Chromaffin Cell Tumors Research Articles

A clinicopathological study of pheochromocytoma and paraganglioma with review of literature

Background and Aim: Pheochromocytoma and paraganglioma (PPGL) are rare chromaffin cell tumors with variable clinical presentation which are derived from neural crest cells. Pheochromocytomas arising from the adrenal glands are sympathetic, and the paragangliomas arising from extra-adrenal sites are either sympathetic or parasympathetic in origin. These tumors usually come to clinical attention due to the catecholamine secretion or maybe detected as incidentalomas while imaging for unrelated symptoms. Our objective is to study the histopathological and histochemical features of PPGL with clinical correlation. Materials and Methods: PPGLs arising from both sympathetic and parasympathetic nervous systems were retrospectively selected from the records for 5 years, and clinical details were obtained. Routine hematoxylin and eosin (H and E) stain and argentaffin and argyrophilic reactions were employed. Immunohistochemistry for chromogranin was done for cases with doubtful histomorphology in H and E sections. Results: Our study material consisted of 10 cases out of which five cases were adrenal pheochromocytomas; 4, carotid body tumors; and 1, paraganglioma of the organ of Zuckerkandl. Three pheochromocytomas out of five and the paraganglioma of organ of Zuckerkandl were functional and clinically presented with palpitation and hypertension. All the carotid body tumors and two of the pheochromocytomas were nonfunctional. The 24 h urinary levels of vanillylmandelic acid was increased in two cases, and urinary fractionated metanephrine levels was increased in one case of pheochromocytoma. Urinary normetanephrine alone increased in paraganglioma of organ of Zuckerkandl. All pheochromocytomas except one were positive for argentaffin reaction, and all paragangliomas at other sites were positive for argyrophilic reaction. Chromogranin immunohistochemistry stain was done for organ of Zuckerkandl lesion which came out to be positive. Conclusion: Proper clinical evaluation, preoperative preparation, and appropriate early surgical treatment can cure the lesion. Preoperative diagnosis, if not done and if there is a delay in the treatment, will lead to complications such as intraoperative hypertensive attack, persistent hypertension even after removal of the tumor, and progression to malignancy.

P3-21: High prevalence of cardiac electric abnormalities in patients with pheochromocytomas and secreting paragangliomas

Background Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumours of chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. Besides hypertension, they can be at the origin of a wide range of cardiovascular manifestations, including cardiac electric abnormalities such as long QT interval, ventricular tachycardia and torsades de pointe. However, knowledge about PPGL-related arrhythmias is scarce and mostly derived from case reports. The aim of our study was to evaluate the prevalence, nature and reversibility of cardiac electric changes and arrhythmias in patients with PPGLs. Methods We retrospectively reviewed the medical records of patients diagnosed with PPGLs at the Cliniques Universitaires Saint-Luc (Brussels) from 1995 to 2015. All patients with secreting PPGLs in whom an electrocardiogram (ECG) was available at the time of diagnosis were eligible. Results Forty-five patients with secreting PPGLs were identified. The mean age at diagnosis was 48 years (12-72), 40% of patients (n=18) were males and location of the tumour was adrenal in 87% of cases (n=39). An ECG was available in 31 patients at the time of diagnosis. Of these, 77% (n=24) presented at least one electric abnormality. While a positive Sokolow index was found in only 3 patients, non-specific ST-abnormalities were documented in 14 patients (45%), a T-wave inversion in at least two precordial leads in 9 (29%) and a predominant U- wave in 7 patients (23%) Furthermore, a corrected QT interval prolongation (>450ms) was present in 55% of patients (n=17, mean: 528ms±93ms). In all nine patients with QTc prolongation at diagnosis in whom a follow-up ECG was available, QTc normalized after surgery (QTc.: 420±20ms after surgery vs. 523±50ms at baseline, p 600ms), two patients presented with polymorphic ventricular tachycardia related to a long QT interval at diagnosis that never recurred after surgery, and one patient was diagnosed with paroxystic atrial fibrillation, which resolved after tumour removal. Conclusions We report a high prevalence (77%) of cardiac electric abnormalities in a retrospective monocentric series of PPGLs. While our findings need confirmation in larger, prospective cohorts, they strongly suggest that cardiac electric abnormalities are an underrecognized, frequent complication of catecholamine excess in patients with PPGLs, and should be an integral part of the work-up and management of these patients.

Semiquantitative 123I-Metaiodobenzylguanidine Scintigraphy to Distinguish Pheochromocytoma and Paraganglioma from Physiologic Adrenal Uptake and Its Correlation with Genotype-Dependent Expression of Catecholamine Transporters.

(123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy plays an important role in the diagnostic evaluation of patients with pheochromocytoma and paraganglioma (PPGL). (123)I-MIBG targets cell membrane and vesicular catecholamine transporters of chromaffin cells and facilitates localization of the primary tumor and metastatic lesions. Its specificity for the diagnosis of adrenomedullary chromaffin cell tumors can be jeopardized by physiologic uptake by the normal adrenal medulla. The aim of this study was to distinguish between PPGLs and normal adrenal glands by evaluating semiquantitative (123)I-MIBG uptake and to examine genotype-specific differences in correlation with expression of catecholamine transporter systems. Sixty-two PPGLs collected from 57 patients with hereditary mutations in SDHA (n = 1), SDHB (n = 2), and SDHD (n = 4) (SDH is succinate dehydrogenase); von Hippel-Lindau (VHL; n = 2); RET (n = 12); neurofibromin 1 (NF1; n = 2); and MYC-associated factor X (MAX; n = 1), and with sporadic PPGLs (n = 33) were investigated. Preoperative planar and SPECT images were semiquantitatively analyzed using uptake measurements. Tumor-to-liver and normal adrenal-to-liver ratios were calculated and correlated with clinical characteristics including genotype, tumor size, and plasma metanephrines concentrations. The expression of norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT-1) was evaluated immunohistochemically in paraffin-embedded tumor tissues. Mean tumor-to-liver ratios of PPGL lesions were significantly higher than normal adrenal-to-liver ratios (P < 0.001). Cutoff values to distinguish between physiologic and pathologic adrenal uptake were established at 0.7 (100% sensitivity, 10.3% specificity) and 4.3 (100% specificity, 66.1% sensitivity). No statistically significant differences in (123)I-MIBG uptake were found across PPGLs of different genotypes. Mean NET expression in hereditary cluster 2 (RET, NF1, MAX) and apparently sporadic tumors was significantly higher than for hereditary cluster 1 (SDHx, VHL) PPGLs (P = 0.011 and 0.006, respectively). Mean VMAT-1 expression in hereditary cluster 1 PPGLs was significantly higher than for cluster 2 tumors (P = 0.010). (123)I-MIBG uptake significantly correlated with maximum tumor diameter (P = 0.002). (123)I-MIBG uptake, however, did not correlate with either NET or VMAT-1 expression. Liver-normalized semiquantitative (123)I-MIBG uptake may be helpful to distinguish between pheochromocytoma and physiologic adrenal uptake. Genotype-specific differences in the expression of NET and VMAT-1 do not translate into differences in (123)I-MIBG uptake.

Succinate Dehydrogenase Gene Mutations in Cardiac Paragangliomas

Pheochromocytomas and paragangliomas are chromaffin cell tumors arising from neuroendocrine cells. At least 1/3 of paragangliomas are related to germline mutations in 1 of 17 genes. Although these tumors can occur throughout the body, cardiac paragangliomas are very rare, accounting for <0.3% of mediastinal tumors. The purpose of this study was to determine the clinical characteristics of patients with cardiac paragangliomas, particularly focusing on their genetic backgrounds. A retrospective chart analysis of 15 patients with cardiac paragangliomas was performed to determine clinical presentation, genetic background, diagnostic workup, and outcomes. The average age at diagnosis was 41.9years. Typical symptoms of paraganglioma (e.g., hypertension, sweating, palpitations, headache) were reported at initial presentation in 13 patients (86.7%); the remaining 2, as well as 4 symptomatic patients, initially presented with cardiac-specific symptoms (e.g., chest pain, dyspnea). Genetic testing was done in 13 patients (86.7%); 10 (76.9%) were positive for mutations in succinate dehydrogenase (SDHx) subunits B, C, or D. Thirteen patients (86.7%) underwent surgery to remove the paraganglioma with no intraoperative morbidity or mortality; 1 additional patient underwent surgical resection but experienced intraoperative complications after removal of the tumor due to co-morbidities and did not survive. SDHx mutations are known to be associated with mediastinal locations and malignant behavior of paragangliomas. In this report, the investigators extend the locations of predominantly SDHx-related paragangliomas to cardiac tumors. In conclusion, cardiac paragangliomas are frequently associated with underlying SDHx germline mutations, suggesting a need for genetic testing of all patients with this rare tumor.

A review of the management of positive biochemical screening for phaeochromocytoma and paraganglioma: a salutary tale.

Phaeochromocytomas (PC) and paragangliomas (PGL) are rare neuroendocrine tumours of chromaffin cells. Diagnosis depends on biochemical evidence of excessive production of catecholamines. This is straightforward when test results are orders of magnitude above the concentrations expected in healthy individuals and those with essential hypertension. Equivocal results pose a management dilemma. We reviewed biochemical screens that were positive and the ensuing management for PC/PGL at our institution. The objective was to inform the development of a standardised approach to investigation and clinical follow-up. All records of positive biochemical screening for PC/PGL were extracted from the laboratory information system between January 2004 and June 2012. Clinical notes of patients with positive results were reviewed. A total of 2749 biochemical screens were performed during the evaluation period. Of these, 106 (3.9%) performed on 82 patients were positive. Chart review determined that 12/82 patients had histologically confirmed PC/PG. Of the 70 patients remaining, the most common indication for biochemical screening was hypertension and the medical subspecialty most frequently requesting the test was Endocrinology. The primary team carried out repeat testing on 35/70 (50%) patients and in 29 results normalised. Notably, 35/70 (50%) patients did not have any follow-up of positive test results. This study highlights the necessity for a standardised diagnostic protocol for PC/PGL. We suggest that appropriate follow-up of borderline-elevated results should first include repeat biochemical testing. This should be performed under standardised pre-analytical conditions and where possible off all potentially interfering medications, measuring plasma free metadrenalines.

A 'giant' paraganglioma in the testis.

SummaryUntil now, less than ten cases of extra-adrenal chromaffin cell tumors have been reported to be localized to the spermatic cord area. All published studies report benign tumors with a diameter <2–3 cm and no invasion of the testis. In this article, we present one case of a giant malignant paraganglioma in the testis of a patient who had initially been operated for a giant mass in the scrotum. The mass developed in approximately 4 months. This is the first study reporting the following findings: i) paraganglioma was found exclusively in the testis, invading the testicle and not the spermatic cord, ii) it was malignant with lung metastasis, and iii) its size was 17.5 cm×10 cm×9.5 cm. We present the first – giant – malignant paraganglioma. Moreover, it is the first case report of a paraganglioma in the testis.Learning points This is the first study reporting the following findings:Paraganglioma found exclusively in the testis, invading the testicle and not the spermatic cord.It is malignant with lung metastasis.It is of the size 17.5 cm×10 cm×9.5 cm.

A paraganglioma presenting with a giant mediastinal mass: A case report

Paragangliomas are considerably rare and usually benign chromaffin cell tumors originating from sympathetic ganglia outside adrenal medulla. They are usually asymptomatic and detected incidentally. Tumor spread is through both lymphatic and hematogenous route. However, they may cause symptoms when excessively grown. They can be successfully treated with surgery even if they reach a gigantic size when they are diagnosed at an early period and lack metastases. From this perspective, early diagnosis and treatment of them is of great importance. In this study we present a patient presenting to emergency department with dyspnea and diagnosed with a giant paraganglioma in the anterior mediastinum.

In vivo fluorescence imaging and urinary monoamines as surrogate biomarkers of disease progression in a mouse model of pheochromocytoma.

Pheochromocytoma (PHEO) is a rare but potentially lethal neuroendocrine tumor arising from catecholamine-producing chromaffin cells. Especially for metastatic PHEO, the availability of animal models is essential for developing novel therapies. For evaluating therapeutic outcome in rodent PHEO models, reliable quantification of multiple organ lesions depends on dedicated small-animal in vivo imaging, which is still challenging and only available at specialized research facilities. Here, we investigated whether whole-body fluorescence imaging and monitoring of urinary free monoamines provide suitable parameters for measuring tumor progression in a murine allograft model of PHEO. We generated an mCherry-expressing mouse PHEO cell line by lentiviral gene transfer. These cells were injected subcutaneously into nude mice to perform whole-body fluorescence imaging of tumor development. Urinary free monoamines were measured by liquid chromatography with tandem mass spectrometry. Tumor fluorescence intensity and urinary outputs of monoamines showed tumor growth-dependent increases (P < .001) over the 30 days of monitoring post-tumor engraftment. Concomitantly, systolic blood pressure was increased significantly during tumor growth. Tumor volume correlated significantly (P < .001) and strongly with tumor fluorescence intensity (rs = 0.946), and urinary outputs of dopamine (rs = 0.952), methoxytyramine (rs = 0.947), norepinephrine (rs = 0.756), and normetanephrine (rs = 0.949). Dopamine and methoxytyramine outputs allowed for detection of lesions at diameters below 2.3 mm. Our results demonstrate that mouse pheochromocytoma (MPC)-mCherry cell tumors are functionally similar to human PHEO. Both tumor fluorescence intensity and urinary outputs of free monoamines provide precise parameters of tumor progression in this sc mouse model of PHEO. This animal model will allow for testing new treatment strategies for chromaffin cell tumors.

A new approach to the treatment of metastatic paraganglioma: sorafenib.

Paragangliomas are relatively rare chromaffin cell tumors which may be cured through resection. Patients with paragangliomas may develop metastatic diseases. There is no consensus regarding refractory chemotherapy for treatment of metastatic disease. In this report, we presented a case of a 43-year-old woman who was admitted to the hospital with a history of episodic headaches, diaphoresis, and weakness. Elevated plasma catecholamine levels and a right paraaortic mass were observed on computed tomography. The mass was excised, and a diagnosis of paraganglioma was confirmed. After 20 months of follow-up, local recurrence and metastases were detected in the thorax, abdomen, and skeletal system. Plasma and urinary catecholamine levels were high. Chemotherapy was administered, and no improvement was observed. Therefore, following this palliative conventional chemotherapy, sorafenib was administered for three months, and, finally, positron emission tomography showed that the patient’s lesions had completely regressed.

Should every patient diagnosed with a phaeochromocytoma have a ¹²³ I-MIBG scintigraphy?

Localization of phaeochromocytomas and paragangliomas (PPGLs) should involve functional imaging as anatomical imaging modalities can either fail to locate the tumour or can be suboptimal due to an anatomical abnormality or previous surgery. Functional imaging is particularly useful to fully delineate the extent of disease using the whole-body scan and the evaluation of multifocality, metastatic or recurrent disease. An increasing number of radiolabeled tracers have become available for tumour visualization during the past decade. (123) I-meta-iodobenzylguanidine scintigraphy is the most widely used functional imaging modality, and its sensitivity to identify chromaffin cell tumours varies from 85 to 88% for phaeochromocytomas and 56-76% for paragangliomas, while specificity ranges between 70 and 100% and 84-100%, respectively.

Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC‐associated factor X

Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.

Succinate Dehydrogenase Subunit D and Succinate Dehydrogenase Subunit B Mutation Analysis in Canine Phaeochromocytoma and Paraganglioma

Phaeochromocytomas (PCs) are tumours of the adrenal medulla chromaffin cells. Paragangliomas (PGLs) arise in sympathetic ganglia (previously called extra-adrenal PCs) or in non-chromaffin parasympathetic ganglia cells that are usually non-secretory. Parenchymal cells from these tumours have a common embryological origin from neural crest ectoderm. Several case series of canine PCs and PGLs have been published and a link between the increased incidence of chemoreceptor neoplasia in brachycephalic dog breeds and chronic hypoxia has been postulated. A similar link to hypoxia in man led to the identification of germline heterozygous mutations in the gene encoding succinate dehydrogenase subunit D (SDHD) and subsequently SDHA, SDHB and SDHC in similar tumours. We investigated canine PCs (n=6) and PGLs (n=2) for SDHD and SDHB mutations and in one PGL found a somatic SDHD mutation c.365A>G (p.Lys122Arg) in exon 4, which was not present in normal tissue from this brachycephalic dog. Two PCs were heterozygous for both c.365A>G (p.Lys122Arg) mutation and an exon 3 silent variant c.291G>A. We also identified the heterozygous SDHB exon 2 mutation c.113G>A (p.Arg38Gln) in a PC. These results illustrate that genetic mutations may underlie tumourigenesis in canine PCs and PGLs. The spontaneous nature of these canine diseases and possible association of PGLs with hypoxia in brachycephalic breeds may make them an attractive model for studying the corresponding human tumours.

Evaluation of a novel fluorescence-based animal model of pheochromocytoma for theragnostic investigations

Pheochromocytoma (PHEO) are potentially lethal tumors of adrenal and extra-adrenal chromaffin cells. Available treatment strategies for malignant PHEO are limited. Interestingly, peptide hormone receptors are frequently overexpressed on PHEO and can be used as specific targets for highly effective cytotoxic and radiolabeled anti-tumor peptide analogs. Here, we focused on the establishment and characterization of a novel preclinical fluorescence-based mouse model of PHEO in order to evaluate combined therapies of malignant pheochromocytoma. In previous in vitro studies we demonstrated strong anti-tumor effects of various peptide analogs specifically targeting SSTR2 and LHRH-R in mouse pheochromocytoma cell lines. These neuropeptide receptors were found to be abundantly expressed also on human PHEO samples studied. Furthermore, we examined the expression of these receptors as potential anti-tumor targets in vivo and ex vivo. To this end we established a subcutaneous mouse model of PHEO based on the injection of mCherry-expressing MPCs into the shoulders of athymic nude mice. Tumor development was followed by multimodal in vivo imaging, including fluorescence, PET, CT and MRI. Additionally, we analyzed urinary catecholamines by recently established LC-MS/MS. Both the SSTR2 and LHRH-R are still abundantly expressed in the tumors and could thus be used as therapeutic targets in ongoing pre-clinical studies. In summery, our current work resulted in the establishment of both an appropriate PHEO model system and methodology for our planned combined peptide receptor cytotoxic/radionuclide therapy studies.

Characterization and plasma measurement of the WE-14 peptide in patients with pheochromocytoma.

Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.

Succinate-to-Fumarate Ratio as a New Metabolic Marker to Detect the Presence of SDHB/D-related Paraganglioma: Initial Experimental and Ex Vivo Findings

Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs.

Concealed pheochromocytoma presenting as recurrent acute coronary syndrome with STEMI

Pheochromocytomas are rare, primarily benign tumors of chromaffin cells that secrete catecholamines. Although they are curable when diagnosed early, they can be fatal if undiagnosed or mistreated. Pheochromocytoma causing acute myocardial infarction has been reported as presenting with either unstable angina with EKG changes and/or non-ST elevation myocardial infarction (NSTEMI), but there have been no reported cases of pheochromocytoma presenting as acute ST segment elevation myocardial infarction (STEMI) in the setting of hyperthyroidism. Herein, we report a 44-year-old female patient with underlying pheochromocytoma who presented with multiple episodes of acute coronary syndrome (ACS) including an episode of STEMI in the setting of thyroid storm with no obstructive coronary artery disease (CAD).

Sequelae and survivorship in patients treated with 131I-MIBG therapy

Background:131I-meta-iodobenzylguanidine (131I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae.Methods:Fifty-eight patients with metastatic NETs and CCTs who had received 131I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated.Results:In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of 131I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of 131I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function.Conclusion:Long follow up of 131I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.

Phaeochromocytoma in Nepal – A Single Centre Experience

Phaeochromocytomas are rare tumors of chromaffin cells of neural crest that classically present with symptoms of catecholamine excess such as palpitations, headache and sweating. They are diagnosed by measuring plasma or urinary levels of catecholamines or their metabolites. Anatomic localization is done by computed tomographic scan or magnetic resonance imaging, or meta-iodobenzyl guanidine scan in certain cases. Adequate preoperative catecholamine blockade prevents perioperative hemodynamic instability. To study the clinical spectrum and management of phaeochromocytomas in a tertiary care centre, Tribhuvan University Teaching Hospital, in Nepal. Retrospective review of case records of histologically proven cases of phaeochromocytomas from 2008 -2011 was done, and data collected on clinical spectrum, diagnostic modalities, perioperative management and follow-up. Twelve cases of phaeochromocytomas were operated. The mean age was 36.41+/-14.07 years. There were 2 bilateral phaeochromocytomas and 1 extraadrenal paraganglioma. Apart from the common symptoms of catecholamine excess, patients had atypical presentations like psychiatric manifestations and blurred vision. A combination of urinary Vanillyl Mandelic Acid and computed tomographic scan was used for diagnosis, and open surgery was done in all cases. Pre-operative blood pressure control was achieved by prazocin or calcium channel blockers. Ten patients had intraoperative surge in blood pressure. There were no major morbidity or mortality. Three patients had high blood pressure postoperatively, but were effectively managed with antihypertensives. Phaeochromocytomas can have variable presentation. Good preoperative preparation and perioperative management can result in an excellent outcome.

Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.

A Not So Simple Retroperitoneal Mass-A Clue from Hypertensive Crisis

Extra adrenal paragangliomas are tumours of chromaffin cells arising from the sympathetic and parasympathetic divisions of the autonomic nervous system. About 75% of them are located between the origin of the inferior mesentric artery and bifurcation of the abdominal aorta known as the organ of Zuckerkandl.1Their clinical presentations are varied and are mostly due to the excessive secretion of catecholamines by the tumour. The incidence of the classic triad of Headache, Palpitations and Diaphoresis is seen in as little as 24% of cases. 2A recent review reports hypertension to be paroxysmal in 48%, persistent in 29% and absent in 13 % of cases. 2 About 49% of cases are incidentally diagnosed during abdominal imaging. 2 These tumours may be confused with other common retroperitoneal neoplasms, especially when the patient is asymptomatic. We report a severe hypertensive crisis in such an asymptomatic patient, which was triggered on induction of anesthesia and manipulation of the tumour and its successful management in a patient with undiagnosed paraganglioma.