-
Critical Reviews in Oncology/hematology Apr 2016Genetic mutations of phaeochromocytoma (PCC) and paraganglioma (PGL) are mainly classified into two major clusters. Cluster 1 mutations are involved with the pseudo... (Review)
Review
Genetic mutations of phaeochromocytoma (PCC) and paraganglioma (PGL) are mainly classified into two major clusters. Cluster 1 mutations are involved with the pseudo hypoxic pathway and comprised of PHD2, VHL, SDHx, IDH, HIF2A, MDH2 and FH mutated PCC/PGL. Cluster 2 mutations are associated with abnormal activation of kinase signalling pathways and included mutations of RET, NF1, KIF1Bβ, MAX and TMEM127. In addition, VHL, SDHx (cluster 1 genes) and RET, NF1 (cluster 2 genes) germline mutations are involved in the neuronal precursor cell pathway in the pathogeneses of PCC/PGL. Also, GDNF, H-ras, K-ras, GNAS, CDKN2A (p16), p53, BAP1, BRCA1&2, ATRX and KMT2D mutations have roles in the development of PCC/PGLs. Overall, known genetic mutations account for the pathogenesis of approximately 60% of PCC/PGLs. Genetic mutations, pathological parameters and biochemical markers are used for better prediction of the outcome of patients with this group of tumours. Immunohistochemistry and gene sequencing can ensure a more effective detection, prediction of malignant potential and treatment of PCC/PCLs.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Germ-Line Mutation; Humans; Immunohistochemistry; Paraganglioma; Pheochromocytoma; Signal Transduction
PubMed: 26839173
DOI: 10.1016/j.critrevonc.2016.01.022 -
European Heart Journal. Cardiovascular... May 2023
Topics: Humans; Pheochromocytoma; Takotsubo Cardiomyopathy; Syndrome; Adrenal Gland Neoplasms
PubMed: 37014047
DOI: 10.1093/ehjci/jead053 -
Frontiers in Endocrinology 2020Pheochromocytomas and paragangliomas (PHEO/PGL) are rare but occasionally life-threatening neoplasms, and are potentially malignant according to WHO classification in... (Review)
Review
Pheochromocytomas and paragangliomas (PHEO/PGL) are rare but occasionally life-threatening neoplasms, and are potentially malignant according to WHO classification in 2017. However, it is also well known that histopathological risk stratification to predict clinical outcome has not yet been established. The first histopathological diagnostic algorithm for PHEO, "PASS", was proposed in 2002 by Thompson et al. Another algorithm, GAPP, was then proposed by Kimura et al. in 2014. However, neither algorithm has necessarily been regarded a 'gold standard' for predicting post-operative clinical behavior of tumors. This is because the histopathological features of PHEO/PGL are rather diverse and independent of their hormonal activities, as well as the clinical course of patients. On the other hand, recent developments in wide-scale genetic analysis using next-generation sequencing have revealed the molecular characteristics of pheochromocytomas and paragangliomas. More than 30%-40% of PHEO/PGL are reported to be associated with hereditary genetic abnormalities involving > 20 genes, including , and others. Such genetic alterations are mainly involved in the pathogenesis of pseudohypoxia, , and kinase signaling, and other intracellular signaling cascades. In addition, recurrent somatic mutations are frequently detected and overlapped with the presence of genetic alterations associated with hereditary diseases. In addition, therapeutic strategies specifically targeting such genetic abnormalities have been proposed, but they are not clinically applicable at this time. Therefore, we herein review recent advances in relevant studies, including histopathological and molecular analyses, to summarize the current status of potential prognostic factors in patients with PHEO/PGL.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Citric Acid Cycle; Diagnosis, Differential; Genetic Testing; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Membrane Proteins; Neoplasm Metastasis; Pheochromocytoma; Prognosis; Protein Kinases; Wnt Signaling Pathway
PubMed: 33193100
DOI: 10.3389/fendo.2020.587769 -
The Journal of Clinical Endocrinology... Dec 2023Pheochromocytomas are increasingly diagnosed in incidentally detected adrenal masses. However, the characteristics of incidental pheochromocytomas are unclear.
CONTEXT
Pheochromocytomas are increasingly diagnosed in incidentally detected adrenal masses. However, the characteristics of incidental pheochromocytomas are unclear.
OBJECTIVE
We aimed to assess the proportion and clinical, biochemical, radiological, genetic, histopathological, and follow-up characteristics of incidental pheochromocytomas.
METHODS
A retrospective review was conducted of patients with pheochromocytoma seen between January 2010 and October 2022 at a large UK tertiary care center. The diagnosis was confirmed histologically or by the combined presence of increased plasma and/or urinary metanephrines (MN), indeterminate adrenal mass on cross-sectional imaging, and metaiodobenzylguanidine avidity.
RESULTS
We identified 167 patients with pheochromocytoma; 144 (86.2%) underwent adrenalectomy, for 23 (13.8%) surgery was either awaited, deemed unsuitable due to frailty or other metastatic malignancy, or declined by the patients. Excluding pheochromocytomas diagnosed via screening genetically predisposed individuals (N = 20), 37 of 132 (28.0%) presented with adrenergic symptoms and/or uncontrolled hypertension, while 91 of 132 (69.0%) patients presented with an incidentally detected adrenal mass. Incidentally detected patients were older (median age 62 years) than those detected due to clinical suspicion (aged 42 years) or after genetic screening (aged 33 years) (all P < .05). Incidentally detected pheochromocytomas were smaller (median 42 mm) than tumors detected due to adrenergic symptoms/uncontrolled hypertension (60 mm), but larger than tumors identified by genetic screening (30 mm) (all P < .05). Increased MN excretion showed a similar pattern (symptomatic/uncontrolled hypertension > incidental > genetic screening) (all P < .05). Hereditary predisposition was detected in 20.4% of patients (incidental, 15.3%; symptomatic/uncontrolled hypertension, 42.9%).
CONCLUSION
The majority of pheochromocytomas are diagnosed incidentally and have distinct clinical, radiological, biochemical, and genetic features. Their detection at older age but smaller size may point to a different underlying tumor biology.
Topics: Humans; Middle Aged; Adrenal Gland Neoplasms; Pheochromocytoma; Hypertension; Adrenergic Agents; Genetic Predisposition to Disease
PubMed: 37417693
DOI: 10.1210/clinem/dgad401 -
Orphanet Journal of Rare Diseases Dec 2006Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extraadrenal chromaffin cells (secreting paragangliomas). Their prevalence is... (Review)
Review
Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extraadrenal chromaffin cells (secreting paragangliomas). Their prevalence is about 0.1% in patients with hypertension and 4% in patients with a fortuitously discovered adrenal mass. An increase in the production of catecholamines causes symptoms (mainly headaches, palpitations and excess sweating) and signs (mainly hypertension, weight loss and diabetes) reflecting the effects of epinephrine and norepinephrine on alpha- and beta-adrenergic receptors. Catecholamine-producing tumors mimic paroxysmal conditions with hypertension and/or cardiac rhythm disorders, including panic attacks, in which sympathetic activation linked to anxiety reproduces the same signs and symptoms. These tumors may be sporadic or part of any of several genetic diseases: familial pheochromocytoma-paraganglioma syndromes, multiple endocrine neoplasia type 2, neurofibromatosis 1 and von Hippel-Lindau disease. Familial cases are diagnosed earlier and are more frequently bilateral and recurring than sporadic cases. The most specific and sensitive diagnostic test for the tumor is the determination of plasma or urinary metanephrines. The tumor can be located by computed tomography, magnetic resonance imaging and metaiodobenzylguanidine scintigraphy. Treatment requires resection of the tumor, generally by laparoscopic surgery. About 10% of tumors are malignant either at first operation or during follow-up, malignancy being diagnosed by the presence of lymph node, visceral or bone metastases. Recurrences and malignancy are more frequent in cases with large or extraadrenal tumors. Patients, especially those with familial or extraadrenal tumors, should be followed-up indefinitely.
Topics: Adrenal Gland Diseases; Adrenal Gland Neoplasms; Catecholamines; Diagnosis, Differential; Genetic Testing; Humans; Hypertension; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Prognosis; Proto-Oncogene Proteins c-ret
PubMed: 17156452
DOI: 10.1186/1750-1172-1-49 -
International Journal of Molecular... Jan 2022Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in... (Review)
Review
Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in tumor tissues. All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. Most of these tumors are benign and their surgical removal will resolve patient management. However, 5-15% of them are malignant and therapeutical possibilities for them are limited. This review provides a brief insight about the tumorigenesis associated with pheochromocytomas/paragangliomas in order to present them as potential therapeutical targets.
Topics: Adrenal Gland Neoplasms; Carcinogenesis; Genetic Predisposition to Disease; Humans; Mosaicism; Mutation; Paraganglioma; Pheochromocytoma
PubMed: 35163370
DOI: 10.3390/ijms23031450 -
Experimental and Clinical Endocrinology... Feb 2019Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare tumours arising from the chromaffin cells of the adrenal medulla (PCC) or the paraganglia located outside the... (Review)
Review
Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare tumours arising from the chromaffin cells of the adrenal medulla (PCC) or the paraganglia located outside the adrenal gland (PGL). However, their incidence is likely to be underestimated; around 10% of all PCC/PGL are metastatic, with higher metastatic potential of PGLs compared to PCCs. If benign, surgery is the treatment of choice, but if metastatic, therapy is challenging. Here we review the currently existing therapy options for metastatic PCCs/PGLs including conventional chemotherapy (the original Averbuch scheme, but updated), radiopharmaceutical treatments (I-MIBG, Y- and Lu-DOTATATE) and novel targeted therapies (anti-angiogenic tyrosine kinase inhibitors and mTORC1 inhibitors), emphasising future therapeutic approaches (HIF-2α and PARP inhibitors, temozolomide alone, metronomic temozolomide, somatostatin analogues) based on the oncogenic signalling pathways related to three different clusters comprising more than 20 well-characterised PCC/PGL susceptibility genes. We suggest that targeted combination therapies including repurposed agents may offer more effective future options worthy of exploration.
Topics: Adrenal Gland Neoplasms; Humans; Neoplasm Metastasis; Pheochromocytoma
PubMed: 30235495
DOI: 10.1055/a-0715-1888 -
The Journal of Clinical Endocrinology... May 2023Pheochromocytomas and paragangliomas (PPGL) are rare causes of secondary hypertension, but when unrecognized, they can lead to serious complications. Data regarding PPGL...
CONTEXT
Pheochromocytomas and paragangliomas (PPGL) are rare causes of secondary hypertension, but when unrecognized, they can lead to serious complications. Data regarding PPGL screening are lacking.
OBJECTIVE
This study aimed to assess the rates and patterns of PPGL screening among eligible patients.
METHODS
We conducted a retrospective review of adults with hypertension seen in outpatient clinics of a large academic center between January 1, 2017, and June 30, 2020. We included patients with treatment-resistant hypertension, hypertension at age < 35 years, and/or adrenal mass(es).
RESULTS
Of 203 535 patients with hypertension identified, 71 088 (35%) met ≥ 1 inclusion criteria, and 2013 (2.83%) were screened for PPGL. Patients screened were younger (56.2 ± 17.4 vs 64.0 ± 17.1 years), more often women (54.1% vs 44.2%), and never-smokers (54.6% vs 47.5%, P < 0.001 for all). The rate of screening was highest in patients with hypertension and adrenal mass(es) (51.7%, vs 3.9% in patients with early-onset hypertension, and 2.4% in those with treatment-resistant hypertension). Multivariable logistic regression showed higher odds ratio (OR) of PPGL screening in women (OR [95% CI]: 1.48 [1.34-1.63]); Black vs White patients (1.35 [1.19-1.53]); patients with adrenal mass(es) (55.1 [44.53-68.15]), stroke (1.34 [1.16-1.54]), dyslipidemia (1.41 [1.26-1.58]), chronic kidney disease (1.40 [1.26-1.56]), and obstructive sleep apnea (1.96 [1.76-2.19]).
CONCLUSION
PPGL screening is pursued in roughly half of patients with adrenal nodules and hypertension, but rarely in patients with treatment-resistant or early-onset hypertension. Similar to screening for other forms of secondary hypertension, PPGL screening occurs more often after serious complications develop.
Topics: Adult; Humans; Female; Pheochromocytoma; Paraganglioma; Risk Factors; Adrenal Gland Neoplasms; Hypertension
PubMed: 36469797
DOI: 10.1210/clinem/dgac701 -
Hormones (Athens, Greece) Jun 2021Pheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ... (Review)
Review
Pheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ damage or dysfunction. As it is associated with a significant mortality rate of approximately 15%, recognizing the signs and symptoms and making the appropriate diagnosis are critical. For this purpose, we report the clinical course of the crisis in four out of a total of six patients with a PPGL crisis from a cohort of 199 PPGL patients of a single tertiary referral center for PPGL patients in the Netherlands diagnosed between 2002 and 2020. Successful treatment of a PPGL crisis demands prompt diagnosis, vigorous pharmacological therapy, and emergency tumor removal if the patient continues to deteriorate.
Topics: Adrenal Gland Neoplasms; Catecholamines; Humans; Paraganglioma; Pheochromocytoma; Tertiary Care Centers
PubMed: 33575936
DOI: 10.1007/s42000-021-00274-6 -
World Journal of Surgical Oncology Sep 2023To compare the surgical effects of lateral transperitoneal approach (LTA) and posterior retroperitoneal approach (PRA) for pheochromocytoma of different sizes.
BACKGROUND
To compare the surgical effects of lateral transperitoneal approach (LTA) and posterior retroperitoneal approach (PRA) for pheochromocytoma of different sizes.
METHODS
Data on patients with pheochromocytoma from 2014 to 2023 were collected from our hospital. According to different surgical approaches and tumor size, all patients were divided into four groups: tumor size < 6 cm for LTA and PRA and tumor size ≥ 6 cm for LTA and PRA. We compared these two surgical methods for pheochromocytoma of different sizes.
RESULTS
A total of 118 patients with pheochromocytoma underwent successful laparoscopic surgery, including PRA group (n = 80) and LTA group (n = 38). In tumor size < 6 cm, the outcomes were no significant difference in LTA and PRA. In tumor size ≥ 6 cm, there was a significant difference in operation time (214.7 ± 18.9 vs. 154.3 ± 8.2, P = 0.007) and intraoperative blood loss (616.4 ± 181.3 vs. 201.4 ± 45.8, P = 0.037) between LTA and PRA.
CONCLUSION
LTA and PRA were performed safely with similar operative outcomes in patients with pheochromocytoma size < 6 cm. While both LTA and PRA were executed with a commendable safety profile and comparable operative results in patients afflicted by pheochromocytomas < 6 cm, the PRA technique distinctly showcased advantages when addressing large-scale pheochromocytomas (≥ 6 cm). Notably, this manifested in reduced operative time, diminished intraoperative blood loss, decreased hospitalization expenses, and a paucity of procedural complications.
Topics: Humans; Pheochromocytoma; Blood Loss, Surgical; Retrospective Studies; Adrenal Gland Neoplasms; Hospitalization
PubMed: 37697366
DOI: 10.1186/s12957-023-03164-w