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

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 extra-adrenal 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.

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

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.

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 pheochromocytoma. Molecular genetic analysis included exons 8, 10, 11, and 13 to 15 of the RET proto-oncogene by analysis of single-strand 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.

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, 23-75 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 extra-adrenal 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.

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).

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.

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-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.

Five patients developed recurrence after unilateral adrenalectomy (mean ± SD disease-free survival, 99.7 ± 141.7 months). In these patients contralateral adrenalectomy 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.

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).

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, 1-375 months).

Data on recurrent pheochromocytoma after adrenal-sparing 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 recurrent disease was a median of 83.5 months (range, 1-375 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 al²¹ 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, 23-375 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

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.

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 proto-oncogene have been associated with a higher frequency of pheochromocytoma. Eng et al²⁵ 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.^25-29 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.

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).

Accepted for Publication: October 14, 2006.

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.