Metastatic Pheochromocytomas and Abdominal Paragangliomas.
The Journal of clinical endocrinology and metabolism
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.
10.1210/clinem/dgaa982
Leptin Induces Epigenetic Regulation of Transient Receptor Potential Melastatin 7 in Rat Adrenal Pheochromocytoma Cells.
American journal of respiratory cell and molecular biology
Obesity elevates the plasma level of leptin, which has been associated with hypertension. Our recent studies in mice demonstrated that leptin increases blood pressure by activating the carotid sinus nerve, which transmits the chemosensory input from carotid bodies (CBs) to the medullary centers, and that the effect of leptin is mediated via (TRP [transient receptor potential] melastatin 7) channels in CB glomus cells. We also found that overexpression and promoter demethylation in CBs correlate positively with the hyperleptinemia and leptin receptor overexpression in CBs. Hence, we postulated that leptin epigenetically regulates expression in CBs. We addressed our hypothesis by using rat adrenal pheochromocytoma (PC12) cells as a model of CB glomus cells. PC12 cells expressing LEPRb (long, active form of leptin receptor) showed dramatic induction of the promoter activity and expression of upon leptin treatment. The increased expression coincided with the reduction of CpG site-specific methylation and trimethylation of H3K27 (H3 [histone 3] K27 [lysine 27]) and the increase of acetylation of H3K27 and trimethylation of H3K4 (H3 lysine 4) at the promoter. The inhibitor of STAT3 (signal transducer and activator of transcription 3) signaling, SD1008, reversed the leptin-induced promoter activity via modulations of the binding of pSTAT3 (phosphorylated STAT3) and DNMT3B (DNA methyltransferase 3B) and modifications of H3K27 and H3K4 at the promoter. Our results suggest that leptin-activated pSTAT3 epigenetically regulates the transcription of through DNA methylation and histone modifications. Because epigenetic changes are reversible, targeting epigenetic modifications of may serve as a new therapeutic approach for the treatment of hypertension in obesity.
10.1165/rcmb.2020-0374OC
Incidence and Clinical Presentation of Pheochromocytoma and Sympathetic Paraganglioma: A Population-based Study.
Ebbehoj Andreas,Stochholm Kirstine,Jacobsen Sarah Forslund,Trolle Christian,Jepsen Peter,Robaczyk Maciej Grzegorz,Rasmussen Åse Krogh,Feldt-Rasmussen Ulla,Thomsen Reimar Wernich,Søndergaard Esben,Poulsen Per Løgstrup
The Journal of clinical endocrinology and metabolism
CONTEXT:Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers. OBJECTIVE:We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study. METHODS:We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data. RESULTS:SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare. CONCLUSION:Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a "new" group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.
10.1210/clinem/dgaa965
VHL-RELATED NEUROENDOCRINE NEOPLASMS AND BEYOND: AN ISRAELI SPECIALIZED CENTER REAL-LIFE REPORT.
Szalat A,Oleinikov K,Nahmias A,Meiner V,Ben-Haim S,Atlan K,Lev-Cohain N,Appelbaum L,Gomori J M,Mazeh H,Khalaileh A,Pe'er J,Lossos A,Shoshan Y,Grozinsky-Glasberg S,Gross D J
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
OBJECTIVE:Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. We described in 1996 a three generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine tumors: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS:All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging and therapeutic characteristics were retrospectively analyzed. RESULTS:We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, one due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22) and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in three. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSIONS:Multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.
10.4158/EP-2020-0220
Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors.
Indio Valentina,Schipani Angela,Nannini Margherita,Urbini Milena,Rizzo Alessandro,De Leo Antonio,Altimari Annalisa,Di Scioscio Valerio,Messelodi Daria,Tarantino Giuseppe,Astolfi Annalisa,Pantaleo Maria Abbondanza
Journal of clinical medicine
BACKGROUND:About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy. METHODS:We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated. RESULTS:SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures. CONCLUSIONS:This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.
10.3390/jcm10051057
Case Report: Totally Laparoscopic Resection of Retroperitoneal Paraganglioma Masquerading as a Duodenal Gastrointestinal Stromal Tumor.
Zhang Zhi,Tu Zhengbin,Lv Zhiqiang,Luo Yang,Yuan Jianmao
Frontiers in surgery
Retroperitoneal paraganglioma (RPGL) is a rare clinical tumor derived from the retroperitoneal sympathetic paraganglion tissue. Since RPGLs are locate deeply and have no specific symptoms and imaging manifestations at the early stage, which easily causes missed diagnosis or misdiagnosis. In addition, reports on totally laparoscopic resection of RPGLs are scarce due to their close proximity to large vessels, giant size, uncertain location, and unknown malignant status. We present here the case of totally laparoscopic resection of a 6.4 × 5.4 cm RPGL that was discovered during a workup for discomfort and upper abdominal pain in a 68-year-old female patient, mimicking a gastrointestinal stromal tumor (GIST) of the duodenum, Which was confirmed as a RPGL based on the histopathological and immunohistochemical findings. RPGL is a rare tumor, and the transperitoneal laparoscopic approach for the RPGL is a safe, applicable method with less trauma and quick recovery, which is worth clinical popularizing and application. Moreover, the survival prognosis of RPGL patients are related to metastasis, and lifelong follow-up should be emphasized.
10.3389/fsurg.2021.586503
Mechanisms for establishment of GABA signaling in adrenal medullary chromaffin cells.
Harada Keita,Matsuoka Hidetada,Toyohira Yumiko,Yanagawa Yuchio,Inoue Masumi
Journal of neurochemistry
γ-Aminobutyric acid (GABA) is thought to play a paracrine role in adrenal medullary chromaffin (AMC) cells. Comparative physiological and immunocytochemical approaches were used to address the issue of how the paracrine function of GABA in AMC cells is established. GABA receptor Cl channel activities in AMC cells of rats and mice, where corticosterone is the major glucocorticoid, were much smaller than those in AMC cells of guinea-pigs and cattle, where cortisol is the major. The extent of enhancement of GABA receptor α3 subunit expression in rat pheochromocytoma (PC12) cells by cortisol was larger than that by corticosterone in parallel with their glucocorticoid activities. Thus, the species difference in GABA receptor expression may be ascribed to a difference in glucocorticoid activity between corticosterone and cortisol. GABA receptor Cl channel activity in mouse AMC cells was enhanced by allopregnanolone, as noted with that in guinea-pig AMC cells, and the enzymes involved in allopregnanolone production were immunohistochemically detected in the zona fasciculata in both mice and guinea pigs. The expression of glutamic acid decarboxylase 67 (GAD67), one of the GABA synthesizing enzymes, increased after birth, whereas GABA receptors already developed at birth. Stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, but not nicotinic or muscarinic receptors, in PC12 cells, resulted in an increase in GAD67 expression in a protein-kinase A-dependent manner. The results indicate that glucocorticoid and PACAP are mainly responsible for the expressions of GABA receptors and GAD67 involved in GABA signaling in AMC cells, respectively.
10.1111/jnc.15345
FDG PET/CT Findings in a Patient With Ovarian Metastasis of Pheochromocytoma.
Jiang Yuanyuan,Hou Guozhu,Cheng Xin,Zhu Zhaohui,Cheng Wuying
Clinical nuclear medicine
Pheochromocytoma metastasizing to the ovary is extremely rare. We report the case of a 59-year-old woman who underwent right adrenal pheochromocytoma resection 14 years ago and remained asymptomatic until recently when she complained of palpitation, perspiration, and hypertension. F-FDG PET/CT revealed a left adnexal mass with increased activity, which was later surgically removed and pathologically confirmed as ovarian metastasis of pheochromocytoma.
10.1097/RLU.0000000000003269
Facial Nerve Canal Paraganglioma.
Arsovic Emina,Montava Marion,Lavieille Jean-Pierre,Pacak Karel,Varoquaux Arthur,Taïeb David
Clinical nuclear medicine
We report the case of a 72-year-old woman presenting with a progressive left peripheral facial paralysis and a facial canal mass extending through the stylomastoid foramen along the posterior edge of the parotid gland. On MRI, the early and intense enhancement was highly suggestive of paraganglioma but could not rule out a nonossifying hemangioma. Laboratory analysis showed normal plasma metanephrines. On F-FDOPA PET/CT, the mass exhibited a typical paraganglioma feature with a marked tumor uptake. Our case demonstrates that F-FDOPA plays a vital role in this rare entity and can avoid any further confirmatory invasive procedure.
10.1097/RLU.0000000000003321
Laparoscopic transperitoneal adrenalectomy in the large adrenal tumor from single center experience.
Prakobpon Thanasit,Santi-Ngamkun Apirak,Usawachintachit Manint,Ratchanon Supoj,Sowanthip Dutsadee,Panumatrassamee Kamol
BMC surgery
BACKGROUND:The role of laparoscopic adrenalectomy (LA) in a large adrenal tumor is controversial due to the risk of malignancy and technical difficulty. In this study, we compared the perioperative outcomes and complications of LA on large (≥ 6 cm) and (< 6 cm) adrenal tumors. METHODS:We retrospectively reviewed all clinical data of patients who underwent unilateral transperitoneal LA in our institution between April 2000 and June 2019. Patients were classified by tumor size into 2 groups. Patients in group 1 had tumor size < 6 cm (n = 408) and patient in group 2 had tumor size ≥ 6 cm (n = 48). Demographic data, perioperative outcomes, complications, and pathologic reports were compared between groups. RESULTS:Patients in group 2 were significant older (p = 0.04), thinner (p = 0.001) and had lower incident of hypertension (p = 0.001), with a significantly higher median operative time (75 vs 120 min), estimated blood loss (20 vs 100 ml), transfusion rate (0 vs 20.8%), conversion rate (0.25 vs 14.6%) and length of postoperative stays ( 4 vs 5.5 days) than in group 2 (all p < 0.001). Group 2 patients also had significantly higher frequency of intraoperative complication (4.7 vs 31.3%; adjust Odds Ratio [OR] = 9.67 (95% CI 4.22-22.17), p-value < 0.001) and postoperative complication (5.4 vs 31.3%; adjust OR = 5.67 (95% CI 2.48-12.97), p-value < 0.001). Only eight (1.8%) major complications occurred in this study. The most common pathology in group 2 patient was pheochromocytoma and metastasis. CONCLUSIONS:Laparoscopic transperitoneal adrenalectomy in large adrenal tumor ≥ 6 cm is feasible but associated with significantly worse intraoperative complications, postoperative complications, and recovery. However, most of the complications were minor and could be managed conservatively. Careful patient selection with the expert surgeon in adrenal surgery is the key factor for successful laparoscopic surgery in a large adrenal tumor. TRIAL REGISTRATION:This study was retrospectively registered in the Thai Clinical Trials Registry on 02/03/2020. The registration number was TCTR20200312004.
10.1186/s12893-021-01080-y
Approach to the Patient: Perioperative Management of the Patient with Pheochromocytoma or Sympathetic Paraganglioma.
Berends Annika M A,Kerstens Michiel N,Lenders Jacques W M,Timmers Henri J L M
The Journal of clinical endocrinology and metabolism
Pheochromocytomas and sympathetic paraganglioma (PPGL) are rare chromaffin cell tumors originating in the adrenal medulla and sympathetic paraganglia, respectively, which share the capacity to synthesize and release catecholamines. The incidence of PPGL has increased in recent years. Surgical resection is the only curative treatment for PPGL. Management of patients with PPGL is complex and should be done by a specialized multidisciplinary team in centers with broad expertise. Surgical resection of a PPGL is a high-risk procedure for which optimal pretreatment with antihypertensive drugs is required in combination with state-of-the-art surgical procedures and anesthesiological techniques. In this article we discuss the underlying evidence and the pros and cons of presurgical medical preparation. Finally, the areas of uncertainty and controversies in this field are addressed.
10.1210/clinem/dgaa441
Glucocorticoid Excess in Patients with Pheochromocytoma Compared with Paraganglioma and Other Forms of Hypertension.
Constantinescu Georgiana,Langton Katharina,Conrad Catleen,Amar Laurence,Assié Guillaume,Gimenez-Roqueplo Anne-Paule,Blanchard Anne,Larsen Casper K,Mulatero Paolo,Williams Tracy Ann,Prejbisz Aleksander,Fassnacht Martin,Bornstein Stefan,Ceccato Filippo,Fliedner Stephanie,Dennedy Michael,Peitzsch Mirko,Sinnott Richard,Januszewicz Andrzej,Beuschlein Felix,Reincke Martin,Zennaro Maria-Christina,Eisenhofer Graeme,Deinum Jaap
The Journal of clinical endocrinology and metabolism
CONTEXT:Catecholamines and adrenocortical steroids are important regulators of blood pressure. Bidirectional relationships between adrenal steroids and catecholamines have been established but whether this is relevant to patients with pheochromocytoma is unclear. OBJECTIVE:This study addresses the hypothesis that patients with pheochromocytoma and paraganglioma (PPGL) have altered steroid production compared with patients with primary hypertension. DESIGN:Multicenter cross-sectional study. SETTING:Twelve European referral centers. PATIENTS:Subjects included 182 patients with pheochromocytoma, 36 with paraganglioma and 270 patients with primary hypertension. Patients with primary aldosteronism (n = 461) and Cushing syndrome (n = 124) were included for additional comparisons. INTERVENTION:In patients with PPGLs, surgical resection of tumors. OUTCOME MEASURES:Differences in mass spectrometry-based profiles of 15 adrenal steroids between groups and after surgical resection of PPGLs. Relationships of steroids to plasma and urinary metanephrines and urinary catecholamines. RESULTS:Patients with pheochromocytoma had higher (P < .05) circulating concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone, and corticosterone than patients with primary hypertension. Concentrations of cortisol, 11-deoxycortisol, and corticosterone were also higher (P < .05) in patients with pheochromocytoma than with paraganglioma. These steroids correlated positively with plasma and urinary metanephrines and catecholamines in patients with pheochromocytoma, but not paraganglioma. After adrenalectomy, there were significant decreases in cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, aldosterone, and 18-oxocortisol. CONCLUSIONS:This is the first large study in patients with PPGLs that supports in a clinical setting the concept of adrenal cortical-medullary interactions involving an influence of catecholamines on adrenal steroids. These findings could have implications for the cardiovascular complications of PPGLs and the clinical management of patients with the tumors.
10.1210/clinem/dgaa423
Clinical description & molecular modeling of novel MAX pathogenic variant causing pheochromocytoma in family, supports paternal parent-of-origin effect.
Richter John E,Hines S,Selvam Pavalan,Atwal Herjot,Farres Houssam,Caulfield Thomas R,Atwal Paldeep S
Cancer genetics
The titular member of the MAX network of proteins, MYC-associated factor X (MAX), serves an important regulatory function in transcription of E-box genes associated with cell proliferation, differentiation, and apoptosis. Wild type MAX dimerizes with both MYC and MAD, both of which are members of the MAX network, and can promote or repress cell functions as needed. However, pathogenic variants in MAX are known to upset this balance, leading to uncontrolled oncogenic activity and disease phenotypes such as paragangliomas and pheochromocytomas. We report a 58-year-old male and his 32-year-old daughter, both of which have a history of pheochromocytoma and the unique nonsense MAX variant c.271C>T (p.Q91X). These individuals were diagnosed with pheochromocytomas in their early twenties that were later removed through corrective surgery. The father now presents with recurrent symptoms of hypertension, hyperhidrosis, and headaches, which accompany new pheochromocytomas of his remaining adrenal gland. Pathogenicity of this MAX variant is proven through molecular modeling. The case of this father-daughter pair supports both heritability of pheochromocytoma and the paternal parent-of-origin effect for MAX pathogenic variants.
10.1016/j.cancergen.2021.01.004
Probability of positive genetic testing in patients diagnosed with pheochromocytoma and paraganglioma: Criteria beyond a family history.
Alobuia Wilson M,Ammar Sabrine,Tyagi Monica,Ghosh Chandrayee,Gunda Viswanath,Annes Justin P,Kebebew Electron
Surgery
BACKGROUND:Genetic testing for germline pheochromocytoma and paraganglioma susceptibility genes is associated with improved patient management. However, data are currently sparse on the probability of a positive testing result based on an individual's clinical presentation. This study evaluates clinical characteristics for association with testing positive for known pheochromocytoma and paraganglioma susceptibility genes. METHODS:This retrospective analysis examined 111 patients with a diagnosis of pheochromocytoma and paraganglioma who underwent genetic testing. Logistic regression and receiver operating characteristic analyses were performed to identify factors associated with a positive genetic testing result. Probabilities were then calculated for combinations of significant factors to determine the likelihood of a positive test result in each group. RESULTS:Of 32 patients with a family history of pheochromocytoma and paraganglioma, 31 (97%) had a germline mutation detected. Of 79 patients without a family history, 24 (30%) had a pathogenic germline mutation detected. In multivariate analysis, a positive family history, aged ≤47 years, and tumor size ≤2.9 cm were independent factors associated with a positive genetic testing result. Patients meeting all 3 criteria had a 100% probability compared with 13% in those without any of the criteria. In addition to a positive family history, having either aged ≤47 years or tumor size ≤2.9 cm resulted in a 90% and 100% probability of a positive result, respectively. In the absence of a family history, the probability in patients who were aged ≤47 years and had a tumor size ≤2.9 cm was 60%. CONCLUSION:In addition to a family history of pheochromocytoma and paraganglioma, aged ≤47 years, and tumor size ≤2.9 cm are associated with a higher probability of testing positive for a pheochromocytoma and paraganglioma susceptibility gene mutation. Patients meeting all 3 criteria have a 100% probability of a positive genetic testing result.
10.1016/j.surg.2020.08.027