in Endocrinology,... Jun 2015About 40% of the neuroendocrine tumors pheochromocytomas and paragangliomas (PPGLs) are caused by an inherited mutation. Diagnostic genetic screening is recommended for... (Review)
Review
PURPOSE OF REVIEW
About 40% of the neuroendocrine tumors pheochromocytomas and paragangliomas (PPGLs) are caused by an inherited mutation. Diagnostic genetic screening is recommended for patients and their families. However, the number of susceptibility genes involved is high and continues to grow, making conventional sequencing costly and burdensome. Next-generation sequencing (NGS) enables accurate, thorough, and cost-effective identification of inherited mutations. Here we review recent successes, limitations, and the future of NGS for diagnosis of pheochromocytoma and paraganglioma syndromes.
RECENT FINDINGS
NGS-based screen of genetic disorders in the clinical setting shows improved diagnostic rates over conventional tests. Both broad, whole-exome sequencing, and targeted NGS approaches have been tested for screening of PPGLs, with accurate mutation detection, higher speed, and reduced costs compared with current assays. Flexibility to expand the targeted gene set is immediate in whole-exome sequencing, and adjustable in targeted NGS, but both methods have limitations.
SUMMARY
The high degree of genetic heterogeneity and heritability of PPGLs make NGS an ideal medium for their diagnostic screening. However, improved detection of large genomic defects and underrepresented gene areas are needed before NGS can fully realize its potential as the premier option for routine genetic testing of these syndromes.
Topics: Adrenal Gland Neoplasms; High-Throughput Nucleotide Sequencing; Humans; Paraganglioma; Pheochromocytoma
PubMed: 25871962
DOI: 10.1097/MED.0000000000000150 -
European Annals of Otorhinolaryngology,... Sep 2014Surgery has been long considered to be the treatment of choice for glomus jugulare paragangliomas, as it is the only modality able to totally eradicate the tumour.... (Review)
Review
Surgery has been long considered to be the treatment of choice for glomus jugulare paragangliomas, as it is the only modality able to totally eradicate the tumour. However, despite considerable progress in interventional radiology and nerve monitoring, surgery is associated with an unacceptably high complication rate for a benign tumour, explaining the growing place of radiotherapy in the management of these tumours. This review of the literature confirms the efficacy of conformal radiotherapy with or without intensity modulation and stereotactic radiotherapy, which both achieve tumour control rates ranging from 90% to almost 100% of cases, but for different tumour volumes, almost constant stabilization or even improvement of symptoms, and a considerably lower rate of adverse effects than with surgery. However, radiotherapy remains contraindicated in the presence of intracranial invasion or extensive osteomyelitis. In the light of these results, together with the improved quality of life and a better knowledge of the natural history of this disease, many authors propose radiotherapy as first-line treatment for all glomus jugulare paragangliomas regardless of their size, particularly in patients with no preoperative deficits.
Topics: Glomus Jugulare; Humans; Paraganglioma; Radiotherapy
PubMed: 24908634
DOI: 10.1016/j.anorl.2014.01.003 -
Clinica Chimica Acta; International... Sep 2022Neuropeptide Y (NPY1-36) is a vasoconstrictor peptide co-secreted with catecholamines by sympathetic nerves, the adrenal medulla, and neoplasms such as pheochromocytomas...
Neuropeptide Y (NPY1-36) is a vasoconstrictor peptide co-secreted with catecholamines by sympathetic nerves, the adrenal medulla, and neoplasms such as pheochromocytomas and paragangliomas (PPGLs). It is produced by the intracellular cleavage of proNPY and metabolized into multiple fragments with distinct biological activities. NPY immunoassays for PPGL have a diagnostic sensitivity ranging from 33 to 100%, depending on the antibody used. We have validated a multiplex micro-UHPLC-MS/MS assay for the specific and sensitive quantification of proNPY, NPY1-39, NPY1-37, NPY1-36, NPY2-36, NPY3-36, NPY1-35, NPY3-35, and the C-flanking peptide of NPY (CPON) (collectively termed NPYs), and determined the NPYs reference intervals and concentrations in 32 PPGL patients before, during, and after surgery. Depending on the peptide measured, NPYs were above the upper reference limit (URL) in 20% to 67% of patients, whereas plasma free metanephrine and normetanephrine, the gold standard for PPGL, were above the URL in 40% and 87% of patients, respectively. Age, sex, tachycardia, and tumor localization were not correlated with NPYs. Plasma free metanephrines performed better than NPYs in the detection of PPGL, but NPYs may be a substitute for an early diagnosis of PPGL for patients that suffer from severe kidney impairment or receiving treatments that interfere with catecholamine reuptake.
Topics: Adrenal Gland Neoplasms; Healthy Volunteers; Humans; Metanephrine; Neuropeptide Y; Paraganglioma; Pheochromocytoma; Protein Precursors; Tandem Mass Spectrometry
PubMed: 35905838
DOI: 10.1016/j.cca.2022.07.018 -
Endocrine Pathology Jun 2021Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although... (Review)
Review
Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community-possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Humans; Immunohistochemistry; Paraganglioma; Pathology, Molecular; Pheochromocytoma
PubMed: 33768452
DOI: 10.1007/s12022-021-09675-0 -
BMC Cardiovascular Disorders Jun 2024Hypertension (HT) is one of the most common manifestations in patients with catecholamine-secreting neuroendocrine tumors. Although the cardiovascular manifestations of...
BACKGROUND
Hypertension (HT) is one of the most common manifestations in patients with catecholamine-secreting neuroendocrine tumors. Although the cardiovascular manifestations of these tumors have been described, there have been no large-scale investigations of the profile of HT and changes in cardiac structure and function that occur in patients with pheochromocytomas and paragangliomas (PPGL).
MATERIALS AND METHODS
In this study, we investigated the prevalence of HT and left ventricular remodeling (LVR) in a cohort of 598 patients who underwent surgery for PPGL at our center between January 2001 and April 2022. Information on demographics, reason for hospitalization, medical history, biochemical parameters, findings on echocardiography, and tumor characteristics were recorded. The LVR index was compared according to whether or not there was a history of HT.
RESULTS
The average age was 47.07 ± 15.07 years, and 277 (46.32%) of the patients were male. A history of HT was found in 423 (70.74%) of the 598 patients. Paraganglioma was significantly more common in the group with HT (26.00% vs. 17.71%, P = 0.030) and significantly less likely to be found incidentally during a health check-up in this group (22.93% vs. 59.43%, P < 0.001). Among 365 patients with complete echocardiography data, left ventricular mass index (86.58 ± 26.70 vs. 75.80 ± 17.26, P < 0.001) and relative wall thickness (0.43 ± 0. 08 vs. 0.41 ± 0.06, P = 0.012) were significantly higher in patients with PPGL and a history of HT. The proportions with left ventricular hypertrophy (LVH) (19.40% vs. 8.25%, P = 0.011) and LVR (53.73% vs. 39.18%, P = 0.014) were also higher when there was a history of HT. After adjusting for age, gender, body mass index, alcohol consumption, smoking status, diabetes, stroke, creatinine level, tumor location, and tumor size, a history of HT was significantly correlated with LVH (odds ratio 2.71, 95% confidence interval 1.18-6.19; P = 0.018) and LVR (odds ratio 1.83, 95% confidence interval 1.11-3.03; P = 0.018).
CONCLUSION
HT is common in patients with PPGL (70.74% in this cohort). PPGL without a history of HT is more likely to be found incidentally (59.43% in our cohort). HT is associated with LVR in PPGL patients with complete echocardiography data. These patients should be observed carefully for cardiac damage, especially those with a history of HT.
Topics: Humans; Pheochromocytoma; Male; Female; Middle Aged; Adrenal Gland Neoplasms; Adult; Ventricular Remodeling; Paraganglioma; Hypertension; Prevalence; Retrospective Studies; Ventricular Function, Left; Risk Factors; Risk Assessment; Aged; Blood Pressure
PubMed: 38926862
DOI: 10.1186/s12872-024-03936-6 -
Clinical Endocrinology Feb 2010Formerly used concepts for phaeochromocytomas and paragangliomas have been challenged by recent discoveries that at least 24% of tumours are familial and thereby often... (Review)
Review
Formerly used concepts for phaeochromocytomas and paragangliomas have been challenged by recent discoveries that at least 24% of tumours are familial and thereby often multiple in various locations throughout the body. Furthermore, tumours are often malignant and perhaps more aggressive if associated with SDHB gene mutations. Some paragangliomas are clinically silent and may present only with dopamine hypersecretion. In the current era where CT and MRI are more commonly used, tumours are more often found as incidentalomas and MRI may be less specific for phaeochromocytoma and paraganglioma than previously thought. Because of unique tumour characteristics (e.g. the presence of cell membrane and intracellular vesicular norepinephrine transporters) these tumours were 'born' to be imaged by means of specific functional imaging approaches. Moreover, additional recent discoveries related to apoptosis, hypoxia, acidosis, anaerobic glycolysis and angiogenesis, often disturbed in tumour cells, open new options and challenges to specifically image phaeochromocytomas and paragangliomas and possibly link those results to their pathophysiology, genotypic alterations and metastatic potential. Functional imaging, especially represented by positron emission tomography (PET), offers an excellent approach by which tumour-specific processes can be detected, evaluated and seen in the context of tumour-specific behaviour and its genetic signature. In this review, we address the recent developments in new functional imaging modalities for phaeochromocytoma and paraganglioma and provide the reader with suggested imaging approaches in various phaeochromocytomas and paragangliomas of sympathetic origin. Current imaging algorithms of head and neck parasympathetic paragangliomas are not discussed. Finally, this review outlines some future perspectives of functional imaging of these tumours.
Topics: Humans; Magnetic Resonance Imaging; Paraganglioma; Pheochromocytoma; Positron-Emission Tomography; Radiography
PubMed: 19508681
DOI: 10.1111/j.1365-2265.2009.03648.x -
Cytogenetic and Genome Research 2016Pheochromocytomas (PCC) and sympathetic paragangliomas (PGL) are rare neuroendocrine tumors, which derive from chromaffin cells occurring in the adrenal medulla and... (Review)
Review
Pheochromocytomas (PCC) and sympathetic paragangliomas (PGL) are rare neuroendocrine tumors, which derive from chromaffin cells occurring in the adrenal medulla and extra-adrenal sympathetic paraganglia. PCC and PGL are often benign, catecholamine-producing tumors, responsible for a myriad of symptoms that may be potentially hazardous to the patient. In contrast, nonsecreting parasympathetic PGL, derived from chief cells, develop mainly in the head and neck region. Although PCC/PGL are more commonly sporadic tumors, germline mutations are present in up to 40% of the patients, ranking these tumors among those with the highest degree of heritability. PCC/PGL are associated with a variety of hereditary syndromes, comprising genetic alterations in RET, NF1, VHL, and SDHx genes, the last 2 being involved in regulating the hypoxia pathway. Additional hypoxia pathway-related genes have been recently associated with PCC/PGL development, namely EGLN1 and EPAS1. Thus, dysregulation of the hypoxia pathway seems to play a major role in PCC/PGL development, in particular through the stabilization of hypoxia-inducible factors and the appearance of a pseudohypoxia signature. This article is focused on reviewing the tumorigenic mechanisms resultant from VHL, SDHx, EGLN1, and EPAS1 mutations, as well as the associated tumors, namely PCC/PGL, and extra manifestations such as polycythemia. In the light of the recent discoveries, hypoxia pathway molecules appear as key players in PCC/PGL development.
Topics: Cell Hypoxia; Humans; Mutation; Neovascularization, Pathologic; Paraganglioma; Pheochromocytoma
PubMed: 28231563
DOI: 10.1159/000457479 -
Current Opinion in Endocrinology,... Jun 2022Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients,... (Review)
Review
PURPOSE OF REVIEW
Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients, have inoperable disease. This has necessitated the development of noninvasive treatments (e.g., radio/chemotherapy), which, in affording disease-modification, have led to an ever-growing population of surviving patients with inoperable PPGL. These patients experience debilitating symptoms arising from discomforts related to the masses themselves (e.g., pain from osseous metastasis) and symptoms from tumoral catecholamine production and release. Unfortunately, management of these conditions is not yet well-defined. Adding further insult-to-injury, these noninvasive treatments can trigger catecholamine release, worsening catecholamine-induced symptoms. Herein, we detail these ailments and their management, especially while patients receive these noninvasive treatments.
RECENT FINDINGS
Improved diagnostic evaluations have allowed for earlier detection of PPGL, prolonging survival in patients with inoperable PPGLs. Accordingly, noninvasive treatment strategies have rapidly evolved alongside state-of- the-art theranostics and genetic testing, which inform ongoing management and therapeutic response.
SUMMARY
While treatments afford improved survival, there must be a corresponding attention to quality-of-life. This is ensured by employing supportive management, which mitigates debilitating symptoms. This is best accomplished with a multidisciplinary approach and familiarity with genetic and biochemical determinants which guide patient education and management.
Topics: Adrenal Gland Neoplasms; Catecholamines; Genetic Testing; Humans; Paraganglioma; Pheochromocytoma
PubMed: 35621181
DOI: 10.1097/MED.0000000000000724 -
Frontiers in Endocrinology 2021Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors which overproduce catecholamines. Heart failure and myocardial infarction caused by... (Review)
Review
BACKGROUND
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors which overproduce catecholamines. Heart failure and myocardial infarction caused by paraganglioma complicated with catecholamine crisis are the most common causes of death in PPGL patients before surgery. When giant paraganglioma is complicated with catecholamine crisis, treatment brooks no delay.
CASE SUMMARY
A 49-year-old man had episodic sweating, tachycardia with irregular pulse, and headaches 5 days before, and then showed up with chest pain and wheezing for 1 day. Meanwhile, he developed symptoms of recurrent severe abdominal pain and loss of consciousness, and his blood pressure was severely unstable (from 70/40 to 300/200 mmHg). First, the electrocardiogram showed ventricular tachycardia, and then we noticed the waves of ST-segment elevation, but we did not find significant abnormalities in coronary angiography. Abdominal CT and MRI revealed a giant lesion with bleeding or infection in the retroperitoneal adrenal area. These imaging findings were confirmed during surgery, and there was vascular adhesion between the retroperitoneal tumor and the inferior vena cava and left and right renal vein. After the successful resection of the tumor, postoperative pathology confirmed paraganglioma, and the patient pulled through and was discharged quickly.
DISCUSSION
This is a rare case of giant paraganglioma complicated with catecholamine crisis and catecholamine cardiomyopathy. We can diagnosis this disease greatly by elevated norepinephrine, and it is a gold biochemical standard at present. Standard treatment is surgical resection, which is effective in treating this rare neuroendocrine tumor.
Topics: Adrenal Gland Neoplasms; Cardiomyopathies; Catecholamines; Humans; Male; Middle Aged; Paraganglioma; Pheochromocytoma
PubMed: 35185782
DOI: 10.3389/fendo.2021.790080