CLINICAL QUESTION
Acute hypercortisolism: what can the surgeon offer?
Emily Davenport* and Tom Lennardt
*Royal Victoria Infirmary, Newcastle Upon Tyne Hospitals NHS Trust and +Newcastle University Newcastle Upon Tyne, UK
Summary
Rapid onset or acute hypercortisolism is a rare critical illness requiring emergency management. The majority of patients will have underlying malignancy with surgery an obvious choice in the minority with resectable disease. For those with unresectable disease, medical management alone has been the traditional approach. However, this often proves inadequate raising interest in the role of surgery as palliation in this setting. Patient selec- tion, timing of surgery and optimal surgical technique are areas of current controversy with little literature available to provide answers. Decisions regarding management of patients with acute hypercortisolism are complex, and these patients are best man- aged in a subspecialized setting.
(Received 20 January 2014; returned for revision 16 February 2014; finally revised 28 April 2014; accepted 1 May 2014)
Introduction
Acute hypercortisolism is a subset of Cushing’s syndrome (CS) distinct from it’s more common insidious counterpart. The underlying diagnosis is usually malignancy, either primary adre- nocortical carcinoma (ACC) or an adrenocorticotropin hormone (ACTH) producing tumour resulting in ectopic ACTH syn- drome. Onset of symptoms is rapid and in addition to the more commonly recognized features of CS, patients can present with overwhelming sepsis, cardiac failure, acute psychosis or severe metabolic disturbances. Effects can be ravaging producing a crit- ical illness which requires co-ordinated management decisions to be made on an emergency basis.
Management discussions must include both medical and sur- gical options. Medical management alone will often fail to con- trol aggressive cortisol production, but may provide some symptomatic relief in those deemed unfit for surgery or with a very limited life expectancy. In all others, surgery should be con- sidered. Little high quality evidence exists to support decision making in these complex cases. Decisions are often guided by
small case studies and personal experience involving similar cases. Management needs to be tailored to the individual, ideally within the context of a multidisciplinary discussion in a special- ist centre.
This review focuses on surgical approaches to acute hypercor- tisolism. We discuss the complexities of patient selection, peri- operative issues and operative techniques.
Patient selection for surgery
Optimal management in acute hypercortisolism, whether due to ACC or ACTH syndrome, is complete resection of the secreting tumour. Unfortunately, this is often not possible due to local tumour invasion, widespread metastatic disease or patient inabil- ity to tolerate surgery. Palliative surgery has previously been con- sidered a last resort in these patients when medical therapy failed to control symptoms in the severely unwell.1 However, recent widespread adoption of a laparoscopic approach to adre- nalectomy, with reduced morbidity and mortality compared with traditional open operation 2, combined with a recognition of the limitations of medical therapies has reopened the debate with regards to the indications for and optimal timing of surgical intervention vs medical therapy. Due to a paucity of literature, decisions regarding the optimal balance between medical and surgical options are often guided by expert opinion rather than high level evidence. With this in mind, we recommend early urgent referral to a tertiary centre to allow centralization of care to those experienced in managing these critically ill patients.
Primary adrenocortical carcinoma
Up to 60% of ACC secrete cortisol and rapidly progressing CS, with or without virilization, is the most common presentation.3 Stage I disease at presentation is rare, but curable. The majority of stage II-III ACCs are potentially resectable, although this may require en bloc resection of surrounding organs. Intracaval extension or tumour thrombus is not a contraindication to sur- gery; resection may be facilitated by cardiopulmonary bypass.4
For nonresectable ACC in the setting of rapid onset hypercor- tisolism, debulking may help control hormone hypersecretion and increase the efficacy of medical treatment.5,6 Patients with unresectable disease have a poor prognosis, on average surviving only 9 months, or in those presenting with acute hypercortiso- lism only 3 months.7 Palliation with medical therapies is
therefore the best option for the majority.8 Rare cases of long term survival in metastatic or recurrent ACC have been described, and these patients may gain considerable quality of life year benefit from palliative adrenalectomy in the setting of hypercortisolism.9 However, predicting which patients may sur- vive long term is challenging. In patients with stage IV disease, Assie et al.1º have identified number of involved organs at first presentation with metastatic disease and tumour mitotic rate as predictors of prognosis and this may be useful in selecting patients for surgery. In our practice, we would consider surgi- cal debulking in those who have failed medical therapy and are left with severe effects of hypercortisolism, who have lim- ited metastatic disease and in whom potential quality of life year benefit is considered significant by our multidisciplinary team.
Ectopic ACTH syndrome
Almost any neuroendocrine tumour has potential for de-differ- entiation with subsequent production of ACTH, or rarely corti- cotrophin releasing hormone (CRH). Hormone secretion rates vary considerably producing a wide range of clinical disease. At one end of the spectrum, more aggressive tumours such as small cell lung and medullary thyroid cancers have a tendency towards acute hypercortisolism. In contrast, tumours such as bronchial neuroendocrine neoplasms, with relatively indolent behaviour, tend to produce insidious onset CS. Surgical resec- tion, including metastatectomy, if feasible, provides optimal control and potential cure in ACTH secreting tumours. Pallia- tive bilateral adrenalectomy is a valid alternative to medical therapy in those with unresectable, metastatic or occult primary disease and provides a rapid method of controlling hypercortis- olism. Recent arguments suggest that surgery should be consid- ered the first line treatment in this situation.11,12 The 5-year survival rate for patients undergoing bilateral adrenalectomy for unresectable or occult ectopic ACTH producing tumours is 51%, and these patients can gain significant benefit in terms of quality of life years from optimal surgical control of excess cor- tisol secretion, while avoiding the adverse effects and unpredict- able long term response of medical therapy.13 These arguments are largely based on evidence from those with relatively indo- lent tumours and insidious onset hypercortisolism; however, even in rapid onset disease, where tumours are more likely to be aggressive with a poorer prognosis, bilateral adrenalectomy can offer considerable benefit.
Bilateral adrenalectomy effectively addresses the ravages of extreme hypercortisolism that often pose a greater immediate risk to the patient than the underlying malignancy itself.13 Effects are immediate, and unlike medical treatments, recurrent CS following adrenalectomy is rare.14 Bilateral laparoscopic adre- nalectomy has already been adopted as first line therapy in recurrent Cushing’s disease following transsphenoidal surgery. In this group, surgery provides patients with considerable improve- ment in their Cushing-related symptoms with concordant increase in quality of life that is on average the same (or better) as patients initially cured by transsphenoidal pituitary tumour
resection.15 Due to the rarity of disease, the same quality of life studies have not been attempted for bilateral adrenalectomy performed in the setting of ectopic ACTH syndrome, but simi- larly positive results could be expected even in those with a poor prognosis from their primary tumour.
Consensus guidelines do not offer advice with regards to patient selection for bilateral adrenalectomy in the setting of unresectable or occult ectopic ACTH syndrome.16 No random- ized controlled trials have compared surgery with optimal medi- cal management alone. Cases must be considered on an individual basis, balancing the clinical effects of hypercortisolism against the aggressiveness of the underlying tumour and opera- tive risk. Our preference is to consider early bilateral adrenalec- tomy in all patients with ectopic ACTH syndrome who are considered fit for surgery, particularly in the case of a poor initial response to medical therapy.
Timing of surgery
Optimal timing for surgery is another area of uncertainty. Patients with acute hypercortisolism are often severely unwell, and emergency resuscitation is the initial priority. This will involve careful correction of metabolic abnormalities such as hypokala- emia, alkalosis, catabolismhypoalbuminaemia and hyperglyca- emia that result from increased cortisol levels. Following initial resuscitation and stabilization, the options are immediate surgery or a period of pre-operative adjunctive medical therapy.
Pre-operative medical therapy may be useful in blocking corti- sol secretion to allow time for appropriate diagnostic work up, better correction of metabolic derangements and control of complications such as acute psychosis, severe hypertension and opportunistic infections.17 Intravenous etomidate can be used to block steroidogenesis and is particularly useful in the emergency setting. It potently lowers circulating cortisol levels with a rapid onset of action, rendering most patients hypocortisolaemic within 24 h. Although it seems a rational approach, no studies have been performed that prove efficacy of cortisol lowering pharmacological therapy in the pre-operative setting.18 Stuijver et al.19 in a large retrospective cohort study suggest that, com- pared with treatment naïve patients, patients treated with corti- sol lowering therapy before surgery seem to have a reduced risk for developing thromboembolic disease postoperatively, although this difference was not statistically significant.
A number of medications have been used successfully in the control of hypercortisolism, further details of which are beyond the scope of this review. Unfortunately, no drug is universally effective, particularly when a long term response is required and medical management can fail to adequately reduce circulating cortisol in a significant proportion.2º Reported rates of response vary widely in the literature with most medications supported by only ‘low’ or ‘very low’ level evidence.21 Progressive disease with a poor response to medical therapy is difficult to manage and associated with poor outcomes following adrenalectomy. Although combination therapy and newer alternatives, such as glucocorticoid receptor antagonists show promise, adverse effects such as gastrointestinal complaints, hypokalaemia, hepato- and
nephrotoxicity can limit use and may worsen an already critical situation.22
In the pre-operative setting, a balance needs to be struck between the unproven benefits of medical control of hypercortis- olism vs the toxicity of pharmacological blockade and the time taken to achieve this along with the risk of a poor response with subsequent delayed surgical treatment. Again decisions should be tailored to the individual, but in general we recommend con- sideration of early bilateral adrenalectomy, particularly in those with poor initial response to medical therapy.23 Surgery should be centralized to centres with experience in adrenalectomy in this setting.
Perioperative care
Perioperative management requires a collaborative team approach involving specialist endocrinology, endocrine surgery and anaesthetic personal. Intensive care support is often required during the resuscitation and immediate postoperative periods. Among the described metabolic effects of acute hypercortisolism, hypokalaemia is particularly common and can prove difficult to reduce to levels safe for general anaesthesia.
Once stabilized, the patient can progress to the operating the- atre where the following specific issues must be considered in the light of acute hypercortisolism. Our practice is for a single prophylactic dose of broad spectrum antibiotic at anaesthetic induction to combat the increased risk of infection due to the immunosuppressive effects of cortisol excess. Glucocorticoid replacement therapy should be initiated intra-operatively. Hypertension, hyperglycemia and obesity, common in CS all contribute to an increased risk of venous thromboembolism in the perioperative period. For thromboprophylaxis, we suggest intra-operative sequential compression devices, as well as gradu- ated compression stockings and prophylactic dose low molecular weight or unfractionated heparin until the patient is fully mobi- lizing postoperatively.
Postoperatively, patients will require careful management of blood pressure and blood sugar levels. Cortisol blocking agents commenced pre-operatively can be stopped immediately. Gluco- corticoid and mineralocorticoid replacement therapy should be continued or commenced and titrated to patient requirements. Weaning of medications such as antihypertensives, insulin or oral hypoglycaemics may be possible. We allow patients to eat and drink as tolerated from day one postoperatively and encour- age early mobilization.
Surgical options
Adrenalectomy can be performed via a transperitoneal or retro- peritoneal approach, either laparoscopically or open. Surgery for acute hypercortisolism should be performed in centres where all options are available. Although patients with acute hypercortiso- lism have high surgical risk in terms of morbidity and mortality, the widespread adoption of a laparoscopic approach, with numer- ous benefits over the traditional open technique, has tipped the balance towards surgery rather than medical therapy alone.
Laparoscopic adrenalectomy was initially described in 199224 and is now considered gold standard for the majority of adrenal pathologies.25 A number of studies have shown benefits over the traditional open technique including lower blood loss and mor- bidity, shorter hospital stay, faster return to normal daily activities and lower postoperative pain.26-28 A review of 2550 patients undergoing laparoscopic adrenalectomy showed an overall com- plication rate of 9-8% including bleeding, gland fragmentation, organ damage, port site hernia and infection. The conversion rate to open surgery was 3-6% and overall mortality rate 0-2%. Only a minority of these patients had hypercortisolism. Surgical complication and mortality rates are known to be higher in patients with CS but are still in the order of 15% and 3%, respec- tively, with the majority experiencing an uneventful recovery.29,30 Patients with acute hypercortisolism are likely to have higher complication rates although no literature exists to support this.
Not all patients are suitable for a laparoscopic approach but the indications are constantly expanding. Where curative resection is the aim in suspected adrenal malignancy, an open approach is generally preferred. This is due to concerns regarding inadequacy of oncological resection, increased local recurrence and peritoneal carcinomatosis with a laparoscopic approach. This has been widely debated with conflicting results in the literature, and a definitive conclusion remains elusive.31 What is clear, however, is that poor outcomes result from inadequate oncological resection, whether performed laparoscopically or open, and surgery for suspected ACC should be performed in high volume specialist centres where oncological outcomes are probably equivalent with either technique.32 Tumour size is an important factor with most regarding an upper limit for laparoscopic resection of 6-10 cm diameter, although others are comfortable up to 15 cm.33 Inva- sion of surrounding structures is a relative contraindication to laparoscopic adrenalectomy, particularly if access to large blood vessels may be required. Cardiac or respiratory disease may render the patient unable to tolerate pneumoperitoneum, mandating open or retroperitoneal surgery. Other relative contraindications include coagulopathy and previous surgery in the area, particu- larly nephrectomy or splenectomy.
Both transperitoneal and retroperitoneal adrenalectomy have been proven safe and effective, with no difference in clinical out- comes between the two techniques.34 In many situations, choice of approach will therefore be dictated by surgeon preference. In certain situations, however, one technique may be preferable. In patients with previous intraperitoneal surgery, a retroperitoneal approach may be safer and easier due to adhesions. For bilateral adrenalectomy, a retroperitoneal or open transperitoneal approach may avoid the difficulties and potential complications of reposi- tioning intra-operatively, which is necessary during a laparoscopic transperitoneal approach if performed in the standard lateral de- cubitus position. A posterior retroperitoneal approach requires the patient to be positioned prone, the associated physiological changes and potential complications of which may be poorly tolerated in these already critically ill patients with little reserve, in which case a transperitoneal approach may be preferred.
Choice of technique should be a balanced collaborative deci- sion. Whatever technique is used, surgery should be performed
by a team experienced in all of the surgical options with the ability to convert intra-operatively if required.
Determinants of success
The goals of treatment, either medical or surgical, in insidious onset CS include the reversal of clinical features, normalization of biochemical changes with minimal morbidity, and long term control without recurrence.16 These outcome measures are lar- gely irrelevant in acute hypercortisolism due to either ACC or ectopic ACTH syndrome, where biochemical cure is unlikely and treatment is essentially palliative. Improvement in hypercor- tisol-related symptoms and increased quality of life are more relevant measures of success for these patients who are hoping for, at best, short term gains.
Conclusion
Acute hypercortisolism is a rare but critical illness in which the surgeon has much to offer. Complete surgical resection of ACC or ACTH producing tumours is the only chance of cure in those with stage I or II disease. In the majority, where disease is unre- sectable, surgery can offer effective palliation of symptoms relat- ing to excess cortisol. In unresectable ACC, poor prognosis and very short life expectancy make medical palliation alone more appropriate, although a minority may still benefit from debul- king surgery. In ectopic ACTH syndrome, bilateral adrenalec- tomy, ideally performed laparoscopically, is a highly effective option for many and its use should not be unnecessarily or inappropriately delayed. Management decisions are complex and require effective collaboration between all members of an experi- enced multidisciplinary team in the absence of level I evidence. Patients presenting with acute hypercortisolism should be referred in a timely fashion to a facility where appropriate medical and surgical expertise exists.
Acknowledgement
No grants or fellowships were received to support the writing of the paper.
Competing interests/financial disclosure
No disclosure of potential conflict of interest required.
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