neurosurgical focus Neurosurg Focus 38 (2):E9, 2015

The role of bilateral in the treatment of refractory Cushing’s disease

Anni Wong, MS,1 Jean Anderson Eloy, MD,1–3 and James K. Liu, MD1–3

1Departments of Neurological and 2Otolaryngology–Head & Neck Surgery, Rutgers University–New Jersey Medical School; and 3Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey, Rutgers University–New Jersey Medical School, Newark, New Jersey

Cushing’s syndrome (CS) results from sustained exposure to excessive levels of free glucocorticoids. One of the main causes of CS is excessive adrenocorticotropic hormone (ACTH) secretion by tumors in the (Cushing’s disease [CD]). Cushing’s disease and its associated hypercortisolism have a breadth of debilitating symptoms associated with an increased mortality rate, warranting urgent treatment. Currently, the first line of treatment for CD is transsphe- noidal surgery (TSS), with excellent long-term results. Transsphenoidal resections performed by experienced surgeons have shown remission rates ranging from 70% to 90%. However, some patients do not achieve normalization of their hypercortisolemic state after TSS and continue to have persistent or recurrent CD. For these patients, various thera- peutic options after failed TSS include repeat TSS, radiotherapy, medical therapy, and bilateral adrenalectomy (BLA). Bilateral adrenalectomy has been shown to be a safe and effective treatment modality for persistent or recurrent CD with an immediate and definitive cure of the hypercortisolemic state. BLA was traditionally performed through an open approach, but since the advent of laparoscopic adrenalectomy, the laparoscopic approach has become the surgical method of choice. Advances in technology, refinement in surgical skills, competency in adrenopathology, and emphasis on multidisciplinary collaborations have greatly reduced morbidity and mortality associated with adrenalectomy surgery in a high-risk patient population. In this article, the authors review the role of BLA in the treatment of refractory CD. The clinical indications, current surgical and endocrinological results reported in the literature, surgical technique (open vs laparoscopic), drawbacks, and complications of BLA are discussed. http://thejns.org/doi/abs/10.3171/2014.10.FOCUS14684 Key Words bilateral adrenalectomy; refractory Cushing’s disease; laparoscopic adrenalectomy; failed ; Nelson’s syndrome

ushing’s syndrome (CS) results from the chronic cardiovascular risks and thromboembolism, musculoskel- exposure to excessive concentrations of glucocor- etal impairments, immunosuppression, and diabetes.4,31 ticoids. More than 80% of cases are adrenocortico- It is associated with increased morbidity and mortality, Ctropic hormone (ACTH) dependent, and the majority of psychological effects, and ultimately decreased quality of these are due to excessive ACTH production from a pi- life.31,43 Patients may present with characteristic features tuitary adenoma, referred to as Cushing’s disease (CD). of CS, including moon facies, central obesity, wide purple The remaining 20% or so are ACTH independent and are striae, proximal muscle weakness, and the development of caused by excessive secretion by adrenal tumors a posterior cervical fat pad, or “buffalo hump.”30,42 Those or by nonpituitary neuroendocrine tumors (ectopic ACTH patients with untreated CS have a 5-fold increased mortal- secretion), which also increases cortisol production.6,30 ity rate with a mean survival time from initial presentation Cushing’s syndrome has a myriad of debilitating ef- of 5 years, and therefore effective treatment is critical.4,15,29 fects on one’s physiology and well-being. These effects Predominant causes of death are due to cardiovascular include cortisol-induced complications, such as increased complications and infections. Cushing’s syndrome also

Abbreviations ACTH = adrenocorticotropic hormone; BLA = bilateral adrenalectomy; CD = Cushing’s disease; CRH = corticotropin-releasing hormone; CS = Cushing’s syndrome; SRS = stereotactic radiosurgery; TSS = transsphenoidal surgery. submitted October 1, 2014. accepted October 30, 2014. include when citing DOI: 10.3171/2014.10.FOCUS14684. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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Unauthenticated | Downloaded 09/25/21 01:39 AM UTC A. Wong, J. A. Eloy, and J. K. Liu takes an incredible toll on a patient’s emotional well- Role of BLA in Refractory Cushing’s Disease 6 being, leading to psychiatric complications and suicide. While TSS is the first-line treatment for CD, it is not The objectives in the treatment of CS are to: 1) reverse always successful due to various factors. One of the fac- the clinical consequences of hypercortisolism; 2) normal- tors may be a large pituitary lesion that invades crucial ize biochemistry and prevent inappropriate ACTH and structures such as the cavernous sinus, hindering proper cortisol secretion; 3) prevent recurrence; and 4) minimize 4,43 complete resection. ACTH-secreting microadenomas may treatment morbidity. be so small that they escape identification and resection During the 1950s, bilateral adrenalectomy (BLA) was during surgery.52 The major advantage of BLA is that it the treatment of choice for CD, boasting a high success provides immediate and effective control of the hypercor- rate in reversing hypercortisolism, ranging from 88% to 21 tisolemic state. It has been documented to be a safe and 100%. Eventually it was found that there was significant definitive treatment for patients with refractory CD who risk of developing Nelson’s syndrome after BLA, where have unsuccessfully attempted multiple treatment options risks started outweighing the benefits and thus its role as 24 4 or require immediate reversal of hypercortisolemia. first-line treatment was abandoned. Soon after, with the As previously mentioned, other treatment alterna- advent of transsphenoidal surgery (TSS) and recognition tives are available after failed TSS for CD. Repeat TSS of the pituitary gland as the primary source of the prob- is a therapeutic option for persistent CS but comes with lem, the treatment strategy shifted to a more targeted ther- an increased risk of inducing panhypopituitarism as well apy toward the aberrant pituitary source. Currently, the as the implications of a second surgery.52 Although TSS first-line treatment of CD is transsphenoidal resection of 16,20,22,24,27 of ACTH-secreting adenomas has shown high initial re- the . mission rates of 64%–93%, long-term remission rates are Transsphenoidal surgery for the treatment of CD has lower and range between 44% and 79%.7,15,50 –52 Repeat served as an effective treatment option, with remission transsphenoidal approaches also present with more com- rates ranging from 70% to 90% when performed by ex- plications due to scar tissue formation and potential loss 9,13,24,32,33,35,36,38–41 perienced surgeons. However, persistent of anatomical references.50 Radiation therapy, including and recurrent disease does occur in 11.5% to 25% of pa- conventional radiotherapy as well as SRS and fractionated tients.3,21,24,43,50 Because of the debilitating manifestations stereotactic radiotherapy, is another secondary treatment and the increased morbidity and mortality of persistent option. Unfortunately, results present very slowly, taking CD, it is critical that physicians are aware of alternative up to 2 years,23 with high failure rates. Radiation thera- treatment options after failed TSS. These options include py also carries the risk of creating pituitary insufficiency, repeat TSS, radiation therapy including Gamma Knife ra- including hypothyroidism, hypogonadism, or growth hor- diosurgery, medical therapy, and BLA.24 Although BLA mone deficiency.45 A study by Wilson et al. showed that is no longer the first-line treatment for CD, it continues only 1 of 36 patients achieved biochemical remission after to play a valuable role in the treatment of CD, especially SRS and 9 demonstrated biochemical improvement but in the management of more challenging patients who are did not achieve serum targets.51 Medical therapy is rarely refractory to TSS or other therapeutic options.44 used as initial therapy. It is typically used as adjuvant ther- apy in recurrent or persistent CD or acts as an ameliorative Indications for BLA bridging treatment until radiation therapy takes effect.24,25 Ketoconazole, a synthesis inhibitor, is commonly BLA may be indicated as a surgical therapeutic option used and shows normalization or reduction in urinary free after failed attempts at treating refractory CD, including cortisol in 43% to 83% of patients.25 Other drugs such as repeat TSS, radiation therapy or stereotactic radiosurgery ACTH-release modulators (i.e., bromocriptine) or glu- (SRS), and medical therapy.1,24,45 This may occur when cocorticoid receptor antagonists are available but have there is persistent hypercortisolemia and residual tumor short-lived efficacy.25 In general, medical therapy is poorly after primary transsphenoidal resection, or if the tumor tolerated due to the adverse side effects of chronic thera- recurs after initial biochemical remission. Nevertheless, py.18 Additionally, medical therapy is only palliative and adrenalectomy is typically reserved as a treatment modal- does not serve as a definitive curative treatment because ity only after therapy directed at the pituitary gland has discontinuation of medical treatment will result in the re- failed,19 such as repeat TSS or radiosurgery if applicable. currence of symptoms.4,24 A study by Morris et al. dem- In ACTH-dependent CS, the is not the onstrated that patients who were treated only medically source of the problem but instead stands as the affected with steroidogenesis inhibition were more likely to die of end organ. However, adrenalectomy can play a role as Cushing’s-related sequelae, whereas those who addition- initial therapy for those patients with severe hypercorti- ally underwent adrenalectomy (steroidogenesis inhibition solism, life-threatening disease, unresectable pituitary tu- + BLA) were not.27 mors, or when a tumor is metastatic or locally invasive.1 Bilateral adrenalectomy therefore plays a crucial role Occasionally, BLA represents the preferred option for in the treatment of refractory CD and provides prompt younger female patients who are concerned with their fer- and reliable relief of hypercortisolemia. However, BLA tility, where their only other therapeutic option is complete mandates lifelong glucocorticoid and mineralocorticoid .25 BLA is also used to alleviate the ef- replacement. Individuals who undergo unilateral adre- fects of ectopic ACTH secretion when the source of ACTH nalectomies for aldosteronoma, , or secretion cannot be localized or excised, or when the side large nonfunctioning tumors do not routinely require glu- effects of adrenolytic medications are intolerable.16,17,27 cocorticoid and mineralocorticoid replacement therapy.

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On the other hand, patients proceeding with adrenalec- However, a disadvantage to this approach is the need to re- tomies as treatment for refractory CD undergo bilateral position the patient for a bilateral procedure. On the other adrenalectomy in which lifelong hormonal management hand, the anterior transabdominal approach allows for a is necessary.46,49 Proper administration of exogenous glu- bilateral adrenalectomy to be performed without reposi- cocorticoids is required to maintain hormonal functioning tioning the patient and also yields a conventional view of and balance.20 Because in CD the pituitary gland is the the abdominal cavity. A disadvantage of this approach is origin of disease, routine observation of growth and secre- that it requires insertion of additional ports and has been tory function of the pituitary gland using MRI and ACTH reported to increase operative time.49 measurements remains essential.6,19 A more direct access to the adrenal glands is provided by the retroperitoneal approach. In addition, no reposition- Open Versus Laparoscopic Approach ing of the patient is required for a bilateral adrenalectomy, which may reduce operative time, and any abdominal ad- Since the introduction of the first laparoscopic adrenal- 14 hesions from previous abdominal can be avoid- ectomy in 1992, the adrenalectomy procedure has been ed. Consequently, exploration of the abdominal cavity is revolutionized, transitioning from predominantly an open unavailable for concomitant pathology.49 Because working to a laparoscopic approach. There are many benefits of the space is more limited in this approach, dissection and ex- laparoscopic approach, including reduced length of recov- posure are more difficult and therefore may not be appro- ery and hospitalization time, lower postoperative morbid- priate for larger lesions. This approach may also be more ity and decreased analgesic requirement postoperatively, difficult, especially in patients with CD as they have more 2,8,12,48 and greater patient satisfaction. With this approach retroperitoneal fat.22 in the hands of an experienced surgeon, there is reduced Lal and Duh compared the lateral transabdominal and 20 operative blood loss, fewer late incisional complications, posterior approaches in a series of 36 nonrandomized and less invasiveness compared with an open adrenalec- patients and found no difference in the mean operative tomy. time, morbidity, or hospital length of stay between the two With an open posterior approach, muscular layers are groups of patients. It was noted, though, that the posterior incised and removal of the twelfth rib is required with approach was more difficult to teach and required routine meticulous attention to the intercostal nerves.1 Posterior intraoperative ultrasonography.22 open adrenalectomy has been associated with a high per- Because patients with CS are predisposed to poor centage of neuromuscular complaints and chronic back wound healing, laparoscopic adrenal surgery presents an pain.1,48 An analysis of 3100 patients in Elfenbein et al.’s ideal surgical approach because it avoids large incisions comparison of laparoscopic versus open adrenalectomy and is minimally invasive. The magnification during lapa- from the American College of Surgeons-National Surgery roscopic adrenalectomy also allows for better visibility of Quality Improvement Project demonstrated that patients the surgical field, leading to a decreased risk of leaving undergoing open adrenalectomy have substantially higher behind adrenal remnants.20,49,52 With CS, most adrenal le- rates of 30-day postoperative morbidity and an average sions are small and pathologically benign, and so are well hospital stay that is 3 days longer than patients who un- suited for laparoscopic excision.20 In addition, patients dergo laparoscopic adrenalectomy, with no difference in with CS typically present with increased adipose tissue, 30-day mortality.12 and for this reason the laparoscopic approach may be Laparoscopic adrenalectomy has consistently been more appealing than an open laparotomy.17 reported to have longer operative times than open adre- Laparoscopic adrenalectomy is contraindicated when nalectomy, primarily due to the learning curve, but also adrenal carcinoma is suspected, as there is a concern of when a bilateral laparoscopic adrenalectomy is performed intraoperative tumor spillage and incomplete tumor clear- it is essentially two separate laparoscopic procedures.1,26,47 ance. It is also not recommended for large tumors because Extra time is required to reposition and prepare the pa- the risk of malignancy increases with size, and larger tu- tient for removal of the second gland.1,49 Nonetheless, the mors are more arduous to remove.22,47,49 increased operative time does not appear to have a nega- Sometimes due to a patient’s physical characteristic or tive impact on the patient’s recovery. In fact, Mikhal et al. scarring from prior surgeries, laparoscopic adrenalectomy found that despite the longer operative times for the lapa- may not be recommended.8 Obesity can interfere with the roscopic group, the estimated blood loss and postoperative proper identification of anatomy and may lead to difficul- hematocrit drop were lower than those in the open group, ty in dissection during laparoscopic surgery. According which may be attributable to the decreased overall trans- to the NIH, obesity is defined as body mass index mea- fusion rate and benefits of pneumoperitoneum.26 surements greater than or equal to 30 kg/m2.28 A study by Various laparoscopic approaches may be used for ad- Chow et al. showed that all patients requiring conversion renal removal, including a transabdominal (anterior or lat- to an open approach were obese.8 Similarly, of 22 patients eral) or retroperitoneal (lateral or posterior) approach. The who underwent laparoscopic adrenalectomy, 1 patient was lateral transabdominal approach, used by an estimated converted to an open surgery because of morbid obesity in 70% of surgical facilities worldwide, is the most common a study by Acosta and colleagues.1 approach for laparoscopic adrenalectomy and allows the It is important to note that laparoscopic adrenalecto- most working space.8,22 The lateral decubitus position of my is not easier or quicker and general anesthesia is still the patient allows gravity to create natural retraction of required. This procedure requires considerable time and the liver, spleen, and bowel away from the surgical field.52 effort, and expert surgeons and interdisciplinary collabo-

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Unauthenticated | Downloaded 09/25/21 01:39 AM UTC A. Wong, J. A. Eloy, and J. K. Liu ration for an effective surgery. However, in the long term, associated with adrenal surgery in patients with CS and laparoscopic adrenalectomy provides greater benefits to CD have dramatically reduced.1,48 the patient and society (as discussed above) compared with the open approach.48 Quality of Life Laparoscopic adrenalectomy has been accepted as the standard of treatment for a majority of adrenal patholo- Without treatment, CD or CS takes an incredible toll gies, especially with benign masses less than 6 cm in size on the patient’s physical and mental well-being. Although and less than 100 g in weight. Masses up to 12–15 cm that patients experience a clinical reversal of hypercortisolism are well encapsulated, without local invasion or nodular and an improvement in their health status after BLA, they involvement, have also been operated on with great suc- continue to have a poorer health status than the general cess.34 The laparoscopic approach is recommended for population. In a study by Hawn et al., 81% of patients re- patients requiring bilateral adrenalectomy for the man- ported in a survey that their health was improved after agement of ACTH-dependent CS with persistent hyper- BLA, but they scored substantially lower on the 36-Item cortisolism.8,26 Short-Form Health Survey compared with the general population. A feeling of poorer health status is not limited to those after treatment of CD with BLA, but has also been Published Studies of BLA for Cushing’s noted in other treatment options as well.18 Overall, patients Disease believe that their health status is better compared with 1 Bilateral adrenalectomy has been shown to be a safe year before BLA. Quality of life questionnaires completed and effective treatment for refractory CD.1,18,26,31,44,46 Sever- by 28 BLA patients in a study by Smith et al. also dem- al studies have demonstrated successful clinical outcomes onstrated similar results, in which 86% of the patients after BLA, including improvement of Cushing’s-specific experienced an improvement in their health and 68% re- comorbidities such as hypertension, diabetes mellitus, ported that their health posed no hindrance to moderate osteoporosis, and muscle weakness.8,31,44 The published activities. The most common complaint observed among results of contemporary surgical series of BLA for CD patients was fatigue.44 from 2002 to 2014 are summarized in Table 1. Overall, the remission rate was 100% with a morbidity rate ranging Pitfalls of BLA from 6% to 26% and a follow-up duration ranging from 29 General Risks to 132 months. The rate of developing Nelson’s syndrome after BLA for CD ranged from 0% to 33%. In a recent Individuals with CD and CS represent a special popula- systematic analysis of 24 published studies (768 patients) tion of patients because their metabolic dysfunction leaves from 1981 to 2012, the average incidence of developing them vulnerable to decreased wound healing, increased Nelson’s syndrome after BLA for CS was 21% (range risk of postoperative infections caused by a compromised 0%–47%). 37 immune system, deep venous thrombosis, and pulmonary In a study by Oßwald et al., all 50 patients who un- embolism. Consequently, a higher rate of surgical morbid- derwent BLA for CD were found to be in remission, and ity and mortality is expected.1 Complication/morbidity all Cushing’s-specific comorbidities, except for psychiat- rates and types of complications noted in recent published ric diseases, improved significantly.31 A recent series of surgical series of BLA for CD are summarized in Table 21 patients who underwent laparoscopic adrenalectomy 2. In addition, CD patients usually are obese or hold ex- for CS also demonstrated normalization of hormones in cessive fatty tissue that may make surgery and complete all patients, with no deaths or major postoperative com- gland resection more difficult.1 As discussed above, be- plications and a morbidity rate of 6.3%.10 Smith et al. also cause of these factors, the laparoscopic approach for BLA demonstrated excellent survival and clinical results with is well suited for patients with CD as it allows minimal tis- BLA in patients with CD. In their series of 40 patients who sue trauma and greater magnification of the surgical field.8 underwent BLA for persistent CD after failed TSS, all the Residual adrenocortical function has also been known patients achieved clinical reversal of hypercortisolism, in- to occur even after intended total adrenalectomy. This cluding patients with ectopic adrenal tissue. There were may occur due to adrenal remnants left during surgery no operative or 30-day deaths, one 90-day death, and or the presence of accessory adrenal tissue. If the patient morbidities were observed in 18% of the patients. Such harbors an ectopic ACTH-secreting lesion and it is not morbidities may include instances of prolonged ventila- excised, the patient will also experience persistent CD tion, urinary tract infections, wound infections, incisional despite complete adrenal gland removal.44 Therefore it is hernias, or arrhythmia. Their study demonstrated an all- important to pay careful attention and achieve optimal vi- cause survival rate of 97% at 1 year, and 87% at 5 years.44 sualization to allow for complete resection of the adrenal Ding et al. also demonstrated survival rates of nearly 90% gland and periadrenal fat. at 5 years, in which the main cause of death was due to Patients with CD are in a poorer health status and have cardiovascular anomalies well outside of the perioperative a higher risk of encountering complications, but the revo- time period.11 lution of sophisticated technology and surgical skills, and With advancements in surgical technology, refinements a better understanding of adrenal pathology, have allowed in surgical technique, and improvements in perioperative laparoscopic adrenalectomy to be a successful option in management, anesthetic management, and understanding the treatment of CD. Despite these setbacks, many studies of adrenal pathophysiology, morbidity and mortality rates have confirmed BLA as a safe and effective treatment for

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TABLE 1. Summary of published contemporary surgical series evaluating outcomes of BLA for CD (2002–2014) No. of Patients No. of Patients Morbidity 30-Day Nelson’s Mean FU Authors & Year Undergoing BLA Undergoing BLA for CD* (%)† Mortality (%) Syndrome (%) (mos) Chow et al., 2008 59 42 17 0 NA NA Ding et al., 2010 43 43 15 0 18 48.5 Gil-Cárdenas et al., 2007 39 39 NA 0 28 53 Hawn et al., 2002 18 18 16 0 5 29 Oßwald et al., 2014 50 34 6 4 24 132 Pugliese et al., 2008 11 8 NA 0 0 32 Smith et al., 2009 40 40 18 0 33 60 Takata et al., 2008 30 16 13 0 NA 31 Tiyadatah et al., 2012 19 19 26 5 17 32.6 FU = follow-up; NA = not available * Results in this chart are for patients undergoing BLA specifically for CD. Patients undergoing BLA for other diseases, such as pheochromocy- toma and primary adrenal tumors, were omitted from the table. † Remission was achieved in 100% in all studies; remission was generally defined as biochemical resolution and/or absence of clinical evi- dence of persistent or recurrent disease or hypercortisolism after BLA.

CD refractory to TSS with a low rate of morbidity and for CD serve to be the source of the tumor that eventu- mortality and good long-term survival.27,31,37,44,49 ally grows and leads to Nelson’s syndrome development. Another school of thought questions if the pituitary ACTH Nelson’s Syndrome adenoma tumor progression reflects a more aggressive mo- Development of Nelson’s syndrome after BLA is a con- lecular programming of the corticotrophic tumors.5 sistent postoperative concern.21,24,44 In 1958 Nelson and col- With the complete removal of adrenal tissue, there is leagues first reported a patient with resolution of CS symp- a loss of negative feedback control of serum cortisol on toms after BLA. Three years later, the patient developed the hypothalamus and pituitary gland, leading to the de- hyperpigmentation and a pituitary tumor, and Nelson con- velopment of Nelson’s syndrome (Fig. 1).5,44 Cortisol levels cluded that the “development of a pituitary tumor is a pos- that previously suppressed hypothalamic corticotropin- sible sequel of bilateral adrenalectomy for Cushing’s syn- releasing hormone (CRH) normalize after BLA, resulting drome.”19 Nelson’s syndrome is characterized by elevated in an increase in CRH production. Because the definition serum ACTH levels, hyperpigmentation, progressively en- of Nelson’s syndrome used in the literature is not consis- larging pituitary tumors that tend to be invasive and rather tent, there are often difficulties comparing rates of Nelson’s aggressive in their growth pattern, and in rare cases, may syndrome development across patient series, and rates may develop into pituitary carcinomas.24,44 It is believed that the vary. 44 The risk of developing Nelson’s syndrome after corticotroph adenoma cells that were primarily responsible BLA, depending on the follow-up length, has been re- TABLE 2. Summary of morbidity/complications of published contemporary series evaluating outcomes of BLA for CD No. of Patients Morbidity Authors & Year Undergoing BLA for CD (%) Morbidity/Complication Type (no. of cases)* Chow et al., 2008 42 17 Wound infection, wound hematoma, pneumonia, prolonged ven­ tilation, myocardial infarction, hydropneumothorax, thrombo- embolism† Ding et al., 2010 43 15 Urinary tract infection, wound infection, pneumonia† Gil-Cárdenas et al., 2007 39 NA NA Hawn et al., 2002 18 16 Intraoperative complication of colotomy (1), pancreatic pseudo- cyst (1), hemorrhage (1) Oßwald et al., 2014 34 6 Infections (2), thromboembolism (1) Pugliese et al., 2008 8 NA NA Smith et al., 2009 40 18 Incisional hernias (3), wound infections (2), hemothorax (1), uri­nary tract infection (1), prolonged ventilator wean (1), ar- rhythmia (1), stroke (1), operative hemorrhage (1) Takata et al., 2008 16 13 Pneumonia (1), infection (1) Tiyadatah et al., 2012 19 26 Wound infection (2), port site hernia (1), pleural effusion (1), atelectasis (1) * Complications are postoperative unless otherwise noted. † Number of cases of complications not specified.

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currently recognized as the standard approach for BLA in most patients with CD, with the lateral transperitoneal technique as the most common laparoscopic approach to the adrenal gland. Because of the loss of negative feed- back, the risk of development of Nelson’s syndrome re- mains an omnipresent event. Lifelong glucocorticoid and mineralocorticoid replacement therapy and long-term rou- tine endocrinological care is required after BLA. After weighing the risks and benefits, BLA stands as a valuable treatment choice as it provides immediate and definitive control of the hypercortisolemic state. References 1. Acosta E, Pantoja JP, Gamino R, Rull JA, Herrera MF: Lapa- roscopic versus open adrenalectomy in Cushing’s syndrome and disease. Surgery 126:1111–1116, 1999 2. Ali JM, Liau SS, Gunning K, Jah A, Huguet EL, Praseedom RK, et al: Laparoscopic adrenalectomy: auditing the 10 year experience of a single centre. Surgeon 10:267–272, 2012 3. Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheri- dan B: Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin Endocrinol (Oxf) 63:549–559, 2005 4. Bademci G: Pitfalls in the management of Cushing’s disease. J Clin Neurosci 14:401–409, 2007 5. Banasiak MJ, Malek AR: Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management. Neu- rosurg Focus 23(3):E13, 2007 6. Bertagna X, Guignat L, Groussin L, Bertherat J: Cushing’s disease. Best Pract Res Clin Endocrinol Metab 23:607– 623, 2009 7. Buchfelder M, Schlaffer S: Surgical treatment of pituitary tu- mours. Best Pract Res Clin Endocrinol Metab 23:677–692, 2009 Fig. 1. Diagram of the hypothalamic-pituitary-adrenal axis. BLA elimi- 8. Chow JT, Thompson GB, Grant CS, Farley DR, Richards nates the ability of adrenal glands to secrete cortisol. It also removes ML, Young WF Jr: Bilateral laparoscopic adrenalectomy for the negative feedback provided by cortisol on ACTH secretion by the corticotrophin-dependent Cushing’s syndrome: a review of anterior pituitary gland and CRH secretion by the hypothalamus. Proper the Mayo Clinic experience. Clin Endocrinol (Oxf) 68:513– hormonal replacement therapy will be required. 519, 2008 9. Ciric I, Zhao JC, Du H, Findling JW, Molitch ME, Weiss RE, ported to range from 0% to 47%, with a significant risk of et al: Transsphenoidal surgery for Cushing disease: experi- major pituitary tumor enlargement.18,21,37,44 In a recent sys- ence with 136 patients. 70:70–81, 2012 tematic analysis of BLA for treatment of CS—consisting of 10. Conzo G, Pasquali D, Gambardella C, Della Pietra C, Es- 37 studies involving 1320 patients with hypercortisolemia posito D, Napolitano S, et al: Long-term outcomes of lapa- from ectopic CS, primary adrenal hyperplasia, or CD— roscopic adrenalectomy for Cushing disease. Int J Surg 12 37 (Suppl 1):S107–S111, 2014 Nelson’s syndrome developed in 21% of patients. One 11. Ding XF, Li HZ, Yan WG, Gao Y, Li XQ: Role of adrenal- reason for the variation in percentages has been speculated ectomy in recurrent Cushing’s disease. Chin Med J (Engl) to be due to the differences in the maintenance dose and 123:1658–1662, 2010 frequency of glucocorticoid administration after BLA.5 12. Elfenbein DM, Scarborough JE, Speicher PJ, Scheri RP: The extent of adrenalectomy, original cause of the hyper- Comparison of laparoscopic versus open adrenalectomy: cortisolemia, and the year the surgery was performed may results from American College of Surgeons-National Surgery also contribute to the varying percentage of individuals Quality Improvement Project. J Surg Res 184:216–220, 2013 19 13. Friedman RB, Oldfield EH, Nieman LK, Chrousos GP, who develop Nelson’s syndrome after BLA. Serial imag- Doppman JL, Cutler GB Jr, et al: Repeat transsphenoidal sur- ing and ACTH measurements after BLA for CD should be gery for Cushing’s disease. J Neurosurg 71:520–527, 1989 conducted routinely. Studies have also noted the potential 14. Gagner M, Lacroix A, Bolté E: Laparoscopic adrenalectomy benefit of prophylactic radiotherapy before BLA, and an in Cushing’s syndrome and pheochromocytoma. N Engl J association with a delayed onset of Nelson’s syndrome,5,21 Med 327:1033, 1992 (Letter) although neither the clinical significance of the association 15. Galiana PA, Montana CF, Suarez PAR, Velas JG, Escriva nor the predictive value is universally accepted5,24 as there CM, Lillo VR: [Predictors of long-term remission after trans- 44 sphenoidal surgery in Cushing’s disease.] Endocrinologia Y are reports showing no association as well. Nutricion 60:475–482, 2013 (Span) 16. Gil-Cárdenas A, Herrera MF, Díaz-Polanco A, Rios JM, Pan- Conclusions toja JP: Nelson’s syndrome after bilateral adrenalectomy for Cushing’s disease. Surgery 141:147–152, 2007 Bilateral adrenalectomy is a safe and effective thera- 17. Gumbs AA, Gagner M: Laparoscopic adrenalectomy. Best peutic option for refractory CD. Laparoscopic surgery is Pract Res Clin Endocrinol Metab 20:483–499, 2006

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Wilson PJ, Williams JR, Smee RI: Cushing’s disease: a single tion of tumor resection after transsphenoidal surgery. J Clin centre’s experience using the linear accelerator (LINAC) for Endocrinol Metab 92:3383–3388, 2007 stereotactic radiosurgery and fractionated stereotactic radio- 33. Prevedello DM, Pouratian N, Sherman J, Jane JA Jr, Vance therapy. J Clin Neurosci 21:100–106, 2014 ML, Lopes MB, et al: Management of Cushing’s disease: 52. Young WF Jr, Thompson GB: Laparoscopic adrenalectomy outcome in patients with microadenoma detected on pituitary for patients who have Cushing’s syndrome. Endocrinol magnetic resonance imaging. J Neurosurg 109:751–759, Metab Clin North Am 34:489–499, xi, 2005 2008 34. Pugliese R, Boniardi M, Sansonna F, Maggioni D, De Carli S, Costanzi A, et al: Outcomes of laparoscopic adrenal- Author Contributions ectomy. Clinical experience with 68 patients. Surg Oncol Conception and design: Liu, Wong. Acquisition of data: Wong. 17:49–57, 2008 Analysis and interpretation of data: Wong. Drafting the article: 35. Ram Z, Nieman LK, Cutler GB Jr, Chrousos GP, Doppman Wong. Critically revising the article: all authors. Reviewed sub- JL, Oldfield EH: Early repeat surgery for persistent Cushing’s mitted version of manuscript: all authors. Approved the final disease. J Neurosurg 80:37–45, 1994 version of the manuscript on behalf of all authors: Liu. Adminis- 36. Reitmeyer M, Vance ML, Laws ER Jr: The neurosurgical trative/technical/material support: Liu, Eloy. Study supervision: management of Cushing’s disease. Mol Cell Endocrinol Liu, Eloy. 197:73–79, 2002 37. Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider Correspondence HJ, Schopohl J, et al: Outcome of bilateral adrenalectomy in James K. Liu, Department of Neurological Surgery, Rutgers Uni- Cushing’s syndrome: a systematic review. J Clin Endocrinol versity–New Jersey Medical School, 90 Bergen St., Ste. 8100, Metab 98:3939–3948, 2013 Newark, NJ 07103. email: [email protected].

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