1. Paraganglioma: An Overview
Matrix Fung
QMH

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

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

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

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

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

9. 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

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

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

12. 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

13. 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 

14. National Cancer Institute PDQ® 2015

15. 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

16. 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

17. 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

18. 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.

19. Bora et al. Endocrine related cancer 2015

20. 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]

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

22. 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.

23. 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

24. 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

25. 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

26. 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 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) [ ]. 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 [ ]. 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.)

27. 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

28. 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

29. 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 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

30. Alexandra et al. Endocrine-Related Cancer 2007

31. 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

32. 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

33. 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

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

35. Laruen et.al Ann Surg Oncol. 2013

36. Lefebvre et al. Curr Oncol 2014

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

38. “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!

39. M. Lefebvre et al. Current Oncol 2014

40. 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

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

42. Thank you!

43. 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, through 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 ;86(11):5210.
Laird AM, Gauger PG, Doherty GM, Miller BS. Paraganglioma: not just an extra-adrenal pheochromocytoma. Langenbecks Arch Surg Feb;397(2): 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:
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:

44. 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) –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

45. 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

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

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

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

49. 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

50. 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

51. 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

52. 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