Paraganglioma: An Overview Matrix Fung QMH

Ms Lam, F/71 Admitted for right upper quadrant pain Hypertensive Frequent headache and palpitations for 3 years

MRI abdomen 1997 in mainland China: Bilateral adrenal tumour Resection done in China No follow up afterwards

USG USG detected 3.2x3.4x2.8cm mass posterior to inferior vena cava and pancreatic head ? Retrocaval LN

CT 3.5x5.6x6cm soft tissue mass with thin rim enhancing oval hypodense component; compressing on the IVC (patent)

MRI 4.8x4.8x2.2cm lesion in right adrenal and aortocaval region; several foci of early arterial bright enhancement ?what sequence is this

Times of Upper Limit of normal (x) 24 Hour Urine Times of Upper Limit of normal (x) Norepinephrine 1.5 Normetanephrine 3.8 Epinephrine 1.4 Metanephrine 2.9 Dopamine 1.3

MIBG I 131 SPECT scan : Focal increased uptake over RUQ on delayed 72 hours scan at the corresponding area Compatible with pheo

Laparotomy findings: Pathology: Previous right adrenalectomy Recurrent tumour at the previous excision site Tumour excised Pathology: Phaeochromocytoma

Paragangliomas Paraganglias Paraganglioma neuroendocrine organs developed from neural crests cells Homeostasis Eg. Adrenal medulla, carotid body, vagal and aortic paraganglia Paraganglioma Highly vascular tumours “ The only true indicator of malignant behavior is metastatic spread” IARC WHO Classification of Tumours 2004

Hereditary predisposition Pheochromocytomas: 57% vs Paraganglioma: 83% Latest WHO says pheo is only adrenal medulla; in other literatures, sometimes pheos also include extra-adrenal i.e. extra-adrenal pheochromocytoma All in all, pheo means sympathetic to be safe The majority of parasympathetic ganglia-derived paragangliomas are located in the neck and skull base along the branches of the glossopharyngeal and vagus nerves (figure 2). They arise most commonly from the carotid body, less commonly from jugulotympanic and vagal paraganglia, and rarely, from the laryngeal paraganglia M. Lefebvre et al. Curr Oncol 2014 Hereditary predisposition Pheochromocytomas: 57% vs Paraganglioma: 83% Laird et. al Langenbecks Arch Surg. 2012 

National Cancer Institute PDQ® 2015

Epidemiology M=F Incidence: 0.8 per 100,000 person per year Presents in the third to fifth decades of life Hereditary cases present ~10 years earlier than sporadic cases Phaeochromocytoma 0.1% to 1% of patients with hypertension the average age at diagnosis is 24.9 years in hereditary cases and 43.9 years in sporadic cases 60 people per year in HK if using this incidence rate Erikson et.al  Clin Endocrinol Metab. 2001 Kulke et.al J Clin Oncol 2006

The 10% Rule? Usual Sayings Current Evidence Bilateral/Multiple 10% 26% Familial 33% - 50% Extra-adrenal 15-20% Malignant 20% (extra-adrenal) 10% (pheo) Malignant: ref 9 of g&m Harrison: ref 122 of uptodate Others: ref 122,123 of uptodate Elder et.al J Surg Oncol 2005 Favier et.al J Med Sci 2012 Parenti et.al J Surg Oncol 2012

Presentation Paroxysms of: A mass Incidental, on imaging Hypertension, headache, perspiration, forceful palpitations, tremor, facial pallor Triggering events: physical stress, foods high in tyramine eg. Red wine, chocolate, cheese A mass Carotid body tumour Abdominal mass Incidental, on imaging Hereditary syndromes / Genetic predisposition

Risk factors Chronic hypoxia Genetics: 25% of apparently sporadic cases a component of an inherited syndrome Neumann et al. NEJM 2002 Eg. SDHx paraganglioma syndromes, VHL, NF1, MEN 2A and 2B Chronic hypoxia Living at high altitudes / Chronic obstructive lung disease Prevalence up to 1 in 10 in humans in high altitude areas Almost 1 in 2 in bovines Rodríguez et al. Head Neck 1998 NEJM – 25% apparatently sporadic cases have genetic mutation Other papers – one half to one third MOLECULAR PATHOGENESIS — The molecular pathogenesis of both sporadic and hereditary paraganglioma is incompletely understood, but there are some data to support the involvement of hypoxia–inducible factors (HIFs) in at least some cases, as indicated by the following observations: ●HIFs are transcription factors that activate several genes that promote adaptation and survival under hypoxic conditions; they control energy, iron metabolism, erythropoiesis, and development. ●VHL and SDHx mutations are linked by their ability to cause a so-called pseudohypoxic response by stabilizing HIFs under normoxic conditions (normally, hypoxia is the stimulus to increase cellular levels of HIFs) [76]. Hypoxia-inducible factor-1 alpha and 2 alpha (HIF-1 and HIF-2) are two of the major proteins regulated by VHL. Paragangliomas harboring mutations in VHL and SDHx genes are characterized by HIF stabilization, dysregulation, and overexpression [76-81]. Furthermore, microarray studies reveal that hereditary pheochromocytomas and paragangliomas cluster into two distinct groups based upon their transcription profile. Tumors with VHL mutations resemble those with mutations in any of the SDHx genes, and the transcription signature associated with the VHL/SDH cluster is associated with angiogenesis, hypoxia, and a reduced oxidative response, suggesting common molecular pathways in the development of these tumors [2,82-84]. In contrast, tumors associated with RET, NF1, or MAX mutations (the RET/NF1 cluster) display a signature of genes involved in translation initiation, protein synthesis, and kinase signaling. ●While dysregulated expression of HIF has been seen in patients with paragangliomas related to mutations in VHL and SDHx, mutations in the HIF gene itself have not been detected until recently when somatic gain of function mutations in the gene encoding the alpha subunit of HIF-2 were identified in four unrelated patients with early onset erythrocytosis, apparently sporadic multiple paragangliomas, and somatostatinoma (histologically documented in three of the four) [85]. The mutations, which were different in all four patients, resulted in HIF proteins with a longer half-life, which upregulated downstream genes, including erythropoietin, which led to polycythemia. This and other reports of somatic HIF-2 mutations in patients with sporadic pheochromocytomas and paragangliomas support the relevance of hypoxia-related mechanisms in the pathogenesis of these tumors [86-88]. ●A link between paragangliomas and hypoxia/HIF is consistent with the findings that persons exposed to chronic hypoxia due to dwelling at high altitude appear to have a higher prevalence of paraganglioma as compared to those living at sea level. (See 'Epidemiology' above.) These findings suggest a critical role for HIF or hypoxia in the development or growth of these tumors, although their precise role in tumor development remains uncertain.

Bora et al. Endocrine related cancer 2015

Diagnosis Biochemical Radiological Biopsy Plasma-free fractionated metanephrines (sensitivity 97-99%) 24hr urine catecholamines and metanephrines (specificity 98%) Radiological Anatomical: USG, CT, MRI Functional: I-MIBG, FDG PET Biopsy CONTRAINDICATED! Biopsy: unless the results of biochemical screening for catecholamine secretion are first negative or the patient is prepared with alpha-adrenergic blockade, because otherwise it can cause severe hypertension from catecholamine crisis. In general, it is reasonable to use measurement of plasma-free fractionated metanephrines for initial case detection, which is followed by 24-hour measurement of urine-fractionated metanephrines and catecholamines for confirmation. Test results can be difficult to interpret because of the possibility of false-positive results. False-positive results can be caused by any of the following:[20,25] Common medications (e.g., tricyclic antidepressants). Physical or emotional stress. Inappropriately low reference ranges based on normal laboratory data rather than clinical data sets.[27] Common foods (e.g., caffeine and bananas) that interfere with specific assays and medications. A mildly elevated catecholamine or metanephrine level is usually the result of assay interference caused by drugs or other factors. Patients with symptomatic pheochromocytoma almost always have increases in catecholamines or metanephrines two to three times higher than the upper limits of reference ranges.[20] Provocative testing (e.g., using glucagon) can be dangerous, adds no value to other current testing methods, and is not recommended.[28]

Trends in Endocrinology and Metabolism 1993 Example of dx algorithm Young et al. Trends in Endocrinology and Metabolism 1993

Anatomical Imaging A vascular tumour at characteristic locations On US, a carotid body tumor typically presents as a solid, well-defined, hypoechoic tumor with a splaying of the carotid bifurcation [165,166]. Duplex sonography typically indicates the mass to be hypervascular, although the absence of hypervascularity does not exclude the diagnosis [166]. The classic CT findings of a paraganglioma at any site include a homogeneous mass with unenhanced Hounsfield units in the 40 to 50 range [11]. There is intense enhancement following administration of intravenous contrast and delayed washout. Cystic changes, necrosis, and internal calcifications are commonly described [167]. CT is the best initial test for suspected jugulotympanic paraganglioma since it represents the best method to evaluate the extent of temporal bone destruction, which is used to classify tumors according to the Fisch classification, an important aspect of selecting the operative approach. (See 'Staging' above.) For skull base and neck paragangliomas, tumor location, displacement of major vessels, and patterns of involvement of invasion of surrounding structures may permit the distinction between carotid body and vagal or jugulotympanic paraganglioma Although CT is the test of choice for evaluation of bone involvement, gadolinium-enhanced MRI provides superior definition of the relationship of paragangliomas to adjacent vascular and skull base structures and is recommended in guidelines from the Endocrine Society [137] (image 3). MRI is also complementary to CT in patients with jugulotympanic paragangliomas for the detection of dural infiltration and intradural tumor growth, as well as to exclude other tumor entities arising in this area. MRI is also the initial imaging test of choice in children and pregnant women, as well as in those with an allergy to CT contrast dye [137]. On T1-weighted MRI, paragangliomas typically have a background tumor matrix of intermediate signal density, with scattered areas of signal void, reflecting high-flow blood vessels (image 3) [89]. On T2-weighted images, an intense hypervascular appearance is present with classic “salt and pepper” appearance in most lesions larger than 1.5 cm, reflecting signal voids intermixed with regions of focally intense signal intensity [89,173]. These MRI findings are not specific for paraganglioma and may be seen with other hypervascular tumors (eg, metastatic renal cell or thyroid carcinoma). However, the typical smooth contour, signal characteristics, and location of paraganglioma coupled with the history and physical examination should enable a correct diagnosis to be made.

Case courtesy of Dr Frank Gaillard, Radiopaedia.org, rID: 4627 Classical splaying of internal and externa(front)l and internal carotid artery of a carotid body tumour On imaging, paragangliomas are often seen as large, well-defined, lobulated mass lesions. Due to hypervascularity, avid contrast enhancement in solid portion is observed. On CT, paraganglioma is usually seen as a large lobular tumor with areas of hemorrhage and necrosis [Figure 16]. Signal voids (due to vascular structures) are seen in T1W images in paraganglioma. Highly hyperintense appearance in T2W images, called "lightbulb," is characteristic of a classic paraganglioma  Case courtesy of Dr Frank Gaillard, Radiopaedia.org, rID: 4627

Turker et al. J Clin Imaging Sci 2015 On imaging, paragangliomas are often seen as large, well-defined, lobulated mass lesions. Due to hypervascularity, avid contrast enhancement in solid portion is observed. On CT, paraganglioma is usually seen as a large lobular tumor with areas of hemorrhage and necrosis [Figure 16]. Signal voids (due to vascular structures) are seen in T1W images in paraganglioma. Highly hyperintense appearance in T2W images, called "lightbulb," is characteristic of a classic paraganglioma  Para-aortic region tumour with contrast enhancement in solid component and cetnral necrosis; tgt with a liver met; Turker et al. J Clin Imaging Sci 2015

Turker et al. J Clin Imaging Sci 2015 Photo a: classical t2w light bulb appearance Photo b: t1w post contrast showing avid contrast enhancement and signal void due to a vascular structure Turker et al. J Clin Imaging Sci 2015

Functional Imaging To look for synchronous tumours and metastases Surveillance in genetically predisposed patients MIBG: Resembles norepinephrine, taken up by paraganglioma Labelled with Iodine radio-isotope Can be used for radioablation as well FDG PET Overall sensitivity 74 – 100% In our view and that of the Endocrine Society [137], FDG-PET is preferred over MIBG to screen for and follow sites metastatic disease. At some institutions, SRS is preferred over MIBG and FDG-PET. (uptodate) PET is as specific yet more sensitive than MIBG ●MIBG – Metaiodobenzylguanidine (MIBG) is a compound resembling norepinephrine that is taken up by adrenergic tissue. A MIBG scan using Iodine-123-labeled MIBG (123I-MIBG) can detect tumors not detected by CT or MRI, or multiple tumors when CT or MRI is positive [143]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'MIBG and FDG-PET'.) For localization of a paraganglioma, 123I-MIBG imaging is associated with a higher false-negative rate (29 to 44 percent [10,144]) than it is for pheochromocytoma [11], but the test does offer a total-body survey, which can be helpful in diagnosing or localizing synchronous tumors or metastases. Another problem for skull base and neck paragangliomas is that 123I-MIBG is accumulated in the salivary glands, and this may interfere with proper diagnosis [145,146]. Finally, false-negative rates are high with dopamine-producing paragangliomas [49,75]. If I-123 is the utilized radiotracer, the patient’s thyroid gland uptake of 1-123 should be blocked with potassium iodide drops [11]. Some institutions (including that of one of the authors [WY]) perform MIBG scanning for all patients with a paraganglioma, while others prefer somatostatin receptor scintigraphy. ●Somatostatin receptor scintigraphy – Paragangliomas, like some other neuroendocrine tumors, have a high density of somatostatin type 2 receptors on their cell surface and can be imaged using SRS using In-111 pentetreotide (OctreoScan) [147-149]. One study evaluated preoperative SRS in 21 patients undergoing surgery for a presumed skull base and neck paraganglioma [147]. Scans were positive in 16 patients with paraganglioma and negative in three with other pathology. The overall test accuracy was 90 percent, and the sensitivity and specificity was 94 and 75 percent, respectively. ●PET scanning – PET imaging utilizes the tracer FDG to detect hypermetabolic tumor in patients with pheochromocytoma/paraganglioma with a high degree of sensitivity [150-152]. More recent studies show that FDG-PET is as specific as MIBG for detection of the primary tumor and metastases and more sensitive than 123I-MIBG and CT/MRI for detection of metastatic disease [150,152]. The utility of integrated FDG-PET/CT imaging as compared with 123I-MIBG and conventional cross sectional imaging with CT or MRI was directly addressed in a prospective study of 216 patients with suspected pheochromocytoma/paraganglioma, 60 of whom had nonmetastatic pheochromocytoma/paraganglioma, 95 had metastatic pheochromocytoma/paraganglioma, and 61 did not have pheochromocytoma/paraganglioma, after a detailed evaluation [150]. For the primary tumor, the sensitivity of PET/CT for nonmetastatic tumors was similar to that of 123I-MIBG but less than that of CT/MRI (77, 75, and 96 percent, respectively). Among the patients who had paraganglioma/pheochromocytoma ruled out, specificity was comparable (90, 92, and 90 percent, respectively). When the analysis was limited to 26 paragangliomas of the head and neck, PET/CT was more sensitive than 123I-MIBG (85 versus 52 percent). Among patients with metastatic disease, sensitivity was greater for PET/CT than for 123I-MIBG. (See 'Screening for synchronous and metastatic disease' below.) The approach to tumor localization varies between institutions. At some institutions, MIBG is the test of choice for tumor localization when the abdomen/pelvis CT is negative, or in a patient with a known paraganglioma to search for metachronous disease. However, FDG-PET is preferred for identifying and following sites of metastatic disease. At other sites, SRS is preferred over MIBG scanning and PET scanning. (See 'Screening for synchronous and metastatic disease' below.)

Fonte et al. Endocr Relat Cancer 2012 Better sensitivity for FDG PET! False negative MIBG scan! Especially in SDHB mutation people who have a high malignant rate Patient with bladder paraganglioma Multiple lymph node and liver met was seen on FDG PET! FDG PET is the gold! Fonte et al. Endocr Relat Cancer 2012

Management Adrenergic blockade and adequate pre/intra-operative volume expansion Loco-regional disease: Surgery eg. Laparoscopic adrenalectomy Radiotherapy (Head & Neck) Radiofrequency ablation Transarterial chemoembolization for liver metastases Preop angiography and embolization sometimes Control venous outflow first as they are vascular tumours Surgery is preferred for all tumours below the neck No data on adjuvant therapy Because pheochromocytomas are rare, a prospective randomized study comparing open with laparoscopic resection is unlikely. Open resection to avoid tumour spillage esp for large adrenal tumours >6cm An endoscopic approach is contraindicated for patients with large tumors, surgically unfavorable anatomy (eg, multiple small paragangliomas arising at the root of the small bowel mesentery), RFA: soft tissue, liver, bone mets can use RFA Stereotactic RT can be used RT does not shrink tumour size significantly, so if size is the symptomatic factor, surgery should always be the first line; but it can achieve 90-95% “cure” i.e. no change in size in benign disease

Management Distant metastases Genetic testing and counselling Surgery Radionuclide therapy with Iodine 131-MIBG Chemotherapy: Cyclophosphamide, Vincristine, Dacarbazine Targeted therapy: Sunitinib Genetic testing and counselling We suggest resection of both the primary and metastatic lesions, if possible (Grade 2C). Even if complete eradication is not achievable, a cytoreductive incomplete resection can improve symptoms, reduce hormone secretion, prevent complications related to tumor in a critical anatomic location, and improve the response to subsequent therapies. However, there is no evidence that surgical debulking prolongs survival in patients with metastatic disease. (See 'Resection' above.) MIBG — The diagnostic and therapeutic value of MIBG is based upon its structural similarity with noradrenaline and a high affinity to, and uptake in, chromaffin cells. Radioactive iodine (I131) is attached to the MIBG molecule to produce 131I-MIBG, which functions as a semi-selective agent for malignant pheochromocytoma/paraganglioma. This treatment only works for the approximately 60 percent of tumors that take up MIBG as determined by 123I-MIBG scintigraphy [52,53]. A lower fraction of dopamine-secreting paragangliomas take up 123I-MIBG [54-56]. External beam RT abolishes the ability of these tumors to take up MIBG, making 131I-MIBG treatment ineffective in any irradiated site [8]. For patients with metastatic disease whose tumors secrete catecholamines and take up MIBG, the therapeutic value of 131I- MIBG to achieve symptom palliation and tumor regression or stabilization has been shown in many small case series [8,19,36,57-64]. Objective response rates are approximately 30 percent, and another 40 percent of tumors remain stable; less than 5 percent have a complete remission. Hormonal response (ie, decrease in catecholamine secretion) is reported in 45 to 67 percent of cases [19,60,61]. In general, better objective responses are achieved in patients with limited disease and in those with soft tissue rather than bone metastases [19]. 131I-MIBG treatment can be repeated, usually at six-month intervals [36]. The optimal dosimetry is not established. Most of the published reports have used single therapy doses between 100 to 200 mCi, with cumulative doses ranging from 557 to 2322 mCi and averaging 400 and 600 mCi [8,19,36,57,58,60-62]. At these doses, treatment is generally well tolerated with the main side effects being transient mild leukopenia and thrombocytopenia. Hypothyroidism was reported in 3 of 28 patients receiving cumulative doses of 111-916 mCi in one series [61], and in 2 of 10 patients in a second report (average cumulative dose 310 mCi) [63]. There is some evidence that higher-dose regimens (single doses 500 to 800 mCi) can result in sustained complete response in a small number of patients, albeit with a higher risk of potentially serious side effects [59,65]: Treatment with 131I-MIBG should be considered in patients with good uptake of 123I-MIBG by dosimetry who fall into one of the following categories: ●  Unresectable progressive pheochromocytoma/paraganglioma ●  Symptoms from disease that is not amenable to locoregional methods of control ●  A high tumor burden and a low number of bone metastases For patients with rapidly progressive tumors or bone-predominant extensive disease, chemotherapy is a preferred option even if 123I-MIBG scintigraphy is positive [4]. Cheno:Systemic chemotherapy should be considered for patients with unresectable and rapidly progressive pheochromocytoma/paraganglioma and patients with high tumor burden or a large number of bone metastases. Under investigation An early trial of CVD (cyclophosphamide [750 mg/m2 on day 1], vincristine [1.4 mg/m2 on day 1], and dacarbazine [600 mg/m2 on days 1 and 2] of each 21- to 28-day cycle) reported high response rates and symptomatic improvement with this regimen in 14 patients [89]. Details of the regimen and long-term outcomes (median follow-up 22 years) in this cohort, as well as four others who met the original eligibility criteria for the trial, were described in a later report [87]. Overall, 10 of 18 patients (56 percent) had a complete or partial objective response to therapy, and three others had a "minor response" [87]. Biochemical responses were seen in 13 (72 percent). Patients whose tumors were scored as complete or partial response received a mean of 27.4 cycles of CVD (median of 23 cycles). The median duration of response was 20 months (range 7 to 126 months), and the median survival for all patients was 3.3 years from the start of chemotherapy [87]. Treatment was well tolerated, with the most prominent side effects being "mild" myelosuppression, peripheral neuropathy, and gastrointestinal toxicity [89]. Targeted therapy: sunitinib, pazopanib, everolimus (mTOR inhibitor) Under inviestiation Because pheochromocytomas are rare, a prospective randomized study comparing open with laparoscopic resection is unlikely. Open resection to avoid tumour spillage MIBG ablation is the only way for metastatic disease; no effective chemo so far

Alexandra et al. Endocrine-Related Cancer 2007

Genetics “Genetic testing should be considered in each patient” Endocrine Society Clinical Practice Guideline 2014 Reasons: Germ-line mutations common SDHB mutations  40% metastatic disease Young, multiple, bilateral, family history, malignant disease 14 genes identified 11 genes of clinical use (the other 3 not confirmed by other studies – probably extremely rare) Considered =/= done Features suggestive of germline mutation: Lefebvre et al. Curr Oncol 2014

Succinate dehydrogenase (SDH) A mitochondrial enzyme with 4 subunits coded by 4 genes: SDHA,SDHB,SDHC,SDHD SDHAF gene – for flavination of the SDHA subunit Mutation Paraganglioma syndromes (PGL) SDHD mutation  PGL1 SDHB mutation  PGL4 The two most common genetic mutations

Characteristic Phenotype Mutation Characteristic Phenotype SDHD / PGL1 Dutch, skull base/neck SDHB / PGL4 Abdomen/pelvis/thorax, metastases, renal cell carcinoma RET/ MEN2 Medullary thyroid cancer, parathyroid hyperplasia NF1 / Neurofibromatosis 1 Neurofibromas, café au lait spots etc. VHL / von Hipplel-Lindau disease Cerebellar/spinal haemangioblastoma, retinal angiomas, clear cell RCC, pancreatic neuroendocrine tumours Carney-Stratakis dyad — The Carney-Stratakis dyad is an autosomal dominant disorder with incomplete penetrance [61]. It is characterized by the dyad of gastrointestinal stromal tumors (GISTs) and paragangliomas (sympathetic or parasympathetic, 73 percent multiple), which are not associated with mutations in KIT or the platelet-derived growth factor receptor alpha, but in many are attributed to germline mutations of SDHB, SDHC, or SDHD ALL AUTOSOMAL DOMINANT

Endocrine Society Clinical Practice Guideline 2014 One of the algorithm No definite gold standard Endocrine Society Clinical Practice Guideline 2014

Laruen et.al Ann Surg Oncol. 2013

Lefebvre et al. Curr Oncol 2014

Mariam et al. Eur J of Endocrinology 2012 Different screening algorithms Mariam et al. Eur J of Endocrinology 2012

“All mutation carriers should receive consideration for annual biochemical surveillance for PPGLs” Endocrine Society Clinical Practice Guideline 2014 Periodic Imaging No need biochemical surveillance for NF1 due to low penetrance No guideline / RCT done as to how surveillance should be done Eg. SDHB should be careful and do more frequent surveillance!

M. Lefebvre et al. Current Oncol 2014

Prognosis Local (Benign) Disease Metastatic (Malignant) Disease Life expectancy not compromised if excised 5 year recurrence 14-33% Metastatic (Malignant) Disease Highly variable Reported 5 year survival 12 – 84% Amar et al. J Clin Endocrinol Metab 2005 Reported recurrences in 20 years Recurrence more common for extra-adrenal tumours Ayala-Ramirez et al. Cancer 2012

Paragangliomas Diagnostics Alpha and beta blockade before investigation/intervention Surgery if possible Systemic therapies under investigation Genetic testing and counselling

Thank you!

References Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations Endocrine-Related Cancer (2015) 22, T71–T82 Beard CM, Sheps SG, Kurland LT, Carney JA, Lie J. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58(12):802. Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, van Heerden JA, Young WF Jr. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab. 2001;86(11):5210. Laird AM, Gauger PG, Doherty GM, Miller BS. Paraganglioma: not just an extra-adrenal pheochromocytoma. Langenbecks Arch Surg. 2012 Feb;397(2):247-53. Epub 2011 Nov 17. Timmers HJ, Kozupa A, Chen CC, et al. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol 2007; 25:2262. Timmers HJ, Chen CC, Carrasquillo JA, et al. Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. J Natl Cancer Inst 2012; 104:700. Parenti G, Zampetti B, Rapizzi E, et al. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. J Oncol 2012; 2012:872713. Elder EE, Elder G, Larsson C. Pheochromocytoma and functional paraganglioma syndrome: no longer the 10% tumor. J Surg Oncol 2005; 89:193. F. Grunwald, S. Ezziddinc131I-Metaiodobenzylguanidine therapy of neuroblastoma dn other neuroendocrine tumors Semin Nucl Med, 40 (2010), pp. 153–163 Amar L, Servais A, Gimenez-Roqueplo AP, et al. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005; 90:2110. .

Suárez C, Rodrigo JP, Bödeker CC, et al Suárez C, Rodrigo JP, Bödeker CC, et al. Jugular and vagal paragangliomas: Systematic study of management with surgery and radiotherapy. Head Neck 2013; 35:1195. Alexandra Chrisoulidou, Gregory Kaltsas, Ioannis Ilias, Ashley B Grossman The diagnosis and management of malignant phaeochromocytoma and paraganglioma. Endocrine-Related Cancer (2007) 14 569–585 Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer 2012; 118:2804

Special Case 1. Bilateral CBT Surgery for the smaller side Surgery for the other side only if vagus and hypoglossal nerves of the previous side functional RT for the other side if these nerves injured

Special Case 2: Bilateral vagal body paraganglioma Surgery for one side RT for the other side Bilateral vagus nerve paralysis can be fatal

Predictors of Recurrence Genetics Large tumour >5cm Multiple tumours Biochemical profile is not related

What happened to our patient? Re-admitted for congestive heart failure symptoms Hypertensive Perspiration

What happened to our patient? 24 Hour Urine Times of Upper Limit of normal (x) Norepinephrine 1.6 Normetanephrine 4.0 Epinephrine 1.2 Metanephrine 1.9 Dopamine 1.0

MIBG Radioablation The main goal of MIBG is palliation, with a symptom response rate of 75–90% and a tumor response rate of 30–47%. F. Grunwald, S. Ezziddinc131I-Metaiodobenzylguanidine therapy of neuroblastoma dn other neuroendocrine tumors Semin Nucl Med, 40 (2010), pp. 153–163

Radiotherapy Durable disease control can be achieved in >90 to 95% However, tumors do not often regress in size. Lower cranial nerve deficits rate than resection Suárez C Head Neck 2013

Chemotherapy Cyclophosphamide, Vincristine, Dacarbazine Hormonal response rates of 50–100%, but with minimal tumoural responses (Kaltsas et al. 2004) Novel therapies: Temozolomide and thalidomide achieved a 40% biochemical and a 33% radiological response in patients with malignant chromaffin-cell tumours. (Kulke et al. 2006) Cyclophosphamide: alkylating agent, inhibits DNA replication Vincristine: Vinca alkaloid, inhibit mitosis by interfering with chromosome separation Dacarbazine: alkylating agent