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Changing trends in the surgical management of phaeochromocytomaGraaf, Joost Sake de

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CHANGING TRENDS IN THE SURGICAL MANAGEMENT OF

PHAEOCHROMOCYTOMA

JOOST S.DE GRAAF

Omslag : "Swilcan Bridge"

Lay-out : Haaring Automatisering, Scherpenzeel

Drukwerk : Drukkerij Elinkwijk B.V., Utrecht

ISBN : 90-367-1077- 4

© J.S. de Graaf 1999. All rights reserved. No part of this book may be reproduced, inany form or by any means, without written permission from the author.

Financial and material support by Merck Sharp & Dohme B.V., Dr. T. de Graaf, AutosutureNederland and the St. Andrews Links Trust for the publication of this thesis is gratefullyacknowledged.

RIJKSUNIVERSITEIT GRONINGEN


PHAEOCHROMOCYTOMA

PROEFSCHRIFT

ter verkrijging van het doctoraat in deMedische Wetenschappen

aan de Rijksuniversiteit Groningenop gezag van de

Rector Magnificus, dr. D.F.J. Bosscher,in het openbaar te verdedigen op

dinsdag 15 juni 1999om 16.00 uur

door

Joost Sake de Graaf

geboren op 27 mei 1966te Paterswolde

Promotores : Prof. dr. R.P. ZwierstraProf. dr. Th.J.M.V. van Vroonhoven

Co-promotor : Dr. R.P.F. Dullaart

Aan mijn oudersAan Annemarie

Beoordelingscommissie : Prof. dr. W.D. ReitsmaProf. dr. A. Vermey (FACS)Prof. dr. I. Molenaar

Paranimfen : Drs. M.S. SietsmaDr. P. Swartbol

TABLE OF CONTENTS

CHAPTER 1 General Introduction 11

CHAPTER 2 Results of 25 years of treatment of Phaeochromocytoma. 25

CHAPTER 3 Comparison of Meta-Iodo-Benzyl-Guanidine scintigraphy 37and Computed Tomography in the localization ofPhaeochromocytoma.

CHAPTER 4 Limited role for Meta-Iodo-Benzyl-Guanidine scintigraphy 47in imaging MEN type 2A related Phaeochromocytoma.

CHAPTER 5 Complications of bilateral adrenalectomy for 57Phaeochromocytoma in MEN type 2.

CHAPTER 6 Subtotal adrenalectomy for Phaeochromocytoma in 69Multiple Endocrine Neoplasia type 2A.

CHAPTER 7 Minimally invasive Surgical approaches for treatment 77of Phaeochromocytoma.

CHAPTER 8 Summary and General Discussion 89

Samenvatting 95

Nawoord 101

Curriculum Vitae 105

General introduction 11

General Introduction

1

12 Chapter 1


GENERAL INTRODUCTION

Phaeochromocytoma is a tumour, which arises from chromaffin tissues in the body.Approximately 85% of phaeochromocytomas are sporadic and are located in theadrenal medulla, occurring with approximately equal frequency in the right and leftadrenal gland 1,2,3,4. Extra-adrenal tumours develop in the paraganglionic chromaffincells of the sympathetic nervous system and have been found from carotid body topelvic floor, but are mostly located in the retroperitoneum, arising from the sympatheticchain or from the organs of Zuckerkandl at the aortic bifurcation 5,6,7,8,9,10. Thesecatecholamine-secreting adrenal tumours and their extra-adrenal counterpart,paraganglioma, have an incidence estimated to be one to two per 100.000 adults, andare present in fewer than 0.1% of hypertensive patients 4,11,12,13. Many cases ofphaeochromocytoma are being diagnosed only on autopsy, and are not symptomaticor remain undiagnosed during lifetime. The incidence rate at autopsy has shown tovary between 0.1% to 0.3% 1,14. The peak incidence of phaeochromocytoma occursbetween the third and fourth decade 15. Although hypertension is the most consistentclinical sign, phaeochromocytoma can be associated with a wide variety of symptomsrelated to catecholamine secretion, which led to the name �the great mimic�. Symptomssuggesting the presence of phaeochromocytoma include the classic triad of headache,palpitations and sweating. The lethal complications of uncontrolled catecholaminerelease warrant an aggressive diagnostic evaluation of patients with clinicallysuggestive symptoms. Moreover, detection of these rare catecholamine- secretingtumours is important, because surgical extirpation is curative in more than 90% of allcases 11,12,16,17.

FAMILIAL PHAEOCHROMOCYTOMAS

Although most phaeochromocytomas are sporadic and solitary, they may also occurin 10-15% of cases in association with a number of familial syndromes. Familialpathologic conditions associated with phaeochromocytomas include simple familialphaeochromocytoma, multiple endocrine neoplasia (MEN) type 2A and 2B and theneuroectodermal syndromes of neurofibromatosis, von Hipple-Lindau disease,tuberous sclerosis, and Sturge-Weber syndrome 19-27. MEN type 2A includes medullarycarcinoma of the thyroid gland, hyperparathyroidism and phaeochromocytoma. MENtype 2B is defined by the association of medullary carcinoma of the thyroid, mucosalneuromas, intestinal ganglioneuromas, phaeochromocytoma and marfanoid habitus.

14 Chapter 1

MEN TYPE 2A RELATED PHEOCHROMOCYTOMA

Phaeochromocytoma will develop in 30 % to 50% of MEN type 2A patients andapproximately two thirds of these familial phaeochromocytomas are located in bothadrenal glands at the time of diagnosis 28,29. In such cases of hereditary phaeochromo-cytoma, adrenal medullary hyperplasia, defined as lesions smaller than one centimetre,is thought to proceed to the development of phaeochromocytoma 21,30,31. Biochemicalscreening appears not to be sensitive for detecting adrenal medullary hyperplasia 20.Advances in the knowledge of the RET proto-oncogene and its role in the MEN 2Asyndrome has led to early detection of MEN 2 carriers. Recent studies have mappedthe gene for MEN 2A and 2B in the region of chromosome 10, (10q11.2) that containsthe RET proto-oncogene 32. This gene encodes a transmembrane tyrosine kinasereceptor and has been shown to be consistently expressed in phaeochromocytomasand medullary thyroid carcinoma 33,34.The RET proto-oncogene is likely to be involvedin the development and differentiation of tissues orginating from the neural crest 36.Mis-sense mutations of the RET proto-oncogene altering one of the cysteine residuesin exons 10, 11 and 13 were found in most MEN type 2A families 37,38,39. In MEN type2B families the mutations were detected only in exon 16 40,41. The application ofDNA analysis for the identification of specific RET proto-oncogene mutations inthese families allows for predictive testing of gene carrier status in individuals whoare at risk to inherit the disease 36. In contrast to phaeochromocytoma, medullarythyroid carcinoma will develop in all patients identified to carry a genetic mutationassociated with MEN type 2A or 2B. Because medullary thyroid carcinoma is highlymalignant and is not curable unless diagnosed at an early stage, a prophylacticthyreoidectomy is strongly recommended in these gene carriers at the earliestconvenient time 36,42,43. In contrast, phaeochromocytoma in MEN type 2 carriers israrely malignant 28. The concern of undiagnosed phaeochromocytoma is unexpectedcatecholamine crisis. Also, despite substitution therapy with gluco- and mineralo-corticoids, the absence of adrenal cortical tissue puts the patient at risk for Addisoniancrisis. The goal of screening for phaeochromocytoma in these patients is to detect thetumour, prior to the onset of symptoms of excess catecholamines 28. DNA analysiscombined with yearly screening for catecholamine excess in MEN 2 carriers makesthat phaeochromocytoma in these particular patients at the time of detection are oftensmall and asymptomatic 24,42. Therefore, when comparing sporadic and MEN 2A-related phaeochromocytoma, there are differences in age at presentation, mode ofpresentation, clinical features and imaging findings 45.

MALIGNANT PHAEOCHROMOCYTOMA

The reported malignancy rates in the literature are variable due to the lack of anuniversally accepted definition of malignancy for these tumours. Approximately 10%


of phaeochromocytomas and up to 40% of paragangliomas follow a malignant courseas demonstrated by the presence of metastasis 1,3,18. Metastases have been reported inlymph nodes, the skeleton, lung, liver, brain and omentum 49,50,51. The evaluation ofchromosomal ploidy in tumour tissue may be of help in predicting a benign course,whereas aneuploid or tetraploid tumours have a 30 to 40% incidence of malignancy46. The DNA ploidy pattern appears to be an important variable associated with thecourse of the disease 47. There are no reliable histologic criteria for the diagnosis ofmalignant phaeochromocytoma. Pathologic findings of invasion in adjacent structureslike perirenal fat or veins are not reliable indicators of malignancy 48. Local recurrenceis also an unreliable indicator of malignancy, because this may only be a reflection ofinadequate excision of the primary tumour. Malignancy, therefore, can only bediagnosed in the presence of tumour cells in sites were chromaffin tissue wouldnormally not occur.

BIOCHEMICAL DIAGNOSIS

Once phaeochromocytoma is suspected on clinical grounds, the cornerstone of thediagnosis is demonstration of catecholamine excess as measured in urine or plasma.The most useful urine tests are measurement of metanephrines (either totalmetanephrines or metanephrines and normetanephrines separately). The sensitivityof urinary total metanephrines (67-91%) and free catecholamines (up to 100%) isbetter than that of vanillylmandelic acid (VMA) (28-56%) 52,53,54,61. Thus urinary VMAmeasurement is not the preferred test to diagnose (or exclude) phaeochromocytoma.Sole reliance on determination of urinary metanephrines can be misleading, potentiallyin small tumours 54. Hence, measurement of plasma catecholamines is of additionalvalue with a reported sensitivity of 88-100%54. Recently, measurement of plasmametanephrines has become available 57. The sensitivity of this laboratory test wasreported to be 100% and may be better than that of plasma catecholaminedetermination .

HISTORICAL PERSPECTIVE OF SURGICAL TREATMENT

The first patient with symptoms typically related to phaeochromocytoma wasdescribed in 1886 by Frankel 58,59. Despite injections of ether and champagne, thispatient died and autopsy revealed bilateral adrenal tumours that were almost certainphaeochromocytomas. In 1902 Kohn demonstrated that the cells of the adrenalmedulla, the carotid body, the abdominal paraganglia and the organs of Zuckerkandlwere similar in appearance and were chromaffin-positive. The name phaeochromo-cytoma was coined in 1905 by Poll because fresh tumour, when exposed to dichromate,turns dark-brown (phaios = dark, chroma = colour) 58. In 1923 Villard of Lyons wasprobably the first to treat a patient with phaeochromocytoma by surgery 58. The patient

16 Chapter 1

died in shock, which was regarded as disproportionate to the severity of the operation.The first successful removal of a phaeochromocytoma was carried out by Roux inSwitzerland and Mayo in the United States in 1926 58. In 1940 approximately 20successful operations had been reported in the literature, but also at least ten deathsfrom operative shock. The biochemical pathways of catecholamine metabolism andurinary measurement of its metabolites were established in the early 1960s andprovided an accurate method to establish the diagnosis 60. In the 1970s the developmentand implementation of computed tomography (CT) produced a quantum leap forwardin the ability to image the adrenal glands and localize these tumours 60. During the1980s many new medications and techniques to safeguard intraoperativehaemodynamics were developed, reducing the risk previously associated with surgicalexcision of phaeochromocytoma 60.

OUTLINE OF THE THESIS

The policy in diagnosis and treatment of phaeochromocytoma has changeddramatically since the first operation on this catecholamine-secreting tumour. Severalnew diagnostic and surgical techniques have been proposed and reported in the past15 years. Therefore, there is a need to evaluate diagnostic and surgical procedures inphaeochromocytoma management. This thesis aims to answer the following questions:

1. In order to provide a suitable standard for comparison of recently developed newsurgical techniques such as minimally invasive approaches for phaeochromo-cytoma instead of the traditional transabdominal approach, we have evaluatedour experience with transabdominal resection and outcome in a large group ofphaeochromocytoma patients. Which are the risks of the transabdominal approach,and should this policy be modified? (Chapter 2)

2. Localization of phaeochromocytoma is of utmost importance, since surgicalextirpation is the only curative therapy. Modern techniques for localization ofphaeochromocytoma are Metaiodobenzyl- Guanidine scintigraphy (MIBGscintigrapy), Computed Tomography (CT) and Magnetic Resonance Imaging(MRI). All these modalities yield an over 80% accuracy in detecting phaeochromo-cytoma. Is there an optimal localization strategy for phaeochromocytoma?(Chapter 3)

3. MEN type 2 related phaeochromocytomas differ from their solitary counterpartby means of presentation. Does this difference have implications for localizationstrategies in this specific patient group? (Chapter 4)


4. There is no consensus about the surgical strategy for MEN type 2 relatedphaeochromocytoma. The traditional operation in these patients has been a totalbilateral adrenalectomy, even in case of unilateral phaeochromocytoma. Dataconcerning long-term complications due to Addissonian crisis are spare andconflicting. Are these complications clinically important and do they warrant moreconservative procedures? (Chapter 5)

5. Subtotal adrenalectomy in MEN type 2A related phaeochromocytoma theoreticallyavoids complications due to inadequate corticosteroid suppletion therapy. Is thissurgical strategy technically feasible with preservation of sufficient adrenal corticalreserve? (Chapter 6)

6. Adrenalectomy for non-catecholamine secreting tumours by laparoscopic andretro-peritoneoscopic approaches has been reported increasingly. Are minimallyinvasive approaches safe and technically feasible for phaeochromocytoma?(Chapter 7)

18 Chapter 1

REFERENCES

1. Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspectedphaeochromocytoma: Review of a 50-years autopsy series. Mayo Clin Proc 1981;56: 354-360.

2. Gordon DL, Atamian SD, Brooks MH et al. Fewer in pheochromocytoma. ArchInt Med 1992; 152; 1269-1272.

3. Stein PP, Black HR. A simplified diagnostic approach to phaeochromocytoma.A review of the literature and report of one institution�s experience. Medicine(Baltimore) 1991; 46: 46-51.

4. Samaan NA, Hickey RC, Shutts PE. Diagnosis, localization and managementof pheochromocytoma. Pitfalls and follow-up in 41 patients. Cancer 1988; 62:2451-2460.

5. Aravot DJ, Banner NR, Cantor Am et al. Location, localization and surgicaltreatment of cardiac pheochromocytoma. Am J Cardiol 1992; 69: 283-287.

6. Lee HH, Brenner WI, Vardhan I et al. Cardiac pheochromocytoma orginating inthe interatrial septum. Chest 1990; 97: 760-763.

7. Rosamond TL, Hamberg MS, Vasec JL et al. Intrapericardial pheochromocytoma.Am J Cardiol 1992: 70; 700-704.

8. Shulkin BL, Koeppe RA, Francis IR et al. Pheochromocytomas that do notaccumulate metaiodobenzylguanidine: localization with PET and administrationof FDG. Radiology 1993; 186: 711-715.

9. Becker G, Jockenhovel F, Bauer R et al. Cervical pheochromocytoma: a rarelocalization and difficult diagnosis. J Endocrinol Invest 1992; 15: 767-769.

10. Dennis PJ, Lewandowski AE, Rohner TJ et al. Pheochromocytoma of theprostate, an unusual location. J Urol 1989; 141: 130-132.

11. Sheps SG, Jiang NS, Klee GG, van Heerden JA. Recent developments in thediagnosis and treatment of pheochromocytomas. Mayo Clin Proc 1990; 64: 88-95.

12. Heerden JA van, Sheps SG, Hamberger B, Sheedy PF, Poston JG, ReMine WH.Current status and changing trends. Surgery 1982; 91: 367-373.


13. Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence ofpheochromocytoma in Rochester, Minnesota, 1950-1979. Mayo Clin Proc 1983;58: 802-804.

14. Minno AM, Bennett WA, Kvale WF. Pheochromocytoma, a study of 15 casesdiagnosed at autopsy. N Engl J Surg 1955; 251: 959-965.

15. Modlin IM, Farndon JR, Shepherd A et al. Phaeochromocytomas in 72 patients:clinical and diagnostic features, treatment and longterm results. Br J Surg 1979;66: 456-465.

16. Obara T, Kanbe M, Okamoto et al. Surgical strategy for pheochromocytoma:emphasis on the pledge of flank extraperitoneal approach in selected patients.Surgery 1995; 118: 1083-1089.

17. Gifford RW, Manger WM, Bravo EL. Pheochromocytoma. Endocrinol MetabClin North Am 1994; 23: 387-404.

18. Heerden JA van, Roland CF, Carney JA, Sheps SG, Grant CS. Long-termevaluation following resection of apperently benign pheochromocytoma(s) /paragangliomas(s), World J Surg 1990; 14: 325-329.

19. Cassanova S, Rosenberg-Bourgin M, Farkas DC et al. Pheochromocytoma inmultiple endocrine neoplasia type 2A; survey of 100 cases, Clin Endocrinol1993; 125: 935-938.

20. Gagel RF, Tashjian AH, Cummings T et al. The clinical outcome of prospectivescreening of multiple endocrine neoplasia 2A: a 18 years experience. N Engl JMed 1988; 318: 478-483.

21. Lairmore TC, Ball DW, Baylin SB et al. Management of pheochromocytomasin patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 1993;217:595-603.

22. Neumann HPH, Berger DP, Sigmund G et al. Pheochromocytomas, multipleendocrine neoplasia type 2, and von Hipple-Lindau disease. N Engl J Med 1993;329: 1531-1538.

23. Padberg BC, Holl K, Schroder S. Pathology of multiple endocrine neoplasia 2Aand 2B: a review. Horm Res 1992; 38: 24-29.

20 Chapter 1

24. Jansson S, Dahlstrom A Hansson G et al. Concomitant occurrence of an adrenalganglioneuroma and a contralateral pheochromocytoma in a patient with vonRecklinghausen�s neurofibromatosis. An immunocytochemical study. Cancer1989; 63: 324-328.

25. Aprill BS, Drake AJ, Lasseter DH et al. Silent adrenal nodules in von Hipple-Lindau disease suggest pheochromocytoma. Ann Int Med 1994; 120: 485-487.

26. Tisherman SE, Tisherman BG, Tisherman SA et al. Three-decade investigationof familial pheochromocytoma. An allele of von Hipple-Lindau disease? ArchIntern Med 1993; 153: 2550-2553.

27. Choyke PL, Glenn GM, Walther MM, Patronas NJ, Lineham WM, Zbar B. VonHipple-Lindau disease: genetic, clinical and imaging features. Radiology 1995;194: 629-642.

28. Evans DB, Lee JE, Merell, RC, Hickey RC. Adrenal medullary disease inmultiple endocrine neoplasia type 2. Endocrin Metab Clinics North Am 1994;23: 167-176.

29. Lips CJM, van der Sluys Veer J et al. Bilateral occurence of pheochromocytomain patients with the multiple endocrine neoplasia syndrome type 2A (Sipple�ssyndrome). Am J Med 1981; 70: 1051-1060.

30. Carney JA, Sizemore GW, Sheps SG. Adrenal medullary disease in multipleendocrine neoplasia, type 2. Pheochromocytomas and its precursors. Am J ClinPathol 1975; 66: 279-290.

31. Carney JA, Sizemore GW, Tyce GM. Bilateral adrenal medullary hyperplasia inmultiple endocrine neoplasia, type 2: the precursor of bilateralpheochromocytoma. Mayo Clin Proc 1975; 50: 3-10.

32. Lairmore TC, Dou S, Howe JR et al. A 1.5 megabase yeast artificial chromosomecintig from human chromosome 10q11.2 connecting three genetic loci (RET,D10S94, D10S102) closely linked to the MEN-2A locus. Proc Natl Acad SciUSA 1993; 90: 492-496.

33. Nagao M, Ishizaka Y, Nakagawara A et al. Expression of RET proto-oncogenesein human neuroblastomas. Jpn J Cancer Res 1990; 81; 309-312.

34. Santoro M, Rosati R, Grieco M et al. The RET proto-oncogene is consistentlyexpressed in human pheochromocytomas and medullary thyroid carcinomas.Oncogene 1990: 5; 1595-1598.


35. Jansson S, Tisell LE, Fjalling M, Lidberg S, Jacobsson L, Zachrisson BF. Earlydiagnosis and surgical strategy for adrenal medullary disease in MEN II genecarriers. Surgery 1988; 103: 11 -18.

36. Frilling A, Dralle H, Eng C, Raue F, Broelsch CE et al. Presymptomatic DNAscreening in families with multiple endocrine neoplasia type 2A and familialmedullary thyroid carcinoma. Surgery 1995; 118: 1099-1104.

37. Donis-Keller H, Dou S, Chi D et al. Mutations in the RET proto-oncogeneassociated with MEN 2A and FMTC. Hum Mol Genet 1993; 2: 851-856.

38. Mulligan LM, Eng C, Healey CS et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet1994; 6: 70-74.

39. Eng C, Smith DP, Mulligan LM et al. A novel point mutation in the tyrosinekinase domain of the RET proto-oncogene in sporadic medullary thyroidcarcinoma and in a family with FMTC. Oncogene 1995; 10: 509-513.

40. Hofstra RMW, Landvater RM, Ceccherini I et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadicmedullary thyroid carcinoma. Nature 1994; 367: 375-376.

41. Carlson KM, Dou S, Chi D et al. Single missence mutation in the tyrosine kinasecatalytic domain of RET protooncogene is associated with multiple endocrineneoplasia type 2B. Proc Natl Acad Sci USA 1994; 91: 1579-1583.

42. Lips CJM, Landsvater RM, Hoppener JWM et al. Clinical screening as comparedwith DNA analysis in families with multiple endocrine neoplasia type 2A. NEngl J Med 1994; 331: 828-835.

43. Wells SA, Chi DD, Toshima K et al. Predictive DNA testing and prophylacticthyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. AnnSurg 1994; 220: 237-250.

44. Arts CHP, Bax NMA, Jansen M, Lips CJM, Vroom ThM, Vroonhoven ThJMVvan. Prophylactic total thyroidectomy for multiple endocrine neoplasia (MEN)2A in childhood: first experiences. Ned Tijdschr Geneesk 1999;143: 98-104.

45. Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ.Differences between sporadic and multiple endocrine neoplasia type 2Aphaeochromocytoma. Clinical Endocrinology 1998; 48: 195-200.

22 Chapter 1

46. Hosaka Y, Rainwater LM, Grant CS, Farrow GM, Heerden JA van, Lieber MM.Pheochromocytoma: Nuclear deoxyribonucleic acid patterns studied by flowcytometry. Surgery 1986: 100: 1003-1010.

47. Nativ O, Grant CS, Sheps SG et al. The clinical significans of nuclear DNAploidy pattern in 184 patients with pheochromocytoma. Cancer 1992; 69:2683-2687.

48. Pommier RF, Vetto JT, Billingsly K, Woltering EA, Brennan MF. Comparisonof adrenal and extraadrenal pheochromocytomas. Surgery 1993; 144: 1160-1106.

49. Mornex R, Badet C, Peyrin L. Malignant pheochromocytoma: A series of 14cases observed between 1966 and 1990. J Endocrinol Invest 1992; 15: 643-647.

50. Proye C, Vix M, Goropoulos A et al. High incidence of malignant pheochromo-cytoma in a surgical unit. 26 cases out of 100 patients operated from 1971 to1991. J Endocrinol Invest 1992; 15: 651-654.

51. Schlumberger M, Gicquel C, Lumbroso J et al. Malignant pheochromocytoma:clinical, biological, histological and therapeutic data in a series of 20 patientswith distant metastases. J Endocrinol Invest 1992; 15: 631-636.

52. Werbel SS, Ober KP. Pheochromocytoma. Update on diagnosis, localizationand management. Medical Clinics of North America 1995; 79: 131-153.

53. Dullaart RPF. Endocrine hypertension. In: Transitional areas between internalmedicine and cardiovascular disease. WD Reitsma ed. Bohn Stafleu Van Loghum1995: 13-27. ISBW 9031319503

54. Bravo EL, Gifford RW, Goldfarb D. Current perspectives in the diagnosis andmanagement of phaeochromocytomas. Endo Rel Cancer 1996; 3: 293-308.

55. Mihai R, Wong NACS, Luckett M, Sheffield E, Farndon JR. No correlationbetween phaeochromocytoma catecholamine secretion and granuleultrastructure. Br J Surg 1998; 85: 1681-1685.

56. Ito Y, Obara T, Okamoto T et al. Efficacy of single voided urine metanephrineand normetanephrine assay for diagnosing pheochromocytoma. World J Surg1998; 22: 684-688.

57. Lenders JWM, Keiser HR, Goldstein DS et al. Plasma metanephrines in thediagnosis of pheochromocytoma. Ann Intern Med 1995; 123: 101-109.


58. Welbourn RB. Early surgical history of phaeochromocytoma. Br J Surg 1987;74: 594-596.

59. Frankel F. Ein Fall von doppelseitigen vollig latent verlaufen Nebennierentumorund gleichseitiger Nephritis mit veranderungen am Circulation suppart andRetinitis. Virchows Archives 1886;103: 224.

60. Orchard T, Grant CS, Heerden JA, Weaver A. Pheochromocytoma, continuingevolution of surgical therapy. Surgery 1993; 114: 1153-1159.

61. Duncan MW, Compton P, Lazarus L, Smythe GA. Measurement of nor-epinephrine and 3,4-dihydroxyphenylglycol in urine and plasma for the diagnosisof pheochromocytoma. N Engl J Med 1988; 319: 136-142.

24 Chapter 1

Results of 25 years of treatment of Phaeochromocytoma 25

Results of 25 years of treatment ofPhaeochromocytoma

2

26 Chapter 2

Abstract

Objective: To evaluate 25 years� experience with localization techniques, operativemanagement and results of treatment for phaeochromocytoma.Design: Retrospective studySetting: University Hospital.Subjects: All 59 patients treated for phaeochromocytoma in the period 1970-1995.Intervention: 41 patients underwent unilateral adrenalectomy, 18 underwentbilateral adrenalectomy.Results: Since the use of MIBG scintigraphy, combined with CT or MRI, all tumoursites were correctly diagnosed preoperatively. The transabdominal approach resultedin considerable morbidity and a low mortality rate. All MEN type 2 patients in thisseries who were treated by unilateral adrenalectomy developed phaeochromocytomain the contra-lateral gland and needed total adrenalectomy 7 to 14 years after theinitial operation.Conclusion: Transabdominal surgical approach for phaeochromocytoma isaccompanied by considerable morbidity. Long-term results after surgery forphaeochromocytoma are excellent. A retro-peritoneal approach is justified in selectedpatients.

J.S.de Graaf, O.E.Nieweg, A.E.Oosterkamp, R.P.Zwierstra.Nederlands Tijdschrift voor Geneeskunde 1997: 141; 148-151. (adapted version)


INTRODUCTION

Phaeochromocytoma is a tumour which arises from chromaffin cells of thesympathicoadrenal system. This rare tumour occurs in fewer than 0.1% of hypertensivepatients 1,2. Due to uncontrolled catecholamine release these tumours are potentiallylethal, but after surgical extirpation prognosis is excellent in over 90% of affectedpatients. Roughly, 70% of phaeochromocytomas are solitary and benign and theyarise unilaterally in one adrenal gland 1. Extra-adrenal phaeochromocytomas are calledparagangliomas and may arise anywhere but are mostly located in the retroperitoneumarising from the sympathethic chain or from the organs of Zuckerkandl at the aorticbifurcation. Over 10% of these tumours are associated with a number of familialneurocrestopatic disorders, including the multiple endocrine neoplasia (MEN)syndrome type 2 3. At presentation, these familial phaeochromocytomas are locatedin both adrenal glands in approximately two-thirds of affected patients3,4. In thisstudy we present our experience with phaeochromocytoma in 59 patients. Localizationtechniques, operative management and outcome of treatment will be discussed.

PATIENTS AND METHODS

The medical records of 59 patients with histologically proven phaeochromocytoma,who had been treated at the University Hospital Groningen, The Netherlands, between1970 and 1995, were reviewed. The patient group comprised 30 female and 29 malepatients with a mean age at the time of diagnosis of 41 years (range 14-73). In twenty-three patients phaeochromocytoma was associated with the MEN syndrome. Twentypatients suffered from the MEN syndrome type 2A (MEN 2A) (medullary carcinomaof the thyroid gland, hyperparathyroidism and phaeochromocytoma) and in 3 fromthe MEN type 2B syndrome (medullary carcinoma of the thyroid gland, mucosalneuromas, intestinal ganglioneuromas, phaeochromocytoma and marfanoid habitus).Five patients had malignant phaeochromocytoma.In all patients the diagnosis phaeochromocytoma was established by measurementof urinary catecholamine metabolites and plasma catecholamines.Localization: tumour localization of patients treated between 1970 and 1980 wasdetermined by intravenous urography (IVP) and selected arteriography. Meanwhilethese diagnostic methods have been abandoned, because these techniques proved tobe potentially strong provocative challenges in patients with phaeochromocytoma 5.At present, scintigraphy with 123I-Meta-lodoBenzylGuanidine (MIBG), ComputedTomography (CT) en Magnetic Resonance Imaging (MRI) are the localizationtechniques of choice 6.

28 Chapter 2

In all but four patients, preoperative pharmacological preparation was employed,mostly with the alpha-blocker phenoxybenzamine, and the beta-blocker propranolol.The operative approach was transabdominal in 51 patients, thoracoabdominal in fourpatients and retroperitoneal in the other four cases. In case of intra-adrenalphaeochromocytoma, total adrenalectomy was performed. After removing the tumour,the abdominal cavity and retroperitoneum were thoroughly explored and examinedfor additional tumours. Forty-one patients underwent unilateral adrenalectomy (22right sided, 19 left sided). Eighteen out of the 23 patients diagnosed with the MENtype 2 syndrome underwent total bilateral adrenalectomy. In five patients, all treatedbefore 1980, only the macroscopically affected adrenal gland was removed. Sixpatients had extra-adrenal phaeochromocytomas, of which four arose from thesympathetic chain, one from the organ of Zuckerkandl with multiple paravertebral

FIGURE 1. Localization techniques in 85 tumours in 59 patients.

N = number of tumours

IVP = Intra-Venous urography

Angio = selective angiography

US = ultra sonography

CT = roentgen computer tomography

MIBG = meta-iodobenzylguanidine scintigraphy

MRI = magnetic resonance imaging

35

IVP Angio US CT MIBG MRI

30

25

20

15

10

5

0

False negative

Correct positive

N


tumours and one tumour was located distal of the renal pole. In this last patientresection was not feasible because of aortic involvement. Instead a nephrectomy wasperformed and biopsy of pathological tissue was taken. In three other patients anephrectomy had to be undertaken as well because of tumour size.

RESULTS

Figure 1 shows the results of the different localization techniques. Mean surgicalward stay was 12 days for patients without complications and 20 days for patients inwhom complications did occur. The peri-operative complication rate was considerable(Table 1). One patient died during emergency laparotomy for tumour bleeding due to

Table 1

Complications during and after surgery for phaeochromocytoma in 59 patients.

Peri-operative complications Number of patients

Per-operative hypertension 4

Post-operative hypotension 4

Pneumonia 9

Wound infection 4

Splenectomy 4

Urinary tract infection 4

Peroperative asystoly 1*

Congestive heart failure 2

Pneumothorax 2

Urinary retention 2

Pancreatitis 2

Intestinal bleeding 1

Paralytic ileus 1

Hyperglycemia 1

Atelectasis 1

Haemothorax 1

Pulmonary embolism 1

* One patient died

30 Chapter 2

irreversible asystoly without adrenal blockage. Phaeochromocytoma had beendiagnosed two years earlier, but elective operation had been refused by this patient.Three patients were lost to follow-up, 6 months to five years after operation. Allthree patients had benign phaeochromocytoma, without evidence of recurrence duringtheir limited follow-up. In the other 56 patients follow-up was complete either untilthe end of the study period (1996) or until death. The mean clinical follow-up was8.1 year (range 1.1-24 years). Besides the patient who died per-operatively, fourother patients died due to causes related to phaeochromocytoma or operation: twopatients died due to (recurrent) malignant phaeochromocytoma, one patient died dueto post-splenectomy sepsis nine years after operation. In this patient a splenectomyhad been performed during adrenalectomy. The fourth patient died from unrecognisedAddisonian crisis, one year after bilateral adrenalectomy for phaeochromocytoma.In 5 out of these 59 patients (8.5%) a recurrent phaeochromocytoma was diagnosed7. One of these recurring tumours was found in the group of patients with non-familiarphaeochromocytomas. In this patient, having been treated initially with a unilateralright-sided �total� adrenalectomy, recurrence of phaeochromocytoma was diagnosed16 years after initial operation. The tumour was removed from the right-sidedsympathetic chain near the previously resected adrenal gland.Eight out of the 23 MEN type 2 patients (35%) had to undergo a second operationdue to residual or recurrent phaeochromocytoma. In four of these patients there wasinsufficient relief of catecholamine excess and a second intervention was necessarywithin one year after the initial operation. In two patients an incompletely resectedtumour was found and removed. In two other patients a contralateral phaeochromo-cytoma was detected and removed. Four patients had recurrent phaeochromocytoma7,8,9 and14 years, respectively, after the initial operation. In three patientsphaeochromocytoma was found in the remaining contralateral adrenal gland andadrenalectomy was performed. The other patient showed unilateral recurrence ofphaeochromocytoma after an apparently incomplete bilateral adrenalectomy. All fiveMEN type 2 patients initially treated with unilateral adrenalectomy needed a secondoperation for contralateral residual or recurrent phaeochromocytoma. Three out ofthe five patients with malignant phaeochromocytoma are still alive, 2, 4 and 7 yearsafter operation respectively, without biochemical signs of recurrence.

DISCUSSION

At present, the diagnosis phaeochromocytoma can be accurately established bymeasurement of urinary catecholamines and their metabolites and plasmacatecholamines8. After the diagnosis has been confirmed, localization of the tumouris of utmost importance with regard to complete surgical resection.


From this study and from the literature it has become evident that at this moment nosingle localization technique exists which has a sufficiently high sensitivity andspecificity to correctly localize phaeochromocytoma. What needs to be foundtherefore, is an optimal combination of the localization modalities which we have atour disposal at this moment: MIBG-scintigraphy, CT and MRI.MIBG scintigraphy has proved to be useful for imaging of intra-, extra-adrenal andmultiple phaeochromocytomas, with a reported level of sensitivity of 87-91% andspecificity of 94-99% ( 9,10,11,12 ). In our series MIBG scintigraphy appeared to be themost accurate localization strategy for phaeochromocytoma, locating 29 out of 33tumours correctly. MIBG-scintigraphy was helpful particularly for the postoperativedetection of small remaining tumour residues. However, a small proportion ofphaeochromocytomas does not accumulate the radiopharmacon due to the biochemicalproperties of the tumour as a result of a low content of neurosecreting granula 11. Allthree false negative results of MIBG scintigraphy occurred in intra-adrenalphaeochromocytoma with a diameter of 2 to 4 cm. Moreover, MIBG scintigraphy isof limited value in discriminating medullary hyperplasia from phaeochromocytomain MEN type 2 patients.CT is able to detect 85-95% of intra-adrenal lesions greater than 1 cm, but sensitivitydecreases when lesions are smaller than 1 cm or when extra-adrenal lesions areinvolved13,14,15. The reported sensitivity of MRI for detecting intra-adrenal lesions isroughly 95%. CT and MRI offer more anatomical information than MIBGscintigraphy. Initial MIBG scintigraphy followed by restricted CT or MRI imagingwould therefore appear to be a solid strategy for detecting solitary phaeochromo-cytomas 17.Surgical extirpation of all pathological tissue is the only curative therapy. Peri-operative mortality is very low with adequate alpha and beta blockage. Until 1996the trans-abdominal approach was preferred by us because of the possibility ofexploring both adrenal areas, the lumbar and para-aortic ganglia, bladder and pelvisfor additional tumour. With the outstanding localization techniques available atpresent, we question the need for extensive abdominal exploration. As shown in thisseries, the trans-abdominal approach is associated with a considerable morbidity. Aretroperitoneal or laparoscopic approach seems to be preferred with these patients,because the higher morbidity of a traditional transabdominal exploration can thus beprevented19,20 ,21, 22.In MEN type 2 patients and unilateral phaeochromocytoma, operative managementis still controversial 4, 23,24,25,26,27,28.The risk of the late development of phaeochromo-cytoma in the opposite gland must be weighted against the risk of an Addisoniancrisis after bilateral adrenalectomy. Advocates of a unilateral adrenalectomy in thisspecific group of patients state that due to the slow progression of the clinical picture

32 Chapter 2

a contralateral phaeochromocytoma sometimes develops not until many years afterinitial operation, which is confirmed by our study.Unilateral adrenalectomy prevents the risk of Addisonian crisis due to inadequatesupplementation. Yearly screening for tumour recurrence minimises the risks ofcatecholamine crisis due to undetected contralateral phaeochromocytoma. In our seriesall MEN type 2 patients treated with unilateral adrenalectomy developedphaeochromocytoma in the contra-lateral gland and needed total adrenalectomy 7 to14 years after initial operation.In conclusion, transabdominal surgery for phaeochromocytoma is accompanied by aconsiderable morbidity and a low mortality rate. Long term results after surgery forphaeochromocytoma are excellent. No consensus exists about the optimal surgicalstrategy for MEN type 2 related phaeochromocytoma. With the outstandinglocalization techniques available, less invasive approaches seem to be justified andmay decrease morbidity.


REFERENCES

1. Karet FE, Brown MJ. Phaeochromocytoma, diagnosis and management .Postgraduate Medical J 1994, 70(823): 326-8.

2. Shapiro RW, Lorraine M. Management of pheochromocytoma. Endocrinol MetabClin North Am 1989; 18: 443-81.

3. Lips CJM, Veer JS, Struyvenberg A, et al. Bilateral occurence ofpheochromocytoma in patients with multiple endocrine neoplasia syndrome type2a (Sipple syndrome). Am J Med 1981; 70: 1051-59.

4. Modigliani E, Vasen HM, Raue K et al. Pheochromocytoma in multiple endocrineneoplasia type 2: European study. The Euromen Study Group. J Internal Med1995. 238(4): 363-7.

5. Shapiro B. Imaging of catecholamine-secreting tumours: use of MIBG indiagnosis and treatment. Ballieres clinical endocrinology and metabolism 1993;7: 491-507.

6. De Graaf JS, Klooster NJJ, de Lange WE, Piers DA, Zwierstra RP. Vergelijkingvan jood MIBG scintigrafie met computer tomografie bij de localisatiebepalingvan het feochromocytoom. Ned Tijdschr Geneeskd 1991; 135: 2383-87.

7. Brennan MF, Keiser HR. Persistent and recurrent pheochromocytoma: the roleof surgery. World J Surg 1982; 6: 397-402.

8. Karet FE, Brown MJ. Phaeochromocytoma: diagnosis and management. PostgradMed J 1994; 70: 326-28.

9. Cheugh SY, Thompson NW, Dmuchowski CF, Sisson JC. Spectrum ofpheochromocytoma in the 131I-MIBG era. World J Surg 1988; 12: 546-51.

10. Chatal JF, Charbonnel B. Comparison of iodobenzylguanidine imaging withcomputed tomography in locating pheochromocytoma. J Clin Endocrinol Metab1985; 61: 769-72.

11. McEwan AJ, Shapiro B, Sisson JC, Beierwaltes WH, Ackerdy DM. Radio-iodobenzylguanidine for the scintigraphic location and therapy of adrenergictumors. Semin Nucl Med 1985; 15: 132-54.

12. Clesham GJ, Kennedy A, Lavender JP et al. Meta-iodobenzylguanidine (MIBG)scanning in the diagnosis of phaeochromocytoma. J Hum Hypert 1993; 7: 353-56.

34 Chapter 2

13. Laursen K , Damgaard-Pederson K. CT for phaeochromocytoma diagnosis. JComp Ass Tomogr 8: 895-99; 1984. AJR 1996: 166; 531-536.

14. Moulton JS. CT of the adrenal glands. Seminars in Roentgenology 1988; 23:288-303.

15. Korobkin M, Broduer FJ, Yutzy GG et al. Differentiation of adrenal adenomasfrom nonadenomas using CT attenuation values. Radiology 1995: 197; 411-418.

16. Falke THM, Gils AP van. MRI of functioning paragangliomas. Magn Reson Q1990; 6: 35-64.

17. Reinig JW, Stutley JE, Leonhardt CM, et al. Differentiation of adrenal masseswith MR imaging: comparison of techniques. Radiology 1994; 192: 41-46.

18. Samaan NA, Hickey RC, Shutts PE. Diagnosis, localization and managementof pheochromocytoma. Pitfalls and follow-up in 41 patients. Cancer 1988; 62:2451-60.

19. Irvin GL, Fishman LM, Sher JA, Yeung LK, Irani H. Pheochromocytoma, lateralversus anterior operative approach. Ann Surg 1989; 209: 774-78.

20. Fahey TJ, Reeve TS, Delbridge L. Adrenalectomy: expanded indications for theextra-peritoneal approach. Aust N Z J Surg 1994; 64: 494-97.

21. Orchard T, Grant CS, van Heerden JA et al. Pheochromocytoma, continuingevolution of surgical therapy. Surgery 1993; 114: 1153-9.22.

22. Obara T, Kanbe M, Okamoto T et al. Surgical strategy for pheochromocytoma:emphasis on the pledge of flank extraperitoneal approach in selected patients.Surgery 1995; 118: 1083-9.

23. Tibblin S, Dymling JF, Ingemansson S, et al. Unilateral versus bilateraladrenalectomy in multiple endocrine neoplasia IIa. World J Surg 1983; 7: 210-08.

24. Jansson S, Tisell LE, Fjälling M, et al. Early diagnosis of and surgical strategy foradrenal medullary disease in MEN II gene carriers. Surgery 1988; 103: 11-18.

25. Lairmore TC, Ball DW, Baylin SB, Wells SA. Management of pheochromo-cytomas in patients with multiple endocrine neoplasia type II syndromes. AnnSurg 1993; 217: 595-603.


26. Van Heerden JA, Sizemore GW, Carney JA, Grant CS, ReMine WH, Sheps SG.Surgical management of the adrenal glands in the multiple endocrine neoplasiatype II syndrome. World J Surg 1984; 8: 612-21.

27. Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in mutipleendocrine neoplasia type II. Appropriate management. Endocrinology andMetabolism Clinics of North America 1994; 23: 167-76.

28. Telenius-Berg M, Ponder MA, Berg B et al. Quality of life after bilateraladrenalectomy in MEN II. Henry Ford Hosp Med J 1989: 37: 169.

36 Chapter 2

Comparison of MIBG scintigraphy and Computed Tomography 37

Comparison of Meta-Iodo-Benzyl-Guanidinescintigraphy and Computed Tomography forlocalization of phaeochromocytoma

3

38 Chapter 3

Abstract

Objective: To compare the results of CT scanning and MIBG scintigraphy in thelocalization of phaeochromocytoma.Design: Retrospective study.Setting: University Hospital.Subjects: 24 patients with phaeochromocytoma who presented between 1983 and 1990.Results: In 21 out of 24 patients MIBG scintigraphy provided accurate localization.In 16 out of 18 patients who underwent CT scanning a correct localization wasobtained.Conclusion: Sensitivity of the two methods is about equal. In patients with non-familial phaeochromocytoma it is advisable to use MIBG scintigraphy as initiallocalization technique, combined with CT directed by scintigraphic results , if moreanatomical information is needed.

Graaf JS de, Klooster NJJ, Lange WE de, Piers DA, Zwierstra RP.Nederlands Tijdschrift voor Geneeskunde 1991; 135: 2383-2387. (adapted version)


INTRODUCTION

Since the first successful operation for phaeochromocytoma in 1926 by César Roux,complete surgical extirpation of all catecholamine-producing tumour tissue is stillthe only curative treatment1. Phaeochromocytoma is diagnosed on biochemicalgrounds by measurement of urinary catecholamines and catecholamine metabolitesand plasma catecholamines. After the diagnosis has been confirmed, localization ofthe tumour is of utmost importance for adequate resection.Angiography with or without venous sampling is technically difficult and can provokehypertensive crisis in these patients 3,4. These techniques have therefore beenabandoned and replaced by less invasive localization modalities. Ultrasonography isa non-invasive technique but its sensitivity is low in small adrenal lesions. Moreover,ultrasonography has a high inter-observer bias 3,5. At present (1991), ComputedTomography (CT) and 123I meta-iodo-benzyl-guanidine (MIBG) scintigraphy are themethods of choice for localizing phaeochromocytoma 2,8-12. CT can detect 85% to95% of intra-adrenal lesions larger than 1 centimetre. Sensitivity decreases in smallerlesions or in case of extra-adrenal phaeochromocytoma 3,4. Meta-iodo-benzyl-guanidine has a high affinity for chromafin granula of the adrenal medulla andsympathetic tissue. Tumours derived from these tissues, like phaeochromocytoma,neuroblastoma and paraganglioma, have a high up-take of this tracer, thereby usingthe functional characteristics of these tumours for their localization 7. Sensitivity of131 I MIBG scintigraphy for detecting phaeochromocytoma is reported to be high(87%-91%). At present, 123I is the preferred isotope labeling compared to 131 I becauseof the lower radiation load with 123I, which enables to use a higher dose.This study compares the advantages and disadvantages of MIBG scintigraphy andComputed Tomography for the localization of phaeochromocytoma.


Between 1983 and 1990, MIBG scintigraphy was performed in all 24 patients withbiochemically proven phaeochromocytoma at the University Hospital Groningen,The Netherlands.The patient group comprised 13 women and 11 men with a mean age of 43 years(range 18-73). In 8 patients phaeochromocytoma was associated with the multipleendocrine neoplasia (MEN) type 2 syndrome. In all patients the diagnosis phaeochromo-cytoma was confirmed by detection of elevated levels of urinary catecholamines(metanephrines and normetanephrines) (Figure 1). Two patients had previous surgeryfor phaeochromocytoma; in both patients a unilateral adrenalectomy had beenperformed for phaeochromocytoma. The procedure for MIBG scintigraphy and CTis described in detail elsewhere (Chapter 4). All patients underwent MIBG scintigraphy

40 Chapter 3

(before 1985 with 131I in 9 patients, from 1985 onwards with 123I in 15 patients). In 18patients preoperative CT scans were obtained, directed by the scintigraphic outcome.Thus, in 15 patients only the adrenal glands were visualized by CT whereas in 3patients with extra-adrenal MIBG uptake a CT scan of the entire abdomen wasobtained. All 24 patients underwent surgery; in 21 patients adrenalectomy wasperformed (14 unilateral, 7 bilateral), in two patients extra-adrenal localizedphaeochromocytoma was removed and in one patient only biopsy of the tumour wasfeasible because of aortic involvement. All patients underwent laparotomy and in allthe diagnosis phaeochromocytoma was confirmed by histopathological examination.Three patients had malignant phaeochromocytoma as proven by metastases. In allpatients urinary catecholamine metabolites were measured post-operatively (Figure 1)15.In three patients catecholamine excess persisted, and residual phaeochromocytomawas suspected. Re-exploration was undertaken in all three after MIBG scintigraphyand Computed Tomography. In two patients incompletely resected phaeochromo-cytoma was found and removed. The third patient showed no postoperative uptakeof MIBG nor a lesion at CT. In this patient the contralateral adrenal gland was removed.Histological examination showed no pathology in this gland. All MIBG and CT studieswere separately evaluated by an expert nuclear medicine specialist and a radiologistwithout prior knowledge of the histopathological diagnosis.

Mediane urine-metanefrine nmol/mol creat

pre-operative

10000

1000

100

10

1

post-operative

FIGURE 1A. Logarithmic reflection of median values (nmol/mol creat.) of metanephrines in urinesamples of 24 patients with phaeochromocytoma.Normal value (N) = < 70 nmol/ mol creat.

N


RESULTS

Scintigraphy was true positive in 21of 24 patients. In two out of three patients withfalse negative scintigraphic results (both patients with MEN type 2), only unilateraluptake of the tracer was seen. Computed Tomography showed in one of these patientsa small contra-lateral lesion. The third patient had a unilateral phaeochromocytomawith a diameter of 2.5 centimetre that was detected only by CT. In 16 patients CTwas correctly positive. In two patients, CT scanning was not able to detect intra-adrenal lesions smaller than 1 centimetre. Both lesions were detected by MIBGscintigraphy. Table 1 compares the results of MIBG scintigraphy and CT in 18 patientswho underwent both localization techniques.

DISCUSSION

Approximately 90% of phaeochromocytomas are located intra-adrenal 3,11. Thesetumours also occur in 10% of cases associated with a number of familial neurocresto-pathic syndromes, including the MEN type 2 syndrome. Ten percent of phaeochromo-cytomas are located extra-adrenal or are malignant2. At present, there is no consensusabout the optimal pre-operative localization strategy. In the present patient group,MIBG scintigraphy localized the tumour correctly in 85% of patients. This percentage

Mediane urine-normetanefrine nmol/mol creat

10000

1000

100

10

FIGURE 1B. Logarithmic reflection of median values (nmol/mol creat.) of normetanephrines in urinesamples of 24 patients with phaeochromocytoma.Normal value (N) = < 260 nmol/mol creat.

N

pre-operative post-operative

42 Chapter 3

is in accordance with other reports 3,14. The cause of the three false negative results isnot clear. A possible explanation is the wide range in uptake of MIBG in phaeochromo-cytoma. This uptake correlates with the content of neuro-secretory granula, and isnot related to plasma levels of catecholamines16. Large tumours with an intensiveuptake of the tracer (as seen in solitary phaeochromocytoma) offer an unambiguousscintigraphic appearance. Scintigraphic differentiation between smallphaeochromocytoma and normal or hyperplastic adrenal glands is often difficult asseen in this series. Mean tumour diameter in correctly positive scintigraphic resultswas 6 cm. Tumour localization was correctly detected in 90% of patients with CTscanning. These data match those of previously reported series (sensitivity 85% -95%) 3,8,13. CT was not able to detect an adrenal lesion smaller than 1 cm in MENtype 2 patients. These familial tumours differ from their solitary counterpart bydevelopment out of hyperplasia and moreover their presentation is different. Theimpact of these differences on localization strategy in MEN type 2 patients will befurther discussed in chapter 4.In conclusion, MIBG scintigraphy and CT both yield a high accuracy for the detectionof phaeochromocytoma. Routine usage of both modalities in all patients is notwarranted. In patients with non-familial phaeochromocytoma it is advisable to useMIBG scintigraphy as initial localization technique because of the possible extra-adrenal location of these tumours. CT can be directed by the scintigraphic results, ifmore anatomical information is needed. In familial phaeochromocytoma, MIBG isthe most sensitive method for detecting hyperfunctioning adrenal tissue, butscintigraphy can not differentiate between hyperplasia and small phaeochromocytoma.Therefore, localization strategy in these patients may be different from preoperativelocalization in sporadic phaeochromocytomas.

Table 1

Results of MIBG scintigraphy and CT in 23 phaeochromocytomas in 18 patients.

Tumour and localization MIBG CP MIBG FN CT CP CT FN

Benign Intra-adrenal 9 1 10 -

Extra-adrenal 1 - 1 -

Malignant Intra-adrenal 2 - 2 -

Extra-adrenal 2 - 2 -

Familial (MEN 2) Intra-adrenal 7 1 5 3

Total 21 2 20 3

CP= Correct Positive, FN =False Negative


MIBG scintigraphy is the technique of choice for localization of post-operativeresidual tumour, because these tumour deposits are often small and the anatomicalrelations have been disturbed by previous surgery11.

ADDENDUM

In 1991 Magnetic Resonance Imaging was not yet widely available and the results ofMRI for detecting phaeochromocytoma therefore were not included in this study. Atpresent, Magnetic Resonance Imaging (MRI) can be regarded as being preferableover computed tomography for detection of adrenal lesions. MRI has a high sensitivityfor detecting adrenal lesions due its multiplanar scan technique 17,18. Sensitivity andspecificity of MRI equals the results obtained by computed tomography in detectingadrenal lesions 6,7.

44 Chapter 3

REFERENCES

1. Welbourn RB. Early surgical history of phaeochromocytoma. Br J Surg 1987;74: 594-596.

2. Bravo EL, Gifford RW. Phaeochromocytoma, diagnosis, localization andmanagement. N Engl J Med 1984; 311: 1298-1303.

3. Shapiro RW, Lorraine M. Management of phaeochromocytoma. EndocrinolMetab Clin North Am 1989; 18: 443-81.

4. Velchik MG, Alavi A, Kressel HY, Engelman K. Localization of pheochromo-cytoma: MIBG ,CT and MRI correlation. J Nucl Med 1989; 31: 328-36.

5. Bowerman RA, Silver TM, Jaffe MH, Stuck KJ, Hinerman DL. Sonography foradrenal phaeochromocytomas. AJR 1981; 137: 1227-1231.

6. Falke THM, Gils AP van. MRI of functioning paragangliomas. Magn Reson Q1990; 6: 35-64.

7. Sisson JC, Frager MS, Valk TW et al. Scintigraphic localization of phaeochromo-cytoma. N Engl J Med 1981; 305: 12-17.

8. Stewart BH, Bravo EL, Haaga J, Meaney TF, Tarazi R. Localization ofphaeochromo-cytoma by computed tomography. N Engl J Med 1978; 299:460-461.

9. Piers DA. Scintigrafische mogelijkheden bij de localisatie van feochromo-cytomen en bijschildklieradenomen. Ned Tijdschr Geneesk 1985; 129: 199-200.

10. Cheung SY, Thopson NW ,Dmuchowski CF, Sisson JC. Spectrum of phaeochromo-cytoma in the

131I-MIBG era. World J Surg 1988; 12: 546-551.

11. Chatal JF, Charbonnel B. Comparison of Iodobenzylguanidine Imaging withComputed Tomography in locating Pheochromocytoma. J Clin Endocrinol Metab1985: 61; 769-772.

12. Quint L, Glazer GM, Francis IR, Shapiro B, Clenevert TL. Pheochromocytomaand paraganglioma: Comparison of MR Imaging with CT and I 131 MIBGScintigraphy. Radiology 1987; 165: 89-93.

13. Korabkin M, White EA, Kressel HY et al. Computed tomography in the diagnosisof adrenal disease. AJR 1979; 132: 231-238.


14. Shapiro B, Copp JE, Sisson JC, Eyre PL, Wallis J, Beierwaltes WH. Iodine 131metaiodobenzylguanidine for the locating of suspected pheochromocytoma:experience in 400 cases. J Nucl Med 1985; 26: 576-585.

15. Muskiet FAJ. Determinations of catecholamines and catecholamine (precursor)metabolites in biological fluids and their clinical applications. Thesis, GroningenUniversity, 1979.

16. Bomanji J, Leviston DA, Flatman WD et al. Uptake of iodine 123 MIBG byphaeochromocytomas, paragangliomas and neuroblastomas: a histopathologicalcomparison. J Nucl Med 1987; 28: 973-978.

17. Huch Boni RA, Debatin JF, Krestin GP: Contrast enhanced MR imaging of thekidneys and adrenal glands. Magn Imaging Clin N Am 1996; 4: 101-131.

18. Maurea S, Cuocolo A, Reynolds JC et al. Iodine 131-metaiodobenzylguanidinescintigraphy in preoperative and postoperative evaluation paragangliomas:comparison with CT and MRI. J Nucl Med 1993; 34: 173.

46 Chapter 3

Imaging Phaeochromocytoma in MEN type 2 patients 47

Limited Role for Meta-Iodo-Benzyl-GuanidineScintigraphy in Imaging Phaeochromocytoma inMEN type 2 patients

4

48 Chapter 4

Abstract

Objective: To compare diagnostic applicability of computed tomography (CT) andmagnetic resonance imaging (MRI) combined with meta-iodo-benzyl-guanidinescintigraphy (MIBG scintigraphy) in the pre-operative localization of MEN type 2-related phaeochromocytoma.Design: Retrospective.Setting: University Hospital.Materials: 17 MEN type 2 patients (33 adrenal glands) who underwent surgery forphaeochromocytoma. MIBG scintigraphy, CT and MRI were used to localizephaeochromocytoma. On histopathology, an adrenomedullary lesion > 1 cm wasclassified as phaeochromocytoma.Main outcome measures: Sensitivity, specificity and diagnostic accuracy of CT andMRI combined and MIBG scintigraphy compared to histopathological findings.Results: Sensitivity of CT and MRI combined (27 adrenal glands) was 87%, with aspecificity of 100% and a diagnostic accuracy of 89%. MIBG scintigraphy (31 adrenalglands) had a sensitivity of 92%, a specificity of only 17% and a diagnostic accuracyof 77%.Conclusion: If the surgical policy is followed that unilateral adrenalectomy isperformed when only one adrenal gland contains phaeochromocytoma, MRI shouldbe the method of choice. Scintigraphy can then be restricted to those cases withnegative MR.

J.S.de Graaf, R.P.F.Dullaart, T.Kok, D.A.Piers, R.P.Zwierstra.Submitted for publication


INTRODUCTION

Phaeochromocytoma will develop in 30% to 50% of patients with Multiple EndocrineNeoplasia type 2 (MEN 2) 1,2 At present , there is no consensus regarding the optimalpreoperative localization strategy for these catecholamine secreting tumours in thispatient category. Modern techniques for localization of phaeochromocytoma areComputed Tomography (CT), Magnetic Resonance Imaging (MRI) and Meta -Iodo-Benzyl-Guanidine (MIBG) scintigraphy. All these modalities yield an accuracy ofover 80% in detecting phaeochromocytoma, each with its own advantages andlimitations 3-11.Thus far, it has been our surgical policy to perform total bilateral adrenalectomy inMEN 2 carriers in whom phaeochromocytoma is diagnosed. While this procedurehas the advantage that development of phaeochromocytoma in an initially uninvolvedadrenal gland is prevented, life long dependence on gluco-and mineralocorticosteroidsreplacement therapy may be associated with a considerable risk of Addisonian crisis12-14. To avoid these risks, an alternative policy of performing only unilateral adrena-lectomy in cases of unilateral phaeochromocytoma has been advocated 13. If thisstrategy is followed, it is of major clinical interest to compare preoperative localizationtechniques of MEN 2 related phaeochromocytomas to avoid unnecessary adrenalec-tomies. In this study, we have compared diagnostic accuracy of MIBG scintigraphywith CT and MRI combined in all MEN patients who underwent bilateraladrenalectomy between 1983 and 1996 at our institution.


From 1983-1996 16 MEN type 2A patients an 1 MEN type 2B patient (mean age 38years, range 19-61) underwent surgery for phaeochromocytoma after localizationwith MIBG-scintigraphy combined with CT or MR Imaging. These cases belongedto MEN 2 families and in all families a clinical diagnosis of MEN syndrome wasconfirmed by the presence of a RET mutation when this genetic marker becameavailable. Bilateral adrenalectomy had been performed in all but one patient. Thispatient underwent unilateral adrenalectomy following contralateral adrenalectomyfor phaeochromocytoma ten years earlier. In all patients, phaeochromocytoma waspre-operatively diagnosed by elevated levels of urinary catecholamine metabolitesand/or plasma catecholamine levels. In 10 patients, no clinical symptoms related tophaeochromocytoma were present. In these patients phaeochromocytoma wasdiagnosed biochemically as part of their clinical follow-up.The sequence of localization examinations was the same as used in non-familialsporadic phaeochromocytoma in our institution. MIBG scintigraphy was the initialexamination followed by CT (before 1987, 4 patients) or MR Imaging (1987- 1996

50 Chapter 4

in 9 patients) directed by the scintigraphic results. In one pregnant patient only MRImaging was performed preoperatively. Three patients underwent only MIBGscintigraphy preoperatively.CT studies were performed with a Philips scanner (Tomoscan 350) with the use ofcontinuous 5-10 mm sections through the adrenal region in the axial plane. MR Imageswere obtained with a 1.5 Tesla superconducting magnet (Philips Gyroscan) with aspin-echo pulse sequence (TR 650-865 msec; TE 20-40 msec and TR 1885-2400msec; TE 80-110 msec) in order to achieve T1 and T2 weighted images, respectively.The images were formatted in axial and coronal planes with a 5 mm slice thickness.MIBG was labelled with 123I. To perform MIBG scintigraphy thyroidal iodine uptakewas blocked by administration of potassium iodide-solution, followed by whole bodyscintigraphy 6 and 24 hours after intravenous injection of 150 MBq of theradiopharmacon. Planar images were obtained by a gamma camera (Siemens LFOVand Siemens DIACAM)). All CT and MRI images were re-evaluated by one expertradiologist, whereas MIBG studies were separately evaluated by an expert nuclearmedicine specialist without prior knowledge of the histopathological diagnosis. Theradiologist and nuclear medicine specialist described their findings independently.CT and MRI images were described as positive or negative. MIBG scintigrams werecategorized as normal, slightly increased uptake or definitely increased uptake. Aslightly increased uptake was categorized as �positive�. These results were comparedwith the histopathological findings after surgery. The histopathological classificationwas as follows: nodules measuring more than 1 cm in diameter were designatedphaeochromocytoma, nodules measuring less than 1 cm were designated nodularmedullary hyperplasia and the term �diffuse medullary hyperplasia� was applied tothose cases in which diffuse enlargement of the medulla without a nodule waspresent15.

RESULTS

Thirty-three adrenal glands from 17 patients were available for histopathologicalexamination. Twenty-seven specimens showed phaeochromocytoma. Mean tumoursize was 3.1 cm (range 1-13 cm). In four adrenal glands (4 patients) diffuse medullaryhyperplasia was seen, one adrenal gland was classified as nodular hyperplasia, andone adrenal gland was histopathologically normal. There was no evidence of extra-adrenal phaeochromocytoma or malignancy in any of these patients, both pre- andperoperatively as well as during follow-up (mean 8 years, range 1.5-14 years). Table1 shows the results of pre-operative localization in these 17 patients with CT or MRIand MIBG scintigraphy. MIBG scintigraphy could not differentiate between medullaryhyperplasia and phaeochromocytoma in 5 adrenal glands. Histopathologic


Table 1

Sensitivity , specificity and diagnostic accuracy of Magnetic Resonance Imaging / Computed Tomographyand MIBG scintigraphy in pre-operative localization of histopathologically proven phaeochromocytoma ina total of 33 adrenal glands in 17 MEN type 2 patients

Phaeochromocytoma

Pos Neg

MRI /CT Yes 20 0

(n=27) No 3 4

Sensitivity 87%

Specificity 100%

Accuracy 89%

Pos Neg

MIBG Yes 23 5

(n=31) No 2 1

Sensitivity 92%

Specificity 17%

Accuracy 77%

examination showed hyperplasia in four out of these five adrenal glands. In oneadrenal gland a small phaeochromocytoma was found.All three false negative results of morphological imaging procedures (CT: 1/8 andMRI: 2/19) occurred in asymptomatic and small phaeochromocytomas. In these threecases, MIBG scintigraphy showed a slightly increased uptake. MRI was true negativein four adrenal glands. In three out of these four glands MIBG scintigraphy could notdiscriminate between hyperplasia and phaeochromocytoma. When intermediate MIBGresults were classified as positive and hyperplasia was not classified asphaeochromocytoma, MIBG scintigraphy had a high sensitivity but a very lowspecificity (Table 1). CT and MRI combined had a similar sensitivity compared toMIBG scintigraphy but also a high specificity.

DISCUSSION

In implementing the surgical policy of performing preventive bilateral adrenalectomyin MEN type 2-related phaeochromocytoma, preoperative determination of uni- orbilateral involvement provides no relevant information and has no influence on thechoice of surgical procedure. Moreover, the risk of extra-adrenal involvement andmalignancy is very low in these familial phaeochromocytomas, in contrast to solitaryphaeochromocytomas 16,17,18,19. Therefore, the need for preoperative localization ofMEN 2-related phaeochromocytomas can be questioned when bilateral preventiveadrenalectomy is the operation of choice.If bilateral preventive adrenalectomy is not performed in MEN 2 patients withunilateral involvement, then determination of the presence of unilateral or bilateralphaeochromocytoma(s) becomes very important. MIBG scintigraphy is the most

52 Chapter 4

MRI ofadrenal glands

Bilateral lesion

Follow-up

Unilateral lesion

Bilateral or subtotaladrenalectomy

Unilateraladrenalectomy

MIBGscintigraphy

Abnormalcatecholamines

Normalcatecholamines

No uptakeUni or bilateral

uptake

MIBGscintigraphy

Follow-up Follow-upUni bi or subtotal

adrenalectomy

No contraadrenal uptake

Contralateraluptake

Follow-upContralateral

(subtotal)adrenalectomy

No lesion

FIGURE 1. Adrenal imaging screening in clinically suspected and / or biochemically proven pheochromocytoma.

sensitive functional imaging procedure for hyperfunctioning adrenal medulla andextra-adrenal phaeochromocytomas 2,20. Therefore, scintigraphy can be of great valuefor localizing sporadic phaeochromocytoma since these tumours are extra-adrenal inover 10% of patients. In contrast, the present study demonstrates that MIBGscintigraphy is of limited value in discriminating medullary hyperplasia from a smallphaeochromocytoma as seen in MEN 2 patients. Medullary hyperplasia is regardedas a histopathological precursor of phaeochromocytoma but progression tophaeochromocytoma does not necessarily occur 15. Adrenalectomy in case of positiveMIBG scintigraphy will lead to excision of not only phaeochromocytomas, but alsohyperplastic adrenals as shown in our study. MRI and CT both have a high sensitivityin detecting adrenal phaeochromocytoma 6,7 . The obvious advantage of thesemorphological imaging procedures over MIBG scintigraphy is the high specificitywith respect to differentiating medullary hyperplasia from small phaeochromocytomas.A limitation of our retrospective study design is the comparison of CT techniques as


used before 1987 with MR-Imaging, but recent literature has shown current CT andMRI techniques to be equivalent in locating adrenal tumours 18. Advantages of MRIover CT and MIBG are the avoidance of ionizing radiation and no need for intra-venous iodinated contrast agents. Moreover, with this technique multiplanar imagescan be obtained. Due to these advantages MR Imaging can be regarded as the preferredimaging procedure in MEN 2 carriers with elevated catecholamine levels 7. If theapproach of carrying out unilateral adrenalectomy in cases of unilateral phaeochromo-cytoma is followed, MIBG scintigraphy should be restricted to those MEN 2 patientswith biochemically proven phaeochromocytoma in whom MRI fails to detect anadrenal mass. Figure 1 is an algorithm following these suggestions.In conclusion, localization strategy for MEN 2-related phaeochromocytomas differsfrom localization of solitary phaeochromocytomas and is strongly related to surgicalpolicy. When standard bilateral adrenalectomy is proposed, preoperative localizationof phaeochromocytoma generally has no or very limited clinical implications andcan be avoided. When only the involved gland is removed, MRI should be the primarychoice for localizing phaeochromocytoma. MIBG remains useful in case of non-diagnostic MRI findings.

54 Chapter 4

REFERENCES

1. Lips CJM, Van der Sluys Veer J, Struyvenberg A, et al. Bilateral occurence ofpheochromocytoma in patients with the multiple endocrine neoplasia syndrometype 2A (Sipple�s syndrome). Am J Med 1981; 70: 1051-1060.

2. Evans DB, Lee JE, Merell, RC, Hickey RC. Adrenal medullary disease in multipleendocrine neoplasia type 2. Endocrin Metab Clinics North Am 1994; 23: 167-176.

3. Chatal JF, Charbonnel B. Comparison of Iodobenzylguanidine Imaging withComputed Tomography in locating Pheochromocytoma. J Clin Endocrinol Metab1985; 61: 769-772.

4. Chatal JF. Can we agree on the best imaging procedure(s) for localisation ofpheochromocytomas? J Nucl Med 1993; 34: 180-181.

5. Huch Boni RA, Debatin JF, Krestin GP. Contrast enhanced MR imaging of thekidneys and adrenal glands. Magn Imaging Clin N Am 1996; 4: 101-131.

6. Francis IR, Korobkin M. Pheochromocytoma. Radiol Clin North Am 1996; 34:1101-1112.

7. Van Gils APG, Falke THM, van Erkel AR et al. MR Imaging and MIBGscintigraphy of pheochromocytoma and extra-adrenal functioningparagangliomas. Radiographics 1991; 11: 37-57.

8. Maurea S, Lastoria S, Cuocolo A, Celentano L, Salvatore M. The diagnosis ofnon-functioning pheochromocytoma. The role of I-MIBG scintigraphy. ClinNucl Med 1995; 20(1): 22-24.

9. Sone H, Okuda Y, Nakamura Y, Ishikawa N, Yamaoka T, Kawakami Y et al.Radio-iodinated metaiodobenzylguanidine scintigraphy for pheochromocytoma.Hormone Res 1996; 46: 138-142.

10. Quint L, Glazer GM, Francis IR, Shapiro B, Clenevert TL.Pheochromocytomaand paraganglioma: Comparison of MR Imaging with CT and I 131 MIBGScintigraphy. Radiology 165; 89-93: 1987.

11. Velchik MG, Alavi A, Kressel HY, Engelman K. Localisation of pheochromo-cytoma: MIBG ,CT and MRI correlation. J Nucl Med 1989; 31: 328-36.


12. Jansson S, Tisell LE, Fjalling M, Lidberg S, Jacobsson L, Zachrisson BF. Earlydiagnosis and surgical strategy for adrenal medullary disease in MEN II genecarriers. Surgery 1988; 103: 11-18.

13. Tibblin S, Symling JF, Ingermansson S Telenius Berg M. Unilateral versusbilateral adrenalectomy in multiple endocrine neoplasia IIA. World J Surg 1983;7: 201-206.

14. Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical sparingadrenalectomy for patients with bilateral pheochromocytoma. Surgery 1996;120: 1067-1071.


16. Cassanova S, Rosenberg-Bourgin M, Farkas DC, Calmettes C, Feingold N,Heshmati M et al. Pheochromocytoma in multiple endocrine neoplasia type 2a;survey of 100 cases. Clin Endocrinol (oxf) 1993; 38: 531-537.

17. Heerden JA van, Sizemore GW, CarneyJA, Grant CSReMine WH, Sheps SG.Surgical management of the adrenal glands in the multiple endocrine neoplasiasyndrome type II syndrome. World J Surg 1984; 8: 612-621.

18. Maurea S, Cuocolo A, Reynolds JC et al. Iodine 131-metaiodobenzylguanidinescintigraphy in preoperative and postoperative evaluation paragangliomas:comparison with CT and MRI. J Nucl Med 1993; 34: 173.

19. Modegiani E, Vasen HFA, Raue K et al. Pheochromocytoma in MultipleEndocrine Neoplasia type 2: European study. J Int Med 1995; 238: 363-367.

20. Shapiro B, Copp JE, Sisson JC, Eyre PL, Wallis J, Beierwaltes WH. Iodine 131

metaiodobenzylguanidine for the locating of suspected pheochromocytoma:experience in 400 cases. J Nucl Med 1985; 26: 576-585.

56 Chapter 4

Complications after bilateral adrenalectomy 57

Complications after bilateral adrenalectomy forPhaeochromocytoma in Multiple Endocrine NeoplasiaType 2: a plea to conserve adrenal function.

5

58 Chapter 5

Abstract

Objective: To evaluate the complications of the adrenocortical supplementationtherapy that is needed after bilateral adrenalectomy for phaeochromocytoma inpatients with multiple endocrine neoplasia (MEN) type 2 syndrome.Design: Retrospective study.Setting: University Hospital.Materials: 28 patients with MEN 2 who underwent total adrenalectomy forphaeochromocytoma between 1972 and 1996.Main outcome measures: Perioperative morbidity and mortality, histopathologicalfindings, complications of adrenocortical supplementation therapy.Results: 22 patients had bilateral phaeochromocytomas on histopathologicalexamination (79%) and 6 patients had initially unilateral phaeochromocytomas. Therewas no operative mortality. Morbidity was 25%, including one splenic injury thatnecessitated splenectomy. During a mean follow-up period of 14 years (range 1-26)nine patients (32%) had a total of 19 Addisonian crises that necessitated admissionto hospital. One patient died of an unrecognised Addisonian crisis.Conclusion: Complications of adrenocortical supplementation therapy areconsiderable, but they can be reduced when unilateral adrenalectomy is done for aunilateral phaeochromoytoma in patients with MEN 2 syndrome, provided that theyare carefully followed up.

Graaf JS de, Dullaart RPF, Zwierstra RP.European Journal of Surgery 1999 in press.


INTRODUCTION

Between 30% and 50% of patients with multiple endocrine neoplasia type 2 syndrome(MEN 2) will develop phaeochromocytoma and the adrenomedullary pathology isusually diffuse and bilateral 1,2,6,14. Nevertheless, the clinical development ofphaeochromocytoma from medullary hyperplasia often occurs asymmetrically or notat all 1. MEN 2- related phaeochromocytomas are unilateral at presentation inapproximately a third of affected patients 8,11,12.The appropriate surgical treatment is still controversial. To prevent the risk ofrecurrence of phaeochromocytoma in the patients with MEN 2 syndrome, totalbilateral adrenalectomy has been advocated, even when only a unilateral tumour hasbeen diagnosed 7,9. This necessitates lifelong glucocorticoid and mineralocorticosteroidreplacement and is associated with the risk of Addisonian crisis. To avoid thesecomplications, more conservative surgical strategies have been proposed includingunilateral and subtotal adrenalectomy in patients with only unilateral involvement5,8,10-13,17,22,24.The aim of this study was to evaluate our policy of routinely removing both adrenalsin patients with MEN 2 and phaeochromocytoma.


From 1972 - 1996 28 MEN 2 patients (27 MEN type 2A, 1 MEN type 2B, 16 women,12 men, mean age 38, range 11-68 years) were operated on for phaeochromocytomaat the University Hospital Groningen, The Netherlands.Medical records of these patients were reviewed and histopathological findings,perioperative morbidity and mortality, recurrence of phaeochromocytoma andcomplications related to adrenocortical supplementation were recorded.Most patients were followed up at our hospital regularly (once or twice a year). If wedid not follow them, they were refered to and followed up by specialists in internalmedicine elsewhere, also on a regular basis. These physicians were all interviewed.In all patients phaeochromocytoma was diagnosed preoperatively by raised excretionof urinary catecholamine metabolites measured during annual screening in potentialMEN type 2 carriers. Transabdominal total bilateral adrenalectomy had been done inall but three patients. In these three patients, all treated before 1980, only themacroscopically involved adrenal gland was excised. All resected adrenal glandswere examined histopathologically, and classified as follows: nodules measuringless than 1 cm were designated � nodular medullary hyperplasia� and the term �diffusemedullary hyperplasia� was applied to those adrenals in which diffuse enlargementof the medulla was evident. Follow-up included medical history, physical examination,and measurement of excretion of urinary catecholamine metabolites.

60 Chapter 5

After bilateral adrenalectomy all patients were given glucocorticoid andmineralocorticosteroid supplements together with instructions to double the dose ofglucocorticoids if they were physically stressed and to seek medical advice if theydeveloped persistent illness or vomiting. Maintenance replacement therapy includedcortisone-acetate 25 to 37.5 mg daily in divided doses in combination withfludrocortisone acetate (0.10 � 0.20 mg daily) or periodic intramuscular injections ofmineralocorticoids (before 1987).After adrenalectomy a patient was diagnosed as having an Addisonian crisis if aclinical syndrome consisting of hypotension, weakness, apathy, anorexia, or feverdeveloped15.

RESULTS

The 28 patients were followed up until January 1998 or death with a mean follow-upperiod of 14 years (range 1-26). There was no operative mortality and the morbidityrate was 25% (Table 1).Four of the 25 patients treated initially with bilateral adrenalectomy needed re-operation for residual or recurrent phaeochromocytoma. In three patients excretionof urinary catecholamine metabolites did not return to the reference range, and residual

Table 1

Operative morbidity and mortality after adrenalectomy for phaeochromocytoma in 28 MEN type 2 patients.

Number (%) of patients

Bilateral adrenalectomy 28

- One stage 25 (89)

- Two stages 3 (11)

Median (range) hospital stay (days) 12 (7-20)

Morbidity 7 (25)

- iatrogenic splenectomy 1 (4)

- wound infection 1 (4)

- urinary retention 1 (4)

- pneumonia 4 (14)

- pneumothorax 1 (4)

- postoperative ileus # 1 (4)

- iatrogenic injury to pancreas # 1 (4)

Mortality 0

# Resolved with conservative treatment.


adrenal phaeochromocytoma was excised at relaparotomy. One patient developed arecurrent phaeochromocytoma nine years after bilateral total adrenalectomy as a resultof histopathologically confirmed incomplete total adrenalectomy at the initialoperation.None of the three patients who initially had an unilateral adrenalectomy experienceda hypertensive crisis or other complications related to phaeochromocytoma duringfollow-up. However, phaeochromocytoma in the remaining adrenal gland (asdiagnosed by increased urinary catecholamine excretion) developed in all of them7,9, and 14 years respectively after the initial operation. These patients then had anadrenalectomy on the other side.In 19 of 25 patients (76%) who had a bilateral adrenalectomy, bilateral phaeochromo-cytoma was present on histopathological examination. Of the six remaining patients,four had diffuse medullary hyperplasia on the other side, one had nodular medullaryhyperplasia on the other side and one had one normal adrenal gland and a unilateralphaeochromocytoma. Histopathological examination confirmed the presence ofphaeochromocytoma in the three patients in whom unilateral adrenalectomy wasinitially performed. Of 56 adrenal glands removed, therefore, 50 contained phaeo-chromocytoma. Seven patients died during follow-up. In five, the cause of death wasunrelated to adrenalectomy (metastatic medullary thyroid carcinoma (n=2),cerebrovascular disease (n=2), and amyotrophic lateral sclerosis (n=1)). One patientdied a year after bilateral adrenalectomy from an unrecognised Addisonian crisisduring an admission for radiotherapy for metastatic medullary thyroid carcinoma.Another patient died seven years after bilateral adrenalectomy during her fourthadmission for Addisonian crisis. Despite adequate treatment including intravenousglucocorticosteroids she died of streptococcal sepsis. This was the patient whosebilateral adrenalectomy had been complicated by splenectomy.Including these two, a total of nine patients (32%) who had had both adrenal glandsremoved subsequently experienced a total of 19 Addisonian crises that requiredhospital treatment with glucocorticosteroids and fluids intravenously. Mean hospitalstay for the treatment of Addisonian crises in these patients was 9 days (range 3-18).The rate of admission for Addisonian crises was 0.05 / year of follow- up ( 95%confidence interval 0.03-0.07) . There were no significant differences in age, sex,doses of adrenal supplements or year of adrenalectomy between the patients who didand did not develop Addisonian crises. None of the 28 patients had evidence ofextra-adrenal or malignant phaeochromocytoma during follow-up.

DISCUSSION

In patients with MEN type 2, the risk of recurrent phaeochromocytoma must beweighed against the risk of Addisonian crisis after bilateral adrenalectomy. Even if

62 Chapter 5

Table 2

Results of bilateral total adrenalectomy for phaeochromocytoma in MEN type 2.

First author Year Reference No of Mean No (%) who No (%) who No (%) withnumber patients follow-up developed died of recurrent phaeo.

(years) Addisonian Addisoniancrisis crisis

Van Heerden 1984 9 17 10 0 0 1

Telenius-Berg 1989 21 26 6 9 (35) 1 not recorded

Lairmore 1993 12 43 19 10 (23) 1 0

Present series 1998 - 28 14 9 (32) 1 1

Total 114 13 28 (25) 3 (3) 2 (2)

Table 3

Incidence of malignant phaeochromocytoma related to MEN type 2, #=recurrence after subtotaladrenalectomy

Reference (No) Year Total Phaeochromocytomas (n*) MalignantPhaeochromocytomas

Present study 1998 28 0

Modigliani 1995 300 12

Obara 1995 15 1

Neumann 1993 24 0

Casanova 1993 100 3

Lairmore 1993 58 0

Oishi 1990 82 4

Gagel 1988 8 0

Jansson 1988 9 0

Shapiro 1985 35 3

Van Heerden 1984 17 3 #

Tibblin 1983 18 0

Wilson 1978 8 2

Total 702 28 (3.9%)


Table 4

Results of unilateral adrenalectomy for phaeochromocytoma in patients with MEN type 2.

First author Year Reference No of Mean follow-up No (%) with recurrentnumber patients (years) phaeo. on the opposite side

Lips 1981 14 4 4 4 (100)

Tibblin 1983 22 13 7 4 (31)

Jansson 1988 11 9 8 1 (11)

Gagel 1988 8 8 11 4 (50)

Lairmore 1993 12 26 9 12 (46)

Obara 1995 17 3 8 2(66)

Present series 1998 - 3 14 3(100)

Total 66 9 30(45)

only one adrenal is affected, bilateral adrenalectomy has been advocated because itminimises the risk of recurrence of tumour or development of distant metastases andbecause adrenocortical substitution in such patients is reported to be uncomplicated 7,9,14.Preventive bilateral adrenalectomy is therefore still done for phaeochromocytoma inover half of all patients with MEN type 2 in Europe and has been our surgical strategyuntil now 16.The present study shows considerable morbidity and even mortality related toadrenocortical substitution after total bilateral adrenalectomy. Combining the reportedseries, Addisonian crises develop in 25% of cases and cause death in as many as 3%(Table 2) 9,12,21. On the other hand, concerns with respect to the development ofcatecholamine crisis or metastatic disease after less than total bilateral adrenalectomyseem to have little documented support. In contrast to solitary phaeochromocytomasthe presence of metastatic disease is rare in MEN-related phaeochromocytoma andits incidence is reported to be less then 4% (Table 3) 8,9,11,12,14,18,19,22,23,26 . The risk fordevelopment of malignant phaeochromocytoma in MEN type 2 also seems to bekindred-specific, or to occur only in large primary tumours, making malignancyextremely unlikely in the absence of a family history of malignancy 22. Initial bilateraladrenalectomy did not prevent recurrence in all patients in accordance with otherreports of residual adrenal cortical function in some patients who underwent supposedtotal adrenalectomy 3,13.

64 Chapter 5

Asymmetric bilateral adrenal medullary abnormalities are often present in patientswith MEN 2 1,2,9. In our series, 19 of the 28 patients (68%) had bilateral phaeochromo-cytomas at presentation. Phaeochromocytoma on the other side in patients withunilateral disease at presentation will eventually develop in roughly 45% of patientswith MEN 2 after a mean follow-up of 4 to 11 years (Table 4). As in this study, nolethal complications of catecholamine crisis or metastatic disease has been documentedin patients who initially underwent unilateral adrenalectomy (Table 4). This is probablythe consequence of slow progression of the disease and strict follow-up. Taken together,the present series supports the policy of doing a unilateral adrenalectomy or, iftechnically possible, subtotal adrenalectomy for phaeochromo-cytoma in MEN 2patients with a unilateral adrenal mass as assessed by magnetic resonance imaging(MRI). With careful follow-up morbidity is minimal and does not outweigh theconsiderable complication rate in relation to adrenocortical suppletation after bilateraladrenalectomy. As MRI is more sensitive than palpation of the adrenal glands duringoperation and because malignancy is rare in MEN 2-related phaeochromocytomas,there is no indication for routine transabdominal bilateral exploration. A minimallyinvasive approach such as with a posterior endoscopic technique can therefore besafely considered 24,25.


REFERENCES


2. Carney JA, Sizemore GW, Tyce GM. Bilateral adrenal medullary hyperplasia inmultiple endocrine neoplasia, type 2: the precursor of bilateralpheochromocytoma. Mayo Clin Proc 1975; 50: 3-10.

3. Chalmers RA, Mashiter K, Joplin GF. Residual adrenal cortical function afterbilateral �total� adrenalectomy for Cushings disease. Lancet 1981;2: 1196-1199.

4. Chevinsky AH, Minton JP, Falko JM. Metastatic pheochromocytoma associatedwith multiple endocrine neoplasia syndrome type II. Arch Surg 1990; 125:935-938.

5. Dralle H, Ipta M, Henschel E et al Surgical therapy of sporadic and familialpheochromocytoma. Acta Med Austriaca 1988; 15: 108-110.

6. Evans DB, Lee JE, Merell, RC, Hickey RC. Adrenal medullary disease inmultiple endocrine neoplasia type 2. Endocrin Metab Clinics North Am 1994;23: 167-176.

7. Freier DT, Thompson NW, Sisson JC,Nishiyama RH, Freitas JE. Dilemmas inthe early diagnosis and treatment of multiple endocrine adenomatosis, type 2.Surgery 1977; 82: 407-413.

8. Gagel RF, Tashjian AH, Cummings T et al. The clinical outcome of prospectivescreening for multiple endocrine neoplasia type 2 A. N Engl J Med 1988; 318:478-479.

9. Heerden JA van, Sizemore GW, CarneyJA, Grant CS,ReMine WH, Sheps SG.Surgical management of the adrenal glands in the multiple endocrine neoplasiasyndrome type II syndrome. World J Surg 1984; 8: 612-621.

10. Hamberger B, Telenius-Berg M, Cedermark B. Subtotal adrenalectomy inmultiple endocrine neoplasia type 2. Henry Ford Hosp Med J 1987; 35: 127-129.

11. Jansson S, Tisell LE, Fjalling M, Lidberg S, Jacobsson L, Zachrisson BF. Earlydiagnosis and surgical strategy for adrenal medullary disease in MEN II genecarriers. Surgery 1988; 103: 11 -18.

66 Chapter 5

12. Lairmore TC, Ball DW, Baylin SB, Wells SA. Management of pheochromo-cytomas in patients with multiple endocrine neoplasia Type 2 Syndromes. AnnSurg 1994; 217: 595-603.

13. Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical sparingadrenalectomy for patients with bilateral pheochromocytoma. Surgery 1996;120:1064-1071.

14. Lips CJM, van der Sluys Veer J et al. Bilateral occurence of pheochromocytomain patients with the multiple endocrine neoplasia syndrome type 2A (Sipple�ssyndrome). Am J Med 1981; 70: 1051-1060.

15. Miller WL, Tyrrell JB. The adrenal cortex. In: Felig P, Baxter JD, Frohman LAeds. Endocrinology and metabolism 3ed. McGraw-Hill, New York 1995; 555-711.

16. Modigliani E, Vasen HFA, Raue K et al. Pheochromocytoma in multipleendocrine neoplasia type 2: European Study. J Intern Med 1995; 238: 236-237.

17. Obara T, Kanbe M, Okamoto T et al. Surgical strategy for pheochromocytoma:emphasis on the plenge of flank extra-peritoneal approach in selected patients.Surgery 1995; 118: 1083-1089.

18. Oishi S, Sasaki M, Yamauchi J et al. Analysis of eight Sipple�s syndrome patientsand review eighty-two cases from Japanese literature. Jpn J Clin Oncol 1990;20: 393-294.

19. Shapiro B, Copp JE, Sisson JC et al. Iodine-131 metaiodobenzylguanidine forthe locating of suspected pheochromocytoma: experience in 400 cases. J NuclMed 1985; 26: 576.

20. Sizemore GW, Carney JA, Gharib H, Capen CC. Multiple endocrine neoplasiatype 2b: eighteen year follow-up of a four generation family. Henry Ford HospMed J 1992; 40: 236-244.

21. Telenius-Berg M, Ponder MA, Berg B et al. Quality of life after bilateraladrenalectomy in multiple endocrine neoplasia type 2. Henry Ford Hosp Med J1989; 37: 160.

22. Tibblin S, Symling JF, Ingermansson S, Telenius-Berg M. Unilateral versusbilateral adrenalectomy in multiple endocrine neoplasia IIA. World J Surg 1983;7: 201-206.


23. Vasen HFA, Feltz M van der, Rave F et al. The natural course of multipleendocrine neoplasia type 2b. Arch Intern Med 1992;152: 1250-1254.

24. Walz MK, Peitgen K, Saller B et al. Subtotal adrenalectomy by the posteriorretroperitoneoscopic approach. World J Surg 1998; 22: 621-627.

25. Walz MK, Peitgen K, Hoermann R, Giebler RM, Mann K, Eigler FW. Posteriorretroperitoneoscopy as a new minimally invasive approach for adrenalectomy.World J Surg 1996; 20: 769-772.

26. Wilson RA, Ibanez ML. A comparative study of 14 cases of familial and non-familial pheochromocytomas. Hum Pathol 1978; 9: 181-188.

68 Chapter 5

Subtotal Adrenalectomy for Phaeochromocytoma 69

Subtotal Adrenalectomy for Phaeochromocytoma inMultiple Endocrine Neoplasia Type 2A

6

70 Chapter 6

Abstract

Objective: To describe our surgical technique for, and results of, subtotaladrenalectomy for phaeochromocytoma in multiple endocrine neoplasia (MEN) type 2A.Design: Retrospective studySetting: University Hospital.Subjects: 6 patients (4 women and 2 men, mean age 35 years, range 31-46) withMEN type 2 who presented between 1993 and 1996.Interventions: Cortical sparing adrenalectomy (n=4) together with contralateraltotal adrenalectomy in bilateral disease.Main outcome measures: Morbidity, mortality, adrenal function postoperatively,and recurrence.Results: Cortical-sparing adrenalectomy leaving adequate adrenal reserve waspossible in all cases. There was no operative morbidity or mortality. Mean follow-up was 40 months (range 13-47). One patient developed a recurrent phaeochromo-cytoma 24 months after subtotal adrenalectomy.Conclusion: Subtotal adrenalectomy with preservation of adequate adrenal corticalreserve was feasible in all cases. Long-term follow-up is necessary to establish itsdefinitive place in the treatment of familial phaeochromocytoma.

Graaf JS de, Lips CJM, Rutter JE, Vroonhoven ThJMV van.European Journal of Surgery 1999 in press.


INTRODUCTION

Phaeochromocytoma will develop in 30%-50% of patients with multiple endocrineneoplasia (MEN) type 2A 5,15. Nowadays, screening of such patients is provided by acombination of DNA analysis, yearly screening for excess catecholamines and theoutstanding localization techniques that are available 6,11,14. Phaeochromocytomas inthese particular patients are therefore often asymptomatic and small at the time ofdiagnosis. Although they are asymptomatic, it can be argued that these tumours shouldbe removed because of the potential danger of a catecholamine crisis. To prevent therisk of recurrence these patients are traditionally treated in many centres by totalbilateral adrenalectomy, even when only a unilateral tumour has been found, becauseadrenal medullary disease in these patients is usually diffuse and bilateral at cellularlevel 3,8. This approach necessitates long-term corticosteroid replacement associatedwith the risk of an Addisonian crisis, the risks of osteoporosis, and the socialimplications of complete dependence on lifelong substitution. Because the disease ishereditary most patients are familiar with the complications of inadequate replacement.In our experience, this knowledge makes these patients whose disease is oftenasymptomatic, hard to motivate to have a total adrenalectomy and they thereforesometimes delay or even refuse operation. For these reasons we have started to treatselected patients with MEN type 2A with cortical-sparing subtotal adrenalectomy.Here we present our surgical technique for, and the results of subtotal adrenalectomyfor phaeochromocytoma associated with MEN type 2A.


Between 1993 and 1996, six patients with MEN type 2A underwent laparotomy at theUniversity Hospital Utrecht, The Netherlands; our intention was to do a cortical-sparing subtotal adrenalectomy for phaeochromocytoma. MEN type 2A was diagnosedfrom the family history, or DNA analysis, or both. The mutation in the RET-gene wasT 2548 C in four patients and C 2550 G in two patients, resulting in replacement ofcysteïne by arginine or cysteïne by tryptophan, respectively. Pre-operative concen-trations of urinary catecholamine metabolites (vanillilmandelic acid, metanephrines,and normetanephrines) and catecholamines (adrenaline and noradrenaline) weremeasured in all patients as part of an annual screening examination and the adrenalglands were visualised by magnetic resonance imaging (MRI).

OPERATIVE TECHNIQUE

The affected adrenal gland was exposed by an open anterior approach. Adequatevenous drainage of the remaining adrenal tissue was obtained by identification andpreservation of the adrenal vein. The arterial supply of the diseased part of the adrenal

72 Chapter 6

gland was divided with special attention to the arterial blood supply of the remainingglandular tissue. If venous and arterial preservation of the remaining tissue wasfeasible, the tumour was resected with a rim of macroscopic normal adrenal tissue.Argon coagulation was used for resection and haemostasis. Final haemostasis wasprovided by fibrin adhesive after completion of the subtotal adrenalectomy.Follow-up in these patients included interval physical examinations and measurementof 24-hour urinary catecholamines and catecholamine metabolites. Postoperative adrenalfunction was evaluated in all patients by measuring the plasma cortisol concentrationand by stimulation with a synthetic analogue of ACTH, tetracosactrin (cosyntropin).All resected specimens were examined histologically. Medical records of these patientswere reviewed to obtain details of operation, perioperative morbidity and mortality,postoperative adrenal function, and recurrence of phaeochromocytomas.

RESULTS

The mean age at operation of the four women and two men was 35 years (range 31-46). Phaeochromocytoma was presymptomatic at the time of screening for adrenalinvolvement and operation in four patients. The other two had mild paroxysmalsymptoms, possibly related to excess catecholamines. In four patients the diagnosisof phaeochromocytoma was confirmed by increased excretion of urinarycatecholamines. In all patients MRI showed small adrenal tumours, unilateral (left) infour and bilateral in two. Two patients had had previous unilateral total adrenalectomyfor phaeochromocytoma two and four years before a metachronous tumour developedon the other side. Cortical sparing adrenalectomy was technically feasible in all patientsand in bilateral involvement (n=2) it was combined with total adrenalectomy on theother side. Histopathological examination of all specimens showed phaeochromo-cytoma with a mean tumour size of 1.7cm (range 1.3-2.2). Mean duration of hospitalstay was 8 days (range 7-9). There was no peri-operative mortality or morbidity.Mean follow-up was 40 months (range 13-47). During follow-up no patients hadsigns or symptoms of adrenal insufficiency and all had normal plasma cortisolconcentrations. All patients made an adequate response to tetracosactrin stimulation,indicating sufficient adrenal cortical reserve.One patient (RET mutation T 2548 C) developed clinical symptoms possibly relatedto a phaeochromocytoma without biochemical evidence of a recurrent tumour, 24months after subtotal left-sided adrenalectomy. MRI showed a small tumour of thepartly resected adrenal gland. After total adrenalectomy, histopathological examinationshowed recurrent phaeochromocytoma of the left adrenal gland. The other five patientshad no clinical or biochemical evidence of recurrent phaeochromocytoma duringfollow-up.


DISCUSSION

We have shown that subtotal adrenalectomy with preservation of adrenocortical functionis feasible in patients with MEN type 2A and asymptomatic phaeochromocytoma.The risk of recurrence of the phaeochromocytoma in these patients must be weighedagainst the risk of producing a permanent Addisonian state by bilateral totaladrenalectomy. Bilateral total adrenalectomy has been advocated because it minimisesthe risk of tumour recurrence or distant metastases and eliminates the risk of acatecholamine crisis18. Complications associated with the lifelong substitution neededafter this operation seem to be a high price to be paid by these patients with asymp-tomatic disease. Phaeochromocytomas in MEN type 2A are rarely malignant andeven in recurrent disease, morbidity or mortality can be minimised by annual screeningand early treatment 4,8,14. No deaths of catecholamine crisis have been reported inpatients with MEN type 2 treated with less then total adrenalectomy, but at least twodeaths have been reported after inadequate supplementation after bilateraladrenalectomy 12,17. Only a few studies have attempted to estimate the complicationsassociated with bilateral adrenalectomy in MEN type 2 patients and they are notconclusive8,12,17.. Because the disease is hereditary, most patients are familiar with thesocial and medical disadvantages of the substitution needed after bilateral totaladrenalectomy. In our experience these patients most of whom have no symptoms,often refuse an operation that will lead to total dependence on medical substitution.For these reasons we have started to treat selected patients with MEN type 2A withcortical-sparing subtotal adrenalectomy. Our selection criteria are: the technicalfeasibility of subtotal adrenalectomy as dictated by tumour size, the absence of familyhistory or RET gene mutation indicating aggressive and recurrent adrenal medullarydisease and complete understanding by the patient of the possible risk of recurrenceafter subtotal adrenalectomy.Subtotal adrenalectomy has been described for MEN type 2- related phaeochromo-cytomas in a few previous reports1,2,7,9,10,15. Adequate postoperative adrenocorticalfunction could not be obtained in all reported patients, in contrast to our results.Most of these reports described timing and techniques of subtotal adrenalectomythat are different from ours. During operation we meticulously preserve the adrenalvein. Other techniques presented preserve only the arterial supply of the remainingadrenal gland and divide the adrenal vein2. Early surgery after screening forphaeochromocytoma offers favourable conditions for a subtotal adrenalectomy.Resection of the tumour with a rim of macroscopically normal adrenal tissue wastherefore feasible in all patients without compromising venous drainage, and leavingan adequate portion of vascularised adrenal tissue behind. We think that preservationof the venous drainage is essential to obtain sufficient postoperative adrenocortical

74 Chapter 6

reserve. This was proved in all our patients by their adequate response to stimulationwith tetracosactrin.In two patients with unilateral phaeochromocytomas we did a unilateral subtotaladrenalectomy leaving the macroscopically normal adrenal gland in place. Thisapproach is in accordance with our previous policy at least to postpone supplementationby doing a unilateral adrenalectomy for patients with unilateral phaeochromocytoma.One patient had a recurrent phaeochromocytoma two years after subtotaladrenalectomy. Because of the relatively short follow-up time (mean 3.3 years) noconclusion can be made about the definitive recurrence rate after subtotal adrenalectomyin our series. Lee et al. found a recurrence rate of 21% after a median follow-up of11.5 years in 14 patients treated by bilateral subtotal adrenalectomy 13. They state thatthis recurrence rate is lower when compared with that of contralateral recurrencerate after unilateral adrenalectomy for clinical unilateral involvement (42%) 8. Nohypertensive crisis or metastatic disease as a result of recurrent phaeochromocytomahas been reported in patients who underwent unilateral or subtotal adrenalectomy.All those who developed recurrent disease were treated successfully because of theslow progression of the disease and the available highly sensitive screening techniques.This is illustrated by our patient whose recurrence was diagnosed by MRI duringfollow-up before abnormal biochemical activity was noted. Although it has not yetbeen reported we expect that cortical-sparing subtotal adrenalectomy might be possibleby a minimally invasive approach in the near future16,19.In conclusion, subtotal adrenalectomy in selected patients by our technique is feasiblewith preservation of adequate adrenal cortical reserve. Long time follow-up is necessaryto establish the definitive place of this cortical-sparing approach in patients with familialphaeochromocytoma.


REFERENCES

1. Albanise CT, Wiener ES. Routine bilateral adrenalectomy is not warranted inchildhood phaeochromocytoma. J Pediatr Surg 1993; 28: 1248-1252.

2. Birnbaum J, Giuliano A, Herle AJ van. Partial adrenalectomy for pheochromo-cytoma with maintenance of adrenocortical function. J Clin Endocrinol Metab1989; 69: 1078-1081.


4. Cassanova S, Rosenberg-Bourgin M, Farkas DC, et al. Pheochromocytoma inmultiple endocrine neoplasia type 2a; survey of 100 cases. Clin Endocrinol 1993;38: 531-537.

5. Evans DB, Lee JE, Merell, RC, Hickey RC. Adrenal medullary disease in multipleendocrine neoplasia type 2. Endocrin Metab Clinics North Am 1994; 23:167-176.

6. Gils APG van, Falke THM, van Erkel AR et al. MR Imaging and MIBGscintigraphy of pheochromocytoma and extra-adrenal functioningparagangliomas. Radiographics 1991; 11: 37-57.

7. Hamberger B, Telenius-Berg M, Cedermark B. Subtotal adrenalectomy inmultiple endocrine neoplasia type2. Henry Ford Hosp Med J 1987; 35; 127.

8. Heerden JA van, Sizemore GW, Carney JA, Grant CS, Remine WH, Sheps SG.Surgical management of the adrenal glands in the multiple endocrine neoplasiasyndrome type 2. World J Surg 1984; 8: 612-21.

9. Heerden JA van Sizemore GW, Carney JA, Bennan MD, Sheps SG. Bilateralsubtotal adrenal resection for bilateral pheochromocytomas in multiple endocrineneoplasia, type IIA: a case report. Surgery 1985; 98: 363-365.

10. Irvin III GL, Fisfman LM, Sher JA. Familial pheochromocytoma. Surgery 1983;94: 938-941.

11. Jansson S, Tisell LE, Fjalling M, Lidberg S, Jacobsson L, Zachrisson BF. Earlydiagnosis and surgical strategy for adrenal medullary disease in MEN II genecarriers. Surgery 1988: 103; 11-18.

76 Chapter 6

12. Lairmore TC, Ball DW, Baylin SB, Wells SA. Management ofpheochromocytomas in patients with multiple endocrine neoplasia Type 2Syndromes. Ann Surg 1993: 217: 595-603.

13. Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical sparingadrenalectomy for patients with bilateral pheochromocytoma. Surgery 1996;120: 1067-1071.

14. Lips CJM, Landsvater RM, Hoppener JWM et al. Clinical screening as comparedwith DNA analysis in families with Multiple Endocrine Neoplasia type 2A. NEngl J Med 1994; 331: 828-35.

15. Lips CJM, Sluys van der, Veer J, Struyvenberg A, et al. Bilateral occurence ofpheochromocytoma in patients with the multiple endocrine neoplasia syndrometype 2A (Sipple�s syndrome). Am J Med 1981; 70;1051-1060.

16. Prinz RA. A comparison of laparoscopic and open adrenalectomies. Arch Surg1995: 130; 489-494.

17. Telenius-Berg M, Ponder MA, Berg B et al. Quality of life after bilateraladrenalectomy in multiple endocrin neoplasia type 2. Henry Ford Hosp Med J1989; 37: 160-162.

18. Tibblin S, Symling JF, Ingermansson S Telenius Berg M. Unilateral versusbilateral adrenalectomy in multiple endocrine neoplasia IIA. World J Surg 1983;7: 201-206.

19. Walz MC, Peitgen K, HoermannR et al. Posterior retroperitoneoscopy as a newminimally invasive approach for adrenalectomy. World J Surg 1996; 29: 769-774.

Minimally invasive surgical approaches for treatment of Phaeochromocytoma 77

Minimally invasive surgical approaches for treatmentof phaeochromocytoma

7

78 Chapter 7

J.S.de Graaf, Th.J.M.V.van Vroonhoven


INTRODUCTION

The paired adrenal glands lie on either side of the vertebral column at the level of theeleventh thoracic vertebra and are in intimate contact with the superomedial aspectsof the kidneys. The glands are asymmetrical, with the left adrenal usually larger,semilunar in shape and having a marked medial projection. The right adrenal is smallerand pyramidal in shape.Conventional approaches for resection of the adrenal gland have been divided intotransabdominal, thoracoabdominal and posterior or flank approaches. Thetransabdominal approach for adrenalectomy provides access to the entire peritonealcavity including the contralateral adrenal bed. This approach, however, is associatedwith the morbidity of a major laparotomy, as shown in chapter 2. Although thethoracoabdominal approach provides the widest exposure to the adrenal gland, it isaccompanied by the morbidity of a thoracotomy. In addition evaluation of intra-peritoneal disease is limited, and only a unilateral adrenalectomy can be performed.The extra-peritoneal posterior approach became accepted as a suitable alternative tothe anterior approach to the adrenal gland during the 1970�s 1. The incidence ofmorbidity associated with this retroperitoneal approach is less than that reported toanterior, transperitoneal exploration of these organs because it minimizes the risk ofmechanical bowel obstruction and pulmonary complications 2,3,4,5. Recently, thisapproach has therefore been advocated as the procedure of choice for the majority ofmost small benign cortical adenomas.Since the first reported case of laparoscopic adrenalectomy in 1992, this procedurehas increasingly gained popularity 6,7,8. The laparoscopic approach for benign adrenaltumours has the advantage of avoiding muscular trauma associated with laparotomyor rib resection as inherent to the extraperitoneal approach. Initial attempts to removethe adrenal gland through the anterior laparoscopic approach were complicated bydifficulties in obtaining sufficient exposure, which resulted in long operating times 9.Thelateral transabdominal laparoscopic approach has improved exposure of the adrenalgland and soon became the preferred technique10. In 1995 the posterior laparoscopicapproach was developed, in which a balloon was used to dissect the retroperitonealspace 11,12,13. With the rapidly advancing endoscopic techniques, the safety and efficacyof these minimally invasive procedures for adrenalectomy in benign cortical diseasehas been confirmed in several reports 8,14. Phaeochromocytomas, however, differ fromadrenal adenoma in several respects. Although the hazard of hypertensive crisis duringsurgery is substantially reduced by preoperative pharmacological blockage, somerisks remain. It has been speculated that this risk may be increased by pressure of thepneumoperitoneum 15,16. In the treatment of these catecholamine producing tumoursthe prerequisite for non manipulative dissection and the search for bilateral, metastaticor extra-adrenal tumours, have traditionally dictated wide exposure by means of an

80 Chapter 7

anterior transabdominal approach and extensive dissection 17,18,19. Therefore, thereported experience with minimally invasive approaches for phaeochromocytoma islimited and only a few reports have included a sufficient large number of patientswith phaeochromocytoma to evaluate the merits of minimally invasive procedures.This chapter summarizes the reported experience with minimally invasive approachesfor phaeochromocytoma until now.

Table 1

Overview of reported transabdominal laparoscopic adrenalectomies for adrenal tumours includingphaeochromocytoma. Reference (year), Total number of reported adrenalectomies per series (Total),Total number of removed phaeochromocytomas (Phaeo), Mean operation time (minutes), MeanHospital stay (days), Total rate of complications (Compl), Total number of performed bilateraladrenalectomies (Bilat) and Mean Tumour diameter (centimetres). Nr = not reported.

Reference Total Phaeo Operation Hospital stay Complications Bilateral Diameter(Year) time (min) (days) (%) (n) (cm)

Gagner (93) 25 5 140 4 16 1 4

Lepsien (93) 1 1 260 10 0 0 5

Suzuki (93) 12 3 280 Nr 30 0 2.3

Guazzoni (95) 20 7 170 3.4 5 0 3

Stuart (95) 14 1 157 3 7 0 Nr

Prinz (95) 10 4 212 2.1 0 0 4.8

Naito (95) 14 1 276 9.8 6 0 2.7

Rutherford (96) 67 6 102 5.1 9 0 Nr

Deans (96) 8 2 120 7 12 0 6

Fernandez (96) 31 9 127 4 6 1 4.1

Duh (96) 22 3 210 2.2 0 0 4.2

Staren (96) 21 7 206 2.2 2 0 3.2

Brunt (96) 24 11 183 3.2 9 3 2.7

Linos (97) 18 3 116 2.2 0 0 4

Thompson (97) 54 20 167 3.1 6 - 2.9

Janetschek (98) 23 23 150 5 10 4 5.7

Total 334 106 180 min 4.4 days 7 % 9 3.8 cm


TRANSABDOMINAL LAPAROSCOPIC ADRENALECTOMY

In 1992, Gagner and his group pioneered the successful laparoscopic resection of theadrenals through the lateral transabdominal approach 10. Since then, 16 studies havereported transabdominal laparoscopic adrenalectomy for phaeochromocytoma. Theseseries report the results of over 300 laparoscopic adrenalectomies, including 106adrenalectomies for phaeochromocytoma 8,10,14,16,20-31. Only one series reports theoutcome of laparoscopic surgery in a group of phaeochromocytomas exclusively 31.Table 1 summarizes the outcomes of these studies. Most authors use a half-lateralsupine position with exaggerated lordosis. Preoperative treatment and anaestheticmanagement did not differ from conventional surgery for phaeochromocytoma. Ofinterest, besides mild peroperative episodes of hypertension due to manipulation ofthe tumour (without influence on operative outcome) as seen in conventional surgery,no major complications due to catecholamine release during laparoscopy has beenreported. Transabdominal laparoscopic adrenalectomy was complicated in 23 (7%)out of all 330 reported cases. These complications include thrombo-emboliccomplications in 4 patients (1.2%), post-operative bleeding requiring blood transfusionin 7 (2.1%), urinary tract infection in 4 (1.2%), pneumothorax in 1 (0.3%), superficialwound infection of the trocart sites in 3 (0.9%), pancreatitis in 1 (0.3%), pulmonary

Table 2

Overview of reported retroperitoneal endoscopic adrenalectomies for adrenal tumours includingphaeochromocytoma. Reference (year), total number of reported adrenalectomies per series (Total),Total number of removed phaeochromocytomas (Phaeo), Mean operation time (Minutes), Meanhospital stay (days), Total rate of complications (Compl), Mean tumour diameter (centimetres).Nr=Not reported.

Reference Total Phaeo Operation Hospital stay Complications DiameterYear time(min) (days) (%) (cm)

Mercan (95) 11 0 150 3 0 3.6

Duh (96) 14 1 180 1.5 0 2.6

Walz (98) 69 * 19 ** 118 Nr 6 3.0

Gasman (98) 23 2 96 3.4 9 1.6

Bonjer (98) 42 8 90 4.0 7 3.0

Total 159 30 127 min 2.9 days 5 % 2.8 cm

* 22 subtotal adrenalectomies** 4 subtotal adrenalectomies

82 Chapter 7

infection in 2 (0.6%) and iatrogenic lesion of the kidney due to the Verres needle(conservatively treated) in 1 patient (0.3%). Two patients (0.6%) developed a herniacicatricalis of a trocart site.

RETROPERITONEAL ENDOSCOPIC ADRENALECTOMY

Retroperitoneal laparoscopy was developed by Gaur in 1992 and combines the methodof the open retroperitoneal approach with the techniques of minimally invasive surgery.In this approach a balloon is used to dissect the retroperitoneal space 32. The patientis placed in the prone Jack-knife position with the operating table flexed at the waist.Retroperitoneoscopy is not as popular as the transabdominal approach because ofthe difficulty in widening and dissecting the peri-adrenal space. The retroperitonealadrenal anatomy is more difficult to identify since there are no intra-abdominallandmarks. Moreover, only a relatively small space is available for preparation andtherefore this technique is limited to removal of small adrenal tumours. The advantageof the retroperitoneoscopy over the transperitoneal minimally invasive approach isthe need for only three trocarts, the lack of intra-abdominal dissection such asmobilization of the colon and therefore its shorter operating time. Table 2 shows thereported experience with the removal of phaeochromocytomas by the retroperitoneo-scopic approach 11,26,33-35. Complications occurred in 5% of all operated patients,including iatrogenic pleural tear (2.5%), haematoma (2.5%), requiring ultrasono-graphic guided drainage in 1 patient. As in the transabdominal laparoscopic approach,no complications due to catecholamine release while dissecting phaeochromocytomahave been reported.

DISCUSSION

As presented in this chapter the safety and efficacy of laparoscopic or retroperitoneo-scopic adrenalectomy in the treatment of benign adrenal tumours has now beendemonstrated in over 400 patients. When compared to conventional transabdominaladenalectomy as discussed in chapter 2, post-operative complications, postoperativelength of hospital stay and return to activity were all considerably lower in patientswho underwent minimally invasive adrenalectomy. Comparison of open posterioradrenalectomy and endoscopic adrenalectomy showed that the endoscopicretroperitoneal technique also is preferable except for operating time 36,37. In allcomparative studies reported to date, operative times have been consistently longerfor laparoscopic (mean 180 minutes) and retroperitoneoscopic adrenalectomy (mean127 minutes) than for open adrenalectomy. However, in our experience these longeroperating times reflect, in part, the learning curve for such minimally invasiveprocedures.


As stated, until now the role of minimally invasive adrenalectomy for phaeochromo-cytoma has been controversial. Traditional management of these catecholaminesecreting tumours dictates wide transabdominal dissection in order to (I) explore theabdominal cavity to exclude extra-adrenal phaeochromocytomas and (II) minimizethe risks of peroperative excessive catecholamine release by minimal manipulationof the tumour and early ligation of the adrenal vein. Modern imaging modalities,especially Magnetic Resonance Imaging, have proven to be more sensitive for detectionof phaeochromocytoma than surgical exploration as shown in chapter 3 and 4. It hasbeen speculated that increased pressure from a pneumoperitoneum would acceleraterelease of catecholamines. Literature presented here shows no evidence in support ofthese postulated concerns. Provided that adequate alfa- and beta-adrenergic blockageand more recently calcium channel blockers are used, intra-operative haemodynamicchanges due to manipulation of the tumour can be reduced to a minimum. Althoughplasma catecholamine concentrations may increase to high values due to tumourhandling, no mortality due to per-operative hypertensive crisis during endoscopicremoval of phaeochromocytoma has been reported 38-41. It has been shown thatlaparoscopic dissection of phaeochromocytomas is associated with less increase ofserum catecholamine levels than conventional open removal of phaeochromocytomas 16.Since cold is a stress factor which may stimulate the sympathetic nervous system andthus induce cardiovascular changes, some authors advise pre-warming of theinsufflated carbon dioxide with a heat exchanger 31-42.Most authors emphasize the need for clipping the adrenal vein before manipulationof the adrenal gland. In the endoscopic approach early ligation is technically difficultand almost impossible because of the medial and deep anatomical location behindthe vena cava on the right and next to the aorta on the left side. Therefore duringminimally invasive procedures, the adrenal vein is clipped and divided during thefinal phase of dissection. The lack of serious complications as demonstrated in thisoverview suggest that the need for early ligation of the central vein may have beenoveremphasized in the past.

LAPAROSCOPIC VERSUS RETROPERITONEOSCOPIC ADRENALECTOMY

Because of surgeon preference and limited experience thus far, only one of theavailable minimally invasive approaches is performed in most surgical centres. Inthe only study that compared both approaches it was concluded that outcomes ofboth minimally invasive approaches are similar, both with its own advantages 26.Relative indications for posterior retroperitoneal laparoscopic approach are smalltumour size (<6cm) because of limited dissection space and in case of bilateraladrenalectomy because in this approach there is no need for repositioning of thepatient. Relative indications for the transabdominal laparoscopic approach are medium

84 Chapter 7

tumour size (6-15 cm) and the need for abdominal exploration. Because at diagnosisphaeochromocytomas mostly are smaller than 6 cm, especially in the MEN type 2syndrome, and there is no longer a need for extensive abdominal exploration, theposterior retroperitoneal approach in these patients is preferable.

In conclusion, minimally invasive approaches for phaeochromocytoma provide asmuch haemodynamic stability as open adrenalectomy. With the preoperative use ofmodern imaging modalities, extensive abdominal exploration in these patients isobsolete. Therefore the laparoscopic or retroperitonoscopic approach is as safe as inother benign adrenal disease, and should be considered as the preferable surgicalapproach for phaeochromocytoma. Clinical outcome for both minimally invasiveapproaches are similar. Since most phaeochromocytomas are relatively small atpresentation and can occur bilateral, the retroperitoneoscopic approach is preferred.


REFERENCES

1. Hamberger B, Russell CF, van Heerden JA et al. Adrenal surgery: Trends duringthe seventies. Am J Surg 1982; 144: 523-526.

2. Cullen ML, Staren ED, Straus AK et al. Pheochromocytoma; operative strategy.Surgery 1985; 98: 927-930.

3. Irvin III GL, Fishman LM, Sher JA, Yeung LK, Irani H. Phaeochromocytoma.Lateral versus anterior operative approach. Ann Surg 1989; 209: 774-778.

4. Russell CF, Hamberger B, van Heerden JA, et al. Adrenalectomy: anterior orposterior approach? Am Surg 1982; 144: 322-324.

5. Chang BB, Paty PK, Shah DM, Leather RP. Selective use of retroperitonealexposure in the emergency treatment of ruptured and symptomatic abdominalaortic aneurysms. Am J Surg 1988; 156: 108-110.

6. Fernandez-Cruz L, Benarroch G, Torres E, Astudillo E, Saenz A, Taura P.Laparoscopic approach to the adrenal tumors. J Laparoendosc Surg 1993; 3: 541.

7. Higashihara E, Tanaka-Horie S, Aruga S, Nutahara K, Minowada S, Aso R.laparoscopic adrenalectomy: the initial 3 cases. J Urol 1993; 149: 973.

8. Prinz RA. A comparison of laparoscopic and open adrenalectomies. Arch Surg1995; 130: 489-492.

9. Go H, Takeda M, Imai T, Komeyama T, Nishiyama T, Morishita H. Laparoscopicadrenalectomy for Cushing�s syndrome: comparison with primary aldosteronism.Surgery 1995; 117: 11-17.

10. Gagner M, lacroix A, Bolte E. Laparoscopic adrenalectomy in Cushing�ssyndrome and pheochromocytoma. N Engl J Med 1992; 327: 1033.

11. Mercan S, Seven R, Ozarmagan S, Tezelman S. Endoscopic retroperitonealadrenalectomy. Surgery 1995; 118: 1071-1076.

12. Kelly M, Jorgensen J, Magarey C, Delbridge L. Extraperitoneal �laparoscopic�adrenalectomy. Aust N Z J Surg 1994; 64: 498-500.

13. Mandressi A, Buizza C, Antonelli D, Chisena S, Servadio G. Retroperitoneo-scopy. Ann Urol (Paris) 1995; 29: 91-96.

86 Chapter 7

14. Guazzoni G, Montorsi F, Bocciardi A, Da Pozzo L, Rigatti P, Lanzi R, PontiroliA. Transperitoneal laparoscopic versus open adrenalectomy for benignhyperfunctioning adrenal tumors: a comparative study. J Urol 1995; 153: 1597.

15. Mann C, Millat B, Boccara G, Atger J, Colson P. Tolerance of laparoscopy forresection of phaeochromocytoma. Brit J Anesth 1996; 77: 795.

16. Fernandez-Cruz L, Taura P, Saenz A, Benarroch G, Sabater L. Laparoscopicapproach to phaeochromocytoma: haemodynamic changes and catecholaminesecretion. World J Surg 1996; 20: 762-763.

17. Caldwell CB, Ricotta JJ. Changes in visceral blood flow with elevatedintraabdominal pressure. J Surg Res 1987; 43: 14-20.

18. Havlik RJ, Cahow CE, Kinder BK. Advances in the diagnosis and treatment ofpheochromocytoma. Arch Surg 1988; 123: 626-630.

19. Van Heerden JA, Sheps SG, Hamberger B, Sheedy PF, Poston JG, ReMine WH.Pheochromocytoma: current status and changing trends. Surgery 1982; 91:367-373.

20. Lepsien G, Neufang T, Ludtke FE. Laparoscopic resection of pheochromocytoma.Surg Endosc 1994; 8: 906-909.

21. Suzuki K, Kageyama S, Ueda D et al. Laparoscopic adrenalectomy: clinicalexperience with 12 cases. J Urol 1993; 150: 1099-1102.

22. Stuart RC, Chung SCS, Lau JYW et al. Laparoscopic adrenalectomy. Br J Surg1995; 82: 1498-1499.

23. Naito S, Uozumi J, Shimura H, Ichimiya H, Tanaka M, Kumazawa J. J Endourol1995; 9: 491-495.

24. Rutherford JC, Stowasser M, Tunny TJ, Appl.Shi M, Klemm SA, Gordon RD.Laparoscopic adrenalectomy. World J Surg 1996; 20: 758-761.

25. Deans GT, Kappadia R, Wedgewood K, Royston CMS, Brough WA.Laparoscopic adrenalectomy. Br J Surg 1995; 82: 994-995.

26. Duh QY, Siperstein AE, Clark OH et al. Laparoscopic adrenalectomy.Comparison of lateral and posterior approaches. Arch Surg 1996; 131: 870-876.


27. Staren ED, Prinz RA. Adrenalectomy in the era of laparoscopy. Surgery 1996;120: 706-711.

28. Brunt LM, Doherty GM, Norton JA et al. Laparoscopic adrenalectomy comparedto open adrenalectomy for benign adrenal neoplasms. J Am Coll Surg 1996;183: 1-10.

29. Linos DA, Stylopoulos N, Boukis M, Souvatzoglou A, Raptis S, PapadimitriouJ. Anterior, Posterior, or Laparoscopic approach for the management of adrenaldiseases? Am J Surg 1997; 173: 120-125.

30. Thompson GB, Grant CS, van Heerden JA. Laparoscopic versus openadrenalectomy: a case-control study in 100 patients. Surgery 1997; 122:1132-1136.

31. Janetschek G, Finkenstedt G, Gasser R. Laparoscopic surgery for pheochromo-cytoma: adrenalectomy, partial resection, excision of paragangliomas. J Urol1998; 160: 330-334.

32. Gaus DD. Laparoscopic operative retroperitoneoscopy: use of a new device. JUrol 1992; 148: 1137.

33. Walz MK, Peitgen K, Saller B. Subtotal adrenalectomy by the posteriorretroperitoneoscopic approach. World J Surg 1998; 22: 621-627.

34. Gasman D, Droupy S, Salomon L et al. Laparoscopic adrenalectomy: theretroperitoneal approach. J Urol 1998; 159: 1816-1820.

35. Bonjer HJ, Harst E van der, Steyerberg EW et al. Retroperitoneal adrenalectomy;open or endoscopic. World J Surg 1998; 12: 1246-1249.

36. Heintz A, Walgenbach S, Junginger T. Results of endoscopic retroperitonealadrenalectomy. Surg Endosc 1996; 10: 633-635.

37. Waltz MK, Peitgen K, Hoermann R, Giebler KM, Mann K, Eigler FW. Posteriorretroperitoneoscopy as a new minimally invasive approach for adrenalectomy:results of 30 adrenalectomies in 27 patients. World J Surg 1996; 20: 769-774.

38. Fernandez-Cruz L, Saenz A, Taura P, Sabater L, Astudillo E, Fontanals J. Heliumand carbon dioxine pneumoperitoneum in patients with pheochromocytomaundergoing laparoscopic adrenalectomy. World J Surg 1998; 22: 1250-1255.

88 Chapter 7

39. Feldman JM, Blalock JA, Fagraeus L, Miller JN, Farrell RE, Wells SA.Alterations in plasma norepinephrine concentration during surgical resectionof pheochromocytoma. Ann Surg 1978; 188: 758- 760.

40. Vater M, Achola K, Smith G. Catecholamine respons during anaesthesia forphaeochromocytoma. Br J Anaesth 1983; 55: 357-359.

41. Newell KA, Prinz R, Brooks MH, Glisson SN, Barbato AL, Freeark RJ. Plasmacatecholamine changes during excision of pheochromocytoma. Surgery 1988;104: 1064-1065.

42. Rashed HM, Leventhal G, Madu E, Reddy R, Cardoso S. Reproducibility ofexercise-induced modulation of cardiovascular responses to cold stress. ClinAuton Res 1997; 7: 93-95.

Summary and General Discussion 89


90 Chapter 8


This thesis illustrates the remarkable progress made in the past decades in localizationand surgical treatment of phaeochromocytomas. In the treatment of thesecatecholamine producing tumours prerequisites for non-manipulative dissection andthe search for bilateral, metastatic or extra-adrenal tumours, traditionally dictate wideexposure by means of an anterior transabdominal approach and extensive dissection.Recent changes in surgical approach of the adrenal glands include the considerationof retroperitoneal or minimally invasive approaches for resection, instead of the strictlytransabdominal route.

Chapter 2 describes a group of 59 patients with phaeochromocytoma treated until1996 with resection by conventional laparotomy. This study shows that haemodynamicchanges due to peroperative catecholamine release during manipulation of the tumourare minimal when adequate alpha- and beta-adrenergic blockers are routinely usedin preoperative management. A considerable morbidity (25%) and even mortality(1 patient) was observed with transabdominal surgery for phaeochromocytoma. Meanhospital stay in these patients was 13 days. Long term results (mean follow-up 8.1years) after surgery for benign phaeochromocytoma were excellent. This series offersa standard for comparison of new surgical techniques for phaeochromocytoma.

After the diagnosis 'phaeochromocytoma' has been confirmed on biochemical grounds,localization of the tumour is of utmost importance for complete resection. At present,123I-Meta-iodo-benzyl-guanidine (MIBG) scintigraphy, computed tomography (CT),and magnetic resonance imaging (MRI) are the methods of choice for localizingphaeochromocytoma. All these modalities yield an over 80% accuracy in detectingthese tumours. Chapter 3 compares MIBG scintigraphy and computed tomographyfor localization of phaeochromocytoma. Advantage of MIBG scintigraphy overadrenal CT is the scanning of the whole body, enabling to detect extra-adrenalphaeochromo-cytoma. In our series MIBG scintigraphy detected all extra-adrenallesions and intra-adrenal solitary phaeochromocytomas. In contrast to asymptomatic,familial phaeochromocytomas, these solitary phaeochromocytomas offer anunambiguous scintigraphic appearance. Routine usage of both modalities is notwarranted. Since solitary phaeochromocytomas are located extra-adrenally in over15% of cases, initial MIBG scintigraphy in these patients is advised, followed by CTor MRI directed by the scintigraphic results, if more anatomical information is needed.These modern imaging modalities are more sensitive than surgical exploration.Therefore, extensive abdominal exploration is no longer needed for locatingphaeochromocytoma. Currently MRI is preferred over CT.

92 Chapter 8

MEN type 2 related phaeochromocytomas differ from their solitary counterparts inseveral aspects. Between 30% and 50% of patients with MEN type 2 will developphaeochromocytomas and the adrenomedullary histopathological lesions are usuallydiffuse and bilateral at the cellular level. Nevertheless, the clinical development ofphaeochromocytoma from medullary hyperplasia often occurs asymmetrically or maynot occur at all. In contrast to solitary phaeochromocytomas, familial phaeochromo-cytomas are rarely malignant or located in extra-adrenal tissues. Advances in theknowledge of RET proto-oncogene and its role in the MEN type 2 syndrome has ledto early detection of MEN 2 carriers. As a result of this DNA analysis combined withyearly screening for catecholamine excess in these carriers, phaeochromocytomas inthese particular patients are often asymptomatic and small at the time of diagnosis.These differences between sporadic and familial phaeochromocytomas dictate adifferent localization strategy and surgical approach.

In Chapter 4 we compare diagnostic applicability of CT and MRI combined withMIBG scintigraphy in preoperative localization of phaeochromocytoma in 17 MENtype 2 patients. Sensitivity of CT and MRI combined (in 27 adrenal glands) was 87%with a specificity of 100% and diagnostic accuracy of 89%. MIBG scintigraphy (31adrenal glands) had a sensitivity of 92% and a diagnostic accuracy of 77%. BecauseMIBG scintigraphy is not able to differentiate between medullary hyperplasia andsmall phaeochromocytomas, specificity of scintigraphy was only 17%. Due to thislow specificity combined with the absence of extra-adrenal phaeochromocytoma inMEN type 2 patients, MIBG scintigraphy has a limited role in imaging phaeochromo-cytoma in MEN type 2 patients. MRI should be the first choice for localization ofthese familial tumours.In patients with MEN type 2, the risk of recurrent phaeochromocytoma must beweighed against the risk of Addisonian crisis due to inadequate gluco- and mineralo-corticosteroid supplementation after bilateral adrenalectomy. Bilateral (preventive)adrenalectomy is the traditional treatment of MEN type 2 associated phaeochromo-cytomas. In Chapter 5 the results and complications are described of bilateraladrenalectomy in 28 patients with MEN type 2 related phaeochromocytoma. In 19 of25 patients (76%) bilateral phaeochromocytoma was present on histopathologicalexamination. Addisonian crises developed in over 30% of cases and one death wasattributable to this complication. On the other hand, concerns with respect to thedevelopment of catecholamine crisis or metastatic disease after less than bilateraladrenalectomy have no documented support. Therefore, this series supports the policyof performing only a unilateral adrenalectomy for phaeochromo-cytoma in MENtype 2 patients with unilateral mass as assessed by MRI.


In order to prevent the considerable morbidity and even mortality related toadrenocortical substitution therapy after bilateral adrenalectomy we have started totreat selected patients with MEN type 2 related phaeochromocytomas with cortical-sparing subtotal adrenalectomy. Chapter 6 describes the surgical technique and resultsof cortical-sparing adrenalectomy in six patients. Cortical sparing adrenalectomy wastechnically feasible in all patients. During follow-up (mean 40 months) no patients hadsigns or symptoms of adrenal insufficiency and all had normal plasma cortisolconcentrations. One patient developed recurrent phaeochromocytoma, 24 monthsafter subtotal adrenalectomy. Recurrent disease was treated successfully because ofthe slow progression of the disease and the available highly sensitive screeningtechniques. As yet, no hypertensive crisis or metastatic disease as a result of recurrentphaeochromocytoma has been reported in patients who underwent unilateral or subtotaladrenalectomy. The study results show that subtotal adrenalectomy is feasible inselected patients with preservation of adequate adrenal cortical reserve.

The role of minimally invasive adrenalectomy for phaeochromocytomas has beencontroversial. Therefore, reported experience with minimally invasive approachesfor these tumours is limited. Chapter 7 offers an overview of reported experiencewith transabdominal and retroperitoneoscopic minimally invasive techniques forresection of phaeochromocytoma in 106 and 30 phaeochromocytomas, respectively.Post-operative complications (7% and 5%, respectively) and postoperative hospitalstay (4.4 and 2.9 days, respectively) were all substantially lower in patients whounderwent minimally invasive adrenalectomy, when compared to conventionaltransabdominal adrenalectomy as described in Chapter 2. No complications due tocatecholamine release during �laparoscopic procedures� for phaeochromocytomashave been reported. This study of the literature shows that minimally invasiveapproaches for phaeochromocytoma provide as much haemodynamic stability as openadrenalectomy. With modern imaging modalities, extensive abdominal explorationin search for phaeochrocytoma in these patients has become obsolete. The laparoscopicor retro-peritoneoscopic approach is safe, as in other benign adrenal disease, andshould be considered as the preferable surgical approach for phaeochromocytoma.

94 Chapter 8

Conclusions:

1. The traditional transabdominal approach to perform adrenalectomy for phaeo-chromocytoma is associated with considerable perioperative morbidity. With theavailability of new techniques this policy can be considered as outdated.

2. Initial MIBG scintigraphy, followed by selective CT or MRI, is a solid localizationstrategy for solitary phaeochromocytomas.

3. MIBG scintigraphy has a limited role in the imaging of MEN type 2 relatedphaeochromocytomas. MRI should be the first method of choice in patients withthese familial tumours.

4. Complications of adrenocortical suppletion therapy after total bilateraladrenalectomy are considerable. Therefore, in MEN type 2 patients with unilateralphaeochromocytoma, unilateral adrenalectomy is the preferred treatment.

5. Subtotal adrenalectomy with preservation of adequate adrenal cortical reserve isfeasible for phaeochromocytoma in MEN type 2.

6. Minimally invasive approaches for phaeochromocytomas are safe and preferableover conventional transabdominal surgical procedures.

Samenvatting en Discussie 95

Samenvatting en Discussie


Dit proefschrift illustreert de opmerkelijke vooruitgang die in het afgelopen deceniumis gemaakt in de lokalisatie en chirurgische behandeling van het feochromocytoom.Traditioneel werd voor de behandeling van deze catecholamine secrenerende tumoreneen anterieure transabdominale benadering verkozen, enerzijds met een uitgebreidedissectie en anderzijds met een zo geringmogelijke manipulatie van de tumor. Opdeze wijze was het mogelijk om bilaterale, gemetastaseerde of extra-adrenale tumorenop te sporen en te verwijderen. Meer recent worden retroperitoneale en minimaalinvasieve benaderingen van de bijnieren toegepast in plaats van de strikt trans-abdominale benadering.

In hoofdstuk 2 wordt een groep van 59 patiënten beschreven met een feochromo-cytoom, behandeld tot 1996 met resectie via een anterieure transabdominalebenadering. Het bleek dat hemodynamische veranderingen ten gevolge vanmanipulatie van de tumor minimaal zijn bij het adequaat en routinematig voorbereidenvan deze patiënten met alfa- en beta- adrenerge blokkers. De transabdominalebenadering ging gepaard met een aanzienlijke morbiditeit (25%) en zelfs een minimalemortaliteit. De gemiddelde opnameduur was 13 dagen. Lange-termijn-resultaten(mediane follow-up 8.1 jaren) na chirurgische behandeling voor benigne feochromo-cytomen waren uitstekend. Deze serie biedt een standaard voor vergelijking metnieuwe chirurgische technieken voor de behandeling van feochromocytomen.Nadat de diagnose feochromocytoom op biochemische gronden is gesteld, islokalisatie van de tumor van groot belang voor de complete verwijdering.Hedentendage zijn 123I-Meta-iodo-benzyl-guanidine (MIBG)-scintigrafie, computer-tomografie (CT) en magnetic resonance imaging (MRI) de methoden van keuze voorde localisatiebepaling van het feochromocytoom. Al deze drie modaliteiten zijn in80% van de gevallen accuraat bij de detectie van feochromocytomen.

In hoofdstuk 3 wordt MIBG-scintigrafie en computer tomografie bij de localisatiebepaling van feochromocytomen vergeleken. Voordeel van MIBG scintigrafie bovenCT van de bijnieren, is dat een afbeelding van het gehele lichaam wordt verkregen,waardoor feochromocytomen kunnen worden gedetecteerd die buiten de bijnier zijngelegen. Alle extra-adrenale en solitaire intra-adrenaal gelegen feochromocytomenwerden met MIBG-scintigrafie juist gelocaliseerd. In tegenstelling tot asympto-matische familiaire feochromocytomen zijn deze solitaire feochromocytomenduidelijk met scintigrafie aantoonbaar. Het routinematig toepassen van beidelocalisatiemethodieken is niet zinvol. Aangezien solitaire feochromocytomen in 15%van de gevallen buiten de bijnier zijn gelegen, wordt MIBG-scintigrafie bij dezepatiënten als eerste onderzoeksmethode aanbevolen, gevolgd door CT of MRI-onderzoek op geleide van de scintigrafische uitkomst, indien meer anatomischeinformatie nodig is. Deze localisatiemethodieken zijn sensitiever dan chirurgische

98

exploratie. Daardoor is hedentendage uitgebreide chirurgische dissectie van debuikholte en het retroperitoneum niet langer noodzakelijk bij de behandeling van hetfeochromocytoom. Momenteel is MRI te verkiezen boven CT.

Feochromocytomen geassociëerd aan het MEN type 2 syndroom verschillen inverschillende opzichten van solitair voorkomende feochromocytomen. Tussen de30% en 50% van de MEN type 2-patiënten ontwikkelen een feochromocytoom, ende adrenomedulaire ziekte is op cellulair niveau meestal diffuus en in beide bijnierengelegen. Toch ontwikkelen feochromocytomen zich vaak asymmetrisch uit medulairehyperplasie in beide bijnieren, of ze ontwikkelen zich in het geheel niet. Integenstelling tot solitair voorkomende feochromocytomen zijn familaire feochromo-cytomen zelden maligne of buiten de bijnier gelegen. Recente kennis van het RETproto-oncogen en zijn rol bij het MEN type 2- syndroom hebben geleid tot vroegeopsporing van MEN carriers. Deze DNA-analyse gecombineerd met jaarlijksebepaling van catacholamines maakt dat feochromocytomen bij deze groep patiëntenvaak asymptomatisch en klein zijn bij diagnose. Deze verschillen tussen familiaireen solitaire feochromocytomen maken dat er een verschil is in localisatiestrategie enchirurgische benadering in beide groepen.

In hoofstuk 4 wordt de diagnostische toepassing van CT en MRI gecombineerd metMIBG-scintigrafie vergeleken bij de preoperatieve localisatie van feochromocytomenbij 17 MEN type 2-patiënten. De gevoeligheid van MRI en CT gecombineerd (bij 27bijnieren) was 87% met een specificiteit van 100% en een diagnostische accuraatheidvan 89%. MIBG-scintigrafie (31 bijnieren) had een gevoeligheid van 92% en wasaccuraat in 77% van de gevallen. Omdat MIBG-scintigrafie niet in staat is omonderscheid te maken tussen medulaire hyperplasie en kleine feochromocytomenwas de specificiteit slechts 17%. Deze lage specificiteit gecombineerd met hetnauwelijks voorkomen van extra-adrenale feochromocytomen bij het MEN type 2-syndroom ,maken dat MIBG-scintigrafie een beperkte rol heeft bij de lokalisatie vanMEN type 2 gerelateerde feochromocytomen. MRI is daarmee de eerste keuze voorde localisatiebepaling van deze familiaire feochromocytomen.

Bilaterale (preventieve) adrenalectomie is de traditionele behandeling van feochromo-cytomen geassocieerd aan het MEN type 2-syndroom. Bij deze patienten moet hetrisico van een zich contralateraal ontwikkelend feochromocytoom echter wordenafgewogen tegen het risico van een Addisonse crisis ten gevolge van inadequatebijnier- suppletietherapie na bilaterale adrenalectomie.Hoofdstuk 5 geeft een overzicht van de resultaten en complicaties na bilateraleadrenalectomie voor feochromocytomen bij 28 MEN type 2-patiënten. Bij 19 van de25 patiënten (76%) was er sprake van een feochromocytoom in beide bijnieren. Meer


dan 30% van deze patiënten ontwikkelden één of meer perioden van een Addisonsecrisis, en één patiënt kwam ten gevolge van deze complicatie te overlijden.De bezorgdheid over een catecholamine crisis na enkelzijdige adrenalectomie wordtniet bevestigd door gegevens uit de literatuur en evenmin door de resultaten van ditonderzoek. Er wordt dan ook aanbevolen om slechts een eenzijdige adrenalectomieuit te voeren bij MEN type 2-patiënten met een met MRI unilateraal aangetoondetumor.Om de aanzienlijke morbiditeit en de overigens beperkte mortaliteit die is gerelateerdaan adrenocorticale substitutie therapie, nodig na bilaterale adrenalectomie, tevoorkomen, is gestart met het uitvoeren van bijnierschorssparende subtotaleadrenalectomieën bij geselecteerde patiënten met MEN type 2 gerelateerdefeochromocytomen.In hoofdstuk 6 wordt de chirurgische techniek en de resultaten van bijnierschors-sparende subtotale adrenalectomieën bij 6 patienten beschreven. Een bijnierschors-sparende operatie was technisch mogelijk bij alle patiënten. Tijdens follow-up(mediaan 40 maanden) vertoonden geen van deze patiënten tekenen van bijnier-insufficientie en allen hadden normale plasma cortisol-concentraties.Eén patient ontwikkelde een recidief feochromocytoom 24 maanden na subtotaleadrenalectomie. Het recidief werd succesvol behandeld tengevolge van het zichlangzaam ontwikkelen van de ziekte en dankzij de zeer sensitieve screenings-methodieken. Tot op heden is er in de literatuur geen melding gemaakt van eenhypertensieve crisis bij patiënten behandeld met een unilaterale of subtotaleadrenalectomie. Deze studie toont aan dat een subtotale adrenalectomie mogelijk isbij geselecteerde patiënten met behoud van adequate bijnierschorsfunctie.

De rol van minimaal invasieve adrenalectomieën voor feochromocytomen iscontroversieel. Hierdoor is de gerapporteerde ervaring met minimaal invasievebenaderingen voor deze tumoren beperkt.

Hoofdstuk 7 geeft een overzicht van de gerapporteerde ervaringen met trans-abdominale en retroperitoneoscopische minimaal invasieve technieken voor deresectie van feochromocytomen bij respectievelijk 106 en 30 tumoren. Postoperatievecomplicaties (respectievelijk 7% en 5%) en postoperatieve opnameduur(respectievelijk 4.4 en 2.9 dagen) waren substantieel lager dan na conventioneletransabdominale adrenalectomie zoals beschreven in hoofdstuk 2. Er zijn geencomplicaties gerapporteerd tengevolge van het vrijkomen van catecholamines tijdens�laparoscopische� adrenalectomie voor feochromocytomen. Deze studie toont aandat de minimaal invasieve benadering voor het feochromocytoom evenveelhemodynamische stabiliteit biedt als open adrenalectomie. Met de modernelokalisatiemethodieken is uitgebreide abdominale exploratie voor additionele

100

feochromocytomen obsoleet geworden. De laparoscopische of retroperitoneo-scopische benadering voor de verwijdering van feochromocytomen, evenals anderebijnier aandoeningen , heeft de voorkeur bij de keuze van de operatieve benadering.

Conclusies:

1. De traditionele transabdominale benadering voor adrenalectomie bij feochromo-cytomen gaat gepaard met een aanzienlijke perioperatieve morbiditeit. Met debeschikbaarheid van nieuwe technieken kan deze benadering als obsoleet wordenbeschouwd.

2. Initiële MIBG-scintigrafie gevolgd door selectief toegepaste CT of MRI, is eenbetrouwbare lokalisatiestrategie voor solitaire feochromocytomen.

3. MIBG scintigrafie is van beperkte waarde bij de localisatiebepaling van MENtype 2 gerelateerde feochromocytomen. MRI is de eerste keuze voor de localisatie-bepaling van deze familiaire tumoren.

4. De complicaties ten gevolge van adrenocorticale suppletietherapie na bilateraleadrenalectomie zijn aanzienlijk. Daarom verdient bij MEN type 2-patiënten meteen unilateraal gelocaliseerd feochromocytoom een unilaterale adrenalectomiede voorkeur.

5. Subtotale adrenalectomie met behoud van adequate bijnierschorsfunctie ismogelijk bij MEN type 2 geassocieerde feochromocytomen.

6. Minimaal invasieve benaderingen voor feochromocytomen zijn veilig en teverkiezen boven de conventionele transabdominale chirurgische benadering.

Nawoord 101

Nawoord

Nawoord 103

Dit proefschrift is het resultaat van onderzoek verricht in het Academisch ZiekenhuisGroningen en het Academisch Ziekenhuis Utrecht. Veel mensen ben ik dankverschuldigd, van wie ik met name wil noemen:

Prof. dr. R. P. Zwierstra, mijn promotor. Beste Rein, als eerste wil ik jou bedankenvoor de buitengewoon prettige wijze waarop je dit onderzoek hebt begeleid. Jouw�educatieve inslag� en betrokkenheid bij meer dan de promotie alleen heb ik zeergewaardeerd.

Prof. dr. Th. J. M. V. van Vroonhoven, mijn promotor. Geachte professor, niet alleenwil ik u bedanken voor uw begeleiding van deze promotie, maar evenzozeer voor uwgrote en kritische aandeel in mijn chirurgische opleiding. Het is een voorrecht u alsopleider te hebben.

Dr. R. P. F. Dullaart, mijn co-promotor. Beste Robin, snelle en kritische correcties inprima sfeer. Bedankt.

De leden van de beoordelingscommissie, bestaande uit Prof. dr. I. Molenaar, Prof. dr.W. D. Reitsma, en Prof. Dr. A. Vermey (FACS). Dank voor de spoedige beoordelingvan dit proefschrift en de gewaardeerde suggesties.

Geen auteur zonder mede-auteurs. Bij dezen wil ik hen bedanken voor de geleverdebijdrage aan de in dit proefschrift opgenomen publicaties.

Cees Haaring, Roger Lapham en Marte Zwierstra. Dank voor de technische entekstuele ondersteuning.

Dr. R. P. Bleichrodt, de maatschap chirurgie van het Twenteborg Ziekenhuis in Almeloen de maatschap chirurgie van het Academisch Ziekenhuis Utrecht wil ik graagbedanken voor hun bijdrage aan mijn opleiding tot algemeen chirurg.

De afgelopen jaren heb ik samengewerkt met een groot aantal mede-assistenten. Velenhiervan zijn voor een belangrijk deel verantwoordelijk geweest voor de primaopleidingstijd tot op heden, in, maar ook buiten het ziekenhuis. Hiervoor dank.

104

Drs. M. S. Sietsma en Dr. P. Swartbol, mijn paranimfen. Beste Maurits en Pøl, jullieals paranimfen was een logische keuze. Bedankt dat jullie mij tijdens de verdedigingvan dit proefschrift ter zijde willen staan. Wellicht verstandig om dit boekje voor dietijd toch even door te lezen.

Dit proefschrift is niet voor niets opgedragen aan Tjeerd en Nynke de Graaf, mijnouders, voor al meer dan 30 jaar niet aflatende steun en belangstelling op alle fronten.

En natuurlijk aan mijn lieve Annemarie.


Curriculum Vitae


De auteur van dit proefschrift werd geboren op 27 mei 1966 in Eelde-Paterswolde.In 1985 behaalde hij zijn Athenaeum B-diploma aan het Thorbecke College teGroningen. Na twee keer te zijn uitgeloot, kon hij in 1987 de studie geneeskundestarten aan de Rijks Universiteit Groningen. De artsenbul werd in april 1994 behaald.Van mei tot december 1994 was hij werkzaam als arts-assistent niet in opleiding opde afdeling chirurgie van het Twenteborg Ziekenhuis te Almelo. In dit zelfdeziekenhuis startte hij in januari 1995 zijn opleiding chirurgie (opleiders DrR.P.Bleichrodt en Dr J.van Baal). Sinds januari 1998 volgt hij de laatste drie jaar vanzijn chirurgische opleiding in het Academisch Ziekenhuis te Utrecht (opleider: Prof.dr.Th.J.M.V.van Vroonhoven). Hij woont samen met Annemarie Bronk in Utrecht.

STELLINGEN

BEHOREND BIJ HET PROEFSCHRIFT


PHAEOCHROMOCYTOMA

JOOST DE GRAAF

UTRECHT, 15 JUNI 1999.

I. Minimaal invasieve operatieve benaderingen voor feochromocytomen

zijn veilig en te verkiezen boven de conventionele transabdominale

chirurgische benadering.

II. MIBG scintigrafie is van beperkte waarde bij de locatie bepaling van

MEN type 2-gerelateerde feochromocytomen.

III. Subtotale adrenalectomie met behoud van adequate bijnierschorsfunctie

is mogelijk bij MEN type 2-gerelateerde feochromocytomen.

IV. Bij MEN type 2-patiënten met een feochromocytoom in slechts één

bijnier verdient een unilaterale (subtotale) adrenalectomie de voorkeur.

V. Het voor histopathologisch onderzoek insturen van resectie preparaten na

adrenalectomie voor een feochromocytoom levert over het algemeen

geen voor de verdere behandeling relevante informatie op.

VI. De eerste keuze van behandeling bij obstructies van het linker colon is

een darmresectie met primaire anastomosering.

VII. Het functionele resultaat na een gecombineerde distale radiusfractuur en

scaphoidfractuur wordt voornamelijk bepaald door de verkregen stand

van de distale radius.

VIII. Intra-medullair osteosynthese materiaal moet worden verwijderd door

een operateur die het ook kan inbrengen.

IX. Het is mogelijk om direct experimenteel aan te tonen dat de aarde om de

zon beweegt.

(Proefschrift �Aspects of neutrino astrophysics�, T de Graaf,

Groningen 1969)

X. Het overwegend negatieve imago van de golfsport in Nederland dient te

worden gekoesterd om een dreigend capaciteitsprobleem te voorkomen.

XI. In Almelo zijn helemaal geen stoplichten.

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