Risk of pheochromocytoma recurrence was 38% after surgery

Overall recurrence risk low; close patient monitoring after surgery recommended.

Issue: February 2007

The risk for recurrence of pheochromocytoma in patients after adrenal-sparing adrenalectomy is about 38%, according to the results of a recent Austrian study.

Adrenal-sparing adrenalectomy is often performed to treat hereditary bilateral pheochromocytoma in patients with multiple endocrine neoplasia type 2A. Pheochromocytomas develop in about 30% to 50% of patients with MEN 2; however, treatment is controversial.

“The risk for 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 and close monitoring of the remnant as the treatment of choice for hereditary bilateral pheochromocytomas,” investigators wrote in the Archives of Surgery.

Estimating the risk

The investigators, from the Medical University of Vienna, conducted a retrospective analysis of prospective data collected during an average follow-up of 81.5 months.

“Because the MEN 2A syndrome is rare, no single center has sufficient experience with the best treatment of this disease,” they wrote. “Therefore, we analyzed our patients in connection with data published in the literature to estimate the risk for recurrence after various types of adrenal surgery, to analyze the risk for malignancy and to evaluate the consequences of total bilateral adrenalectomy.”

In their analysis, they also looked at research of pheochromocytoma and MEN 2A published between 1975 and 2004.

Seventy-seven patients (46 women; mean age, 39.9 years) with various mutations of the RET proto-oncogene were included in the study. Unilateral or bilateral pheochromocytomas were documented in 17 patients at the time of diagnosis or during the course of MEN 2A, according to the researchers.

Twelve patients had unilateral and five had bilateral tumors at the time of diagnosis of catecholamine excess. This was their first manifestation of MEN 2A.

Adrenal-sparing surgery was performed in 13 patients (group 1), synchronous bilateral total adrenalectomy in four (group 2A) and metachronous bilateral total adrenalectomy in five (group 2B).

The researchers measured 24-hour urinary catecholamine levels (noradrenaline, adrenaline and dopamine) and imaging studies to localize tumors on one or both of the adrenal glands to determine the size and exclude extra-adrenal tumors and distant metastasis in patients with high catecholamine levels.

Risk for recurrence

The mean estimated five and 10-year cumulative risk for recurrence was 38.5% in all patients. Five (38%) of 13 patients in group 1 developed recurrence in the contralateral gland after a mean of 79.9 months. Two (22%) of nine patients in groups 2A and 2B developed several episodes of addisonian crisis; one patient died. None of the patients who underwent total bilateral adrenalectomy had a recurrence of disease.

Five patients (38%) with unilateral adrenalectomy had recurrence within 81.5 months. According to the researchers, the cumulative risk for patients who underwent unilateral adrenalectomy with or without contralateral subtotal resection was 51.8%.

One patient developed an extra-adrenal pheochromocytoma 13 years after adrenalectomy and primary bilateral total adrenalectomy.

Different codon mutations in the RET proto-oncogene were associated with a higher frequency of pheochromocytoma; the codon 634 was most common, the researchers wrote. In 15 (88%) of the 17 patients, pheochromocytomas were documented in connection with a mutation in the cysteine-rich extracellular domain of the RET proto-oncogene; it was only documented in two patients with a mutation in the intracellular domain.

Fatigue, worry and noncompliance have occurred in patients after adrenalectomy, based on results from a study that evaluated the quality of life in 27 patients with MEN 2 after they underwent bilateral total adrenalectomy. In the same study, one-third of patients needed more hospital admissions after surgery, experienced chronic psychological pressure and had difficulty in taking prescribed medications.

According to study researcher Reza Asari, MD, with the section of endocrine surgery at the university, all patients with uni-, bilateral and/or extraadrenal pheochromocytoma must be screened for hereditary disease; in the case of hereditary pheochromocytoma, total bilateral adrenalectomy is not the first choice for surgical treatment.

“The adrenal tumors of patients with hereditary disease must be treated individually in units specialized for endocrine surgery. Adrenal-sparing surgery is the aimed treatment, however these patients may not be cured by a single operation. Therefore, life-long follow-up examinations are mandatory,” Asari said in an interview with Endocrine Today.

Pheochromocytoma operation

The ideal pheochromocytoma operation is to remove the pheochromocytoma and medulla while saving the adrenal cortex, Quan-Yang Duh, MD, wrote in an accompanying editorial. Residual medullary tissue can become hyperplastic or lead to recurrent pheochromocytomas, he explained, and, similarly, insufficient adrenal cortex can cause 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 for recurrent pheochromocytoma and adrenocortical insufficiency,” Duh wrote.

Because extra adrenal and medullary tissue can put patients at a higher risk for developing catecholamine excess, the theory that a surgical strategy (radical, bilateral or subtotal) is best for each patient is still being evaluated, according to the researchers.

“To minimize the risk for recurrence in the contralateral adrenal gland or the remnant left in situ, some authors advocate bilateral total adrenalectomy in all patients,” the researchers wrote. “The price for this kind of radical surgical treatment is the necessity of adrenocortical hormone substitution with the risk for osteoporosis, the social implications of complete dependence on lifelong substitution and potential development for an addisonian crisis.” Addisonian crisis has been documented in nearly 35% of patients, resulting in a 3% mortality rate, according to the previous literature the researchers reviewed. One patient died during an addisonian crisis followed by a gastrointestinal infection in the current study.

According to Duh, the majority of endocrine surgeons prefer a unilateral total adrenalectomy because it leaves a functioning adrenal gland. In bilateral pheochromocytoma after a prior adrenalectomy, most would attempt to spare as much of the cortex as possible, he explained.

“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,” Duh wrote. –by Katie Kalvaitis

For more information:
Asari R, Scheuba C, Kaczirek K, Niederle B. Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Arch Surg. 2006;141:1199-1205.
Duh Q-Y. Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A: Invited critique. Arch Surg. 2006;141:1205.
Telenius-Berg M, Ponder MA, Berg B, et al. Quality of life after bilateral adrenalectomy in MEN 2. Henry Ford Hosp Med J. 1989;37:160-163.