In the JournalsPerspective

Cortical-sparing adrenalectomy reduces steroid replacement therapy in adrenal tumors

Adults with bilateral pheochromocytomas treated with cortical-sparing adrenalectomy were less likely to need steroid replacement therapy and had a low risk for tumor recurrence over 8 years when compared with similar patients who underwent total bilateral adrenalectomy, according to a retrospective database analysis published in JAMA Network Open.

Charis Eng

Total adrenalectomies have been performed for decades, and we noticed that especially with bilateral pheochromocytomas, whether synchronous or metachronous, replacement cortisol could be problematic. We saw over-dosing as well as underdosing,” Charis Eng, MD, PhD, FACP, chair of the Genomic Medicine Institute and director of the Center for Personalized Genetic Healthcare at Cleveland Clinic, told Endocrine Today. “This is the 21st century, so we sought to find out if indeed what we anecdotally noticed — over-replacement, under-replacement in bilateral total adrenalectomies — was true. If so, how can we avoid these side effects?”

Study design

Neumann and colleagues from the International Bilateral Pheochromocytoma Registry Group analyzed registry data from 625 patients treated for bilateral pheochromocytomas between 1950 and 2018 (48% women; median age at diagnosis, 30 years). All participating centers recontacted patients, and 57% of registrant information was updated in 2018. Researchers assessed demographic, clinical and molecular genetic data, including year of operation, size, location and number of tumors, as well as data on surgical treatment. Researchers considered cortical-sparing adrenalectomy unsuccessful when the patient became steroid dependent.

Within the cohort, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas, and 224 (36%) were diagnosed with metachronous pheochromocytomas. In 505 of 526 tested patients (96%), researchers observed germline mutations in the genes RET (n = 282), VHL (n = 184) and others (n = 39). Among 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical-sparing and were successful in 248 of 324 patients (76.5%), according to researchers. Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy.

One-third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing’s syndrome, the researchers wrote. Of 377 patients who became steroid dependent, 67 (18%) developed at least one adrenal crisis and 50 (13%) developed iatrogenic Cushing’s syndrome during a median follow-up of 8 years.

Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy, according to researchers. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median follow-up of 8 years, all of which were successfully treated with another surgery.

“Hormone replacement after bilateral total adrenalectomy resulted in adrenal crisis or Cushing’s syndrome,” Eng said. “Conversely, the cortical-sparing procedure was not associated with worse outcomes or higher morbidity, even when tumors recurred. Importantly, more than 95% of those with bilateral involvement, with many presenting with unilateral disease initially, have a gene mutation. Said another way, those with a gene mutation have a high risk of bilateral disease.”

Cortical-sparing surgery safe

The researchers found that cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma. Among 63 patients who died, only three (5%) died of metastatic pheochromocytoma. During follow-up, overall survival of steroid-dependent patients was lower vs. steroid-independent patients (85% vs. 99%; P = .01); however, most of the difference was due to higher rates of multiple endocrine neoplasia type 2 in the steroid-dependent patients, according to researchers.

“Our study suggests that cortical-sparing surgery for pheochromocytoma is appropriate and safe in the right setting,” the researchers wrote. “All patients with pheochromocytomas, even when presenting with apparently sporadic, unilateral disease, should be offered genetic analysis preoperatively to ensure gene-informed surgical and medical management.”

Eng said referral to highly specialized adrenal centers for multidisciplinary assessment and treatment should be considered, especially in patients with hereditary pheochromocytoma syndromes.

“Always refer all adrenal pheochromocytoma patients for genetics evaluation for genetic testing of the pheochromocytoma genes in the setting of genetic counseling,” Eng said. “If one of the genes is mutation-positive, then it will guide the type of surgery, eg, cortex-sparing adrenal surgery. This is because if a gene is mutation-positive, there is a very high likelihood of bilateral disease, and preserving cortical function with bilateral disease would avoid having to replace mineralocorticoids.” – by Regina Schaffer

For more information:

Charis Eng, MD, PhD, FACP, can be reached at the Genomic Medicine Institute, Center for Personalized Genetic Healthcare, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; engc@ccf.org.

Disclosure: One of the authors reports she serves as an advisory board member for HRA Pharma.

Adults with bilateral pheochromocytomas treated with cortical-sparing adrenalectomy were less likely to need steroid replacement therapy and had a low risk for tumor recurrence over 8 years when compared with similar patients who underwent total bilateral adrenalectomy, according to a retrospective database analysis published in JAMA Network Open.

Charis Eng

Total adrenalectomies have been performed for decades, and we noticed that especially with bilateral pheochromocytomas, whether synchronous or metachronous, replacement cortisol could be problematic. We saw over-dosing as well as underdosing,” Charis Eng, MD, PhD, FACP, chair of the Genomic Medicine Institute and director of the Center for Personalized Genetic Healthcare at Cleveland Clinic, told Endocrine Today. “This is the 21st century, so we sought to find out if indeed what we anecdotally noticed — over-replacement, under-replacement in bilateral total adrenalectomies — was true. If so, how can we avoid these side effects?”

Study design

Neumann and colleagues from the International Bilateral Pheochromocytoma Registry Group analyzed registry data from 625 patients treated for bilateral pheochromocytomas between 1950 and 2018 (48% women; median age at diagnosis, 30 years). All participating centers recontacted patients, and 57% of registrant information was updated in 2018. Researchers assessed demographic, clinical and molecular genetic data, including year of operation, size, location and number of tumors, as well as data on surgical treatment. Researchers considered cortical-sparing adrenalectomy unsuccessful when the patient became steroid dependent.

Within the cohort, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas, and 224 (36%) were diagnosed with metachronous pheochromocytomas. In 505 of 526 tested patients (96%), researchers observed germline mutations in the genes RET (n = 282), VHL (n = 184) and others (n = 39). Among 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical-sparing and were successful in 248 of 324 patients (76.5%), according to researchers. Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy.

One-third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing’s syndrome, the researchers wrote. Of 377 patients who became steroid dependent, 67 (18%) developed at least one adrenal crisis and 50 (13%) developed iatrogenic Cushing’s syndrome during a median follow-up of 8 years.

Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy, according to researchers. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median follow-up of 8 years, all of which were successfully treated with another surgery.

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“Hormone replacement after bilateral total adrenalectomy resulted in adrenal crisis or Cushing’s syndrome,” Eng said. “Conversely, the cortical-sparing procedure was not associated with worse outcomes or higher morbidity, even when tumors recurred. Importantly, more than 95% of those with bilateral involvement, with many presenting with unilateral disease initially, have a gene mutation. Said another way, those with a gene mutation have a high risk of bilateral disease.”

Cortical-sparing surgery safe

The researchers found that cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma. Among 63 patients who died, only three (5%) died of metastatic pheochromocytoma. During follow-up, overall survival of steroid-dependent patients was lower vs. steroid-independent patients (85% vs. 99%; P = .01); however, most of the difference was due to higher rates of multiple endocrine neoplasia type 2 in the steroid-dependent patients, according to researchers.

“Our study suggests that cortical-sparing surgery for pheochromocytoma is appropriate and safe in the right setting,” the researchers wrote. “All patients with pheochromocytomas, even when presenting with apparently sporadic, unilateral disease, should be offered genetic analysis preoperatively to ensure gene-informed surgical and medical management.”

Eng said referral to highly specialized adrenal centers for multidisciplinary assessment and treatment should be considered, especially in patients with hereditary pheochromocytoma syndromes.

“Always refer all adrenal pheochromocytoma patients for genetics evaluation for genetic testing of the pheochromocytoma genes in the setting of genetic counseling,” Eng said. “If one of the genes is mutation-positive, then it will guide the type of surgery, eg, cortex-sparing adrenal surgery. This is because if a gene is mutation-positive, there is a very high likelihood of bilateral disease, and preserving cortical function with bilateral disease would avoid having to replace mineralocorticoids.” – by Regina Schaffer

For more information:

Charis Eng, MD, PhD, FACP, can be reached at the Genomic Medicine Institute, Center for Personalized Genetic Healthcare, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; engc@ccf.org.

Disclosure: One of the authors reports she serves as an advisory board member for HRA Pharma.

    Perspective
    Richard Auchus

    Richard Auchus

    These findings are what you would expect in that everyone who underwent bilateral adrenalectomy had adrenal insufficiency. One of the surprises was that two of those people experienced a recurrence. We do occasionally see recurrence following total adrenalectomy due to a rupture of the tumor, and some of the cells seeded into the tumor bed. The success rate for the partial adrenalectomy was good. Roughly 20% to 25% of patients, depending on whether it was a first or a second operation, still had adrenal insufficiency. A person is more likely to have adrenal insufficiency if undergoing a total bilateral adrenalectomy vs. partial, but the rate for partial adrenalectomy is not zero; about 25% wind up with adrenal insufficiency. The recurrence rate for total bilateral adrenalectomy is also not zero, but it is pretty low, and risk for recurrence is higher if you try to do a partial.

    That said, what this shows is that the odds are pretty good overall that if you have this partial procedure you will not have adrenal insufficiency and that you will not have a recurrence, at least for some time. A lot of the people in this cohort were young and have a long way to go, so we don’t know the true recurrence rate yet. It’s worth a try to prevent people from undergoing a total adrenalectomy; however, you can’t make guarantees either way. It is encouraging to think that, most of the time, this can be done successfully. It should be an option that is discussed with all patients when the second adrenal has a pheochromocytoma and needs to come out. If the patient is young and facing a lifetime of adrenal insufficiency, it might be better to offer that individual the cortical-sparing option, even if they go on to another surgery later. If a person has several medical conditions, is older and in 10 years they would not be a candidate for another adrenalectomy, then the surgeon probably wants to take it out. It depends which priority is higher — preserving adrenal cortical function or preventing a recurrence.

    • Richard Auchus, MD, PhD
    • Professor of Pharmacology and Internal Medicine
      Division of Metabolism, Endocrinology and Diabetes
      The University of Michigan

    Disclosures: Auchus reports he is a consultant for Quest Diagnostics.