Case Report: A Case of Moyamoya Syndrome Associated With Multiple Endocrine Neoplasia Type 2A.

To the best of our knowledge, we report a case of MEN2A complicated by moyamoya syndrome. A 52-year-old woman presented with vertigo. Magnetic resonance angiography (MRA) revealed bilateral supraclinoid stenosis of the internal carotid artery and abnormal moyamoya-like vessels around the basal ganglia. She had a heterozygous variant of RNF213, which is the susceptibility gene for moyamoya disease. She had also previously received diagnoses of medullary thyroid carcinoma (MTC) at age 23 and left-sided pheochromocytoma (PHEO) at age 41. Genetic testing revealed heterozygosity for a mutation at codon 634 in exon 11 (TGC-TTC mutation; p.Cys634Phe) of the Ret gene. Intracranial vascular stenosis may have been caused by a genetic mutation of RNF213 and hypersecretion of catecholamines by MEN2A. Physicians should recognize that MEN2A can be present with moyamoya syndrome.

Perioperative hemodynamic instability in pheochromocytoma and sympathetic paraganglioma patients.

For pheochromocytoma and sympathetic paraganglioma (PPGL), surgery can be used as a curative treatment; however, the life-threatening risk of perioperative hemodynamic instability (HI) presents challenges. This study aimed to analyze the incidence and predictive factors of perioperative HI. The electronic medical records of 114 consecutive patients who underwent surgery for PPGLs at our institution were retrospectively reviewed. HI was defined as one or more episodes of systolic blood pressure > 200 mmHg or mean blood pressure < 60 mmHg during surgery. The factors predictive of perioperative HI were determined using both univariate and multivariate analyses. Intraoperative HI occurred in 79 (69.3%) patients. In multivariate analysis, α-adrenergic receptor blocker duration (days) (odds ratio, 1.015; 95% confidence interval, 1.001-1.029) was a predictor for intraoperative HI. Postoperative hypotension occurred in 36 (31.6%) patients. Higher urine epinephrine levels, and greater preoperative highest heart rate (HR) were predictive factors for postoperative hypotension in PPGL patients. Caution should be taken in perioperative management for PPGL, especially with long duration of α-adrenergic receptor blocker use, higher urine epinephrine levels, and greater preoperative highest HR.

Composite phaeochromocytoma with malignant peripheral nerve sheath tumour: A case report with summary of prior published cases.

Composite phaeochromocytomas (CP) are extremely uncommon adrenal medullary tumours where phaeochromocytoma coexists with another adrenal medullary tumour also of neural crest origin. CP includes combination of phaeochromocytoma along with a component of neuroblastoma, ganglioneuroblastoma, ganglioneuroma, benign nerve sheath tumour or a malignant peripheral nerve sheath tumour (MPNST). Here we describe the morphological and immunohistochemical details of a case of CP with MPNST in a 30 years old lady, without history of neurofibromatosis. Only 6 cases of CP with MPNST have been reported so far. We have tabulated a summary of these prior published cases of phaeochromocytoma with MPNST. To our knowledge, this is the first literature review describing the clinico-pathological characteristics of these rare tumours.

Effect of surgical treatment on myocardial strain in patients with pheochromocytoma and paraganglioma: a mini-review and meta-analysis.

AIM: Information on systolic dysfunction, as assessed by left-ventricular (LV) mechanics, in patients with pheochromocytoma after surgical treatment is scanty. We performed a systematic meta-analysis of speckle tracking echocardiographic studies to provide an updated comprehensive information on this issue. METHODS: The PubMed, OVID-MEDLINE, and Cochrane library databases were analyzed to search for articles published from the inception up to May 31st 2021. Studies were identified using MeSH terms and crossing the following search items: "myocardial strain" "left ventricular mechanics", "speckle tracking echocardiography", "systolic dysfunction", "pheochromocytoma", and "paraganglioma". RESULTS: A total of 92 surgically treated patients with pheochromocytoma/paraganglioma were included in 3 longitudinal studies. Successful surgical treatment was associated with a decrease in relative wall thickness (SMD - 0.25 ± 0.10, CI - 0.45/- 0.05, p < 0.01) and an improvement in global longitudinal strain (SMD - 0.45 ± 0.10, CI - 0.66/- 0.24, p < 0.0001). The favorable effects of treatment on LV geometry and mechanics were not accompanied by significant changes in ejection fraction (SMD - 0.07 ± 0.10, CI - 0.27/0.12, p = 0.44). CONCLUSIONS: This meta-analysis adds a new piece of evidence, suggesting that surgical treatment of patients with pheochromocytoma impacts favorably on LV geometry and LV mechanics, and, more importantly, the assessment of LV changes in this setting can no longer rely on conventional echocardiographic parameters such as ejection fraction.

Case Report: Irreversible Watery Diarrhea, Severe Metabolic Acidosis, Hypokalemia and Achloridria Syndrome Related to Vasoactive Intestinal Peptide Secreting Malignant Pheochromocytoma.

Background: Pheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP). Clinical Case: A 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on 68GaDOTA-octreotate positron emission tomography. Metastasis in lumbar region and lung were present. Both chromogranin A and VIP levels were high (more than10 times the normal value) with slightly elevated urine normetanephrine and metanephrine excretion. Right adrenalectomy was performed and a somatostatin analogue therapy with lanreotide started. Immunostaining showed chromogranin A and VIP co-expression, with weak somatostatin-receptor-2A positivity. In two months, patient clinical conditions deteriorated with severe WDHA and multiple liver and lung metastasis. Metabolic acidosis and hypokalemia worsened, leading to hemodynamic shock and exitus. Conclusions: A rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells.

Seven Novel Genes Related to Cell Proliferation and Migration of VHL-Mutated Pheochromocytoma.

Pheochromocytoma, as a neuroendocrine tumor with the highest genetic correlation in all types of tumors, has attracted extensive attention. Von Hipper Lindau (VHL) has the highest mutation frequency among the genes associated with pheochromocytoma. However, the effect of VHL on the proteome of pheochromocytoma remains to be explored. In this study, the VHL knockdown (VHL-KD) PC12 cell model was established by RNA interference (shRNA). We compared the proteomics of VHL-KD and VHL-WT PC12 cell lines. The results showed that the expression of 434 proteins (VHL shRNA/WT > 1.3) changed significantly in VHL-KD-PC12 cells. Among the 434 kinds of proteins, 83 were involved in cell proliferation, cell cycle and cell migration, and so on. More importantly, among these proteins, we found seven novel key genes, including Connective Tissue Growth Factor (CTGF), Syndecan Binding Protein (SDCBP), Cysteine Rich Protein 61 (CYR61/CCN1), Collagen Type III Alpha 1 Chain (COL3A1), Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type V Alpha 2 Chain (COL5A2), and Serpin Family E Member 1 (SERPINE1), were overexpressed and simultaneously regulated cell proliferation and migration in VHL-KD PC12 cells. Furthermore, the abnormal accumulation of HIF2α caused by VHL-KD significantly increased the expression of these seven genes during hypoxia. Moreover, cell-counting, scratch, and transwell assays demonstrated that VHL-KD could promote cell proliferation and migration, and changed cell morphology. These findings indicated that inhibition of VHL expression could promote the development of pheochromocytoma by activating the expression of cell proliferation and migration associated genes.

Preoperative Amlodipine Is Efficacious in Preventing Intraoperative HDI in Pheochromocytoma: Pilot RCT.

CONTEXT: Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce. OBJECTIVE: We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL. METHODS: In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure). RESULTS: The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ±â€…18.4% vs 2.44 ±â€…2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine). CONCLUSION: Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted.

Determinants of anxiety and depression among pheochromocytoma patients: A case-control study.

ABSTRACT: Phaeochromocytomas are catecholamine-producing neuroendocrine tumors that may manifest in many ways, specifically as sustained or paroxysmal hypertension. Data, including data from mental status screening, were prospectively collected from suspected patients. The Hospital Anxiety and Depression Scale was used as a screening tool to identify abnormal mental status. Results showed phaeochromocytoma patients were more likely to experience anxiety and depression. For future phaeochromocytoma treatment, early screening for anxiety and depression should be recommended.

A Nomogram for Predicting Intraoperative Hemodynamic Instability in Patients With Pheochromocytoma.

Purpose: Surgical removal of pheochromocytoma (PCC), including open, laparoscopic, and robot-assisted adrenalectomy, is the cornerstone of therapy, which is associated with high risk of intraoperative and postoperative life-threatening complications due to intraoperative hemodynamic instability (IHD). This study aims to develop and validate a nomogram based on clinical characteristics as well as computed tomography (CT) features for the prediction of IHD in pheochromocytoma surgery. Methods: The data from 112 patients with pheochromocytoma were collected at a single center between January 1, 2010, and December 31, 2019. Clinical and radiological features were selected with the least absolute shrinkage and selection operator regression analysis to predict IHD then constitute a nomogram. The performance of the nomogram was assessed in terms of discrimination, calibration, and clinical utility. Results: Age, tumor shape, Mayo Adhesive Probability score, laterality, necrosis, body mass index, and surgical technique were identified as risk predictors of the presence of IHD. The nomogram was then developed using these seven variables. The model showed good discrimination with a C-index of 0.773 (95% CI, 0.683-0.862) and an area under the receiver operating characteristic curve (AUC) of 0.739 (95% CI, 0.642-0.837). The calibration plot suggested good agreement between predicted and actual probabilities. Besides, calibration was tested with the Hosmer-Lemeshow test (P = 0.961). The decision curve showed the clinical effectiveness of the nomogram. Conclusions: Our nomogram based on clinical and CT parameters could facilitate the treatment strategy according to assessment of the risk of IHD in patients with pheochromocytoma.

Acute Stress Cardiomyopathy: Heart of pheochromocytoma.

Stress cardiomyopathy (SCM) is a syndrome characterized by transient regional systolic dysfunction of the left ventricle in the absence of angiographic evidence of coronaropathy. This abnormality is associated with high levels of catecholamines. Stress cardiomyopathy is also called Takotsubo (TS) cardiomyopathy. Pheochromocytoma crisis can occur spontaneously or can be precipitated by manipulation of the tumor, trauma, certain medications or stress for example during non-adrenal surgery. The main drugs leading to pheochromocytoma crisis include D2 dopamine receptor antagonists, noncardioselective ß-adrenergic receptor blockers, tricyclic antidepressants and related neurotransmitter uptake blockers, sympathomimetics, certain peptide and steroid hormones and several agents used during induction of anesthesia. Patients can develop symptoms of heart failure associated with tachyarrhythmia, cardiogenic shock with hypotension and collapse, or apparent acute coronary syndromes. This review describes pathophysiology, epidemiology, diagnosis criteria and management of SCM.

The effect of combined Epidural-general Anesthesia on Hemodynamic Instability during Pheochromocytoma and Paraganglioma Surgery: A multicenter retrospective cohort study.

Objectives: The purpose of this study was to compare the effects of combined epidural-general anesthesia with those of general anesthesia alone on hemodynamic instability (intraoperative hypotension and hypertensive crisis) during pheochromocytoma and sympathetic paraganglioma surgery. Methods: A total of 119 patients' medical records were reviewed who were diagnosed as having pheochromocytoma and sympathetic paraganglioma on the basis of histological findings. Intraoperative hypotension was defined as a mean blood pressure < 60 mmHg or a decrease > 30% in baseline systolic blood pressure after adrenal vein ligation. Hypertensive crisis was defined as a systolic blood pressure > 200 mmHg or an increase > 30% in baseline systolic blood pressure during the operation. The predictor variables for intraoperative hypotension and hypertensive crisis were analyzed with logistic regression models. Data were presented as adjusted odds ratio with 95% confidence interval. Results: The independent predictors of intraoperative hypotension were an increased attenuation number on unenhanced computed tomography (1.112 [1.009-1.226], p = 0.033), a high baseline mean blood pressure (1.063 [1.012-1.117], p = 0.015), and the combined epidural-general anesthesia (5.439 [1.410-20.977], p = 0.014). In contrast, an increased attenuation number on unenhanced computed tomography was the only independent predictor of hypertensive crisis (1.087 [1.021-1.158], p = 0.009). Conclusions: The combined epidural-general anesthesia was not effective in attenuating hypertensive responses, but could have exacerbated intraoperative hypotension. These findings should be taken into account before selecting the anesthetic technique in pheochromocytoma and sympathetic paraganglioma surgery.

Global longitudinal strain as a marker for systolic function in patients with pheochromocytomas.

Cardiomyopathy is a frequent complication of pheochromocytoma, and echocardiography is the most accessible method for its evaluation. The objective of this study was to assess the clinical significance of classical and novel echocardiographic parameters of cardiac function in 24 patients with pheochromocytomas (PPGL) compared to 24 subjects with essential hypertension (EH). Fourteen PPGL patients were reassessed after successful surgery. Left ventricular hypertrophy was four times more prevalent in patients with PPGL vs EH (75% vs 17%; P = 0.00005). Left ventricular mass index (LVMi) significantly correlated with urine metanephrine (MN) (rs = 0.452, P = 0.00127) and normetanephrine (NMN) (rs = 0.484, P = 0.00049). Ejection fraction (EF) and endocardial fractional shortening (EFS) were normal in all participants and did not correlate with urine metanephrines. Global longitudinal strain (GLS) was significantly lower in PPGL compared to EH group (-16.54 ± 1.83 vs -19.43 ± 2.19; P < 0.00001) and revealed a moderate significant positive correlations with age (rs = 0.489; P = 0.015), LVMi (rs = 0.576, P < 0.0001), MN (rs = 0.502, P = 0.00028) and NMN (rs = 0.580, P < 0.0001). Relative wall thickness (RWT) showed a strong positive correlation with urine MN (rs = 0.559, P < 0.0001) and NMN (rs = 0.689, P < 0.00001). Markedly decreased LVMi (118.2 ± 26.9 vs 102.9 ± 22.3; P = 0.007) and significant improvement in GLS (-16.64 ± 1.49 vs -19.57 ± 1.28; P < 0.001) was observed after surgery. ΔGLS depended significantly on the follow-up duration. In conclusion, classical echocardiographic parameters usually used for assessment of systolic cardiac function are not reliable tests in pheochromocytoma patients. Instead, GLS seems to be a better predictor for the severity and the reversibility of catecholamine-induced myocardial function damage in these subjects. RWT should be measured routinely as an early indicator of cardiac remodeling.

Glucocorticoid Excess in Patients with Pheochromocytoma Compared with Paraganglioma and Other Forms of Hypertension.

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.

The use of doxazosin before adrenalectomy for pheochromocytoma: is the duration related to intraoperative hemodynamics and postoperative complications?

PURPOSE: No conclusion exists for the optimum duration of preoperative administration of doxazosin (DOX) before adrenalectomy for pheochromocytoma. The purpose of this study is to investigate whether perioperative hemodynamics and postoperative outcomes are related to the duration of DOX administration. METHODS: In total, 132 patients managed preoperatively with single α-receptor blocker DOX were enrolled. All patients underwent adrenalectomy for pheochromocytoma in the Department of Urology, Peking University First Hospital, between January 2001 and July 2019. Patients were divided into three groups based on the duration of preoperative administration of DOX: group A (≤14 days), group B (15-30 days), and group C (>30 days). Patient and tumor characteristics, intraoperative hemodynamics, and postoperative outcomes were recorded and compared. RESULTS: These patients included 57 men and 75 women, with an average age of 48 years. Clinical characteristics, preoperative hemodynamics, medicine management and surgical approaches were comparable between the three groups. Among the three groups, we found that group C (>30 days) had the lowest intraoperative minimum heart rate [group A vs. group B vs. group C = 60 (52-67) vs. 59 (50-61) vs. 51.5 (50-58.75), p = 0.024] and highest risk of postoperative hypotension requiring vasopressor support [group A vs. group B vs. group C = 14 (20.3%) vs. 12 (27.9%) vs. 10 (50.0%), p = 0.032]. CONCLUSION: The current study indicated that preoperative management of pheochromocytoma with single α-receptor blocker DOX for more than 30 days after final dose adjustment might lead to intraoperative bradycardia and more postoperative hypotension requiring vasopressor support. Thus, our study does not support long-term (over 30 days) preoperative administration of pheochromocytoma with single α-receptor blocker DOX in the final dose.

Recurrent Pheochromocytoma in an Elderly Patient.

Pheochromocytomas are rare neuroendocrine tumors that can affect people of all ages and are commonly diagnosed in the 4th and 5th decades of life. Familial pheochromocytomas are diagnosed mostly between the 2nd and 3rd decades of life. They can be benign or metastatic and often present as isolated tumors or along with other neuroendocrine syndromes. We present a case of an elderly man who underwent laparoscopic adrenalectomy for pheochromocytoma at the age of 60 years but developed recurrence of metastatic pheochromocytoma after ten years. We also conducted a literature review to understand the epidemiology and presentation of the tumor and to emphasize that there should be a low threshold of suspicion for timely diagnosis and management of recurrent pheochromocytoma.