Extra-adrenal Chromaffin Cells Research Articles

Animal and Cell Culture Models of PPGLs - Achievements and Limitations.

Research on rare tumors heavily relies on suitable models for basic and translational research. Paragangliomas (PPGL) are rare neuroendocrine tumors (NET), developing from adrenal (pheochromocytoma, PCC) or extra-adrenal (PGL) chromaffin cells, with an annual incidence of 2-8 cases per million. While most PPGL cases exhibit slow growth and are primarily treated with surgery, limited systemic treatment options are available for unresectable or metastatic tumors. Scarcity of appropriate models has hindered PPGL research, preventing the translation of omics knowledge into drug and therapy development. Human PPGL cell lines are not available, and few animal models accurately replicate the disease's genetic and phenotypic characteristics. This review provides an overview of laboratory models for PPGLs, spanning cellular, tissue, organ, and organism levels. We discuss their features, advantages, and potential contributions to diagnostics and therapeutics. Interestingly, it appears that in the PPGL field, disease models already successfully implemented in other cancers have not been fully explored.

Abstract #1003799: Persistent Hypertension After Adrenalectomy for Pheochromocytoma/Paraganglioma (PPGL) in Young Adult: A Possible Case of Noradrenergic Extra Adrenal PPGL?

The prevalence of secondary hypertension in young adults is approximately 30%, most of which are endocrine disorders such as primary aldosteronism, pheochromocytoma/paraganglioma (PPGL), and Cushing syndrome. Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors that arise from adrenal or extra-adrenal chromaffin cells, and they can occur either sporadically or hereditary. It is a necessity to establish an accurate diagnosis through careful workup to provide optimal treatment.

Catecholamine-induced cardiomyopathy: an endocrinologist's perspective.

Although many endocrine diseases can be associated with acquired cardiomyopathy and heart failure, conditions except hypothyroidism, hyperthyroidism, phaeochromocytoma-paraganglioma (PPGL), and primary hyperaldosteronism are rare. PPGL is a rare catecholamine-secreting neuroendocrine tumour arising from the adrenal gland in 80-85% or extra-adrenal chromaffin cells of the autonomic neural ganglia in the remainder. The annual incidence of PPGL is 3-8 cases per million per year in the general population. Catecholamine-induced cardiomyopathy (CICMP) has got a prevalence of 8-11% among patients with PPGL. Hypertension, either sustained or episodic, is present in the vast majority (95%) of PPGL patients. However, among patients with CICMP, hypertension is present only in 65% of cases and the classical triad of paroxysmal headache, sweating, and palpitation is present only in 4%. Based on the cardiac remodelling in response to endogenous catecholamine excess, PPGL patients might present with one of the three CICMPs, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or Takotsubo cardiomyopathy (TCM). Regardless of the subtypes, all CICMPs have many features in common - a dramatic clinical presentation, reversible cardiomyopathy, similar repolarisation electrocardiography changes, mild-moderate cardiac biomarker elevation, and normal coronary arteries on coronary angiography. CICMP should be suspected in patients with non-ischaemic, non-valvular forms of cardiomyopathy, even in those without definite features of catecholamine excess. PPGL associated TCM should be suspected in all acute coronary syndrome (ACS) patients exhibiting pronounced blood pressure variability with no culprit lesions on coronary angiography. This article will provide a review of the various CICMPs, their pathophysiology, clinical features, and the management options.

Haemorrhagic retroperitoneal paraganglioma initially manifesting as acute abdomen: a rare case report and literature review

BackgroundParagangliomas (PGLs) are extremely rare neuroendocrine tumours arising from extra-adrenal chromaffin cells. PGLs are clinically rare, difficult to diagnose and usually require surgical intervention. PGLs mostly present catecholamine-related symptoms. We report a case of Acute abdomen as the initial manifestation of haemorrhagic retroperitoneal PGL. There has been only one similar case reported in literature.Case presentationWe present a unique case of a 52-year-old female with acute abdomen induced by haemorrhagic retroperitoneal PGL. The patient had a 5-h history of sudden onset of serve right lower quadrant abdominal pain radiating to the right flank and right lumbar region. Patient had classic symptoms of acute abdomen. Abdominal ultrasound revealed a large abdominal mass with a clear boundary. A Computed Tomography Angiography (CTA) of superior mesenteric artery was also performed to in the emergency department. The CTA demonstrated a large retroperitoneal mass measured 9.0 × 7.3 cm with higher density inside. A provisional diagnosis of retroperitoneal tumour with haemorrhage was made. The patient received intravenous fluids, broad-spectrum antibiotics and somatostatin. On the 3rd day of admission, her abdominal pain was slightly relieved, but haemoglobin decreased from 10.9 to 9.4 g/dL in 12 h suggesting that there might be active bleeding in the abdominal cavity. Thus, we performed a midline laparotomy for the patient. Haemorrhage was successfully stopped during operation. The retroperitoneal tumour with haemorrhage was completely removed. The abdominal pain was significantly relieved after surgery. The patient initially presented with acute abdomen instead of catecholamine-related symptoms. The diagnosis of retroperitoneal PGL with haemorrhage was finally confirmed by postoperative pathological and immunohistochemical results. The postoperative course was uneventful. At the 1-year follow-up visit, no tumour recurrence was observed by Single Photon Emission Computed Tomography. A literature review was performed to further understand and analyse the aforementioned disease.ConclusionAcute abdomen as the initial manifestation of haemorrhagic retroperitoneal paraganglioma is extremely rare. Abdominal Computed Tomography is essential to locate the lesion and differentiate between other causes of acute abdomen. PGLs are hypervascular tumours. We should be aware that ruptured retroperitoneal PGL with massive bleeding could be life threatening and require emergency laparotomy.

Paraganglioma in the posterior mediastinum: a case report

BackgroundParagangliomas are tumors that arise from extra-adrenal chromaffin cells. Herein, we present a rare case of a functional paraganglioma in the posterior mediastinum.Case presentationA 36-year-old man presented with paroxysms of chest pain and headache. At presentation, the patient’s blood pressure was 190/120 mmHg. Chest computed tomography and magnetic resonance imaging revealed a left paravertebral mass in the posterior mediastinum. 123I-metaiodobenzylguanidine scanning revealed focally high tracer uptake in the left paravertebral area. The metanephrine level in the urine was elevated, confirming a rare, catecholamine-producing, functional paraganglioma in the posterior mediastinum. Before surgery, the patient was prepared by orally administering α- and β-adrenergic blockers. The mass was then resected via a lateral thoracotomy. The metanephrine level in urine was normal 24 h after surgery.ConclusionsParagangliomas in the posterior mediastinum are very rare, but more than half of all cases are functional. The associated symptoms are curable with complete resection, and long-term follow-up for recurrence is important.

Simple, rapid, and cost-effective microextraction by the packed sorbent method for quantifying of urinary free catecholamines and metanephrines using liquid chromatography-tandem mass spectrometry and its application in clinical analysis.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells. They produce excessive amounts of catecholamines and their metabolites. A newly analytical procedure based on the semi-automated microextraction by packed sorbent (MEPS) technique, using a digitally controlled syringe (eVol) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), was developed to quantify free urinary catecholamines and metanephrines. The important parameters affecting MEPS performance, namely the type of sorbent material (porous graphitized carbon (PGC), polar enhanced polymer (PEP), cation-exchange (CX) and C18), number of extraction cycles, and elution solvent system, were evaluated. The optimal experimental conditions involved the loading of sample mixture in seven extraction cycles through a C18 sorbent in a MEPS syringe, followed by using elution solutions (water/acetonitrile/formic acid, 95/4.75/0.25). The entire sample preparation took about 4min. Chromatographic separation was well achieved with an HSS PFP column using the gradient elution. The linearity range of the method was 0.167-33.4ng/mL for epinephrine, 0.650-130ng/mL for norepinephrine, 1.53-306ng/mL for dopamine, 1.34-268ng/mL for metanephrine, 3.43-686ng/mL for normetanephrine, and 1.33-265ng/mL for 3-methoxytyramine. The intra- and interassay precisions were ≤ 12.8%, and the respective accuracies were 88.4-112.0% and 89.0-109.5%. The carryover and sample stability without acidification were also investigated. Validation using clinical urine specimens showed that the proposed method had higher sensitivity compared with other urinary biochemical tests. The developed MEPS-LC-MS/MS method was simple, fast, and cost-effective; it helped to obtain information about multiple metabolites. It is applicable in routine clinical laboratories for the screening of PPGL. Graphical abstract.

Therapies targeting the signal pathways of pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma (PCC/PGL) are rare tumors that originate from adrenal or extra-adrenal chromaffin cells. A significant clinical manifestation of PCC/PGL is that the tumors release a large number of catecholamines continuously or intermittently, causing persistent or paroxysmal hypertension and multiple organ functions and metabolic disorders. Though majority of the tumors are non-metastatic, about 10% are metastatic tumors. Others even have estimated that the rate of metastasis may be as high as 26%. The disease is most common in individuals ranging from 20 to 50 years old and the age of onset strongly depends on the genetic background: patients with germline mutations in susceptible genes have an earlier presentation. Besides, there are no significant differences in the incidence between men and women. At present, traditional treatments, such as surgical treatment, radionuclide therapy, and chemotherapy are still prior choices. However, they all have several deficiencies so that the effects are not extremely significant. Contemporary studies have shown that hypoxia-associated signal pathway, associated with the cluster 1 genes of PCC/PGL, and increased kinase signal pathways, associated with the cluster 2 genes of PCC/PGL, are the two major pathways involving the molecular pathogenesis of PCC/PGL, indicating that PCC/PGL can be treated with targeted therapies in emerging trends. This article reviews the progress of molecular-targeted therapies for PCC/PGL.

SUN-LB060 Paraganglioma in Pregnancy: Challenges to Treatment

Background: Paragangliomas are rare neuroendocrine tumors that arise from extra-adrenal chromaffin cells derived from the embryonic neural crest. Sympathetic paragangliomas secrete catecholamines and present with episodic hypertension and tachycardia. Paragangliomas in pregnancy are extremely rare. Here we describe a complicated case of a paraganglioma in pregnancy that highlights the special considerations taken during this state. Case Presentation: A 17-year-old pregnant female presented with chest pain and dyspnea on exertion at 32 weeks of gestation secondary to hypertensive urgency. Further history revealed several paternal family members with tumors and resistant hypertension. A work-up for secondary causes of hypertension was performed. Pertinent studies included plasma normetanephrines >50 nmol/L (0-0.89 nmol/L) and normal plasma metanephrines. Plasma fractionated catecholamines revealed a norepinephrine level of 18,977 pg/mL (85-1250 pg/mL), a dopamine level of 83 pg/mL (0-20 pg/mL), and a normal epinephrine level. MRI revealed an 8.0 cm hyperintense left infrarenal mass consistent with a paraganglioma. The patient was started on increasing doses of phenoxybenzamine followed by metoprolol to reduce her blood pressure and heart rate, keeping placental perfusion in mind. At 35 weeks of gestation she underwent successful cesarean delivery immediately followed by surgical resection of the tumor. Pathology revealed a 9.1 cm mass with nests of tumor cells, prominent vascularity, and foci of necrosis. A periaortic lymph node infiltrated by tumor indicated malignancy. Immunostaining was positive for neuron specific enolase, chromogranin, and synaptophysin. The patient briefly required vasopressors post-operatively, but she and the neonate recovered well with intensive monitoring. Genetic testing revealed a mutation in the succinate dehydrogenase B gene, increasing her risk for recurrent malignant paragangliomas and necessitating genetic testing of her child. Conclusions: Paragangliomas discovered during pregnancy are extraordinarily rare and present several challenges to management. While alpha and beta blockade should be initiated to correct volume depletion and avoid hemodynamic lability, caution must be taken to avoid excessive reductions in blood pressure and heart rate that may precipitate uteroplacental insufficiency and intrauterine growth restriction. Cesarean delivery is preferred over vaginal delivery to reduce the risk of precipitating hypertensive crisis. Furthermore, phenoxybenzamine crosses the placenta and neonates should be monitored in the NICU for hypotension in the first few days of life. Lastly, as approximately one quarter of all paragangliomas are associated with a genetic mutation, it is imperative to discuss genetic testing with the patient and the implications of a positive result for both the patient and offspring. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-398 Clinical Case Of Retroperitoneal Paraganglioma

Background: Paraganglioma is a rare neuroendocrine tumor from extra-adrenal chromaffin cells of the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. In most cases paragangliomas produce catecholamines in large concentrations and the lack of treatment can lead to cardiovascular and cerebral catastrophes [1]. That is why early diagnosis of this tumor is so important and, consequently, knowledge of its diagnostic criterion, too. Clinical case: A 59-year-old man was presented to a cardiologist for rapid increasing of blood pressure (up to 220/120 mmHg), which was accompanied by severe headache and epigastric pain in September 2017. From anamnesis it is known: the disease began suddenly and had paroxysmal flow. The first attack lasted for about 3 minutes and finished itself. Then such attacks occured with different frequency (from 1 per month to several times per week) and were connected with physical activity. The cardiologist suspected diagnosis of pheochromocytoma. The result of urinary fractionated metanephrines measurement showed its levels higher than normal rage but did not confirm suspected diagnosis reliably, so antihypertensive therapy was prescribed to minimize the symptoms. Despite this, the attacks persisted and the patient referred to a surgeon in May 2018. On the basis of patient’s complaints on epigastric pain during the attacks and the neck inflection of the gallbladder revealed by the ultrasound examination, it was decided to carry out cholecystectomy. A week after the operation the patient referred to the endocrinologist because of the continuing attacks. The diagnosis of pheochromocytoma was suspected again, the urinary fractionated metanephrines measurement was repeated, which revealed elevated normetanephrine level (1008 µg/day). A CT of retroperitoneal space revealed a spherical mass sized about 17х16х18 mm in paraaortal region under the left renal vein. The retroperitoneal tumor was removed laparoscopically in August 2018. Pathological examination of the removed mass showed a paraganglioma with uncertain potential of biological behaviour. BP was normal and remained within range without the need of any antihypertensive medication until discharge from hospital. The patient is asymptomatic and normotensive during his follow-up visits. Conclusion: This clinical case shows how a tumor with bright and specific symptoms can be revealed only in several years and after referring to several specialists. Also, this case highlights the importance of knowledge of diagnostic process of different diseases. In the present case the paraganglioma would have been revealed earlier if only the CT of retroperitoneal space had been done just after getting the results of free metanephrines, which were higher than normal.

SAT-318 A Case of Metastatic Paraganglioma

Background: Paraganglioma is a tumor derived from extra-adrenal chromaffin cells of the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. Malignancy is defined as the presence of metastases in nonchromaffin tissue (1). We discuss a case of metastatic paraganglioma for unusual course of disease and multiple challenges that arose in the management. Case presentation: 51-year-old female with mosaic turner presented to emergency with nausea, vomiting and abdominal pain. She had recent history of episodic high blood pressure and newly diagnosed diabetes mellitus. An abdominal CT scan which was done to assess abdominal pain revealed a retroperitoneal mass suspicious for paraganglioma. Subsequent blood work showed high plasma normetanephrine (x7 upper limit of normal). She underwent surgical resection of intra abdominal mass after blood pressure control with adequate alfa blockade treatment. Surgical pathology result confirmed the diagnosis of paraganglioma and showed high Ki-67 level and mitoses count. Three months post surgery, she developed severe blood pressure difficult to control; and her blood work revealed high plasma and urine normetanephrine suggestive of paraganglioma recurrence. The pre-op imaging including CT chest and abdomen were negative for any evidence of malignancy. However, repeat imaging three months post surgery showed multiple bone lesion in the skull, sternum, spine, and pelvic suggestive of metastatic disease. One week after the diagnosis of metastatic disease, she developed acute onset right eye proptosis due to retro-orbital mass which was resected. Surgical pathology was positive for metastatic paraganglioma. To determine extent of the disease and therapeutic choice, an octreotide scan was done which showed mild octreotide uptake in bone lesions. Therefore, peptide receptor radionucleotide radiation treatment (PRRT) was not considered for her metastatic disease treatment. In consultation with medical oncology, systemic chemotherapy was suggested, but it was also declined given her poor functional status. Eventually, she was started on targeted molecular therapy with sunitinib with good tolerance and response. We report this patient, first for the unusual course of disease given progression of metastatic disease over three months after surgical resection; second for the challenging therapeutic decision given the patient and disease unique characteristics. Conclusion: This case demonstrates an aggressive course of metastatic paraganglioma disease over a short period of time following surgical resection of primary tumor mass which shows the importance of earlier follow up post surgical resection of paraganglioma. This case might also justify broader work up such as MIBG or octreotide scan to determine the extent of disease and plan for the best therapeutic approach in certain cases prior to surgery.

SAT-312 A Rare Case of Metastatic Paraganglioma with Positive SDHB Mutation: An Incidentally Found Silent Monster

Introduction: Although paragangliomas (PG) are derived from extra-adrenal chromaffin cells of sympathetic paravertebral ganglia in the thorax, abdomen, and pelvis, they can also arise from parasympathetic ganglia located along the glossopharyngeal and vagal nerves in the neck and at the base of the skull. Non-secretory PG have a low prevalence, are often silent, and can present as a malignant tumor with mass effects. Symptoms often include: unilateral hearing loss, pulsatile tinnitus, cough, hoarseness, pharyngeal fullness, swallowing difficulty, pain, and/or problems with tongue motion. Case: A 25 year old African American woman presented with 2 yrs of exertional presyncope, night sweats, subjective fevers, 20 lb. weight loss and a nontender enlarging left neck mass. Family history: Mother had thyroid cancer. Physical exam- BMI 21 kg/m2, BP 118/72 mmHg, HR 74, with indurated, fixed, nontender mass in left upper neck, inferior to mandibular angle. Laboratory-Hgb 6.9 g/dl, MCV 71.7, Iron 137 mcg/dl, TIBC 151 mcg/dl, Ferritin 155 ng/ml, CRP 65.20 mg/dl, ESR 122 mm/hr, AST 107 U/l, ALT 7 U/L, Alk Phos 81 U/l. EGD and Colonoscopy-normal. CT scan of neck, abdomen and pelvis: 6.0x3.5x2.7 cm heterogeneously enhancing mass in left neck involving skull base at carotid canal level, within the internal carotid space, causing external compression of left internal jugular vein, with multiple hypervascular lesions in bilateral lungs, liver and spleen, as well as cervical, thoracic, lumbar and sacral spine. Packed red blood cells were transfused. Liver Biopsy-metastatic paraganglioma with SDHB mutation. Laboratory tests- normal plasma catecholamines, thyroid function tests, prolactin, cortisol, ACTH, LH, FSH. A few weeks later, she reported new onset left sided tinnitus, orbital pain and vision changes. MRI Brain/orbit- 10 x 11 mm enhancing lesion centered in left cavernous sinus near orbital apex without intra or extraconal lesion. Chemotherapy was started with vincristine, cyclophosphamide and dacarbazine. After 12 weeks of chemotherapy, the left neck mass size decreased, tinnitus, and vision changes resolved. She was referred for genetic counseling and multidisciplinary care. Discussion: Our patient had malignant head and neck PG with SDHB mutation. Mutations in the gene encoding SDH subunit B (SDHB) can lead to metastatic disease in ≥ 40% of patients, are frequently familial, and are associated with other malignancies (renal cell carcinoma, pituitary adenoma, breast and thyroid cancer). Although there are current guidelines regarding diagnosis and management of non-malignant secretory paraganglioma/pheochromocytoma, screening and management of metastatic disease is not clear. Therefore, it is important to have a low threshold of suspicion for early diagnosis. Provider awareness and education regarding diagnosis and management is needed.

Laparoscopic Resection of Subclinical Functioning Para-aortic Paraganglioma

Introduction: Extra-adrenal pheochromocytomas (paragangliomas) are neuroendocrine tumors derived from extra-adrenal chromaffin cells. Although laparoscopic resection of adrenal pheochromocytomas is a common procedure, there are few reports of the use of this approach in extra-adrenal para-aortic paragangliomas. Here, we report the case of a patient with a subclinical functioning para-aortic paraganglioma that was successfully resected laparoscopically. Case presentation: A 58-year-old man was referred to our department for treatment of a para-aortic tumor after endoscopic submucosal dissection of early-stage colorectal cancer. Positron emission tomography-computed tomography showed abnormal accumulation by the para-aortic tumor. During its laparoscopic resection, the patient's blood pressure unexpectedly rose to over 180 mmHg, which suggested that the tumor was a paraganglioma. The diagnosis was confirmed by immunohistochemical staining, which showed chromogranin-positive cells forming a Zellballen pattern. The operation was successfully completed, and the patient's postoperative course was uneventful. Conclusion: Laparoscopic resection may be a suitable procedure for the treatment of retroperitoneal paraganglioma.

Middle mediastinal paraganglioma with blood supply by branch of left coronary artery: one case report

Paragangliomas are neuroendocrine tumors arising from extra-adrenal chromaffin cells of the autonomic nervous system and mediastinal paragangliomas are thought to deriving from para-aortic and para-vertebral ganglion chain. We present a 40-year-old woman with a middle mediastinal mass that was fed by branch of left coronary artery, and was finally diagnosed as primary mediastinal non-functional paraganglioma. The thoracic paraganglioma is extremely rare and it was unreliable to predict biologic behavior from the perspective of morphology. Excluding metastatic lesion and complete surgical resection are important to prognosis.

SEVERE HYPERTENSION IN A YOUNG BOY WITH PARAGANGLIOMA OF THE ORGAN OF ZUCKERKANDL TREATED WITH THERMOABLATION

Objective: Paragangliomas are tumors of the paraganglia, chromaffin tissue complexes of the neuroendocrine system distributed along the paravertebral and para-aortic axes. A small number of these tumors arise from the organ of Zuckerkandl that is the smallest endocrine gland, composed by paraganglia. These organs are accessory tissues of the autonomic nervous system that undergo involution during childhood. By adulthood distinct microscopic groups of extra-adrenal chromaffin cells endure and have the potential to develop into tumors that are rare cases of secondary hypertension. Design and method: A 19-year-old professional footballer, since two years, developed severe symptomatic hypertension forcing him to stop all activities. During each episode he reported headache, sweating, tachycardia, blurred vision and paradoxycal hypotension. No drugs were effective to lower blood pressure. Laboratory hormonal assessment were discordant, with high daily urinary cathecolamines but daily adrenaline, noradrenaline and dopamine in range. We performed a CT scan and a MRI of the abdomen that showed a nodular lesion of 7 mm near the left crus of diaphragm, where the left superior mesenteric artery originates (Figure 1). An iodine-123-meta-iodobenzylguanidine scan revealed an abnormal radiotracer uptake in the region of the mass identified by CT.Results: A multidisciplinary team composed by cardiologist, anesthesiologists and interventional radiologist, previous a particular preoperative management, performed an innovative surgical technique consisting in a two-steps CT-guided percutaneous radiofrequency ablation of the mass (Figure 2), at 65 and 100 W of energy for 5 minutes, after appropriate hydrodissection of perilesional tissues. A small tissue sample was obtained and pathology found the tissue was suggestive of an organ of Zuckerkandl. Conclusions: This is absolutely the first case in literature, since exist only few cases of robot-assisted laparoscopic excision, laparoscopic resection or laparotomy. The patient recovered well from the operation and was eventually discharged in a stable state. He's no longer suffering from hypertension and he started playing football again. 24-hour ambulatory blood pressure monitoring, after 15 days from discharge, shows satisfying blood pressure values (Figure 3).

Pheochromocytoma as a reversible cause of cardiomyopathy: Analysis and review of the literature

ContextPheochromocytoma and paraganglioma are rare neuroendocrine tumors which overproduce catecholamines and arise from the adrenal gland or extra-adrenal chromaffin cells of the sympathetic and parasympathetic ganglia (1). Excessive catecholamine-induced stimulation of cardiac myocytes leads to damage which manifests in several forms ranging from Takotsubo to dilated cardiomyopathy. Diagnosis of pheochromocytoma-related cardiomyopathies is often delayed due to the atypical presentation associated with many cases. ObjectiveLimited data exists on the presentation and outcomes of the various forms of pheochromocytoma-induced cardiomyopathies. We performed a literature review to assess the association of pheochromocytoma and cardiomyopathy to aide in further understanding this clinical entity. Design163 cases from 150 articles published between 1991 and November 2016 were included from a PubMed search. ResultsThere were 163 occurrences of pheochromocytoma and cardiomyopathy (63 dilated cardiomyopathy, 38 Takotsubo cardiomyopathy, 30 inverted Takotsubo cardiomyopathy, 10 HOCM, 8 myocarditis, and 14 unspecified cardiomyopathy). Many patients lacked classic signs or symptoms of pheochromocytoma with hypertension as a presenting symptom in 65% and the triad of headache, palpitations, and diaphoresis only in 4%. Resection of the pheochromocytoma led to improvement of the cardiomyopathy in 96% while lack of resection was associated with death or cardiac transplantation in 44%. ConclusionPheochromocytoma should be considered in the evaluation of non-ischemic, non-valvular cardiomyopathy even in the absence of symptoms of catecholamine excess. Our study highlights the importance of early suspicion and diagnosis of pheochromocytoma in cases of idiopathic heart failure as early resection may prevent progression to irreversible myocardial remodeling and death.

Raynaud's Phenomenon: Revisiting a Rare Sign of Pheochromocytoma and Paraganglioma

Paraganglioma (PGL) are rare tumors arising from extra-adrenal chromaffin cells and occasionally secret catecholamines. The patient commonly presents with headache, palpitation, anxiety, diaphoresis, and episodic or sustained hypertension. Rarely patient can present with Raynaud's phenomenon. We present a case of adolescent girl who presented with isolated Raynaud's phenomenon as only manifestation of metastasis of PGL 3 years after undergoing surgical excision of normetanephrine secreting abdominal PGL.

Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations

Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.

Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway.

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

Ectopic Cushing's syndrome due to retroperitoneal ACTH-producing paragangliomas.

Extra-adrenal pheochromocytomas, or paragangliomas, are rare tumours that derive from extra-adrenal chromaffin cells. Cushing's syndrome (CS) caused by paragangliomas is extremely rare. We report a 53-year-old man with hypertension, diabetes, and symptoms of hypokalemia. Computer tomography (CT) revealed two retroperitoneal masses and bilateral adrenal hyperplasia. Together with the laboratory examinations, ectopic CS caused by multiple paragangliomas was highly suspected. The patient underwent resections of retroperitoneal tumours, left kidney, and left adrenal; postoperative histopathology confirmed two paragangliomas that were both positively stained for adrenocorticotropic hormone (ACTH). He got clinical and biochemical recoveries without any recurrent evidence at the nine-month followup.

Pheochromocytoma with Ventricular Tachycardia as the Presenting Symptom

To the Editor: Although the triad of palpitations, headaches, and sweating is generally recognized as the classic presentation for pheochromocytoma, we reported the case of a patient with pheochromocytoma who first presented with ventricular tachycardia (VT). This case shows the importance of a broad differential diagnosis when the clinical presentation is unusual. A 17-year-old woman presented with episodic palpitation and headaches during physical activities for 4 years. The symptoms resolved after 3–5 min of rest. Two days before admission, she was admitted to the emergency department with persistent palpitations and headaches, and the blood pressure (BP) was 180/90 mmHg. The admission echocardiography (ECG) revealed a sinus rate of 92 beats/min. There was no family or personal history of syncope, cardiac arrest, and sudden death. The physical examination was unremarkable. The admission and peak creatine kinase-MB was 153 U/L and 157 U/L, respectively. During follow-up, the patient presented with recurrent palpitation and headaches when sitting or standing. During these episodes the BP was 160–200/90–100 mmHg and the pulse rate was elevated at 148 beats/min. Cardiac monitoring showed VT with a heart rate (HR) of 150 beats/min [Figure 1a]. Three episodes of VT were recorded during persistent hypertension. The symptoms were relieved after maintaining a recumbent position for 1–2 min. The 24 h urinary catecholamines and urinary vanillylmandelic acid levels were elevated. Abdominal ultrasound revealed a right adrenal mass with a diameter of 6 cm which was confirmed on abdominal computed tomography [Figure 1b]. A pheochromocytoma was diagnosed. Figure 1 (a) Echocardiography showing ventricular tachycardia. (b) Contrast-enhanced computed tomography scan of the upper abdomen revealing a tumor of the right adrenal gland. The patient was hemodynamically stabilized in the supine position with the administration of phentolamine (a nonspecific α-adrenergic blocker) and metoprolol (a selective β-antagonist). A right adrenalectomy was performed, yielding a 6.0 cm nodule confirmed to be a pheochromocytoma by histology. The hypertension was controlled and no arrhythmias were documented during 12 months of follow-up. Pheochromocytoma is a catecholamine-producing tumor that originates from the adrenal medulla or extra-adrenal chromaffin cells. The main clinical manifestation of pheochromocytoma is paroxysmal or persistent hypertension, accompanied by arrhythmias, such as sinus tachycardia, paroxysmal supra VT, atrial fibrillation, or ventricular premature contractions. We have reported a rare case of pheochromocytoma with VT as the presenting symptom. Frequent episodes of VT are almost always preceded by vital sign fluctuation (elevated HR and BP). Paulin et al.[1] reported that the sudden release of catecholamine from the pheochromocytoma is associated with the mechanism underlying VT. Excessively elevated catecholamine levels could lead to abnormal myocardial electrical activity, such as over opening of ion channels, enhanced ion exchange pump function, thus causing extremely large amounts of sodium, potassium, and calcium ion flow through the membranes, resulting in intensive myocardial autorhythmicity, conductivity, and triggered activities. Furthermore, increased catecholamine levels can reduce the cardiac ventricular fibrillation threshold, predispose to ventricular fibrillation, lead to sudden death,[2] and contribute to abnormal repolarization, thus causing all types of rapid arrhythmia. Ceremuzynski et al.[3] have shown that plasma catecholamine concentrations are increased in dogs during acute myocardial ischemia and a relationship between the blood catecholamine concentration and the severity of ventricular arrhythmias. Cardiac abnormalities caused by pheochromocytoma includes myocarditis, acute myocardial infarction, transient left ventricular systolic dysfunction, and cardiomyopathy. Bravo et al.[4] reported that catecholamines cause myocardial necrosis, focal myofibrillar degeneration, and subsequent fibrous scar formation. Left ventricular systolic dysfunction may resemble stress-induced cardiomyopathy, also known as takotsubo cardiomyopathy and is reversible in patients with pheochromocytoma.[5] Moreover, long-term high catecholamine levels can lead to myocardial hypertrophy and heart failure. The presence of sustained VT can be treated with radio-frequency ablation but such treatment would not abolish the systemic arrhythmogenic mechanism and would not resolve the symptoms or prevented the potential onset of other tachyarrhythmias. This case illustrates the importance of a complete differential diagnosis when the clinical presentation is unusual. In a hypertensive patient with a typical presentation consisting of palpitations and headache, and an ECG demonstrates VT or other tachyarrhythmias, a pheochromocytoma should be included in the differential diagnosis. In addition, biochemical testing and imaging studies will guide the diagnosis and allow complete resolution of symptoms following resection of the pheochromocytoma. The preoperative use of phentolamine, a nonspecific α-adrenergic blocker has a theoretical pharmacologic basis. The β-blocker propranolol is used when tachycardia or catecholamine-induced arrhythmias are present and should only be started after α-blocker has been established to avoid life-threatening hypertension. In conclusion, this case shows that VT is an unusual and initial cardiovascular presenting symptom in patients with a pheochromocytoma. Pheochromocytoma must be considered in patients with frequent VT plus sudden changes in BP. Resection of chromaffin cell tumor will completely relieve the symptoms. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.