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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 -
The New England Journal of Medicine Aug 2019
Review
Topics: Adrenal Gland Neoplasms; Diagnosis, Differential; Female; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Male; Paraganglioma, Extra-Adrenal; Pheochromocytoma
PubMed: 31390501
DOI: 10.1056/NEJMra1806651 -
Endocrine Regulations Jul 2019Pheochromocytomas are rare tumors originating in the adrenal medulla. They may be sporadic or in the context of a hereditary syndrome. A considerable number of... (Review)
Review
Pheochromocytomas are rare tumors originating in the adrenal medulla. They may be sporadic or in the context of a hereditary syndrome. A considerable number of pheochromocytomas carry germline or somatic gene mutations, which are inherited in the autosomal dominant way. All patients should undergo genetic testing. Symptoms are due to catecholamines over production or to a mass effect. Diagnosis is confirmed by raised plasma or urine metanephrines or normetanephrines. Radiology assists in the tumor location and any local invasion or metastasis. All the patients should have preoperative preparation with α-blockers and/or other medications to control hypertension, arrhythmia, and volume expansion. Surgery is the definitive treatment. Follow up should be life-long.
Topics: Adrenal Gland Neoplasms; Adult; Child; Female; Genetic Predisposition to Disease; History, 20th Century; History, 21st Century; Humans; Male; Pheochromocytoma; Pregnancy
PubMed: 31517632
DOI: 10.2478/enr-2019-0020 -
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 -
The Veterinary Clinics of North... Mar 2022Surgical removal is the standard of care for adrenal tumors greater than 2.0 cm diameter. For tumors smaller than 2.0 cm, imaging techniques evaluating patterns of... (Review)
Review
Surgical removal is the standard of care for adrenal tumors greater than 2.0 cm diameter. For tumors smaller than 2.0 cm, imaging techniques evaluating patterns of contrast washout may offer a promising avenue for early identification of adrenal malignancy. Pretreatment of pheochromocytoma with phenoxybenzamine is associated with reduced surgical mortality risk. Surgical technique can be laparoscopic or open, depending on tumor anatomy and the experience of the surgeon. Vascular invasion is a contraindication for a laparoscopic technique. This review provides a summary of minimally invasive and open adrenalectomy techniques, including a discussion of management of vascular invasion and partial cavectomy.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Animals; Laparoscopy; Pheochromocytoma
PubMed: 35210060
DOI: 10.1016/j.cvsm.2021.12.005 -
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 -
Anesthesiology Clinics Mar 2020Although endocrine emergencies are not common occurrences, their identification and careful perioperative management are of paramount importance for reduction of patient... (Review)
Review
Although endocrine emergencies are not common occurrences, their identification and careful perioperative management are of paramount importance for reduction of patient morbidity and mortality. The most common critical endocrine abnormalities are associated with functional tumors, such as pheochromocytomas, insulinomas, and carcinoid tumors, leading to carcinoid syndrome, abnormal thyroid function, or disturbances in the hypothalamus-pituitary-adrenal axis, causing adrenal insufficiency. This article aims to discuss the pathophysiology, diagnosis, and perioperative management of pheochromocytomas, hyperthyroidism, hypothyroidism, adrenal insufficiency, carcinoid disease, and insulinomas.
Topics: Adrenal Gland Neoplasms; Adrenal Insufficiency; Anesthesia; Emergencies; Endocrine System Diseases; Humans; Hypothyroidism; Insulinoma; Malignant Carcinoid Syndrome; Perioperative Care; Pheochromocytoma; Thyrotoxicosis
PubMed: 32008649
DOI: 10.1016/j.anclin.2019.10.006 -
Pediatric Nephrology (Berlin, Germany) Apr 2020Pheochromocytomas and paragangliomas (PPGLs) generally grouped together are rare catecholamine-secreting endocrine tumors. Symptoms of catecholamine excess are... (Review)
Review
Pheochromocytomas and paragangliomas (PPGLs) generally grouped together are rare catecholamine-secreting endocrine tumors. Symptoms of catecholamine excess are non-specific and therefore a high index of suspicion in children with sustained hypertension, family history of endocrine tumors, or features of syndromes associated with PPGLs leads to a timely diagnosis and treatment. Free metanephrines in the plasma or 24-h urine are the preferred tests to establish catecholamine excess. Considerations for false-positive conditions improve diagnostic yield and accuracy. Functional imaging, targeting either specific cell membrane transporters or vesicular catecholamine transport systems, is indicated for incidental lesions suspicious for PPGLs with inconclusive biochemical testing, assessment of regional extension or multifocality, and exclusion of metastases. Surgery is the mainstay of treatment for PPGLs. Preoperatively, sequential use of alpha adrenergic receptor blockade and volume expansion followed by beta blockade is mandatory to reduce intraoperative intravascular instability and blood pressure fluctuation due to tumor manipulation. Since genetic mutations have been reported in tumor susceptibility genes in nearly 50% of patients with PPGLs, genetic counselling and testing should be considered in all patients with a confirmed tumor.
Topics: Adolescent; Adrenal Gland Neoplasms; Catecholamines; Child; Female; Genetic Testing; Germ-Line Mutation; Humans; Male; Paraganglioma; Pheochromocytoma
PubMed: 30603807
DOI: 10.1007/s00467-018-4181-2 -
Best Practice & Research. Clinical... Mar 2020Pheochromocytomas are rare neuroendocrine chromaffin-derived tumors that arise within the adrenal medulla. They are usually benign, but if not diagnosed or if left... (Review)
Review
Pheochromocytomas are rare neuroendocrine chromaffin-derived tumors that arise within the adrenal medulla. They are usually benign, but if not diagnosed or if left untreated, they can have devastating consequences. Clinical consideration of the diagnosis is paramount, as they may have protean manifestations, and a high index of suspicion is essential if serious consequences are to be avoided. An accurate biochemical diagnosis is crucial for the management of these patients: either plasma or urinary metanephrines are both highly sensitive and specific if correctly employed, but knowledge of pre- and post-analytic interference is essential. Diagnostic imaging with cross-sectional CT and/or MRI offers high sensitivity in their detection, but lack specificity. The introduction of PET/CT/MR has led to a dramatic improvement in the localization of both pheochromocytomas and paragangliomas, together with the increasing availability of new functional imaging radionuclides. Optimal investigation and accurate diagnosis is best achieved at 'centers of excellence' with expert multidisciplinary teams.
Topics: Adrenal Gland Neoplasms; Blood Chemical Analysis; Cross-Sectional Studies; Diagnostic Techniques, Endocrine; Humans; Magnetic Resonance Imaging; Metanephrine; Pheochromocytoma; Positron Emission Tomography Computed Tomography; Sensitivity and Specificity; Urinalysis
PubMed: 31708376
DOI: 10.1016/j.beem.2019.101346 -
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