Persistent or recurrent Cushing disease: Surgical bilateral adrenalectomy

INTRODUCTION — 

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 treatment of choice for patients with Cushing disease is transsphenoidal surgery and resection of the pituitary tumor. However, for patients with persistent or recurrent Cushing disease, adrenalectomy is sometimes recommended for definitive cure. Adrenalectomy can be achieved either surgically or medically (with mitotane).

Surgical adrenalectomy for persistent or recurrent Cushing disease is reviewed here. An overview of the treatment of Cushing syndrome, medical therapy for hypercortisolism, and primary therapy for Cushing disease are reviewed separately.

●(See "Overview of the treatment of Cushing syndrome".)

●(See "Medical therapy of hypercortisolism (Cushing syndrome)".)

●(See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation".)

INDICATIONS FOR SURGICAL ADRENALECTOMY

●General approach to treatment of Cushing disease – A stepwise approach to the treatment of Cushing disease (corticotropin [ACTH]-secreting pituitary tumor) is shown in the algorithm (algorithm 1). This approach is largely consistent with the Endocrine Society Clinical Practice Guideline [1].

Transsphenoidal adenomectomy is the treatment of choice for Cushing disease. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Transsphenoidal surgery'.)

Patients with persistent or recurrent disease after transsphenoidal surgery have five therapeutic options (see "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Treatment if surgery fails'):

•Repeat transsphenoidal surgery

•Pituitary irradiation

•Surgical adrenalectomy

•Medical adrenalectomy

•Medical therapy with adrenal enzyme inhibitors or corticotroph-directed agents

●Surgical adrenalectomy – In patients with persistent or recurrent Cushing disease, surgical bilateral adrenalectomy provides definitive treatment when rapid cure of hypercortisolism is necessary or when all other therapies have failed. Surgical adrenalectomy also may be indicated for individuals with persistent or recurrent Cushing disease who desire pregnancy.

The choice of therapeutic strategy is individualized. For example, a young woman desiring fertility might choose to undergo adrenalectomy to avoid hypogonadism due to radiotherapy or the teratogenicity of mitotane. Adrenalectomy also offers greater certainty of cure than repeat transsphenoidal exploration. In a patient with extreme hypercortisolism, adrenalectomy might be preferred to achieve rapid control.

PRE- AND PERIOPERATIVE MANAGEMENT

Preoperative medical therapy for hypercortisolism

●Patients not taking medical therapy – In patients who can undergo surgery without delay (eg, within one month of diagnosis), medical therapy for hypercortisolism generally does not need to be initiated.

In patients with moderate to severe hypercortisolism who have an anticipated delay in surgery (eg, longer than one month after diagnosis), initiating medical therapy to manage hypercortisolism is reasonable. Nonetheless, adequate management of hypercortisolism can take weeks to achieve and poses risk of overtreatment; these risks must be weighed against the benefits of treatment. Options for medical therapy for hypercortisolism are reviewed separately. (See "Medical therapy of hypercortisolism (Cushing syndrome)".)

●Patients on chronic medical therapy – Patients taking chronic medical therapy for hypercortisolism can stop treatment the day before surgery. (See "Medical therapy of hypercortisolism (Cushing syndrome)".)

Patients who are treated with a "block and replace" strategy or mitotane therapy have iatrogenic hypocortisolism and require glucocorticoid replacement therapy. In such patients, chronic glucocorticoid replacement regimens should be continued until the day of surgery. On the day of surgery, perioperative, stress-dose glucocorticoid treatment is initiated to cover surgical stress. (See 'Perioperative glucocorticoid treatment' below and "Medical therapy of hypercortisolism (Cushing syndrome)", section on 'Replacement glucocorticoid therapy'.)

Preoperative pituitary irradiation — We suggest against routine pituitary irradiation prior to surgical bilateral adrenalectomy [2]. However, in patients with detectable residual tumor, the decision regarding preoperative pituitary irradiation should be individualized.

Undetectable tumor — We do not administer preoperative pituitary irradiation to patients without residual tumor on pathology or magnetic resonance imaging (MRI) scan. Such patients have a lower risk of Nelson syndrome, and the risks of pituitary irradiation outweigh the benefit.

Detectable residual tumor — Pituitary irradiation may be considered prior to bilateral adrenalectomy in patients with Cushing disease and either of the following:

●Radiologically detectable residual corticotroph tumor (and repeat transsphenoidal surgery is not an acceptable or feasible alternative for management)

or

●Microscopic dural invasion by tumor

In patients with detectable residual tumor, the decision regarding preoperative pituitary irradiation should be individualized and, ideally, reviewed at a multidisciplinary tumor board [2]. In such patients, preoperative pituitary irradiation decreased the risk of Nelson syndrome (corticotroph tumor progression) in some [3-6], but not all [7,8], studies. Despite pituitary irradiation, some patients develop Nelson syndrome after adrenalectomy [4,5,7,8]. One case of fatal Nelson syndrome with accelerated tumor growth was reported following pituitary irradiation; a P53 mutation was found in that tumor [9]. (See 'Monitor for Nelson syndrome' below.)

Perioperative glucocorticoid treatment — On the day of adrenalectomy, stress-dose glucocorticoid treatment should be initiated. Patients should receive hydrocortisone 50 to 100 mg intravenously (IV) prior to the procedure followed by a total daily dose equivalent to hydrocortisone 150 to 200 mg. This is administered in divided doses (eg, 50 mg IV every six to eight hours) for one to three days perioperatively. If the postoperative course is uncomplicated, a rapid taper can follow (eg, daily dose reduction by 50 percent until the planned replacement hydrocortisone dose is achieved). Stress-dose hydrocortisone also may be administered by intramuscular injection.

By the third or fourth postoperative day, most patients are able to transition to an oral regimen for adrenal hormone replacement. When the hydrocortisone dose is tapered below 40 mg daily, we initiate fludrocortisone for mineralocorticoid replacement therapy. Patients will require lifelong adrenal hormone replacement therapy, which is reviewed briefly below and in detail separately. (See 'Optimize adrenal hormone replacement' below and "Treatment of adrenal insufficiency in adults", section on 'Chronic adrenal insufficiency'.)

Thromboprophylaxis — Given the lack of high certainty data regarding thromboprophylaxis in patients with Cushing disease, the approach to management is the same as for other populations undergoing abdominal surgery. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

CHOICE OF PROCEDURE

Surgical bilateral total adrenalectomy (preferred) — For patients in whom rapid cure of hypercortisolism is necessary or when all other therapies have failed, we suggest surgical bilateral total adrenalectomy as the definitive treatment [7,10,11]. Bilateral adrenalectomy has also been successfully used in several pregnant women with Cushing syndrome [12]. (See "Diagnosis and management of Cushing syndrome during pregnancy", section on 'Management'.)

Historical concerns about bilateral adrenalectomy in patients with refractory Cushing disease have diminished over time.

●Surgical morbidity – Surgical morbidity is now much lower with laparoscopic rather than open adrenalectomy. (See "Adrenalectomy techniques", section on 'Approach by indication'.)

●Nelson syndrome – MRI and corticotropin (ACTH) measurements are now used to monitor for Nelson syndrome. MRI avoids radiation exposure and can detect Nelson syndrome in early stages of tumor growth. (See 'Monitor for Nelson syndrome' below.)

●Quality of life – Concerns have existed about reduced quality of life due to postoperative adrenal insufficiency. However, some studies show patients who undergo bilateral adrenalectomy exhibit an improvement in quality of life similar to that in patients who undergo curative transsphenoidal surgery [13-15]. Nonetheless, this has not been a universal finding [16,17]. (See 'Optimize adrenal hormone replacement' below.)

Surgical approach — The laparoscopic approach, which can be done via either the anterior or posterior approaches, has become standard as this approach leads to shorter hospital stays (usually one to five days) and fewer complications compared with open surgery [14,16,18]. Regardless of the approach used, the adrenal glands must be removed en bloc. Care also must be taken to ensure that the fragile capsule is not broken [19] because cells released locally can become hyperplastic and cause recurrent disease; this ectopic tissue is not usually amenable to surgical removal. (See "Adrenalectomy techniques", section on 'Selection of operative approach'.)

Other adrenalectomy procedures (not recommended) — In contrast to bilateral adrenalectomy, unilateral or subtotal adrenalectomy is virtually never successful in ACTH-dependent Cushing syndrome. The only exceptions are if the patient develops a greater response to prior pituitary irradiation so ACTH secretion is partially inhibited or if the adrenalectomy becomes complete due to subsequent infarction of the remnant gland [10]. Therefore, we do not suggest this approach.

Incomplete adrenalectomy typically fails because the adrenal remnant eventually can become hyperplastic. For the same reason, total adrenalectomy with subcutaneous adrenal autotransplantation is likely to fail; for example, in one report, three of eight patients treated with this technique developed recurrent Cushing syndrome [20].

POSTOPERATIVE MANAGEMENT

Assess for cure — A morning serum cortisol level should be measured within two weeks after adrenalectomy, once the patient is on a stable, oral glucocorticoid replacement regimen. The blood sample should be drawn before the patient takes the morning glucocorticoid dose. If hydrocortisone is used for glucocorticoid replacement, doses should be given as scheduled on the previous day. However, if a longer-acting glucocorticoid is used, at least five half-lives should elapse between the last dose and the cortisol measurement. An undetectable serum cortisol level is consistent with cure. Serum cortisol should be remeasured if any clinical features of Cushing syndrome recur. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

Up to 3 percent of patients have recurrence due to ACTH-stimulated growth of an adrenal remnant or adrenal rest tissue [15]. Surgical removal may be possible if the location of the remnant or rest tissue can be identified. Medical therapy for hypercortisolism is an alternative. (See "Medical therapy of hypercortisolism (Cushing syndrome)", section on 'Initial treatment regimen'.)

Optimize adrenal hormone replacement — Following adrenalectomy, patients require lifelong adrenal hormone replacement therapy for primary adrenal insufficiency (algorithm 2).

●Glucocorticoid replacement – A daily dose of 15 to 25 mg hydrocortisone or its equivalent is optimal glucocorticoid replacement for most patients, and a smaller dose may be adequate for some individuals [21,22]. However, many patients receive excessive doses of glucocorticoid therapy after adrenalectomy [21-23]. As an example, in a report of 14 women receiving glucocorticoid therapy after adrenalectomy for Cushing disease, the average replacement glucocorticoid dose was equivalent to 27.3 mg hydrocortisone daily [23]. These women exhibited similar bone mineral density but higher body fat mass and lower fat-free mass compared with 14 control women of similar age, body mass index, and menopausal status.

A detailed approach to glucocorticoid replacement therapy, including alternatives to hydrocortisone, is presented separately. (See "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid replacement for all patients'.)

●Mineralocorticoid replacement – Fludrocortisone is required for mineralocorticoid replacement therapy. The initial dose is typically 0.05 to 0.1 mg daily and depends on whether the agent used for glucocorticoid replacement has mineralocorticoid activity. Mineralocorticoid therapy in patients with primary adrenal insufficiency is reviewed in detail elsewhere. (See "Treatment of adrenal insufficiency in adults", section on 'Primary adrenal insufficiency (all patients)'.)

●Patient education and safety – Patient education and safety precautions are essential for all patients with adrenal insufficiency (table 1). Key components of patient safety include always wearing a medical alert bracelet or necklace, having injectable glucocorticoid available in case of emergency, and adjusting the glucocorticoid dose during illness or other physiologic stressors. These are reviewed in detail separately. (See "Treatment of adrenal insufficiency in adults", section on 'Patient education and safety'.)

Monitor for Nelson syndrome — Patients who have had bilateral adrenalectomy for Cushing disease may develop corticotroph tumor progression, known as Nelson syndrome. The pathogenesis of this tumor progression is uncertain. These tumors represent the accelerated growth of corticotroph cells in preexisting microadenomas and exhibit variable loss of glucocorticoid negative feedback inhibition [24].

These tumors are similar to microadenomas causing Cushing disease with regard to light microscopic structure, ultrastructure, response to corticotropin-releasing hormone (CRH), and the proopiomelanocortin products they produce. It is unknown why only some tumors continue to grow.

Monitoring strategy — In all patients who have undergone bilateral adrenalectomy, we monitor with MRI of the pituitary and plasma corticotropin (ACTH) measurements. We monitor annually for seven years and then intermittently (eg, two to four years) if no tumor progression is evident [25-30]. We also monitor for clinical features of recurrent Cushing disease at every follow-up visit and at least annually. Corticotroph tumor progression becomes apparent several months to many years after adrenalectomy, on average after approximately three years.

In one series of 53 patients who had undergone adrenalectomy without preoperative pituitary irradiation and were evaluated by MRI, Nelson syndrome was found in 47 percent of patients and typically occurred within three years of adrenalectomy [25]. Four patients developed a macroadenoma, and one presented with pituitary apoplexy. Patients with a shorter duration of Cushing syndrome and higher postoperative plasma ACTH concentrations were more likely to develop tumor progression. Data are conflicting on the impact of patient age on the risk of developing Nelson syndrome [25,31].

In older studies using a less sensitive imaging technique (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 [8,26,32-37]. Nelson syndrome is less common after medical adrenalectomy with mitotane [38,39].

Magnetic resonance imaging — MRI allows early detection and management of corticotroph tumor progression. Tumor progression is defined as an enlarging pituitary tumor, either detection of a new mass or an increase ≥2 mm in diameter for an existing tumor.

Biochemical monitoring — A baseline, postoperative ACTH level should be measured as soon as the patient is on a clinically appropriate regimen of both glucocorticoid and mineralocorticoid replacement. The timing of measurement in relation to the most recent glucocorticoid dose should be recorded, and subsequent measurements should be obtained at the same interval after the previous glucocorticoid dose. This allows interpretation of subsequent measurements based on the patient's actual baseline ACTH level (ie, tumor activity), which already may be elevated. This strategy also avoids misdiagnosis of progression if baseline samples were collected sooner after the glucocorticoid dose than subsequent samples; in this case, baseline ACTH values will be lower if the tumor retains some physiologic ACTH suppression to glucocorticoid.

Plasma ACTH is the only laboratory test that predicts the evolution of Nelson syndrome, as plasma ACTH levels rise substantially more in patients who subsequently develop Nelson syndrome than in those who do not [5,8]. No consensus exists for a diagnostic ACTH criterion for Nelson syndrome. Some investigators have used plasma ACTH values as low as 200 pg/mL, in association with hyperpigmentation, as criteria for diagnosing Nelson syndrome [4]. 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 without a history of Cushing disease after bilateral adrenalectomy. In patients with Nelson syndrome, plasma ACTH concentrations typically range from as low as 800 pg/mL (175 pmol/L) to >25,000 pg/mL (5500 pmol/L).

Clinical monitoring — Hyperpigmentation is a primary clinical manifestation of Nelson syndrome [32]. Clinical signs and symptoms due to tumor enlargement include headaches, visual field defects, and cranial nerve palsies.

Prior to the availability of MRI for sensitive detection of tumor growth, hyperpigmentation was a key diagnostic criterion for Nelson syndrome [40]. Most patients are now diagnosed by MRI and ACTH values before the onset of any clinical manifestations [25].

Management

Early transsphenoidal resection (preferred) — In patients with Nelson syndrome, transsphenoidal surgery should be performed before the tumor becomes a macroadenoma [2,25,29,30,41]. Once the tumor becomes large enough to expand the sella, it is often locally invasive, difficult to cure, and may develop into a pituitary carcinoma.

The goal of careful monitoring is to prevent extrasellar extension through 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 for these macroadenomas varied from 10 to 70 percent [32,42,43]. Surgical morbidity is significant with panhypopituitarism in up to 70 percent of patients, cerebrospinal fluid leak in 15 percent, and meningitis in 8 percent [32,43].

Residual tumor post-resection — Very large Nelson syndrome tumors may progress even after surgical intervention [43]. Therefore, postoperative pituitary irradiation is suggested for patients with any evidence of residual tumor. The optimal type of radiation therapy has not been determined, and the choice of radiation strategy is informed by availability, cost, and patient preference regarding treatment duration. Options include the following:

●Conventional radiation – 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 – Stereotactic radiosurgery also has been used to manage Nelson syndrome [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, did not change in 8, and increased in 2 [47]. Targeted stereotactic radiosurgery should only be performed if the precise extent of the tumor is known. Otherwise, stereotactic radiosurgery should be directed to the entire sella. (See "Stereotactic cranial radiosurgery".)

Medical therapy (less effective) — Medical therapy of Nelson syndrome is relatively ineffective, and therefore, we do not suggest its use. Agents that have been tested for medical management include bromocriptine, cabergoline, pasireotide, octreotide, cyproheptadine, and valproic acid.

In one report of six women with Nelson syndrome, bromocriptine lowered plasma ACTH concentrations acutely by 52 percent, whereas cyproheptadine and valproic acid showed no significant acute effect on ACTH secretion [48]. Only a single case report documented sustained remission of Nelson syndrome with cyproheptadine [49]. Two case reports have shown that long-term cabergoline administration decreased ACTH levels and tumor size [50,51]. In an open-label study in eight patients with Nelson syndrome, pasireotide lowered plasma ACTH concentrations over 28 weeks of treatment [52].

Aggregate data from very small studies demonstrate that rosiglitazone was effective in only 1 of 19 patients [53-56]. The somatostatin analog octreotide reduced ACTH secretion and tumor size in a few patients with Nelson syndrome for as long as two years [31]. One report showed regression of tumor size after temozolomide treatment in two of four patients with aggressive corticotroph tumors or carcinoma [57]. Naloxone and indomethacin are not effective.

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

●Indications for surgical bilateral adrenalectomy – In patients with persistent or recurrent Cushing disease, surgical bilateral adrenalectomy provides definitive treatment when rapid cure of hypercortisolism is necessary or when all other therapies have failed (algorithm 1). Surgical adrenalectomy also may be indicated for individuals with persistent or recurrent Cushing disease who desire pregnancy. (See 'Indications for surgical adrenalectomy' above.)

●Pre- and perioperative management

•Preoperative pituitary irradiation – In patients with Cushing disease who are undergoing surgical bilateral adrenalectomy, we suggest against routine preoperative pituitary irradiation (Grade 2C). For patients without residual tumor on pathology or MRI scan, we do not administer preoperative radiotherapy. However, for patients with detectable residual corticotroph tumor on pathology or MRI scan and for whom repeat transsphenoidal resection is not an option, the decision regarding preoperative pituitary irradiation should be individualized and, ideally, reviewed at a multidisciplinary tumor board. In such patients, preoperative radiotherapy may reduce the risk of Nelson syndrome, but data are inconsistent. (See 'Preoperative pituitary irradiation' above and 'Monitor for Nelson syndrome' above.)

•Perioperative glucocorticoid therapy – Patients should receive hydrocortisone 50 to 100 mg intravenously (IV) prior to adrenalectomy followed by a total daily dose equivalent to hydrocortisone 150 to 200 mg. This is administered in divided doses (eg, 50 mg IV every six to eight hours) for one to three days perioperatively. (See 'Perioperative glucocorticoid treatment' above.)

●Surgical bilateral adrenalectomy – We suggest surgical bilateral total adrenalectomy as the definitive treatment for patients in whom rapid cure of hypercortisolism is necessary or when all other therapies have failed (Grade 2C). In contrast to bilateral total adrenalectomy, unilateral or subtotal adrenalectomy is virtually never successful in corticotropin (ACTH)-dependent Cushing syndrome and should not be performed. (See 'Pre- and perioperative management' above.)

The laparoscopic approach leads to shorter hospital stays and fewer complications compared with open surgery. (See 'Surgical approach' above and "Adrenalectomy techniques", section on 'Selection of operative approach'.)

●Postoperative management

•Assess for cure – A morning serum cortisol level should be measured within two weeks after adrenalectomy, once the patient is on a stable, oral glucocorticoid replacement regimen. The blood sample should be drawn before the patient takes the morning glucocorticoid dose. An undetectable level is consistent with cure. (See 'Assess for cure' above.)

•Adrenal hormone replacement – Following adrenalectomy, patients require lifelong adrenal hormone replacement therapy for primary adrenal insufficiency (table 1 and algorithm 2). (See 'Optimize adrenal hormone replacement' above and "Treatment of adrenal insufficiency in adults", section on 'Chronic adrenal insufficiency'.)

•Monitor for Nelson syndrome – Patients who have had bilateral adrenalectomy for Cushing disease may develop corticotroph tumor progression (Nelson syndrome). (See 'Monitor for Nelson syndrome' above.)

-Monitoring strategy – We monitor with MRI of the pituitary and plasma ACTH measurements, annually for seven years, and then intermittently if no tumor progression is evident. We also monitor for clinical features of recurrent Cushing disease at every follow-up visit and at least annually. (See 'Monitoring strategy' above.)

-Management of Nelson syndrome – For patients who develop Nelson syndrome, we suggest early transsphenoidal surgery (before the tumor becomes a macroadenoma) (Grade 2C). Once the tumor becomes large enough to expand the sella, it is locally invasive, difficult to cure, and may develop into a pituitary carcinoma. (See 'Early transsphenoidal resection (preferred)' 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.