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The Role of Bilateral Adrenalectomy in the Treatment of Refractory Cushing's

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The Role of Bilateral Adrenalectomy in the Treatment of Refractory Cushing's NEUROSURGICAL FOCUS Neurosurg Focus 38 (2):E9, 2015 The role of bilateral adrenalectomy 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 Surgery 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 pituitary gland (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 transsphenoidal surgery; 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 cortisol 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. ©AANS, 2015 Neurosurg Focus Volume 38 • February 2015 1 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 pituitary adenoma. 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 steroid 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
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