ORIGINAL ARTICLE. Estimated Risk of Pheochromocytoma Recurrence After Adrenal-Sparing Surgery in Patients With Multiple Endocrine Neoplasia Type 2A

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1 ORIGINAL ARTICLE Estimated Risk of Pheochromocytoma Recurrence After Adrenal-Sparing Surgery in Patients With Multiple Endocrine Neoplasia Type 2A Reza Asari, MD; Christian Scheuba, MD; Klaus Kaczirek, MD; Bruno Niederle, MD Hypothesis: Adrenal-sparing adrenalectomy is considered the treatment of choice for hereditary bilateral pheochromocytoma in patients with multiple endocrine neoplasia type 2A (MEN 2A). Design: Retrospective analysis of prospectively documented data with a mean±sd follow-up of 81.5±85.3 months. The PubMed database was searched for articles published between 1975 and 2004 to identify published series and/or case reports. Setting: University hospital referral center. Patients: In 17 (22%) of 77 patients with various mutations of the RET proto-oncogene, unilateral (n=12) or bilateral (n=5) pheochromocytomas were documented at the time of diagnosis or during the course of MEN 2A. Adrenal-sparing surgery was performed in 13 patients (group 1), synchronous bilateral total adrenalectomy in 4 patients (group 2A), and metachronous bilateral total adrenalectomy in 5 patients after adrenal-sparing adrenalectomy (group 2B). Main Outcome Measures: Measurement of 24-hour urinary catecholamine levels (noradrenaline, adrenaline, and dopamine) and, in case of high catecholamine levels, imaging studies to localize the tumors in 1 or both adrenal glands to determine the size and exclude extraadrenal tumors and distant metastasis. Results: The mean±sd estimated 5- and 10-year cumulative risk of developing recurrence in both groups was 38.5%±15.7%. Five (38%) of 13 patients in group 1 developed recurrence in the contralateral gland. Two (22%) of 9 patients in groups 2A and 2B developed several episodes of an addisonian crisis, 1 of whom died. Conclusions: Substantial morbidity and mortality are associated with addisonian crisis after bilateral adrenalectomy. Adrenal-sparing adrenalectomy and close monitoring of the remnant may be the treatment of choice for hereditary bilateral pheochromocytoma in MEN 2A, since overall recurrence is low. Arch Surg. 2006;141: Author Affiliations: Division of General Surgery, Section of Endocrine Surgery (Drs Asari, Scheuba, and Kaczirek), and Department of Surgery (Dr Niederle), Medical University of Vienna, Vienna, Austria. PHEOCHROMOCYTOMAS DEvelop in 30% to 50% of patients with multiple endocrine neoplasia type 2 (MEN 2). 1 On the cellular level, patients with MEN 2 are uniformly at risk for circumscribed bilateral tumors and/or have hyperplasia of the adrenal medulla even if this is not clinically or radiologically apparent at first presentation. 2 See Invited Critique at the end of article The treatment of pheochromocytoma in patients with MEN 2A is controversial. Because both adrenal glands are affected, total bilateral adrenalectomy has been proposed by some authors as an appropriate therapy in patients with RET proto-oncogene mutations. This procedure may prevent the development of persistent or recurrent adrenal disease with the risk of hypertensive crisis after any kind of adrenal-sparing surgery. 3 However, this approach necessitates long-term corticosteroid therapy with the social implications of complete dependence on lifelong substitution and the risk of osteoporosis with inadequately high substitution. A too low substitution is associated with the risk of life-threatening addisonian crisis. Therefore, other physicians have recommended a more selective approach of only resecting localized tumors with subsequent close monitoring of the remnants. 4 This study aims to evaluate the risk of recurrence after adrenal-sparing surgery and the consequences of total bilateral adrenalectomy in patients with MEN 2A. METHODS Seventy-seven patients (31 men and 46 women; mean±sd age, 39.9±20.3 years) with various mutations of the RET proto-oncogene were analyzed for the presence of pheochromocy- 1199

2 Table 1. Demographics of the Study Population* Demographics Adrenal-Sparing (Group 1; n = 13) Total (Group 2A; n = 4) Total (Group 2B; n = 5) Total (Groups 2A and 2B; n = 9) Mean age at diagnosis, y Sex, No. Male Female Tumor site, No. Unilateral 12 Left 7 Right 5 Bilateral 1 4 Extra-adrenal Recurrence, No. (%) 5 (38) 0 1 (20) 1 (11) Cumulative ± SD estimated recurrence, % 5 y 51.8 ± 18.7 (3 patients at risk) 10 y 51.8 ± 18.7 (2 patients at risk) 15 y 51.8 ± 18.7 (1 patients at risk) 34 ± 24.3 (1 patient at risk) Adrenocortical substitution, No Addisonian crisis, No. (%) 0 2 (50) 0 2 (22) Mean ± SD follow-up, mo ± ± ± ± *Group 1 underwent adrenal-sparing surgery (subtotal adrenalectomy or unilateral adrenalectomy with or without contralateral subtotal resection); group 2A, synchronous total bilateral adrenalectomy; and group 2B, metachronous total adrenalectomy. toma. Molecular genetic analysis included exons 8, 10, 11, and 13 to 15 of the RET proto-oncogene by analysis of singlestrand conformation polymorphisms and direct sequencing in all patients. 5 Biochemical diagnosis of pheochromocytoma included measurement of 24-hour urinary catecholamine levels (noradrenaline, adrenaline, and dopamine), and in case of high catecholamine levels, imaging studies were performed to localize the tumors in 1 or both adrenal glands to determine the size and exclude extra-adrenal tumors and distant metastasis. These imaging studies included meta-iodobenzylguanidine scintigraphy, computed tomography, and/or magnetic resonance imaging. If a catecholamine-producing tumor was diagnosed, patients were operated on either by adrenal-sparing surgery (subtotal adrenalectomy indicates unilateral adrenalectomy with or without contralateral subtotal resection) in circumscribed tumors or by synchronous or metachronous total bilateral adrenalectomy in large bilateral lesions. All patients were operated on by an experienced endocrine surgeon (B.N.). The surgical procedure was performed by a conventional open approach in 8 patients. An endoscopic transperitoneal access was favored and chosen in 9 patients. In 1 patient, a conversion from an endoscopic to an open procedure was necessary because of an injury of the tumor capsule during tumor mobilization. After surgery, all patients were observed by means of clinical examinations, including computed tomography and/or magnetic resonance imaging and measurement of 24-hour urinary catecholamine levels once a year. Recurrence of pheochromocytoma was defined as the new development of elevated urinary catecholamine levels and the presence of a documented new intra-abdominal mass. Patients with recurrence were treated by endoscopic adrenalectomy of the adrenal remnant, thus resulting in metachronous total adrenalectomy in all patients. Data analysis was performed using the statistical package SPSS version 11.5 for Windows (SPSS Inc, Chicago, Ill) to perform Kaplan-Meier estimations. Because of the limited experience in treating patients with pheochromocytoma in MEN 2A in general and the recurrence and malignancy of these tumors, an analysis of the literature seemed necessary to find more patients with MEN 2A observed by other centers. An extensive search of the literature between January 1975 and December 2004 was conducted to identify published series and/or case reports. For this purpose, the PubMed database was consulted. The keywords adrenal-sparing surgery, subtotal/total adrenalectomy, MEN 2, and recurrence were used. The bibliographies of the retrieved articles were reviewed to find additional sources of data. All articles in English and German were initially considered. When articles that described the same patient(s) were reviewed, only those containing the most information on patient characteristics and outcomes were included. Thus, only references (case reports and articles) that provided sufficient data on diagnosis, surgical procedures, and outcome (recurrence and malignancy of tumor) were included in the analysis. References with insufficient data were excluded from further evaluations. Patients with MEN 2B were excluded from all analyses. RESULTS Seventeen (22%) of 77 RET proto-oncogene carriers had pheochromocytoma. Twelve patients (71%) had unilateral and 5 (29%) had bilateral tumors at the time of the diagnosis of catecholamine excess. The mean±sd age at the first diagnosis was 47.7±17.8 years (range, years). There were 8 men (47%) and 9 women (53%). In 12 (71%) of 17 patients (15%), the catecholamine-producing tumor was the first manifestation of MEN 2A (Table 1). Two patients (12%) experienced additional extraadrenal pheochromocytomas during the initial operation. In 1 of them, the extra-adrenal pheochromocytoma was localized above the renal vein on the left side and the other behind the inferior caval vein. In none of the patients was malignancy documented at the time of surgery or during follow-up. 1200

3 Table 2. Results of Genetic Testing in Patients With Multiple Endocrine Neoplasia Type 2A and Pheochromocytoma RET Mutation Exon Codon No. (%) Amino Acid Exchange, No. Recurrence, No. Extra-adrenal Tumor, No (29) TGC TAC(cys tyr), TGC TTG(cys trp), (18) TGC CGC (cys arg), (41) TGC CGC (cys arg), TGC TAC(cys tyr), TGC AGC(cys ser), (6) TAT TTT(tyr phe), (6) TCG GCG(ser ala), Total 17 (100) 5 3 Table 3. Effect of Adrenal Tumor on Thyroid and Parathyroid Glands Patient No. Exon Genetic Testing Codon Pheochromocytoma Localization Type of MTC PHPT Study Group* Unilateral Subtotal Yes No Unilateral Subtotal Yes No Unilateral Subtotal No No Unilateral Subtotal Yes No Unilateral Subtotal Yes No Unilateral Subtotal Yes No Unilateral Subtotal Yes No Bilateral Synchronous, subtotal Yes No Bilateral Metachronous, total Yes No 1 2B Bilateral Metachronous, total Yes No 1 2B Bilateral Metachronous, total Yes No 1 2B Bilateral Metachronous, total Yes Yes 1 2B Bilateral Metachronous, total Yes No 1 2B Bilateral Synchronous, total Yes No 2A Bilateral Synchronous, total Yes Yes 2A Bilateral Synchronous, total Yes Yes 2A Bilateral Synchronous, total Yes No 2A Abbreviations: MTC, medullary thyroid cancer; PHPT, primary hyperparathyroidism. *1 2B indicates patients who belonged to group 1 after the first operation and to group 2B after the second operation. Seven patients (41%) had a mutation at codon 634, 5 (29%) at codon 611, 3 (18%) at codon 620, 1 (6%) at codon 791, and 1 (6%) at codon 891 (Table 2). All patients except 1 (patient 8) had medullary thyroid cancer, and 3 patients (patients 4, 15, and 16) had primary hyperparathyroidism (Table 3). GROUP 1 Four (31%) of 13 patients had a mutation at codon 634, 4 patients (31%) had a mutation at codon 611, 3 patients (23%) had a mutation at codon 620, and 2 patients (15%) had mutations at codon 791 and 891. Twelve of 13 patients underwent primary unilateral adrenalectomy on the affected side without involvement of the contralateral adrenal gland. One patient who had bilateral pheochromocytomas at the time of diagnosis underwent subtotal adrenal resection with the remnant on the right side after total removal of the left tumor-bearing adrenal gland. After surgery, all patients had sufficient adrenal function without hormone therapy. Within the observation period of 81.5 months, 5 (38%) of 13 patients with unilateral adrenalectomy developed recurrence (mean±sd disease-free survival, 79.9±95.7 months). Three of them had a mutation at codon 634, and 2 had a mutation at codon 611. In further descriptions and analysis, these patients are included in group 2B. Further follow-up analysis continued with the subsequent operation. None of the patients with mutations at codon 620, 891, or 791 developed a recurrence during the observation period. No operative or perioperative mortality or morbidity occurred. GROUP 2A Four patients who had tumors in both adrenal glands that measured 10 to 60 mm underwent primary synchronous bilateral adrenalectomy. Three patients had a mutation at codon 634 and 1 of codon 611. No operative or perioperative mortality or morbidity occurred in this group. During the observation period (mean±sd, 79.0±68.8 months), no recurrence of disease was seen (mean±sd disease- 1201

4 Estimated Cumulative Recurrence Rate, % Estimated Cumulative Recurrence Rate, % Time to Recurrence or Last Follow-up, y Time to Recurrence or Last Follow-up, y Figure 1. Estimated cumulative recurrence-free survival (Kaplan-Meier curve) of all patients independent of the surgical strategy at 5 years (38.5%±15.7%; 5 patients at risk) and 10 years (38.5%±15.7%; 3 patients at risk). Figure 3. Estimated cumulative recurrence-free survival (Kaplan-Meier curve) of groups 2A and 2B (metachronous total adrenalectomy) at 15 years (34%±27.2%; 1 patient at risk). Estimated Cumulative Recurrence Rate, % was performed, resulting in metachronous total adrenalectomy. Because of the size of the pheochromocytoma that involved the whole gland, no organ-sparing adrenal resection was possible. All patients except for 1 were cured of the catecholamine excess. This patient, with a mutation at codon 634, developed an extra-adrenal pheochromocytoma on the left side of the aorta 13 years after metachronous total adrenalectomy. ESTIMATED CUMULATIVE RISK OF RECURRENCE The mean±sd estimated 5- and 10-year cumulative risk of developing recurrence was 38.5% ±15.7% (3 patients at risk), analyzing all patients (Figure 1). The mean±sd estimated 5- and 10-year cumulative risk for patients in group 1 was 51.8%±18.7% (2 patients at risk; Figure 2); the mean±sd estimated 15-year cumulative risk for group 2 (A and B) was 34%±27.2% (1 patient at risk; Figure 3) Time to Recurrence or Last Follow-up, y Figure 2. Estimated cumulative recurrence-free survival (Kaplan-Meier curve) of group 1 (adrenal-sparing adrenalectomy) at 5 years (51.8%±18.7%; 3 patients at risk) and 10 years (51.8%±18.7%; 2 patients at risk). free survival, 78.9±68.7 months). All patients needed postoperative hormone therapy. Two of them developed an addisonian crisis, 1 of whom died during it. GROUP 2B Five patients developed recurrence after unilateral adrenalectomy (mean±sd disease-free survival, 99.7±141.7 months). In these patients contralateral adrenalectomy REVIEW OF LITERATURE By definition, 21 publications were found to describe patients with MEN 2A (Table 4A and 4B). Four studies 6,8,10,15 had no data concerning recurrent pheochromocytoma or surgical procedure, and 1 publication described a case report. 19 Altogether, these 118 patients were excluded from further analysis. Including this series, 348 patients were suitable for evaluating surgical strategy in case of recurrence, malignancy, or addisonian crisis. The mean follow-up of these patients was 89 months (range, months). Data on recurrent pheochromocytoma after adrenalsparing adrenalectomy were given in 15 studies. 3,7,9-18,20,22,23 Fifty-eight (31%) of 187 patients developed a recurrent pheochromocytoma in either the ipsilateral or contralateral adrenal remnant. The interval to developing recur- 1202

5 Table 4. Results of in Patients With Multiple Endocrine Neoplasia Type 2A (Literature Review, ) Source, y No. of Patients Median Follow-up (Range), mo Recurrence Median Interval (Range), mo Therapy Addisonian Crisis Adrenal-Sparing Wilson and Ibanez, NG NG NG NG NG 0 Tibblin et al, (12-180) 4 48 (12-120) TAR NG 0 van Heerden et al, (15-375) Shapiro et al, NG NG NG NG NG 3 Jansson et al, (24-180) TAR NG 0 Oishi et al, NG ( ) TAR 0 0 Oishi et al, * NG NG NG NG NG 3 Casanova et al, NG 9 70 (1-180) TAR NG 0 Lairmore et al, (8-342) (5-254) TAR 0 0 Goretzki et al, (5-182) 3 84 (4-432) TAR 0 0 Edstom et al, (96-156) 0 NG 0 Neumann et al, (16-179) 1 72 NG 0 0 de Graaf and Zwierstra, (12-312) (84-168) TAR 0 0 Inabnet et al, (6-288) 5 86 (unknown) TAR 0 0 Nguyen et al, (18-120) 2 60 (54-72) TAR 0 0 Takami, NG (case report) NG Brunt et al, ± 27 4 NG TAR 0 Walz et al, (1-106) STAR 0 0 Brauckhoff et al, (1-81) 0 NG 0 Yipetal, (0-412) 7 55 (22-244) TAR 0 0 Asari (present article) (11-348) 5 36 (24-353) TAR 0 0 Total Bilateral Wilson and Ibanez, NG NG NG NG NG 2 Tibblin et al, (12-180) NG 0 van Heerden et al, (15-375) (23-375) TAR 0 0 Oishi et al, NG Casanova et al, NG 0 NG 3 Lairmore et al, (8-342) Goretzki et al, (5-182) Goldstein et al, (36-264) de Graaf and Zwierstra, (12-312) (84-168) TAR 9 0 Inabnet et al, (6-288) 0 NG 1 Nguyen et al, (18-120) Yipetal, (0-412) Asari (present article) 4 85 (11-348) Abbreviations: NG, data not given; STAR, subtotal adrenalectomy of recurrent tumor; TAR, total adrenalectomy of the recurrent tumor. *A review of Japanese literature. Four patients had a previous unilateral adrenalectomy owing to pheochromocytoma 9 years before. Malignant rent disease was a median of 83.5 months (range, months). Surgical procedures for the recurrent pheochromocytoma included a total adrenalectomy of the affected adrenal gland in 57 of 58 patients. One patient described by Walz et al 21 was treated by an adrenal-sparing procedure of the affected gland during a subsequent operation (Table 4). A total of 161 patients underwent total bilateral adrenalectomy for the initial procedure. Five (3%) of these patients developed a recurrent pheochromocytoma after a median interval of 234 months (range, months) (Table 4). Fourteen patients with a malignant pheochromocytoma due to MEN 2A were described in the literature. Six of these patients underwent adrenal-sparing surgery 8,10 ; unfortunately, no data were available on their follow-up. Eight patients with a malignant pheochromocytoma were treated by a synchronous total bilateral adrenalectomy 6,10,11,13,17 ; 2 of them had a mean follow-up of 84 and 59 months, and none of them developed recurrence. 13,17 No data were available on follow-up in the other 6 patients. 6,10,11 COMMENT Approximately 50% of MEN 2A gene carriers develop pheochromocytomas. 1 Seventeen (22%) of 77 patients with various types of RET mutations had unilateral or bilateral pheochromocytomas at the time of diagnosis or during follow-up. Because the MEN 2A syndrome is rare, no single center has sufficient experience with the best treatment of this disease. Therefore, we analyzed our patients in connection with data published in the literature to estimate the risk of recurrence after various types of adrenal surgery, to analyze the risk of malignancy, and to evaluate the consequences of total bilateral adrenalectomy. 1203

6 Early diagnosis and treatment of catecholamine excess are mandatory to avoid life-threatening complications. Thus, in genetically determined hereditary medullary thyroid cancer, an extended search for pheochromocytoma is the rule before treating the disease and during follow-up, if the initial test results are negative. Catecholamine-producing tumors may develop synchronously or metachronously. Different codon mutations in the RET protooncogene have been associated with a higher frequency of pheochromocytoma. Eng et al 25 described a strongly associated presence of pheochromocytoma in any mutation in codon 634. They also found pheochromocytomas in patients with mutations of codons 611, 618, and 620. Other mutations in RET codons 609, 790, 791, 804, and 891 have also been associated with pheochromocytoma in patients with MEN 2A The development of pheochromocytoma seems to be associated with specific codon mutations. In 15 (88%) of 17 patients, pheochromocytomas were documented in connection with a mutation in the cysteine-rich extracellular domain of the RET proto-oncogene and only in 2 patients with a mutation in the intracellular domain. Up to now (contralateral) recurrence was observed only in patients with mutations of codons 634 and 611. On the basis of its pathophysiologic features, all adrenal and extra-adrenal medullary tissue is affected by the molecular defect and incorporates the risk of developing catecholamine excess; thus, the theory that a surgical strategy (radical, bilateral, or subtotal) is best for each patient is still under discussion. The mean±sd cumulative estimated risk of developing recurrent pheochromocytoma in 5 or 10 years was 38.5% ±15.7%, analyzing all patients. The cumulative estimated risk of developing recurrent contralateral pheochromocytoma in patients who underwent unilateral adrenalectomy with or without contralateral subtotal resection was 51.8%±18.7%. Even in patients with a primary bilateral total adrenalectomy, 1 patient developed an extra-adrenal pheochromocytoma 13 years after total adrenalectomy. When a recurrence in the remnant gland developed, an additional subtotal adrenalectomy could be performed without perioperative morbidity to avoid permanent adrenocortical hormone therapy. 30 A subsequent operation can be performed endoscopically with success. 21 To minimize the risk of recurrence in the contralateral adrenal gland or the remnant left in situ, some authors advocate bilateral total adrenalectomy in all patients. 3 The price for this kind of radical surgical treatment is the necessity of adrenocortical hormone substitution with the risk of osteoporosis, the social implications of complete dependence on lifelong substitution, and potential development of an addisonian crisis. Addisonian crisis after bilateral adrenalectomy is described in up to 35% of patients, with a 3% mortality rate reported in the literature. 3,12,31 In the literature review (Table 4), 25 (15%) of 164 patients who underwent a total bilateral adrenalectomy procedure developed an addisonian crisis during their postoperative follow-up. Although every patient undergoing an adrenal surgical procedure is informed of the potential medical hazards and necessity of treatment for different stress situations, 2 (22%) of 9 patients in our series who underwent a total bilateral adrenalectomy developed an addisonian crisis, with frequent hospital admissions for adjustment of corticosteroid therapy. One female patient (11%) died during an addisonian crisis followed by a gastrointestinal infection. In a study that evaluated quality of life after bilateral total adrenalectomy in 27 patients with MEN 2, 32 fatigue, worry, and noncompliance were encountered in 40% of the patients. One third of these patients needed more hospital admissions than usual and described, besides chronic fatigue, constant psychological pressure and difficulties in taking medicine as prescribed. Malignant pheochromocytomas are rare in MEN 2A. 23 Only 6 (2%) of 348 patients with MEN 2A had a malignant histopathologic tumor. 6,8,10,11,13 In our series, we could not find any patient with a malignant pheochromocytoma. In case of malignant recurrence, morbidity and mortality can be minimized by close monitoring and early therapy. The risk of slowly growing, benign, recurrent pheochromocytoma seems low and must be weighed against the morbidity and mortality associated with addisonian crisis after bilateral adrenalectomy. Therefore, we recommend adrenal-sparing adrenalectomy (unilateral adrenalectomy in unilateral tumors and unilateral adrenalectomy with subtotal contralateral adrenalectomy in small bilateral tumors) and close monitoring of the remnant as the treatment of choice for hereditary bilateral pheochromocytomas. Accepted for Publication: October 14, Correspondence: Reza Asari, MD, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria (reza.asari@meduniwien.ac.at). Author Contributions: Study concept and design: Niederle. Acquisition of data: Asari, Scheuba, and Kaczirek. Analysis and interpretation of data: Asari. Drafting of the manuscript: Asari. Critical revision of the manuscript for important intellectual content: Scheuba, Kaczirek, and Niederle. Statistical analysis: Asari. Obtained funding: Asari, Scheuba, and Kaczirek. Administrative, technical, and material support: Asari. Study supervision: Niederle. Financial Disclosure: None reported. REFERENCES 1. Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in multiple endocrine neoplasia type 2: appropriate management. Endocrinol Metab Clin North Am. 1994;23: Lips KJ, Van der Sluys Veer J, Struyvenberg A, et al. Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple s syndrome). Am J Med. 1981;70: van Heerden JA, Sizemore GW, Carney JA, et al. Surgical management of the adrenal glands in the multiple endocrine neoplasia type II syndrome. World J Surg. 1984;8: Neumann HP, Reincke M, Bender BU, Elsner R, Janetschek G. Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromocytoma. J Clin Endocrinol Metab. 1999;84: Fink M, Weinhusel A, Niederle B, Haas OA. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET protooncogene. 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7 6. Wilson RA, Ibanez ML. A comparative study of 14 cases of familial and nonfamilial pheochromocytomas. Hum Pathol. 1978;9: Tibblin S, Dymling JF, Ingemansson S, Telenius-Berg M. Unilateral versus bilateral adrenalectomy in multiple endocrine neoplasia IIA. World J Surg. 1983; 7: Shapiro B, Copp JE, Sisson JC, et al. Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med. 1985;26: Jansson S, Tisell LE, Fjalling M, et al. Early diagnosis of and surgical strategy for adrenal medullary disease in MEN II gene carriers. Surgery. 1988;103: Oishi S, Sasaki M, Yamauchi J, Umeda T, Sato T. Analysis of eight Sipple s syndrome patients and review of eighty-two cases from the Japanese literature. Jpn J Clin Oncol. 1990;20: Casanova S, Rosenberg-Bourgin M, Farkas D, et al. Phaeochromocytoma in multiple endocrine neoplasia type 2 A: survey of 100 cases. Clin Endocrinol (Oxf ). 1993;38: Lairmore TC, Ball DW, Baylin SB, Wells SA Jr. Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg. 1993;217: Goretzki PES, Dotzenrath D, Röher C. Surgery for pheochromocytoma in MEN II patients: a radical versus a limited approach. Acta Chir Aust. 1996;28: Edstrom E, Grondal S, Norstrom F, et al. Long term experience after subtotal adrenalectomy for multiple endocrine neoplasia type IIa. Eur J Surg. 1999; 165: Neumann HP, Bender BU, Reincke M, et al. Adrenal-sparing surgery for phaeochromocytoma. Br J Surg. 1999;86: de Graaf JSD, Zwierstra RPF. Complications after bilateral adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2: a plea to conserve adrenal function. Eur J Surg. 1999;165: Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery. 2000;128: Nguyen L, Niccoli-Sire P, Caron P, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. Eur J Endocrinol. 2001;144: Takami H, Ikeda Y, Takayama J, et al. Adrenal-sparing adrenalectomy in hereditary bilateral phaeochromocytoma. ANZ J Surg. 2001;71: Brunt LM, Lairmore TC, Doherty GM, et al. for familial pheochromocytoma in the laparoscopic era. Ann Surg. 2002;235: Walz MK, Peitgen K, Neumann HP, et al. Endoscopic treatment of solitary, bilateral, multiple, and recurrent pheochromocytomas and paragangliomas. World J Surg. 2002;26: Brauckhoff M, Nguyen Thanh P, Bar A, Dralle H. Subtotal bilateral adrenalectomy preserving adrenocortical function [in German]. Chirurg. 2003;74: Yip L, Lee JE, Shapiro SE, et al. Surgical management of hereditary pheochromocytoma. J Am Coll Surg. 2004;198: Goldstein RE, O Neill JA Jr, Holcomb GW, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg. 1999;229: Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA. 1996; 276: Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H. Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2005;90: Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86: Igaz P, Patocs A, Racz K, et al. Occurrence of pheochromocytoma in a MEN2A family with codon 609 mutation of the RET proto-oncogene. J Clin Endocrinol Metab. 2002;87: Jimenez C, Habra MA, Huang SC, et al. Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation. J Clin Endocrinol Metab. 2004;89: Brauckhoff M, Gimm O, Brauckhoff K, Dralle H. Repeat adrenocortical-sparing adrenalectomy for recurrent hereditary pheochromocytoma. Surg Today. 2004; 34: de Graaf JS, Lips CJ, Rutter JE, van Vroonhoven TJ. Subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2A. Eur J Surg. 1999; 165: Telenius-Berg M, Ponder MA, Berg B, Ponder BA, Werner S. Quality of life after bilateral adrenalectomy in MEN 2. Henry Ford Hosp Med J. 1989;37: Invited Critique A n ideal operation for a pheochromocytoma in a patient with multiple endocrine neoplasia type 2A (MEN 2A) would be to remove the pheochromocytoma and all of the medulla while saving the adrenal cortex. Residual medullary tissue can become hyperplastic or develop recurrent pheochromocytoma. The cortex is necessary for adrenocortical steroid production, and insufficient cortex causes Addison disease. The adrenal gland is like a peanut butter sandwich: the medulla is the peanut butter and the cortex, the bread. The ideal operation of removing all the peanut butter (medulla) but keeping the bread (cortex) is a nearly impossible task. In practice, cortex-sparing adrenalectomy is a compromise, weighing the risks of recurrent pheochromocytoma and adrenocortical insufficiency. Most endocrine surgeons do not prophylactically resect a normal-appearing adrenal gland in patients with MEN 2, and many would attempt to spare the adrenal cortex when Addison disease is a significant risk. Thus, for pheochromocytoma that involves only 1 gland, most prefer a unilateral total adrenalectomy because then a functioning adrenal gland remains. For bilateral pheochromocytomas or for subsequent operation on the contralateral gland after a prior adrenalectomy, most would attempt to spare as much of the cortex as possible. When performing a cortex-sparing adrenalectomy, the extent of resection is determined by tumor size and location. A large tumor in an unfavorable location may preclude sparing of a significant amount of the adrenal cortex. Cutting into the tumor capsule and spilling tumor cells is not acceptable. If the pheochromocytoma recurs, a subsequent laparoscopic operation is possible but more difficult. Some patients can have a small remnant cortex that is marginally sufficient, but they are still at risk for addisonian crisis during stress. Since the tradeoff is between recurrent disease and adrenal insufficiency, each with its own problems, the patient should be involved in making the decision for cortex-sparing adrenalectomy. Quan-Yang Duh, MD Correspondence: Dr Duh, Department of Surgery, Veterans Affairs Medical Center San Francisco, 4150 Clement St, San Francisco, CA (DuhQ@surgery.ucsf.edu). Financial Disclosure: None reported. 1205