P

O

RaL

(m

1

rogrès en urologie (2018) 28, 488—494

Disponible en ligne sur

ScienceDirectwww.sciencedirect.com

RIGINAL ARTICLE

etro-peritoneal paraganglioma, diagnosisnd managementes paragangliomes retro-peritoneaux : diagnostic et prise en charge

O. Karray ∗, A. Saadi, M. Chakroun, H. Ayed,M. Cherif, A. Bouzouita, M.R.B. Slama, A. Derouiche,M. Chebil

Urology department, Charles Nicolle hospital, Faculty of Medecine of Tunis, Tunis El ManarUniversity, Tunis, Tunisia

Received 17 December 2017; accepted 7 June 2018Available online 5 July 2018

KEYWORDSParaganglioma;Retroperitonealneoplasms;Anesthesia;Surgery

SummaryIntroduction. — Paragangliomas, defined as extra-adrenal chromaffin-cells tumors, are rarelylocated in the retro-peritoneum. Clinical presentation is similar to pheochromocytoma, andmainly depends on the producing character of the tumor. Positive diagnosis requires plasmaticand urinary hormonal assays. Radiological and isotopic explorations are essential before surgery.The only curative therapeutic strategy is surgical, associated to peri-operative prevention andmonitoring of the frequently reported hemodynamic and cardiovascular disorders. Outcomedepends of the metastatic character of the tumor, the presence of tumor remnant after surgi-cal resection. Genetic study is recommended; the risk of recurrence and association to otherneoplasm is more described in genetic forms.Material and methods. — Authors report 5 cases of retro-peritoneal paraganglioma, operatedin the department of urology of Hospital, between 2013 and 2017. Observations are about2 men and 3 women. Clinical presentation is not always specific and paraganglioma may bediscovered fortuitously. Two patients have been operated by coelioscopic approach, midline

incision was performed in two other cases, and dorsal lumbotomy associated to a Rutherford-Morrison incision in a patient.

∗ Corresponding author.E-mail addresses: omar.karray.88@gmail.com (O. Karray), dr.saadi.ahmed@gmail.com (A. Saadi), marouen chakroun82@yahoo.fr

M. Chakroun), ayed.haroun@yahoo.fr (H. Ayed), mejdacherif@yahoo.fr (M. Cherif), bouzouitabder@yahoo.fr (A. Bouzouita),.riadh.bslama@yahoo.fr (M.R.B. Slama), amine derouiche@yahoo.fr (A. Derouiche), chebil.mohamed@yahoo.fr (M. Chebil).

https://doi.org/10.1016/j.purol.2018.06.003166-7087/© 2018 Elsevier Masson SAS. All rights reserved.

Retro-peritoneal paraganglioma, diagnosis and management 489

Results Two patients presented resistant hypertension and palpitation associated to sus-pect retro-peritoneal masses in imagery and elevated urinary methoxylated derivates beforesurgery. One patient was asymptomatic and the tumor was discovered in imagery. Per-operativehypertensive crisis and sinus tachycardia occurred in a case. The average follow-up period is22.8 months. Hypertension and palpitation disappeared after surgery. There was no recurrencefor all the operated patients.Conclusion. — Retro-peritoneal paraganglioma is a rare condition. Symptoms are not specificand clinical presentation may be similar to pheochromocytoma. Abdominal CT-scan and MRI,in association with MIBG scintigraphy are strongly evocative. Histological examination ensuresdiagnosis. Per-operative cardio-vascular disorders are to consider and must prevented and man-aged by anesthesiologists. Complete surgical resection is the only curative treatment and avoidsrecurrences.© 2018 Elsevier Masson SAS. All rights reserved.

MOTS CLÉSParagangliomes ;Tumeursretro-péritonéales ;Anesthésie ;Chirurgie.

RésuméIntroduction. — Les paragangliomes, définis par des tumeurs à cellules chromaffines extra-surrénaliennes, sont rarement localisées dans le rétro-péritoine. La présentation clinique estsimilaire au phéochromocytome, et dépend essentiellement de la sécrétion hormonale dela tumeur. Le diagnostic positif nécessite des dosages hormonaux plasmatiques et urinaires.L’imagerie et les explorations isotopiques sont essentielles avant la chirurgie. La chirurgie estla seule option thérapeutique curative. Elle s’associe à la prévention et au monitorage destroubles hémodynamiques et cardio-vasculaires, fréquemment observés. Le pronostic dépenddu caractère métastatique de la tumeur et de la présence d’un résidu tumoral post-opératoire.L’étude génétique est recommandée ; la récidive et l’association à d’autres tumeurs sont plusrapportées dans les formes génétiques.Materiels et methodes. — Les auteurs rapportent 5 observations de paragangliomes rétro-péritonéaux, opérés dans le service d’urologie de l’hôpital, entre 2013 et 2015. Les casconcernent 2 hommes et 3 femmes. Les données cliniques ne sont pas spécifiques et la décou-verte peut être fortuite. L’abord coelioscopique était pratiqué chez 2 patients. Deux autrespatients étaient abordés par voie médiane, et un autre par une lombotomie postéro-latéraleassociée à une incision iliaque antérieure.Résultats. — Deux patients avaient présenté une hypertension rebelle au traitement avec despalpitations, associées à des masses rétro-péritonéales suspectes à l’imagerie et à une élévationdes dérivés méthoxylés urinaires en préopératoire. Un patient était complétement asymptoma-tique et la découverte était fortuite à l’imagerie. Une crise hypertensive peropératoire associéeà une tachycardie sinusale était observée dans un cas. Le suivi moyen était de 22,8 mois.L’hypertension et les palpitations avaient régressé après la chirurgie. Aucun cas de récidiven’était documenté.Conclusions. — Les paragangliomes rétro-péritonéaux sont rarement observés. La symptoma-tologie n’est pas spécifique, et peut être similaire à celle du phéochromocytome. Latomodensitométrie et l’IRM abdominales, associées à la scintigraphie au MIBG sont fortementévocateurs. L’anatomopathologie assure la certitude diagnostique. Les troubles cardio-vasculaire peropératoires doivent être prévenus et gérés par les anesthésistes. L’excisioncarcinologique complète de la tumeur est la seule option curative, permettant d’éviter lesrécidives.© 2018 Elsevier Masson SAS. Tous droits reserves.

ipn

INTRODUCTION

Paraganglioma, formerly called extra-adrenal pheochromo-

cytoma, is an endocrine tumor, usually observed in youngadults. Compared to more frequent locations, such as thecarotid body and the truncus sympathicus, retro-peritoneum

opt

s an uncommon site [1]. Management of retro-peritonealaraganglioma is multidisciplinary, implying radiologists,uclear medicine physicians, anesthesiologists and urol-

gists [2]. The major concern of the retro-peritonealaraganglioma surgery are the cardio-vascular troubles andhe risk of bleeding [3].

4

M

Apttrt

R

TTagpswac

Cw

ctw2ita

u2

puo

90

ETHODS

uthors studied retrospectively five cases of retro-eritoneal paraganglioma operated in the period from 2013o 2017. The reported data concerned the past medical his-ory, the clinical presentation, the hormonal assays, theadiological and imagery findings, the surgical procedure andhe post-operative follow-up.

esults

he study is about 5 patients, 2 men and 3 women (Table 1).he average age is 42.4 years (25—62 years). One patient had

history of polycythemia before the diagnosis of paragan-lioma. Two patients consulted for a resistant hypertension,alpitation and increased sweating. Two other patients pre-

ented a lower back pain and voiding disorders. One patientas asymptomatic and the tumor was discovered in imagerys he suffered from a vaso-occlusive crisis related to a sickle-ell anemia. All the patients were explored by an abdominal

v

io

Table 1 Clinical, pre-operative and surgical findings.

Agemedical history

Symptoms Hormonal dosage

25 years old femalepatient

Cephalalgia,sweating,palpitationResistanthypertension

Elevated urinarymetanephrines, in6 times the normarate

40 years old malepatientSickle-cell anemia

AsymptomaticAbdominalultra-sound(vaso-occlusivecrisis)

Plasmatic andurinary hormonalassay in the normrate.

40 years old malepatientDiabetesDyslipemiaPolycythemia

Cephalagia,sweating,palpitationHypertensionLoss of weight

Elevated urinarymethoxyatedderivates level

62 years old femalepatientDiabetes, asthma

Right lumbalgia,Painful urinationNormal bloodpressure

Urinary hormonalassay in the normrate.

45 years old femalepatientMitral valvestenosis

Right lumbalgiaMictional disordersNormal bloodpressure

Urinary hormonalassay in the normrate.

O. Karray et al.

T-scan. Adrenal MRI was performed in two patients forhom the aspect wasn’t clearly defined by CT-scan.

Three patients presented a unique tumor. Two of themonsulted for non-specific symptoms; the third patient’sumor was discovered in imagery. In two cases, the tumoras peri-adrenal, measuring 12 × 3 mm (right side) and2 × 27 mm (left side). Six months after diagnosis, anncrease of the size of the nodules; 30 mm and 34 mm respec-ively; associated to a suspect wash out; measured at 40%nd 20%; led us to operate. (Fig. 1).

In another patient, there was an aspect suggesting anpper urinary tract tumor in the right renal pelvis, measuring0 × 14 mm.

Patients with multiple-site tumors in CT-scan are thoseresenting catecholamine-excess symptoms and elevatedrinary markers. The nodules, (2 in a patient and 7 for thether) were firmly adhering to the aorta and the inferior

ena cava. (Fig. 2).

MIBG scintigraphy was performed for both of them, show-ng a pathological fixation in the nodules. There were nother fixation sites than the masses viewed in scan. (Fig. 3).

Explorations Surgery

l

Abdominal CT-scanMIBG scintigraphy

Midline incisionResection of 2paragangliomas, adhering tothe aorta and the vena cavaHypertensive crisis and sinustachycardia

al

Abdominal CT-scanAdrenal MRI

Lomboscopic explorationConversion: lumbar incision,left adrenalectomyHemodynamic andcardio-vascular stability

AbdominalangioscanMIBG scintigraphyAdrenal MRI

Midline incision4 paragangliomas betweenthe aorta and the vena cava3 paragangliomas in the leftside of the aortaHemodynamic andcardio-vascular stability

alAbdominal CT-scan Lomboscopic exploration

Normal macroscopic aspectof the adrenal glandSuspect nodule adhering tothe posterior wall of therenal veinResection of the nodule, rightadrenalectomyHemodynamic andcardiovascular stability

alAbdominal USAbdomianl CT-scan

Dorsal lumbotomy,Rutherford Morrison incisionNephro-ureterectomyHemodynamic andcardiovascular stability

Retro-peritoneal paraganglioma, diagnosis and management

wct

aw

waaaw

ni

st

psctp

Figure 1. A heterogeneous tissular mass developed from the leftadrenal gland. The Wash-Out is estimated at 20%.

Urinary markers were elevated in patients withcatecholamine-excess symptoms and multiple-site tumors

p(

Figure 2. Multiple hypervascularized lesions in the retro-peritoneum,

Figure 3. Pathological fixation of MIBG in two masses, adhering to larg

491

ith pathological MIBG fixation. For those with non specificlinical signs and the asymptomatic patient, with a uniqueumor, dosage was in the normal rate.

A 7 days pre-operative medication, using � blockers,llowed a blood pressure control in the two patients forhom the diagnosis was strongly suspected.

Lomboscopic approach was attempted in the patientsith peri-adrenal nodules. In one case, we converted to

lumbar incision as a sub-cutaneous emphysema occurredt the beginning of the procedure. In the other case,drenalectomy and resection of the nodule were performedithout incidents.

The patient with a renal pelvis tumor underwent a rightephro-ureterectomy (lumbotomy and Rutherford-Morrisonncision).

Midline incision was preferred in patients with multiple-ite tumors, to allow a better control of the dissection ofhe tumors in proximity to the aorta and the vena cava.

Only the patient with two nodules presented high bloodressure levels and sinus tachycardia during the operation,uccessfully controlled using anti-arrhythmic agents and cal-ium channel inhibitor. The resection was complete in thewo cases; there were no hemorrhagic incidents during therocedures. (Fig. 4).

Post-operative course was uneventful for the fiveatients. Average post-operative hospital stay was 5.6 days4—7 days). Histological examination of the surgical

firmly close to the aorta and the inferior vena cava.

e vessels.

492

Ft

sopspd

D

Ps

csa[r

hucuavUcg

pndimttaas

u

ip

polawa

C

Tgmdb�pipUcfto

sTtpnci

lbma

aprfwt

nea

parfisiformed. As a Japanese retrospective study of 49 patients,

igure 4. Operative exploration: An encapsulated tumor, anterioro the aorta, measuring 40 mm.

pecimen concluded to a paraganglioma without signsf malignancy or aggressiveness. The average follow-uperiod was 22.8 months (6—29 months). There were noigns of clinical or radiological signs of recurrence. Bloodressure level was normal and catecholamine-excess signsisappeared in the patients with multiple-site tumors.

iscussion

araganglioma is a rare entity, sharing the same clinical pre-entation as pheochromocytomas.

Symptoms usually include the classical association ofephalalgia, increased sweating and palpitation. Blood pres-ure is commonly high and poorly controlled [4]. Diffusebdominal pain, anxiety and tremor less often described5]. Catecholamine-related cardiomyopathy has also beeneported [6].

Positive diagnosis of chromaffin cell tumors is based onormonal assays. Measurement of the plasma free or therine fractionated metanephrines identifies most of theases of paragangliomas. A recent German laboratory eval-ation suggests that the first-morning spot urines offers anccurate measurement and can be considered as a more con-enient option than the 24 hours collection of urines [7].rinary normetanephrines and plasmatic Chromogranin Aorrelates well with the tumor mass and the risk of pro-ression [8].

Imagery remains essential to locate the tumor and toredict the most appropriate surgical attitude. Abdomi-al CT-scan is indicated in first intention. As it preciselyescribes the tumors, its measurements and composition,t can be sufficient in localized forms. MRI is useful inetastatic paragangliomas, affording a better resolution

han CT-scan. It’s also indicated when the risk of irradia-ion should be limited in some patients. Metastatic, extradrenal and multiple site tumors are better explored by

MIBG-scintigraphy; even small and not obvious locations

how a pathological fixation [2].

In our cases, symptoms were found in two patients,rinary hormonal dosage was in a pathological level. The

csa

O. Karray et al.

ndication for the MIBG scintigraphy before surgery was theresence of multiple retro-peritoneal tumors.

Paragangliomas are known to be more aggressive thanheochromocytomas. Malignancy; defined by the presencef metastasis; concern 10 to 15% of the forms. Metastaticesions are usually observed in the lungs, the liver, the spleennd the skeleton [9]. It’s mainly suspected when the tumoreights more than 80 gr, or when it’s described in imagerys a heterogeneous mass with irregular margins [10].

For the symptomatic patients, abdominal and thoracicT-scan didn’t reveal any metastatic lesion.

The curative treatment of paragangliomas is surgical.he surgical management of a hormonally functional para-anglioma must be preceded by a 7 days preoperativeedication, by � blockers, to prevent peri-operative car-iovascular events [11]. �-blockers and calcium channellockers can also be prescribed, only in association with-blockers [2]. Prescribing � Blockers alone may expose toer-operative troubles as it increases the catecholamine’s-nduced vasoconstriction by blocking vasodilatation. Somerotocols have been proposed, using a 3 days-infusion ofrapidil and Magnesium sulfate, offering better treatmentompliance [12]. Preoperative medication is justified by theact that a high level of catecholamines and their deriva-ives is associated with a higher incidence of per and postperative cardio-vascular incidents [13].

The challenge of the anesthesia is to control blood pres-ure and volume and to prevent cardiac rhythm disorders.herefore, an invasive monitoring is necessary. Even ifhere are no recommendations for the induction agents,ropofol remains the most indicated. Ketamine and phe-othiazines should be avoided, as they indirectly increaseatecholamine secretion. Etomidate has a beneficial effectn patients with hemodynamic instability [14].

The major risk after tumor resection is circulatory col-apse explained by vasomotor paralysis. It can be anticipatedy decreasing progressively the vasodilating agents, opti-izing volume status and the careful use of catechoamines

fter the tumor’s vessels ligation [14].In the cases we report, 7 days � Blocker premedication

llowed an acceptable control of blood pressure levels foratients with hypertension. Per-operative hemodynamic andhythmic troubles were observed in one patient, success-ully managed by the anesthesiologists. The surgery durationas longer, as the manipulation of the tumor increased the

roubles.Due to the low incidence of paragangliomas, there are

o prospective studies comparing the superiority end thefficiency between the open surgery and the coelioscopicpproaches.

As paraganglioma are more frequently malignant thanheochrocytomas, open surgery remains the recommendedttitude, affording a better control while handing andesecting the mass [2]. Coelioscopic approach can be per-ormed by experienced surgeons, in small paragangliomas,n accessible locations, with no radiological signs of inva-iveness [3]. An exploration of the entire abdominal cavitys possible once the trans-peritoneal approach is per-

omparing coeliosocpy in pheochromocytoma and single-ite-paraganglioma concluded that the operation is longernd post-operative cardio-vascular incidents are more

C

AdprPappmn

D

Ti

R

[

[

[adrenalectomy for pheochromocytoma Perioperative blockadewith urapidil. Ann Fr Anesth Reanim 2002 [editors].

[13] Chang RY, Lang BH-H, Wong KP, Lo C-Y. High pre-operative

Retro-peritoneal paraganglioma, diagnosis and management

frequent, it’s reasonable and more secure to treat parangan-liomas by open surgery [15]. The indication of coelioscopyneeds further studies on a larger series of patients to bestrengthened.

The surgery related-risks must be considered by surgeons.The most important difficulty is the frequently observedproximity of paragangliomas to the large vessels, increas-ing the risk of bleeding. A meticulous dissection is requiredto avoid hemorrhagic accidents while liberating the tumormass. The capsule rupture is a dread complication thatoccurs mainly in voluminous tumors, firmly adhering to adja-cent organs and structures. It causes an intra and retroperitoneal dissemination of the tumor cells. Recurrencehas been described after capsule rupture, even years afterremission [16].

Disappearance of clinical troubles, normalization ofblood pressure levels and hormonal assays are credible cri-teria to judge the efficiency of the surgical treatment.

We performed open surgery in the two patients present-ing multiple-site paraganglioma. The location of the tumors,firmly adhering to the abdominal aorta and the inferior venacava, led us to opt for a midline incision, affording a bet-ter control of the tumor dissection to minimize the risk ofbleeding. Lomboscopic exploration was attempted in twopatients, presenting a single paraganglioma, described as asuspect adrenal adenoma in imagery. Sub-cutaneous emphy-sema and hypercapnia compelled us to convert to dorsallumbotomy in one case.

Data regarding outcome and survival rates regardingchromaffin cells tumors is limited and mainly concernpheochromocytomas, few cases of paragangliomas areincluded. The Mayo Clinic experience of a 66 paragangliomasstudy group reported by O’Riordian, risk factors for per-sistent or recurrent disease are the tumor size, thelocal invasion and distant metastasis. A complete surgicaltumor resection clearly improves outcome [17]. Surgicalremoval and debulking remains the recommended atti-tude for recurrent or metastatic disease. Once surgeryisn’t conceivable, palliation medical treatment is discussed.Chemotherapy and high dose I-MIBG radionuclide therapyhave been attempted. Larger studies are required for a bet-ter evaluation of the efficiency and the disease’s control[18,19].

According to The Task Force recommendations (2014),all patients presenting a paraganglioma should be engagedin a genetic study. Identified mutations are found in 30%of the cases [20]. The most common is the Succinate-Deshydrogenase (SDH) mutation; the sub-unit B mutation(SDH-B) is found in 40% of the metastatic paragangliomas[21]. Other less frequent mutations have been mentioned,like the HIF-2A mutation, observed in the association ofpolycythemia to paraganglioma [22].

The five patients didn’t show any clinical signs suggest-ing recurrence or distant metastasis. A longer follow-up isrequired to make recovery certain and to detect preco-ciously a possible recurrence or distant metastasis. Geneticstudy should be included in the medical management of ourpatients, to identify possible mutations and to prevent fur-ther syndromic manifestations. The HIF-2A is particularlyworthy of attention in the patient presenting polycythemia,geneticist must be informed of the patient’s medical

history.

493

onclusion

n awareness of clinical symptoms is required to evoke theiagnosis of chromaffin cell tumors. Hormonal assays ensureositive diagnosis and recent studies conclude to interestingesults concerning more specific methods and biomarkers.hysicians have to keep in mind the possibility of extra-drenal sites, better identified by MIBG scintigraphy. Thearticular difficulty of the retro-peritoneal location is theroximity to large blood vessels, thus open surgery looksore secure. Further studies in larger patient’s groups are

eeded to strengthen the indication of coelioscopy.

isclosure of interest

he authors have not supplied their declaration of compet-ng interest.

eferences

[1] Disick GI, Palese MA. Extra-adrenal pheochromocytoma: diag-nosis and management. Curr Urol Rep 2007;8(1):83—8.

[2] Lenders JW, Duh Q-Y, Eisenhofer G, Gimenez-Roqueplo A-P,Grebe SK, Murad MH, et al. Pheochromocytoma and paragan-glioma: an endocrine society clinical practice guideline. J ClinEndocrinol Metab 2014;99(6):1915—42.

[3] Wang J, Li Y, Xiao N, Duan J, Yang N, Bao J, et al.Retroperitoneoscopic resection of primary paraganglioma:single-center clinical experience and literature review. JEndourol 2014;28(11):1345—51.

[4] Badaoui R, Delmas J, Dhahri A, Mahjoub Y, Fumery M, RiboulotM, et al. Prise en charge d’un paragangliome rétropéritonéal.Rev Med Interne 2011;32(5):e62—5.

[5] Bonomaully M, Khong T, Fotriadou M, Tully J. Anxiety anddepression related to elevated dopamine in a patient withmultiple mediastinal paragangliomas. Gen Hosp Psychiatry2014;36(4):449 [e7-e8].

[6] Sharkey SW, McAllister N, Dassenko D, Lin D, Han K, MaronBJ. Evidence that high catecholamine levels produced bypheochromocytoma may be responsible for Tako-tsubo car-diomyopathy. Am J cardiol 2015;115(11):1615—8.

[7] Eisenhofer G, Peitzsch M. Laboratory evaluation ofpheochromocytoma and paraganglioma. Clin chem2014;60(12):1486—99.

[8] Algeciras-Schimnich A, Preissner CM, Young Jr WF, et al. Plasmachromogranin A or urine fractionated metanephrines follow-uptesting improves the diagnostic accuracy of plasma fraction-ated metanephrines for pheochromocytoma. J Clin EndocrinolMetab 2008;93(1):91—5.

[9] Liang C, Li W, Wang H, Luo L, Chen C, Ling C, et al. Acase of retroperitoneum-originated paraganglioma with mul-tiple intracranial and bony metastases. Clin Neurol Neurosurg2014;117:65—7.

10] He J, Wang X, Zheng W, Zhao Y. Retroperitoneal paragangliomawith metastasis to the abdominal vertebra: a case report. DiagnPathol 2013;8(52):1596—8.

11] Mannelli M. Management and treatment of pheochro-mocytomas and paragangliomas. Ann N Y Acad Sci2006;1073(1):405—16.

12] Tauzin-Fin P, Krol-Houdek M, Gosse P, Ballanger P. Laparoscopic

urinary norepinephrine is an independent determinant

4

[

[

[

[

[

[

[

[

94

of peri-operative hemodynamic instability in unilateralpheochromocytoma/paraganglioma removal. World J Surg2014;38(9):2317—23.

14] Kinney MA, Narr BJ, Warner MA. Perioperative manage-ment of pheochromocytoma. J Cardiothoracic Vasc Anesth2002;16(3):359—69.

15] Hattori S, Miyajima A, Hirasawa Y, Kikuchi E, Kurihara I,Miyashita K, et al. Surgical outcome of laparoscopic surgery,including laparoendoscopic single-site surgery, for retroperi-toneal paraganglioma compared with adrenal pheochromocy-toma. J EndouroL 2014;28(6):686—92.

16] Rafat C, Zinzindohoue F, Hernigou A, Hignette C, Favier J,Tenenbaum F, et al. Peritoneal implantation of pheochromo-cytoma following tumor capsule rupture during surgery. J ClinEndocrinol Metab 2014;99(12):E2681—5.

17] O’Riordain DS, Young Jr WF, Grant CS, Carney JA, Van Heerden

JA. Clinical spectrum and outcome of functional extraadrenalparaganglioma. World J Surg 1996;20(7):916—22.

18] Cai Y, Han-Zhong L, Zhang Y-S. Successful treatment ofcoexisting paraganglioma of the retroperitoneum and uri-

[

O. Karray et al.

nary bladder by intermediate-dose 131i-mibg therapy: a casereport. Medicine 2015;94(41.).

19] Niemeijer N, Alblas G, Hulsteijn L, Dekkers O, CorssmitE. Chemotherapy with cyclophosphamide, vincristine anddacarbazine for malignant paraganglioma and pheochromocy-toma: systematic review and meta analysis. Clin Endocrinol2014;81(5):642—51.

20] Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Line-han WM, et al. High frequency of SDHB germline mutationsin patients with malignant catecholamine-producing paragan-gliomas: implications for genetic testing. J Clin EndocrinolMetab 2006;91(11):4505—9.

21] Amar L, Baudin E, Burnichon N, Peyrard Sv, Silvera S, BertheratJrm, et al. Succinate dehydrogenase B gene mutations pre-dict survival in patients with malignant pheochromocytomas orparagangliomas. J Clin Endocrinol Metab 2007;92(10):3822—8.

22] Toyoda H, Hirayama J, Sugimoto Y, Uchida K, Ohishi K,Hirayama M, et al. Polycythemia and paraganglioma witha novel somatic hif2a mutation in a male. Pediatrics2014;133(6):e1787—91.