Version May 2024
INTRODUCTION — The treatment of choice for patients with Cushing disease (corticotropin [ACTH]-secreting pituitary tumor) is transsphenoidal surgery and resection of the pituitary tumor. However, for patients with persistent or recurrent Cushing disease, adrenalectomy, which can be achieved either surgically or medically (with mitotane), is sometimes recommended for definitive cure.
Surgical adrenalectomy for persistent or recurrent Cushing disease is reviewed here. An overview of the treatment of Cushing syndrome, medical therapy of hypercortisolism, and primary therapy for Cushing disease are reviewed separately. (See "Overview of the treatment of Cushing syndrome" and "Medical therapy of hypercortisolism (Cushing's syndrome)" and "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation".)
GENERAL APPROACH TO CUSHING DISEASE — Cushing disease is caused by pituitary corticotropin (ACTH)-secreting tumors. These corticotroph tumors are almost always benign and are usually microadenomas (ie, <10 mm in diameter). The progressive stages of treatment that may be required to cure a patient of Cushing disease are shown in the algorithm (algorithm 1). This approach is largely consistent with the Endocrine Society Clinical Practice Guideline [1].
Transsphenoidal microadenomectomy is currently the treatment of choice for Cushing disease. A neurosurgeon with expertise in transsphenoidal surgery for Cushing patients can achieve an initial cure rate of 80 to 90 percent with microadenomas but less than 60 percent with macroadenomas. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Transsphenoidal surgery'.)
For patients with clear persistent disease after transsphenoidal surgery or later recurrence, there are five therapeutic options (see "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Treatment if surgery fails'):
●Repeat surgery of residual corticotroph adenoma, particularly if residual tumor is visible on magnetic resonance imaging (MRI). However, reoperation has a lower success rate than initial surgery, and many patients develop other pituitary hormone deficiencies as a result of the second procedure.
●Irradiation of the pituitary gland. Radiation therapy may decrease the occurrence of Nelson syndrome in patients not cured by irradiation for whom adrenalectomy becomes necessary. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Pituitary irradiation'.)
●Medical therapy with adrenal enzyme inhibitors or other agents. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)
●Medical adrenalectomy with mitotane, an adrenolytic agent, may be used during or after pituitary irradiation in patients with Cushing disease. (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Mitotane'.)
●Surgical adrenalectomy. (See 'Surgical adrenalectomy' below.)
The choice for therapy is individualized. For example, a young woman desiring fertility might choose to have adrenalectomy or repeat transsphenoidal exploration to avoid hypogonadism associated with radiotherapy and the teratogenicity of mitotane. A patient with extreme hypercortisolism might choose adrenalectomy to achieve rapid control.
SURGICAL ADRENALECTOMY
Preoperative pituitary irradiation — We suggest pituitary irradiation prior to bilateral adrenalectomy in patients with Cushing disease and radiologically detectable residual corticotroph tumor or in whom microscopic dural invasion by tumor is documented (to decrease the risk of Nelson syndrome). We do not administer pituitary irradiation to patients without residual tumor on pathology or MRI scan. (See 'Prevention' below.)
Choice of procedure — We suggest bilateral total surgical adrenalectomy as the definitive treatment for patients in whom rapid cure of hypercortisolism is necessary or when all other therapies have failed [2-4].
Bilateral adrenalectomy has also been successfully used in several pregnant women with Cushing syndrome [5]. (See "Diagnosis and management of Cushing syndrome during pregnancy", section on 'Management'.)
There had been reluctance historically to recommend bilateral adrenalectomy in patients with refractory Cushing disease for several reasons, all of which have become less of a concern:
●Surgical morbidity with open adrenalectomy – Complication rates are now much lower as a result of laparoscopic adrenalectomy. (See "Adrenalectomy techniques", section on 'Approach by indication'.)
●The risk of Nelson syndrome (corticotroph tumor progression with increased corticotropin [ACTH]) can now be monitored with MRI. (See 'Nelson syndrome' below.)
●Concerns about impaired quality of life related to the postoperative need for chronic glucocorticoid and mineralocorticoid replacement. However, patients who undergo bilateral adrenalectomy appear to experience an improvement in quality of life that is similar to that in patients initially cured by transsphenoidal surgery [6]. (See 'Quality of life' below.)
In contrast to bilateral adrenalectomy, unilateral or subtotal adrenalectomy is virtually never successful in ACTH-dependent Cushing syndrome, unless the patient has improved in response to pituitary irradiation (ACTH secretion is partially inhibited) or the adrenalectomy becomes complete, because of subsequent infarction of the remnant [2]. Therefore, we do not suggest this approach.
The failure of incomplete adrenalectomy is related to the ability of the adrenal remnant eventually to become hyperplastic. For the same reason, total adrenalectomy with subcutaneous adrenal autotransplantation is likely to fail; three of eight patients treated with this technique developed recurrent Cushing syndrome in one report [7].
Surgical approach — The laparoscopic approach, which can be done via either the anterior or posterior approaches, has become standard, as hospital stays appear to be shorter (usually one to five days) and complications fewer, as compared with open surgery [8-10]. Regardless of the approach used, the glands must be removed en bloc. Care also must be taken to ensure that the fragile capsule is not broken [11] because cells spilled locally can become hyperplastic and cause recurrent disease; they are then not usually amenable to surgical removal. (See "Adrenalectomy techniques", section on 'Selection of operative approach'.)
Hormone replacement — On the day of adrenalectomy, most surgeons administer glucocorticoids (50 to 100 mg hydrocortisone, intravenous [IV], on call to the operating room and every eight hours). Generally, the dose is tapered rapidly to 50 and then 25 mg IV every eight hours over the next two days. This agent and dose provide both glucocorticoid and mineralocorticoid coverage.
By the third postoperative day, most patients are able to take oral replacement doses of hydrocortisone and fludrocortisone (see "Treatment of adrenal insufficiency in adults"). A daily dose of 15 to 25 mg hydrocortisone or its equivalent is thought to be optimal glucocorticoid replacement (table 1) [12,13].
However, many patients receive excessive doses of glucocorticoid therapy after adrenalectomy [12-14]. As an example, in a report of 14 women receiving glucocorticoids post-adrenalectomy for Cushing disease, bone mineral density was similar, body fat was higher, and fat-free mass was lower when compared with 14 control women of similar age, body mass index (BMI), and menopausal status [14]. The replacement glucocorticoid doses were: cortisone acetate (n = 10) 15 to 50 mg per day, hydrocortisone (n = 1) 20 mg per day, prednisone (n = 2) 5 or 7.5 mg per day, or dexamethasone (n = 1) 0.5 mg per day, an average of 27.3 mg hydrocortisone equivalents per day.
Postoperative management — After adrenalectomy in Cushing disease, one should not wait for the occurrence of Nelson syndrome; modern imaging allows early detection and management of corticotroph tumor progression.
●Assess for cure – Between three days and two weeks after adrenalectomy (or possibly later), if clinical features of Cushing syndrome recur, a morning blood sample should be drawn before the replacement glucocorticoid dose is taken to confirm that serum cortisol is undetectable. Up to 3 percent of patients have recurrence because of an adrenal remnant [15]. Surgical removal of the remnant depends on whether it can be located. Medical therapy can be given as an alternative.
●Monitor for Nelson syndrome – In addition, because of the potential risk of corticotroph tumor progression (Nelson syndrome), we suggest that adrenalectomized patents be followed with MRI of the pituitary and plasma ACTH measurements, annually for seven years, and then intermittently if there has been no tumor progression [16-21]. (See 'Nelson syndrome' below.)
OUTCOMES
Quality of life — Patients show improved quality of life after bilateral adrenalectomy that is similar to that seen after transsphenoidal surgery [6,8,15]. However, other studies have reported impaired quality of life [9,22].
Nelson syndrome — Patients who have had bilateral adrenalectomy for Cushing disease may develop corticotroph tumor progression, defined as an enlarging pituitary tumor (new mass, or an increase of at least 2 mm in diameter) on MRI. In one study, this was noted after adrenalectomy in nearly 50 percent of patients without prior pituitary irradiation [16]. Most changes were noted within three years of surgery. Only four of these patients developed a macroadenoma, and only one presented with pituitary apoplexy. Logistic regression analysis showed that patients with a shorter duration of Cushing syndrome and higher postoperative plasma corticotropin (ACTH) concentrations were more likely to develop tumor progression.
Before MRI allowed for measurement of small changes in tumor size, Nelson syndrome was defined using sellar radiograms as the association of an enlarging pituitary tumor with progressive hyperpigmentation caused by very high plasma ACTH concentrations after bilateral adrenalectomy for Cushing syndrome [23]. In addition to hyperpigmentation, other clinical manifestations due to the enlarging tumor were common, including headaches, visual field defects, and, sometimes, cranial nerve palsies [24]. Most patients are now diagnosed at an earlier stage by MRI [16]. Therefore, symptoms related to the tumor itself are somewhat less common, but hyperpigmentation is still an important clinical manifestation [24].
Incidence — When judged using sellar radiograms, Nelson syndrome was reported in up to 25 percent of adults and in over 50 percent of children with Cushing disease after total adrenalectomy without prior pituitary irradiation [17,24-30], and in 47 percent of similar patients evaluated by MRI [16]. It is less common after medical adrenalectomy with mitotane [31,32]. Data are conflicting on the impact of patient age on the risk of developing Nelson syndrome [16,33]. In one study, few patients developed corticotroph tumor progression more than seven years after adrenalectomy, suggesting that monitoring frequency could decrease at this time [16].
There are no predictive clinical or laboratory indexes for the development of Nelson syndrome except the plasma ACTH value. Plasma ACTH concentrations increase much more in patients who subsequently develop Nelson syndrome than in those who do not:
●During the first year after adrenalectomy while taking equivalent glucocorticoid replacement therapy (greater than 700 pg/mL [154 pmol/L]) [28].
●One report suggested that the risk of Nelson syndrome was greater in patients with suboptimal glucocorticoid replacement therapy [34].
Pathogenesis — Corticotroph progression becomes apparent several months to many years after adrenalectomy, the average being approximately three years. The pathogenesis of these tumors is uncertain. They presumably represent the accelerated growth of ACTH-secreting cells in preexisting microadenomas when the effect of glucocorticoid negative feedback inhibition is reduced [35].
Other than differences attributable to the larger tumor cell mass and lack of glucocorticoid inhibition of adenomas causing Nelson syndrome, these tumors are similar to microadenomas causing Cushing syndrome with regard to light microscopic structure, ultrastructure, response to corticotropin-releasing hormone (CRH), and the proopiomelanocortin products they produce. However, it is not clear why only some, but not all, tumors continue to grow.
Biochemical criteria — Plasma ACTH concentrations in patients with Nelson syndrome range from as low as 800 pg/mL (175 pmol/L) to values that may exceed 25,000 pg/mL (5500 pmol/L). Some investigators have used plasma ACTH values as low as 200 pg/mL, in addition to hyperpigmentation, as the criteria for diagnosing Nelson syndrome [36]. These values are much higher than the normal 8 AM values for ACTH (20 to 50 pg/mL [4.4 to 11.3 pmol/L]) and overlap with values that are normally seen in patients after adrenalectomy. (See "Measurement of ACTH, CRH, and other hypothalamic and pituitary peptides".)
Prevention — We suggest pituitary irradiation before adrenalectomy in patients with Cushing disease with radiologically detectable residual corticotroph tumor or in whom microscopic dural invasion by tumor is documented. It has been reported to prevent this complication in some [34,36-38], but not all [3,28], studies.
●The protection is not complete, as some adrenalectomized patients do develop Nelson syndrome despite prior pituitary irradiation [3,28,34,36].
●There is one report of fatal Nelson syndrome with accelerated tumor growth following pituitary irradiation; a P53 mutation was found in that tumor [39].
Treatment — Once the tumor in a patient with Nelson syndrome becomes large enough to expand the sella, it is locally invasive, difficult to cure, and may develop into a pituitary carcinoma. Transsphenoidal surgery should be performed before the tumor becomes a macroadenoma [16,20,21,40,41].
With careful follow-up, extrasellar extension should be prevented by early intervention. In older series that did not use this approach, a transcranial approach was sometimes necessary for tumors with extrasellar extension (14 of 43 patients in one series, 33 percent) [42]. Success rates vary from 10 to 70 percent [24,42,43]. Surgical morbidity is significant with up to 70 percent developing panhypopituitarism, 15 percent a cerebrospinal fluid leak, and 8 percent develop meningitis [24,43].
Progression of very large Nelson syndrome tumors may occur even after surgical intervention [43]. Therefore, postoperative radiation is suggested for patients with any evidence of residual tumor. This type of radiation chosen is typically dictated by availability, cost, and patient preference regarding treatment time.
●The optimal type of radiation therapy has not been determined. In one report of conventional radiation in 15 patients with Nelson syndrome, satisfactory results, including regression of hyperpigmentation and tumor shrinkage, were reported in 14 of the 15 patients followed for a median of 9.6 years [44].
●Stereotactic radiosurgery has been used [45,46]. In one report of 10 patients, one type of stereotactic radiosurgery stopped tumor growth [46].
●In a second study of 22 patients, tumor volume decreased in 12, had no change in 8, and increased in 2 [47]. (See "Stereotactic cranial radiosurgery".)
Medical therapy of Nelson syndrome is relatively ineffective, and therefore, we do not suggest its use. Although there is a case report of sustained remission with cyproheptadine [48], neither this drug nor valproic acid had a significant acute effect on ACTH secretion in six women with Nelson syndrome in one report [49]. In contrast, bromocriptine lowered plasma ACTH concentrations acutely by 52 percent in these women. Long-term cabergoline administration decreased ACTH levels and tumor size in two patients [50,51]. Rosiglitazone was effective in only 1 of 19 patients [52-55].
Naloxone and indomethacin are not effective. The somatostatin analog octreotide reduced ACTH secretion and tumor size in a few patients with Nelson syndrome for as long as two years [33].
One report showed regression of tumor size after temozolomide treatment in two of four patients with aggressive corticotroph tumors or carcinoma [56].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)
SUMMARY AND RECOMMENDATIONS
●Transsphenoidal surgery – The treatment of choice for patients with Cushing disease (corticotropin [ACTH]-secreting pituitary tumor) is transsphenoidal surgery and resection of the pituitary tumor. The progressive stages of treatment that may be required to cure a patient of Cushing disease are shown in the algorithm (algorithm 1).
●Patients with persistent or recurrent disease – For patients with persistent or recurrent Cushing disease, adrenalectomy, which can be achieved either surgically or medically (with mitotane), is sometimes recommended for definitive cure. (See 'General approach to Cushing disease' above.)
●Bilateral surgical adrenalectomy – We suggest bilateral total surgical adrenalectomy as the definitive treatment for patients in whom rapid cure of hypercortisolism is necessary or when all other therapies have failed (Grade 2C). (See 'Surgical adrenalectomy' above.)
The laparoscopic approach for adrenalectomy, which can be done via either the anterior or posterior approaches, has become standard as hospital stays appear to be shorter (usually one to five days) and complications fewer, as compared with open surgery. (See 'Surgical approach' above and "Adrenalectomy techniques", section on 'Selection of operative approach'.)
●Preoperative pituitary irradiation
•For patients with Cushing disease with radiologically detectable residual corticotroph tumor, we suggest pituitary irradiation prior to adrenalectomy to reduce the risk of Nelson syndrome (Grade 2C). (See 'Preoperative pituitary irradiation' above and 'Nelson syndrome' above.)
•For patients without residual tumor on pathology or MRI scan, we do not administer preventive radiotherapy, but perform regular MRI and ACTH measurements after adrenalectomy. (See 'Postoperative management' above.)
●Postoperative management
•Assess for cure – Cure should be confirmed by measuring serum cortisol.
•Hormone replacement – Glucocorticoid coverage is similar to that for transsphenoidal surgery, except that, in addition to lifelong glucocorticoid replacement, mineralocorticoid replacement with fludrocortisone must also be begun soon after surgery (table 1). (See 'Hormone replacement' above.)
•Monitor for Nelson syndrome – Patients who have had bilateral adrenalectomy for Cushing disease may develop corticotroph tumor progression (Nelson syndrome). We monitor with MRI of the pituitary and plasma ACTH measurements, annually for seven years, and then intermittently if there has been no evidence of tumor progression. (See 'Postoperative management' above.)
●Management of Nelson syndrome – For patients who develop Nelson syndrome, we suggest early transsphenoidal surgery (before the tumor becomes a macroadenoma) (Grade 2C). Treatment is reviewed in detail above. (See 'Treatment' above.)
ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
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