19 Pheochromocytoma in MEN-2A, MEN-2B, and von Hippel-Lindau Disease

contents

19.1 Introduction . . . 195 19.2 MEN-2A, MEN-2B . . . 195 19.3 von Hippel-Lindau Disease . . . 196 19.4 Screening MEN-2 and VHL Patients

for Pheochromocytoma . . . 197 19.5 Preoperative Preparation . . . 197 19.6 Surgical Management . . . 198 19.7 Paragangliomas . . . 199 19.8 Summary . . . 199

References . . . 199

19.1 Introduction

Pheochromocytomas in MEN-2A, MEN-2B, and von Hippel-Lindau disease (VHL) may be bilateral and, less often, extra-adrenal (paragangliomas) [8, 30].

Historically, such patients were explored via an open anterior, transperitoneal approach to provide ready access to both adrenal glands and the paraganglia.

Bilateral total adrenalectomy was the preferred opera- tion, to avoid future recurrence in residual adreno- medullary tissue. Pheochromocytomas can be associ- ated with sudden, life-threatening events, especially in the perioperative and peripartum periods [2, 8]. With the likely need for multiple operative procedures, in these familial disorders, over the course of a patient’s lifetime,missing a small or occult pheochromocytoma could have disastrous perioperative consequences.

The downside of bilateral total adrenalectomy (BTA) is the lifelong commitment to exogenous steroid dependence. More recent follow-up studies have doc- umented the true incidence of acute adrenal insuffi- ciency following bilateral total adrenalectomy. The numbers are not inconsequential,and morbidity is sig- nificant [4, 9, 20].

The risk of malignancy [2, 8, 33] in patients with fa- milial pheochromocytoma is so low that concerns re-

garding malignancy should be, at best, a very weak argument supporting routine bilateral total adrenal- ectomy.

With a better understanding of the genetics and natural history of these disorders, coupled with im- proved methods of diagnosis, localization, and resec- tion, more conservative operations can now be made available to patients with MEN2 and VHL, so as to avoid lifelong steroid dependence.

19.2 MEN-2A, MEN-2B

Multiple endocrine neoplasia type 2 (MEN-2) is an au- tosomal dominant genetic syndrome characterized by multiple endocrine tumors, including medullary thy- roid carcinoma (seen in 100% of patients),parathyroid neoplasia, and pheochromocytoma. In MEN-2A, pheochromocytomas are seen in approximately 50%

of affected kindred members. The same is true of MEN-2B patients. In MEN-2B, the marfanoid habitus is seen in virtually all patients, along with mucosal neuromas and occasional intestinal ganglioneuromas.

Parathyroid disease is seen in 10–20% of MEN-2A pa- tients, and is not seen in MEN-2B kindreds [15].

Germline mutations in the RET proto-oncogene have been found to be responsible for both inherited syndromes.The causative gene was mapped to the cen- tromeric chromosome 10 in 1987 [22, 35]. The RET proto-oncogene is a tumor-suppressor gene and en- codes a tyrosine kinase receptor. In more than 95% of patients with MEN-2A, a germline mutation affects one of five codons specifying a conserved cysteine residue within the extracellular ligand-binding do- main of RET. All MEN-2A patients exhibit allelic het- erogeneity. Ninety-eight percent of patients with MEN-2B syndrome harbor a single point mutation lo- cated within the tyrosine kinase catalytic domain of RET [5,12,24,34].Through direct mutational analysis, it is now possible to determine the genetic status of pa-

and von Hippel-Lindau Disease

Geoffrey B. Thompson

tients at risk for the development of MEN-2 in most cases.

The reported incidence of pheochromocytomas in affected MEN-2 patients ranges from 30% to 55%

[30]. Pheochromocytoma is the first presenting fea- ture in only 10–25% of MEN-2 patients. Medullary thyroid carcinoma is diagnosed before or simultane- ously in 75–90% of cases. The average age at diagno- sis for pheochromocytoma in MEN-2 patients is approximately 37 years.When medullary thyroid car- cinoma is diagnosed first, there is an average interval of at least 10 years before a pheochromocytoma becomes evident either clinically or biochemically.

Pheochromocytomas in MEN-2 are rarely malignant and paragangliomas occur in less than 1% of MEN-2 patients [25].

It is absolutely necessary to exclude the presence of pheochromocytoma in any patient in whom thy- roidectomy is planned for medullary thyroid carcino- ma, particularly when a family history of MEN-2 is suspected or known.

The diagnosis of pheochromocytoma in MEN-2 pa- tients is made by a combination of history, biochemi- cal screening, and imaging. Today, because of genetic screening and surveillance, 50–80% of patients with adrenomedullary tumors are asymptomatic. When symptomatic, headache (69%), palpitations (62%), hypertension (57%), and diaphoresis (50%) are the most common signs and symptoms [25]. Combined measurement of 24-h fractionated urinary cate- cholamines and total metanephrines is diagnostic in over 90% of patients with (familial) pheochromocy- tomas [8, 28]. Measurement of plasma metanephrines and normetanephrines may be more sensitive, result- ing in more false positive studies [13]. We find plasma levels helpful when the clinical and radiographic sus- picion is high,but the 24-h urinary levels are repeated- ly normal.

Computed tomography (CT), magnetic resonance imaging (MRI), and nuclear scintigraphy (MIBG) are all very accurate at localizing pheochromocytomas (85–90%) [25]. Somatostatin receptor scintigraphy has also been used with some success. Because of the low rate of malignancy and extra-adrenal tumors, there is little role for meta-iodobenzyl guanidine (MIBG) imaging in early screening. In addition, MIBG will light up hyperplastic glands in MEN 2, thereby creating both diagnostic and management dilemmas [11].

Lairmore et al. [20] have published the most im- portant study with regard to the operative manage- ment of MEN-2 pheochromocytomas. In 23 patients

undergoing unilateral adrenalectomy alone, 48% had not developed a contralateral tumor with a mean fol- low-up time of 5.2 years. In those that did develop a contralateral pheochromocytoma (52%), the mean follow-up was 11.9 years. In addition, of their patients undergoing bilateral total adrenalectomy, 25% had at least one episode of acute adrenal insufficiency re- quiring hospital admission and intravenous corticos- teroid infusion.

19.3 von Hippel-Lindau Disease

VHL is an autosomal dominant tumor predisposition syndrome characterized by multiple benign and ma- lignant tumors of the central nervous system,kidneys, pancreas, adrenal medulla, and paraganglia (Table 1) [2,8].Renal cell carcinomas are the most lethal tumors seen in over 50% of VHL patients [2, 8]. Retinal an- giomas and central nervous system hemangioblas- tomas are the hallmarks of this disease [2, 8]. Approx- imately 7–20% of VHL patients develop pheochromo- cytomas [2, 8].

The incidence of VHL is roughly 1 per 40,000, and it has been observed across all ethnic groups and both sexes [2,8].Genetic testing is available and can be used to determine whether an individual carries a mutation of the VHL gene.VHL is due to germline mutations in a tumor suppressor gene mapped to the chromosomal region 3p25–26 [8]. Deleterious mutations in the VHL gene can be identified in 80% or more of the VHL fam- ilies [8]. In kindreds where a mutation has been iden- tified,genetic testing can rule out VHL in family mem- bers lacking that specific mutation, thus avoiding the

Table 1. von Hippel-Lindau tumor types seen in 109 patients, January 1975 to June 2000

Tumor type No. (%)

Renal cell carcinoma 50 (46)

Cerebellar/cerebral hemangioblastomas 83 (76)

Retinal angiomas 69 (63)

Pheochromocytomas (adrenal masses) 17 (16)

Paragangliomas 3 (3)

Benign renal cysts 66 (61)

Spinal cord hemangioblastoma 33 (30)

Pancreatic lesions 47 (43)

Ovarian cysts 7 (6)

Epididymal cysts 10 (9)

Endolymphatic sac tumors 5 (5)

Hepatic hemangiomas 7 (6)

expense, anxiety, and inconvenience of lifelong sur- veillance. There appears to be a strong correlation be- tween the type of mutation and the clinical phenotype in VHL. In VHL type 2 (with pheochromocytomas), 96% of families have missense mutations. However, not all missense mutations are associated with pheo- chromocytoma [8].

Minimal clinical diagnostic criteria for VHL of known family members require documentation of at least one major lesion (retinal angioma, central nerv- ous system hemangioblastoma, renal cell cancer, or pheochromocytoma) [8]. In a suspected proband, the individual must demonstrate two or more retinal or CNS vascular tumors or one vascular tumor and one characteristic visceral lesion [8].

Pheochromocytomas in VHL tend to occur in younger patients and are more frequently smaller, multiple, bilateral, and extra-adrenal, compared to their sporadic counterparts [8]. Similar to MEN-2 pa- tients, metastasis is rare. Clustering of pheochromo- cytomas in a subset of VHL families is well recognized in VHL, VHL 2A (pheochromocytomas but no renal call carcinoma), and VHL 2B (pheochromocytomas and renal cell carcinoma) [8].

In our most recent review of 109 VHL patients at Mayo Clinic [2], the mean age at VHL diagnosis was 29 years (range, 7–66 years). One-third of patients had no first-degree relatives with VHL. Seventeen (16%) patients had an adrenal mass, and three (3%) had paragangliomas. In six patients (6%), pheochromocy- toma or paraganglioma was the first documented VHL tumor. Forty-one percent of patients were asympto- matic, but 29% presented with significant cardiac manifestations (arrhythmia and/or cardiomyopathy).

The urinary excretion of fractionated catecholamines and total metanephrines was elevated in only two- thirds of VHL patients with pheochromocytomas. CT scanning detected 83% of the known tumors.

I- MIBC scintigraphy detected the remaining lesions.Six- teen patients underwent surgical resection during this 25-year period at our institution. Fifty percent of the patients underwent concurrent abdominal surgery for renal and/or pancreatic tumors.In only two cases were bilateral total adrenalectomies performed. Mean tu- mor size was 2.7 cm (range, 1.5–6.5 cm). No malignant tumors were identified.There were no deaths,and only two transient perioperative complications (atrial fib- rillation and pancreatitis; each in one patient). Of the three excised paragangliomas, two were located in the inner ear, and one was in the juxtarenal, para-aortic position.Of the adrenalectomies performed,nine were unilateral procedures (three laparoscopic; of which

one was partial), four were bilateral (two bilateral to- tal adrenalectomies; two were cortical-sparing – one of which was laparoscopic). Only the two patients who underwent bilateral total adrenalectomy remain steroid dependent. No metastases or recurrences have developed with a mean follow-up of 6.8 years (range, 3 months to 37 years) in the entire group and 1 year (range, 11–47 months) in the cortical-sparing group.

19.4 Screening MEN-2 and VHL Patients for Pheochromocytoma

Biochemical screening for pheochromocytoma in affected kindred members should begin during early adolescence in MEN-2 patients and childhood in VHL patients, seeing that the earliest reports of pheochromocytoma in these patients appear to be ap- proximately 10 years later [8, 25]. Screening should consist of 24-h urinary catecholamines and meta- nephrines and CT scanning on a yearly basis for both MEN-2 and VHL patients. Elevated urinary studies in the face of a negative CT scan should prompt an MRI examination in MEN-2 patients and an MRI or MIBG scan in VHL patients. Normal urinary studies in the face of an adrenal mass on CT should prompt the measurement of plasma metanephrines and normetanephrines. If normal, MIBG scanning or MRI should be considered. Lack of symptoms or nor- motension is not an indication for continued obser- vation in a patient with a documented pheochromo- cytoma. The quiescent nature of these smaller famil- ial tumors makes screening and early detection essential to avoid life-threatening crises during sur- gery, trauma, or childbirth.

19.5 Preoperative Preparation

Once the diagnosis of pheochromocytoma is estab- lished, preoperative pharmacologic blockade with the a-blocker dibenzyline is our preferred agent of choice.

The drug is titrated for 7–10 days to orthostatic hy-

potension and nasal congestion. Replenishment of the

patient’s effective circulating volume with added salt

and fluid intake is imperative for safe perioperative

management. b-Blockers are added 2–3 days prior to

surgery if tachyarrhythmias are present. Alternative,

effective regimens utilizing calcium channel blockers

or labetalol have been described.

19.6 Surgical Management

Anesthetic management is similar to that described for sporadic cases and is presented elsewhere in this text. Surgical management in MEN-2 and VHL has evolved as a result of a better understanding of the natural history of these disease processes. Given the low incidence of malignancy and the low risk of (ear- ly) recurrence, adrenal-sparing procedures [2, 8, 30]

have become increasingly popular and are proving to be both safe and efficacious. Autotransplantation of devascularized cortical tissue is fraught with unac- ceptably high failure rates [16, 27], but the preserva- tion of a vascularized remnant (as little as one-third of one gland) of adrenal cortex can provide sufficient cortisol secretion at rest and during times of stress [2, 3, 7].We and others have demonstrated the safety and success of the laparoscopic approach for pheochro- mocytomas both unilateral and bilateral, total and cortical-sparing (Table 2) [1, 2, 4, 10, 14, 17, 18, 21, 23, 26,29,31,32,38,39].The availability of ultrasound and harmonic ultrasonic dissectors for both open and la- paroscopic procedures has made cortical-sparing surgery an appropriate alternative to bilateral total adrenalectomy in most patients with bilateral pheo- chromocytomas (Fig. 1). Although minimal steroid supplementation may be necessary for short periods of time after cortical-sparing surgery, most can be weaned based on the results of cortrosyn stimulation testing.

Cortical-sparing surgery (either unilateral or bilat- eral) is easier with smaller tumors (<1.5–2.0 cm) and tumors at either pole (away from the central hilum)

but is possible under a variety of situations (see Chap. 36). Contraindications to cortical-sparing sur- gery include large, centrally located, invasive or malig- nant tumors and multiple tumors throughout the gland.Open anterior procedures are still utilized when concomitant intra-abdominal operations are planned in VHL patients, such as nephron-sparing surgery and pancreatic surgery for islet cell tumors,or in many cas- es requiring a completion adrenalectomy.

When performing laparoscopic or open adrenalec- tomy in MEN-2 patients, the liver should be carefully inspected for evidence of metastatic medullary thy- roid carcinoma. Open posterior adrenalectomy re- mains an option for patients with extensive intra- abdominal adhesions, but the morbidity (muscu- loskeletal) is not insignificant [36].An extraperitoneal

Table 2. Laparoscopic and cortical-sparing adrenalectomy for MEN 2 and VHL pheochromocytomas (recent literature review) Author Patients VHL or Cortical Laparoscopic Mean FU Recurrence Steroid

(no.) MEN 2 sparing (months) independence

Lee et al. 1996 [21] 15 Both 15 0 138 3 93%

Janetschek et al. 1998 [18] 4 VHL 4 4 13.5 0 All

de Graaf et al. 1999 [10] 6 MEN 2 6 0 40 1 All

Mugiya et al. 1999 [23] 1 MEN 2 1 1 3 0 All

Neumann et al. 1999 [26] 4 VHL 4 4 2–24 0 All

Walther et al. 1999 [38] 14 VHL 12 0 18 2 92%

Inabnet et al. 2000 [16] 5 Both 5 0 84 3 40%

Radmayr et al. 2000 [32] 1 VHL 1 1 24 0 All

Walther et al. 2000 [39] 3 VHL 3 3 13 0 All

Al-Sobhi et al. 2002 [1] 1 VHL 1 1 3 0 All

Baghai et al. 2002 [2] 5 VHL 3/5 4/5 12 0 All

Brunt et al. 2002 [4] 18 Both 0 18 57 4/12 MEN 2 N/A

Porpiglia et al. 2002 [31] 1 MEN 2 1 1 12 0 All

Fig. 1. Laparoscopic ultrasound demonstrating non-visible

tumor in lower pole

endoscopic approach is another option in this situa- tion, but is technically quite demanding [23].

One remaining controversy focuses on the appro- priateness of cortical-sparing surgery in MEN-2 pa- tients. Virtually all MEN-2 patients have nodular or diffuse adrenomedullary hyperplasia [6, 19, 37]. These hyperplastic and neoplastic cells are the precursor cells for MEN-2 pheochromocytomas. Adrenomedul- lary hyperplasia is not found in other cases of familial pheochromocytoma. Is it then appropriate to transect an adrenal gland with adrenomedullary hyperplasia, assuming that some neoplastic precursor cells will be spilled into the retroperitoneum? No definitive answer is available. Numerous cortical-sparing adrenalec- tomies have been performed on MEN-2 patients with- out any reported cases of pheochromocytomatosis.

Remnant recurrences are reportedly low,but follow-up in most cases is short. Definitive answers regarding this question may not be available for another 15–20 years.

19.7 Paragangliomas

Paragangliomas can occur anywhere from the base of the skull to the bladder along the sympathetic para- ganglia. Because of their location and the reactive tis- sue that often surrounds these tumors, open surgical excision is our procedure of choice, but laparoscopic resection of such tumors has been performed [18].Un- like their sporadic counterparts, paragangliomas in MEN-2 (exceedingly rare) and VHL tend to behave in a benign fashion.

19.8 Summary

Fifty percent of MEN-2 patients develop pheochro- mocytomas, and 10–20% of affected members of VHL families will do the same. Familial pheochromocy- tomas are more often bilateral, multiple, small, and asymptomatic compared to their sporadic counter- parts. Genetic testing is available for both disorders, and when mutations are present, patients should be screened regularly for pheochromocytoma with bio- chemical and imaging studies. After preoperative pharmacologic blockade, resection of all pheochro- mocytomas should be performed either in an open or laparoscopic fashion. Adrenal-sparing surgery and cortical-sparing surgery seem appropriate in most cases, given the low risk of malignancy, the acceptable rate of contralateral or remnant recurrence, and the

clear advantage for avoidance of prolonged exogenous steroid dependence. Concerns (at least theoretic) re- garding gland transection remain in MEN-2 patients with adrenomedullary hyperplasia, and further study is warranted.

References

1. Al-Sobhi S, Peschel R, Zihak C, Bartsch G, Neumann H, Janetschek G (2002) Laparoscopic partial adrenalectomy for recurrent pheochromocytoma after open partial adrenalectomy in von Hippel-Lindau disease. J Endourol 16:171–174

2. Baghai M, Thompson GB,Young WF Jr, Grant CS, Michels VV, van Heerden JA (2002) Pheochromocytomas and paragangliomas in von Hippel-Lindau disease.Arch Surg 137:682–689

3. Barker NW (1929) The pathologic anatomy in twenty- eight cases of Addison’s disease. Arch Pathol 8:432–450 4. Brunt LM, Lairmore TC, Doherty GM, Quasebarth MA,

DeBenedetti M, Moley JF (2002) Adrenalectomy for fa- milial pheochromocytoma in the laparoscopic era. Ann Surg 235:713–721

5. Carlson KM, Dou S, Chi D, et al. (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple en- docrine neoplasia type 2B. Proc Natl Acad Sci USA 91:1579–1583

6. Carney JA, Sizemore GW, Sheps SG (1976) Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Pathol 66:279–290

7. Cedemark BJ, Sjoberg HE (1981) The clinical significance of metastases to the adrenal glands. Surg Gynecol Obstet 152:607–610

8. Couch VMS, Lindor NM, Karnes PS, Michels VV (2000) von-Hippel-Lindau disease. Mayo Clin Proc 75:265–

272

9. de Graaf JS, Dullaart RPF, Swierstra RP (1999) Compli- cations after bilateral adrenalectomy for phaeochromo- cytoma in multiple endocrine neoplasia type 2 – a plea to conserve adrenal function. Eur J Surg 165:843–846 10. de Graaf JS, Lips CJM, Rütter JE, van Vroonhoven TJMV

(1999) Subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2A. Eur J Surg 165:535–538

11. de Graaf JS, Dullaart RPF, Kok T, Piers DA, Swierstra RP (2000) Limited role of meta-iodobenzylguanidine scintigraphy in imaging phaeochromocytoma in patients with multiple endocrine neoplasia type II. Eur J Surg 166:289–292

12. Donis-Keller H,Dou S,Chi D,et al.(1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851–856

13. Eisenhofer G, Lenders JW, Linehan WM, Walther MM,

Goldstein DS,Keiser HR (1999) Plasma normetanephrine

and metanephrine for detecting pheochromocytoma in

von Hippel-Lindau disease and multiple endocrine neo- plasia type 2. N Engl J Med 340:1872–1879

14. Gagner M, Breton G, Pharand D, Pomp A (1996) Is la- paroscopic adrenalectomy indicated for pheochromocy- tomas? Surgery 120:1076–1080

15. Howe JR, Norton JA, Wells SA Jr (1993) Prevalence of pheochromocytoma and hyperparathyroidism in multi- ple endocrine neoplasia type 2A: results of long-term fol- low-up. Surgery 114:1070–1077

16. Inabnet WB, Caragliano P, Pertsemlidis D (2000) Pheo- chromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery 128:1007–1012

17. Janetschek G, Neumann HP (2001) Laparoscopic surgery for pheochromocytoma. Urol Clin North Am 28:97–105 18. Janetschek G,Finkenstedt G,Gasser R,Waibel UG,Peschel

R, Bartsch G, Neumann HPH (1998) Laparoscopic sur- gery for pheochromocytoma: adrenalectomy, partial re- section, excision of paragangliomas. J Urol 160:330–334 19. Koch CA, Mauro D, Walther MM, Linehan M, Vortmeyer

AO, Jaffe R, Pacak K, Chrousos GP, Zhuang Z, Lubensky IA (2002) Pheochromocytoma in von Hippel-Lindau dis- ease: distinct histopathologic phenotype compared to pheochromocytoma in multiple endocrine neoplasia type 2. Endocr Pathol 13:17–27

20. Lairmore TC, Ball DW, Baylin SB, et al. (1993) Manage- ment of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217:595–603

21. Lee JE, Curley SA, Gagel RE, Evans DB, Hickey RC (1996) Cortical-sparing adrenalectomy for patients with bilater- al pheochromocytoma. Surgery 120:1064–1071

22. Mathew CG, Chin KS, et al. (1987) A linked genetic mark- er for multiple endocrine neoplasia type 2A on chromo- some 10. Nature 6130:527–528

23. Mugiya S, Suzuki K, Saisu K, Fujita K (1999) Unilateral la- paroscopic adrenalectomy followed by contralateral retroperitoneoscopic partial adrenalectomy in a patient with multiple endocrine neoplasia type 2a syndrome. J Endourol 13:99–104

24. Mulligan LM, Kwok JBJ, Healey CS, et al. (1993) Germ-line mutations of the RET proto-oncogene in multiple en- docrine neoplasia type 2A. Nature 363:458–460

25. Mutch MG, Lairmore TC (2001) Pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2. In: Doherty GM, Skogseid B (eds) Clinical endo- crinology. Lippincott Williams & Wilkins, Philadelphia, p 569

26. Neumann HPH, Reincke M, Bender BU, Elsner R, Janetschek G (1999) Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma. J Clin Endocrinol Metab 84:2608–2610

27. Okamoto T, Obara T, Ito Y, Yamashita T, Kanbe M, Iihara M, Hirose K, Yamazaki K (1996) Bilateral adrenalectomy with autotransplantation of adrenocortical tissue or uni- lateral adrenalectomy: treatment options for pheochro- mocytomas in multiple endocrine neoplasia type 2A. En- docr J 43:169–175

28. Orchard T, Grant CS, van Heerden JA, Weaver A (1993) Pheochromocytoma – continuing evolution of surgical therapy. Surgery 114:1153–1158

29. Pautler SE, Choyke PL, Pavlovich CP, Caryanani K, Walther MM (2002) Intraoperative ultrasound aids in dis- section during laparoscopic partial adrenalectomy. J Urol 168:1352–1355

30. Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Par- rilla P, Tebar FJ (1998) Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocy- toma. Clin Endocrinol 48:195–200

31. Porpiglia F, Destefanis P, Bovio S, Allasino B, Orlandi F, Fontana D, Angeli A, Terzolo M (2002) Cortical-sparing laparoscopic adrenalectomy in a patient with multiple en- docrine neoplasia type IIA. Horm Res 57:197–199 32. Radmayr C, Neumann H, Bartsch G, Elsner R, Janetschek

G (2000) Laparoscopic partial adrenalectomy for bilater- al pheochromocytomas in a boy with von Hippel-Lindau disease. Eur Urol 38:344–348

33. Scopsi L, Castellani MR, Gullo M, Cusumano F, Camerini E, Pasini B, Orefice S (1996) Malignant pheochromocy- toma in multiple endocrine neoplasia type 2B syndrome:

case report and review of the literature. Tumori 82:

480–484

34. Seizinger BR, Rouleau GA, Ozelius LJ, et al. (1988) von Hippel-Lindau disease maps to the region of chromo- some 3 associated with renal cell carcinoma. Nature 332:

268–269

35. Simpson NE, Kidd KK, et al. (1987) Assignment of multi- ple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 6130:528–530

36. Thompson GB, Grant CS, van Heerden JA, et al. (1997) La- paroscopic versus open posterior adrenalectomy: a case- control study of 100 patients. Surgery 122:1132–1136 37. van Heerden JA, Sizemore GW, Carney JA, et al. (1984)

Surgical management of the adrenal glands in the mul- tiple endocrine neoplasia type II syndrome. World J Surg 8:612–621

38. Walther M, Keiser HR, Choyke PL, Rayford W, Lyne JC, Linehan WM (1999) Management of hereditary pheochromocytoma in von Hippel-Lindau disease kin- dreds with partial adrenalectomy. J Urol 161:395–398 39. Walther MM, Herring J, Choyke PL, Linehan WM (2000)

Laparoscopic partial adrenalectomy in patients with hereditary forms of pheochromocytoma. J Urol 164:

14–17