Surg Today (2004) 34:715–718DOI 10.1007/s00595-004-2782-9

A Functioning-Desensitization Paraganglioma Which CausedHemodynamic Instability During Tumoral Resection:Report of a Case

Mustafa Turan1, Sinan Gursoy2, Metin Sen1, Kursat Karadayi1, Esin Yildiz3, and Sebile Dokmetas4

Departments of 1 General Surgery, 2 Anesthesiology, 3 Pathology, and 4 Internal Medicine-Endocrinology, Faculty of Medicine,Cumhuriyet University, Sivas, Turkey

ment.2,3 The successful management of such tumors isassociated with many problems. We herein present acase of paraganglioma, which was incidentally foundand in which the clinical and previous operative behav-ior was functioning desensitization, and in which nopreoperative medication was performed. However, dur-ing a tumor resection the patient demonstrated hemo-dynamic instability.

Case Report

A 22-year-old man presented to the Emergency Servicedue to a stab wound in his left flank region. He was inshock and a physical examination revealed generalizedtenderness in his abdomen. The heart rate was 148beats/min, and the arterial blood pressure was 70/42mmHg. His upper extremity pulses were feeble,femoral pulses were absent, and the lower extremitieswere cold and cyanotic with decreased capillary filling.Laboratory investigations revealed hemoglobin of 7.2g/dl and a platelet count of 42000/µl. Blood gases showedthe patient to demonstrate metabolic acidosis with ablood pH of 7.28. He thus underwent an emergencyoperation, and a splenectomy and a left renal vein re-pair were performed. The patient had no problemsperioperatively and his postoperative period was alsouneventful. He was discharged 7 days after the surgery.

Two months after the first operation he was admittedto another hospital with diffuse abdominal pain. He wasoperated on with a diagnosis of acute abdomen. Theperioperative diagnosis was primary peritonitis, but thesurgeon noticed a 4 � 5-cm conglomerated soft elasticmass in the iliac bifurcation and made an incisionalbiopsy from it. The patient’s perioperative and postop-erative course was uneventful, and he was discharged6 days after surgery. A histopathologic examination ofthe specimen revealed paraganglioma, composed ofnests of rounded regular cells surrounding a delicate

AbstractParagangliomas are uncommon tumors arising from theneuroendocrine elements of the paraganglia. Their suc-cessful management is associated with many problems.We herein present the findings of a 22-year-old man inwhom a paraganglioma was incidentally found and inwhich the clinical and previous operative behavior wasfunctioning desensitization. As a result, preoperativemedication was not performed; however, during the tu-mor resection the patient demonstrated hemodynamicinstability.

Key words Paraganglioma · Functioning · Desensitiza-tion

Introduction

Paraganglia are groups of cytochemically and morpho-logically similar cells derived from the neural crest.Paragangliomas are uncommon tumors arising from theneuroendocrine elements (chief cells) of the paragan-glia and symmetrically distributed along the aorta inclose association with the sympathetic chain. This tissueeither accumulates in the adrenal medulla, where itgives rise to intra-adrenal paraganglioma, also known aspheochromocytoma, or remains in its para-aortic sites,where it may develop into extra-adrenal, retroperito-neal paragangliomas.1

Because of their rarity, little is known about the natu-ral history of these tumors and the results of treat-

Reprint requests to: M. Turan, Gokcebostan Mah. 2, Sok.Hurriyet Apt. Daire No: 2, 58070 Sivas, TurkeyReceived: January 31, 2003 / Accepted: January 20, 2004

716 M. Turan et al.: Paraganglioma Causing Hemodynamic Instability

vasculature and illustrating a nestlike or Zellballen pat-tern (Fig. 1). These well-defined nests were encircled bya thin layer of S-100 protein-positive sustentacular cells.Immunohistochemically, the chief tumor cells showeda positive reaction with neuron-specific enolase,chromogranin, and synaptophysin (Fig. 2).

The patient was admitted again to our hospital. Hewas a nonsmoker, nondiabetic, nonhypertensive, and hehad no concurrent history of sweating, myocardialinfarction, or syncope. He also had no complaints ofdiarrhea, flushing, or headache. The preoperative arte-rial blood pressure (BP) schedule for 20 days was 110 �20/70 � 15 mmHg, and the rest of a general examinationrevealed no abnormalities. Routine investigations (he-mogram, urine analysis, serum urea, and creatinine) andan electrocardiogram were within the normal limits. A

24-h urinary vanillylmandelic acid (VMA) level was21 mg (normal: 1–8 mg), metanephrine 561µg (normal:52–341 µg), and normetanephrine 1084µg (normal:88–444 µg). A computed axial tomography scanshowed a mass in the iliac bifurcation.[131I]Metaiodobenzylguanidine (MIBG) scintigraphyshowed two different localizations of the tumor (Fig. 3).The patient was examined for the presence of multipleendocrine neoplasia II-A and -B, but normal laboratoryvalues and physical examination ruled out thesesyndromes.

Although the urinary VMA, metanephrine, andnormetanephrine levels were high, the patient had nosymptoms related to paraganglioma and also had noabnormality in two previous operations. As a result, hewas considered to demonstrate desensitization and pre-operative medication with an α-adrenergic blocker wasnot performed.

The patient received 10mg diazepam the night beforesurgery and 5mg midazolam on the morning of thesurgery. His first BP reading in the operating room was120/70 mmHg and heart rate 87 beats/min. After 0.1mgfentanyl I.V. infusion, the patient breathed oxygen for3 min, and anesthesia was induced with 425mg thiopen-tal Na, 7 mg vecronium was given I.V., and endotrachealintubation was performed. Anesthesia was maintainedusing 2%–3% sevoflurane in a 50% O2/N2O mixture.Central venous and arterial cannulation wereperformed. The patient had no problem with the tumorresection, but after starting the resection the BPincreased to 240/142 mmHg. Sodium nitroprusside was

Fig. 1. Low-power view of the retroperitoneal paragangliomaillustrating a nestlike or Zellballen pattern (arrows) (H&E,�75)

Fig. 2. The paraganglioma comprising nests of rounded regu-lar cells (arrows) at a higher magnification (H&E, X150). Theinset shows neuron-specific enolase immunopositivity (arrow)in the cytoplasm of the tumoral cells (ABP, �300)

Fig. 3. [131I]Metaiodobenzylguanidine scintigraphy demon-strated two different localizations of the tumor at 24h (left)and 48 h (right)

717M. Turan et al.: Paraganglioma Causing Hemodynamic Instability

given over the next few minutes and anesthesiawas deepened; after 5min the BP decreased to150/84 mmHg and the heart rate stabilized at 90beats/min.

During the course of the operation, which lastedapproximately 3h, there were several hypertensive epi-sodes, which were effectively managed by altering thesodium nitroprusside infusion rate and sevoflurane con-centration. During the operation, a large tumor mass (4� 5 � 3cm) was found in the iliac bifurcation (Fig. 4),while another tumor mass (2 � 1 � 1 cm) was found inthe posterior-left localization of the superior mesentericartery as shown by [131I]MIBG (Fig. 3). After excisingthe tumors, the BP decreased to 80/42mmHg, and thisreaction was managed effectively by the administrationof crystalloids (5.0 l).

A perioperative analysis of arterial blood gases re-vealed: pHa 7.19; PaO2 151 mmHg; PaCO2 37mmHg;HCO3 17; base excess �10.2; and oxygen saturation99.8%. Metabolic acidosis became normal towards theend of the operation. The patient’s postoperative periodwas uneventful. Grossly tumor masses had a lobular,beefy, red-brown appearance with incomplete capsulesof connective tissue. The cut sections were lobular, col-ored tan to red. A histopathologic examination of thetumor masses confirmed the examination of a biopsyspecimen taken in the previous operation. The patient isstill asymptomatic 1 year after surgery with normal uri-nary VMA, metanephrine, and normetanephrine levels.

Discussion

The retroperitoneum may be the site of both function-ing and nonfunctioning tumors of the paraganglionicsystem.4,5 The literature states that extra-adrenal retro-peritoneal paragangliomas are functional in only up to60% of patients.6 Functional tumors are easier to diag-nose due to the clinical findings caused by excess secre-tion of catecholamines and an elevation of the urinarycatecholamine levels.7 In nonfunctional extra-adrenalretroperitoneal paragangliomas, diagnosis usually de-pends on nonspecific factors related to the growth of aretroperitoneal mass or occasionally showing incidentalsymptoms of metastases, as in this patient.8

Correlation of symptoms and laboratory values ofcatecholamines is the most efficacious way to identify asoft-tissue retroperitoneal mass detected by computedtomography (CT) as an extra-adrenal retroperitonealparaganglioma. With nonfunctional paragangliomas,the CT features of extra-adrenal paragangliomas over-lap those of other retroperitoneal neoplasms, and thediagnosis is more difficult. In recent years [131I]MIBGscintigraphy has shown encouraging results (positivein 85%–90%) and high specificity.9 We also used[131I]MIBG scintigraphy and thus were able to find thesecond localization of the tumor.

Previous reports in the literature reveal a malignancyrate of 22%–50%.3 By comparison, the rate of malig-nancy is about 10% for paragangliomas of the adrenalgland. Malignant tumors tend to be large, necrotic, andpoorly marginated. However, these same features maybe found in tumors that are not malignant, and there-fore they cannot be used as predictors of the benign ormalignant nature of the tumor.10 In addition to clinicallybenign forms, there are also some aggressive caseswhich are associated with locoregional recurrences andremote metastases.5 The criteria that are applicable toother tumors such as cellular atypia, necrosis, vascularinvasion, and mitotic activity cannot be used to definemalignancy and are therefore of no use for an assess-ment of prognosis.10 The only reliable indicators of ma-lignancy are an extensive invasion of the surroundingorgans and remote metastatic spread.

Immunohistochemical methods have recently beenused in an effort to find additional ways of assessingprognosis. Although there was no significant correlationbetween chromogranin-A positivity of the tumor chiefcells and the clinical course, there was slightly morereaction to neuron-specific enolase in those cases withthe worst prognosis.11 S-100 protein antibody reactivityand the presence of sustentacular cells also correlatewith the clinical course. The prognosis deteriorated pro-gressively with a decrease in the number of sustentacu-lar cells.12 Sustentacular cells, which are located eitherat the periphery of nests of chief cells or are dispersed

Fig. 4. Perioperative view of the bigger mass (arrows) locatedin the iliac bifurcation

718 M. Turan et al.: Paraganglioma Causing Hemodynamic Instability

between the tumor cells, were graded semi-quantitatively by cell density unit area counting theS-100 protein-positive cells. In our patient there wasslightly more reaction to neuron-specific enolase and aweak S-100 protein antibody reactivity; therefore, wesurmised that the prognosis of this patient may not be sofavorable, and we thus plan to follow him more fre-quently than similar patients.

Once the diagnosis of retroperitoneal paragangliomais made, every attempt should be made to perform acomplete surgical resection. These tumors progressslowly, and patients have a fairly good survival rate evenwhen they recur locally and develop remote meta-stases.11 The 10-year disease-free survival was 45%, andmetastases could be seen up to 7 years after resection.For this reason, patients should continue to be followedcarefully for recurrence. For metastatic tumors, chemo-therapy may be used for the palliation of symptoms,although its benefits remain questionable.13 Radio-therapy may also offer palliation for symptomatic me-tastases, though surgical decompression in combinationwith radiotherapy may be most helpful in cases or cordcompression secondary to spinal metastases.

The clinical picture of pheochromocytoma is mani-fested by a variety of symptoms connected with either apermanent or paroxysmal release of catecholaminesinto the systemic circulation.14 The dominant symptomis arterial hypertension with a characteristic clinicalcourse, usually resistant to conventional treatment andwith paradoxical deterioration when �-adrenergic an-tagonists are applied without adequate α-adrenergicblockade.15 Although no controlled, randomized, pro-spective clinical studies have yet evaluated the benefitsand risks of the preoperative use of α-adrenergicreceptor-blocking drugs, the use of such drugs has beengenerally recommended for use before surgery.16,17 Inaddition, �-adrenergic antagonists are used as a secondline of therapy to control associated tachycardia.

There have been several case reports on the reap-pearance of bronchial hyper-reactivity following a re-section of catecholamine-secreting tumors in patientswith asthma.18,19 It is thought that the desensitization of�-receptors due to chronic catecholamine excess resultsin decreased �-stimulation and consequent broncho-spasm following surgical removal of the tumor. In addi-tion, a preoperative �-blockade appears to worsen thesymptoms of bronchospasm.20

The urinary VMA, metanephrine, and norme-tanephrine levels of this patient were high, but he hadno symptoms related to paraganglioma and also had noabnormality in two previous operations. Furthermore,in the second operation his tumor mass was manipu-lated and an incisional biopsy was made. He wasconsidered to demonstrate desensitization and no pre-operative medication was performed. However, the pa-

tient demonstrated hemodynamic instability during thetumor resection, so we think that although the patienthad no symptoms related to the pheochromocytoma,preoperative medication with α-adrenergic blockadeshould be considered in such patients, while great care isalso needed during the tumor resection.

References

1. Hayes WS, Davidson AJ, Grimley PM, Hartman DS. Extra-adrenal retroperitoneal paraganglioma: clinical, pathologic, andCT findings. Am J Roentgenol 1990;155:1247–50.

2. Scott HW, Dean RH, Oates JA. Surgical management of pheo-chromocytoma. Am Surg 1981;47:8–13.

3. Sclafani LM, Woodruff JM, Brennan MF. Extraadrenal retroperi-toneal paragangliomas: natural history and response to treatment.Surgery 1990;108:1124–9.

4. Hall GM, Morris DM, Mason GR. Nonfunctioning retroperito-neal paragangliomas. Am J Surg 1980;139:257–61.

5. Lack EE, Cubilla AL, Woodruff JM, Lieberman PH. Extra-adrenal paragangliomas of the retroperitoneum: a dinico-pathologic study of 12 tumors. Am J Surg Pathol 1980;4:109–20.

6. Enzinger FM, Weiss SW. Paraganglioma. In: Enzinger FM, WeissSW, editors. Soft tissue tumors. St. Louis: Mosby; 1988. p. 836–60.

7. Samaan NA, Hickey RC. Pheochromocytoma. Semin Oncol1987;14:297–305.

8. Law NW, Alfano L. Non-functioning retroperitoneal paragan-glioma. J R Soc Med 1987;80:246–7.

9. Thompson NW, Allo MD, Shapiro B, Sisson JC. Extra-adrenaland metastatic pheochromocytoma: The role of 131I MIBG inlocalization and management . World J Surg 1984;8:605–11.

10. Glenn F, Gray GF. Functional tumors of the organ ofZuckerkandl. Ann Surg 1976;183:578–86.

11. Montresor E, Iacono C, Nifosi F, Zanza A, Modena S, ZamboniG, et al. Retroperitoneal paragangliomas: role of immunohis-tochemistry in the diagnosis of malignancy and in assessment ofprognosis. Eur J Surg 1994;160:547–52.

12. Jovonovic R, Hacker GW, Falkmer U. Paragangliomas: neuroen-docrine features and cytometric DNA distribution patterns.Virchows Arch A Pathol Anat 1991;419:455–61.

13. Averbach S, Steakley C, Gelmann E. Malignant pheochromocy-toma: treatment with combination of cylophosphamide, vincris-tine and dacarbazine. Proc Am Soc Clin Oncol 1987;6:241.

14. Shapiro B, Lorraine M. Management of pheochromocytoma.Endocrinol Metab Clin North Am 1989;18:2.

15. McManus BM, Fleury TA, Roberts WC. Fatal catecholaminecrisis in pheochromocytoma: curable cause of cardiac arrest. AmHeart J 1981;102:930–2.

16. Witteles RM, Kaplan EL, Roizen MF. Safe and cost-effectivepreoperative preparation of patients with pheochromocytoma.Anesth Analg 2000;91:302–4.

17. Morikawa T, Suzuki M, Unno M, Endo K, Katayose Y, MatsunoS. Malignant pheochromocytoma with hepatic metastasis diag-nosed 10 years after a resection of the primary incidentalomaadrenal lesion: report of a case. Surg Today 2001;31:80–4.

18. Harvey JN, Dean HG, Lee MR. Recurrence of asthma followingremoval of a noradrenaline secreting pheochromocytoma.Postgrad Med J 1984;60:364–5.

19. Nishikawa T, Doshi S, Anzi Y. Recurrence of bronchial asthmaafter adrenelectomy for pheochromocytoma. Can Anesth Soc J1986;33:109–11.

20. Sandur S, Dasgupta A, Shapiro JL, Arroliga AC, Mehta AC.Thoracic involvement with pheochromocytoma: a review. Chest1999;115:511–21.