REVIEWS
Surgical management of adrenocortical tumours
Barbra S. Miller and Gerard M. Doherty
Abstract | The surgical treatment of adrenal tumours has evolved over the past century, as has our understanding of which hormones are secreted by the adrenal glands and what these hormones do. This article reviews the preoperative evaluation of patients with adrenal tumours that could be benign or malignant, including metastases. The biochemical evaluation of excess levels of hormones is discussed, as are imaging characteristics that differentiate benign tumours from malignant tumours. The options for surgical management are outlined, including the advantages and disadvantages of various open and laparoscopic approaches. The surgical management of adrenocortical carcinoma is specifically reviewed, including controversies in operative approaches as well as surgical management of invasive or recurrent disease.
Miller, B. S. & Doherty, G. M. Nat. Rev. Endocrinol. 10, 282-292 (2014); published online 18 March 2014; doi:10.1038/nrendo.2014.26
Introduction
Despite ancient allusions to adrenal-related conditions and the first anatomical reference to an adrenal gland in animals by Greek physician Claudius Galen in the second century AD, the first planned adrenalectomy was only performed in 1914, and is credited to Perry Sargent. Adrenalectomies had previously been performed as part of other procedures or for misdiagnosed tumours.1,2 In 1926, Perry’s report of an adrenalectomy was followed by Cesar Roux and Charles Mayo performing adrenalectomies to treat patients with phaeochromocytoma. The first adrenal- ectomy to cure a patient with Conn syndrome was carried out in 1954 by urologist William Baum.
The technique used for adrenalectomy has slowly evolved since these first procedures were performed. A T- shaped incision or an incision low in the abdomen was initially used; however, the position of the incision was progressively moved superiorly. Transthoracic, trans- pleural, and retroperitoneal approaches for adrenalectomy began to be mentioned over the past century, and many surgeons favoured the posterior-lumbar incision similar to that used to expose the kidney. In the early 1990s, Gagner and colleagues performed the first laparoscopic adrenalec- tomy.3,4 A number of other minimally invasive approaches have subsequently been described. Minimally invasive adrenalectomy has become the gold standard for resection of benign lesions, when the patient’s medical and surgical history, as well as their physique, is suitable. However, the role of minimally invasive adrenalectomy in resection of malignant adrenocortical carcinomas (ACC) is still con- troversial. Indeed, some experts have advocated partial adrenalectomy for selected benign lesions.
University of Michigan Health System, 1500 East Medical Center Drive, 2920F Taubman Center, Ann Arbor, MI 48109-5331, USA (B.S.M.). Department of Surgery, Boston University, 75 East Newton Street, Boston, MA 02118, USA (G.M.D.).
Correspondence to: B.S.M.
Competing interests The authors declare no competing interests.
This article examines these two topics in detail, in addition to other areas of controversy, including the role of surgery in patients with metastatic ACC. The surgi- cal management and choice of approach to the adrenal gland requires a clear understanding of the biochemi- cal function, the influence of any genetic mutation and the advantages and disadvantages of the different tech- nical approaches in the context of benign or malignant disease. This Review will focus on the surgical manage- ment of adrenocortical tumours and discuss some of the controversies surrounding such approaches for various tumours. Adrenal tumours of medullary origin (phaeo- chromocytomas) will not be discussed; however, any patient with an adrenal tumour should be confirmed as not having a phaeochromocytoma before undergoing any further diagnostic testing or interventions.
Preoperative considerations
The preoperative evaluation and preparation of patients for surgery is very important and includes thorough biochemical evaluation of the hypothalamic-pituitary- adrenal axis.5-7 Electrolyte abnormalities and hypertension in patients with Conn syndrome or Cushing syndrome should be corrected before surgery. Detailed imaging should be obtained; CT imaging is used most often, but MRI and PET-CT, (either FDG or 11C-metomidate) also have roles. Preoperative evaluation must also consider the cardiac, pulmonary and nutritional status of the patient.
Benign versus malignant tumours
Before any surgical resection is performed, the benign, malignant, or metastatic nature of an adrenal tumour must be assessed, as the type of operation required is consider- ably different for primary malignancies. Size and imaging characteristics (Figure 1) can give insight into the nature
Key points
· A thorough biochemical evaluation is required before a patient with an adrenal tumour can be considered for surgery
· Careful assessment of imaging characteristics is required to provide an optimum operative approach for patients with suspected adrenocortical carcinoma
· Transperitoneal and posterior retroperitoneal open or laparoscopic approaches have distinct advantages and disadvantages
· The treatment of patients with adrenal cancer should be managed by clinicians with experience in treating this rare disease
a
b
Left kidney
Right adrenal gland
Left adrenal gland (3.7×4.2cm)
Left adrenal gland (6.4×5×7.5cm)
of the tumour, but the sensitivity and specificity profiles of each technique are imperfect.8-18 Characteristics of benign adrenal tumours (Table 1) include small size, smooth bor- ders, lack of invasion of adjacent structures and no lym- phadenopathy or evidence of metastatic disease. However, these factors must be considered in the context of inter- nal imaging characteristics, including solid versus cystic; homogeneous versus heterogeneous; lipid-rich versus lipid-poor; unenhancing versus enhancing; brisk con- trast washout versus little contrast washout; no necrosis versus necrosis; and no calcifications versus presence of calcifications.
The risk of a primary ACC in a tumour <4 cm is ~2%, and 6% in patients with tumours 4-6 cm.7,19 This risk rises to over 25% in tumours >6 cm.7,19 Both CT and MRI can underestimate final pathologic adrenal size by up to 40%. Therefore, some clinicians suspect an increased risk of malignancy in tumours >3 cm.20 The size of tumours that are producing excess levels of aldosterone should be care- fully considered.21,22 In our experience at the University of Michigan, the median size of benign aldosteronomas is 1.5 cm (range of 0.4-3.1 cm). The median size of ACCs that only produce excess levels of aldosterone is 6.5 cm (range of 3.9-18.0 cm), which is considerably smaller than the median tumour size of other ACCs at 9.3 cm (range of 3.2-24.0 cm). For all malignant aldosteronomas exam- ined, internal imaging characteristics were indeterminate and could not confirm a benign aetiology.
The use of FDG-PET-CT can help to differenti- ate benign from malignant tumours in some cases, but specificity is suboptimal.23-28 The use of 11C-metomidate PET-CT in ACC has also been investigated.28 The adrenal glands can also be targeted by infectious organisms
(such as Mycobacterium tuberculosis and Histoplasmosis capsulatum); such infection might be suspected by clinical presentation and antibody titre levels.29-33
Metastases in the adrenal glands
An evaluation of any adrenal tumour must include inves- tigation of the possibility of metastatic disease. A thorough history and physical examination should evaluate the patient for previous malignancy or signs or symptoms of a current occult malignancy. If metastatic disease is sus- pected, a dedicated evaluation should be performed and imaging obtained, including a PET-CT. In general, needle biopsy of the adrenal gland has a limited role, especially for primary adrenal tumours. If metastatic disease is suspected, there are often other sites of metastasis that are more ame- nable to biopsy than the adrenal gland. Lymphoma, often bilateral, can involve the adrenal glands primarily or as metastases.34 Along with clinical symptoms and a sugges- tive appearance on CT, a biopsy should be performed in this situation to direct non-operative treatment.5-7
Functional versus non-functional
In addition to assessing imaging characteristics, adrenal tumours must be investigated for evidence of excess hor- mone production (Table 2), as up to 25% of patients with an adrenal mass have subclinical levels of excess hor- mones. Any adrenal mass should be investigated for evi- dence of primary hyperaldosteronism, hypercortisolism and excess production of catecholamine. In addition, levels of estradiol (only in postmenopausal women and men), dehydroepiandrosterone-sulphate, testosterone, 17-hydroxyprogesterone and androstenedione should be assessed, as tumours can produce multiple hormones that can be used as tumour markers for assessment of recurrence and disease course.5
Primary hyperaldosteronism
The diagnosis of primary hyperaldosteronism is made by observation of a raised aldosterone:renin ratio.35,36 This ratio, as well as the units measured, varies between insti- tutions, but a ratio >20-30 in the setting of raised levels of aldosterone is often used. Further confirmation could be pursued in several forms. After clear biochemical confirmation, dedicated imaging should be performed to detect and characterize any adrenal abnormality present. In one study, CT findings correlated with the site of excess aldosterone production in only about half of cases.37 An adrenal gland that appears normal can be the source of excess aldosterone secretion in the setting of a contralateral incidental non-functional adrenal nodule. Adrenal-vein sampling (AVS) should be performed in most patients to confirm whether the origin of the excess secretion is unilateral or bilateral, and to determine which adrenal gland the excess aldosterone originates from.38-44 Some groups have suggested selective use of AVS in patients <35 years old with a unilateral adrenal abnor- mality, but there is inadequate data from studies inves- tigating AVS to confirm the assumption for selective use at this time.45,46 An expert consensus statement published in 2013 stated that AVS might not be needed in patients
| Table 1 | Imaging characterization of adrenal masses to evaluate for ACC | ||
|---|---|---|
| Characteristic | Benign | Indeterminate or malignant |
| Size (cm) | <4 if benign internal characteristics | >4-625 |
| Unenhanced (CT hounsfield units) | <10 | >10 |
| Percentage washout (CT hounsfield units) | >50 or 60 | <50-60 |
| MRI chemical shift | Present | Absent |
| Internal attenuation | Homogeneous | Heterogeneous |
| Calcium | Absent | Present |
| Necrosis | Absent | Present |
| Borders | Regular, smooth | Irregular, indistinct |
| Invasion of adjacent structures | Absent | Possibly present |
| Intravenous tumour thrombus | Absent | Possibly present |
| Lymphadenopathy | Absent | Possibly present |
| Tumour SUV on PET CT28 | <3.4 | >3.4 |
| Tumour: liver SUV ratio on PET CT28 | <1.45 | >1.45 |
| Abbreviations: ACC, adrenocortical carcinoma; SUV, standardized uptake value. | ||
<40 years old who have biochemically confirmed Conn syndrome and a clear adenoma with a normal contra- lateral adrenal gland; however, bilateral hypersecretion might occur in young patients, which could not be ruled out without the use of AVS.47 Limitations of AVS that should be considered at each clinician’s institution as to the utility of this procedure include variation in proce- dural protocol, differing degrees of success in the cannula- tion of bilateral adrenal veins,48 use of adrenocorticotropic hormone (ACTH) stimulation and standardization of interpretation of the results.49-51 An alternative imaging modality, 11C-metomidate PET, can also be used to identify the source of excess aldosterone secretion.52
The optimal preoperative treatment of patients with Conn syndrome includes spironolactone or eplerenone. Potassium supplementation is given as needed and serial laboratory work is obtained, as are records of blood pres- sure and heart rate so that they can be optimized before surgery. These medications are withdrawn in the post- operative period and the patient is observed to determine if and how much antihypertensive medication is required after surgery.53
Hypercortisolaemia
Excess production of cortisol can be mediated by several mechanisms, including dysregulation of the hypothalamic-pituitary-adrenal axis in various forms, benign and malignant adrenal tumours and ectopic sources of ACTH.54,55 Cortisol is the most common hor- mone produced in excess in patients with ACC. Evalu- ation for hypercortisolism should include measurement of plasma levels of ACTH, 24h urine free cortisol and a 1 mg overnight dexamethasone suppression test (DST). Current DST guidelines suggest that a level of cor- tisol >138 nmol/l indicates abnormal cortisol regula- tion.5,6,56-58 However, the threshold to use is debated, with
other cut-off values for the 1 mg DST being considered (for example, <49.7 nmol/l and <83.0 nmol/l).54,59-63 Improvement in cortisol levels after adrenalectomy in patients with subclinical Cushing syndrome is difficult to assess,64 but several studies suggest benefit.65-69 Agree- ing upon a definition of true subclinical Cushing syn- drome is challenging, and existing studies of subclinical Cushing syndrome probably include some patients with overt Cushing syndrome.
Preoperative treatment of patients with hypercortiso- laemia can include various medications depending on the cause of hormone excess, but steroids, mitotane, metyrapone, ketoconazole and/or mifepristone are the drugs most likely to be used. As each of these medica- tions can have adverse effects, monitoring of other labora- tory values might be required. Electrolytes, intravascular volume status and blood pressure should be carefully managed and optimized as much as possible.65
Operative technique
Multiple operative approaches to the adrenal gland exist; however, prospective randomized trials are lacking to suggest benefit of one approach over the other, as the surgical approach chosen is individualized to the patient and their particular disease process. Most comparative studies are retrospective, which results in notable selec- tion bias. In general, laparoscopic approaches are acknow- ledged to have several advantages compared with open surgical approaches.
Laparoscopic
Since Gagner first performed a laparoscopic adrenalec- tomy in 1991,7 multiple minimally invasive approaches have been developed.4,70-72 The benefits of these approaches include less pain, decreased morbidity and a shorter hospital stay than open approaches.73 Laparo- scopic resection of very large tumours is more difficult than for small tumours, but can be accomplished.74-79 Patients are placed supine for an anterior approach, and the liver or spleen and pancreas are elevated anteriorly to access the adrenal gland. For lateral approaches, patients are placed in a lateral recumbent position, and ports are placed in a subcostal position. The liver or spleen and pancreas are fully mobilized, which enables improved visualization and access to the adrenal gland.
Posterior retroperitoneoscopic approach
The posterior retroperitoneoscopic approach in humans was originally described by Mercan in 1995;80 however, a group from Essen, Germany, led by Martin Walz, is recognized as having refined and popularized this tech- nique.81-85 A posterior retroperitoneal approach, whether open or minimally invasive, requires the surgeon to invert the mental picture of where to expect usual structures. Patients are placed prone with the hips and knees bent at 90° angles to open the space between the twelfth rib and the pelvis. Ports are placed, and the retroperitoneum is often insufflated to >20 mmHg. No mobilization of other organs need occur as direct access to the gland is possi- ble once the Gerota’s fascia has been separated from the
| Table 2 | Initial laboratory evaluation of an incidentally discovered adrenal mass | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Syndrome of hormone excess | Laboratory test | ||||||||
| BMP | Aldosterone | Renin | ACTH | Cortisol | DST | 24h UFC | DHEA-S | Testosterone | |
| Cortisol | × | – | – | × | × | × | × | – | – |
| Aldosterone | × | × | – | – | – | – | – | – | – |
| Testosterone | × | – | – | – | – | – | – | × | × |
| Adrenal nodule and/or mass | × | × | × | × | × | × | × | × | × |
Additional laboratory studies are often indicated dependent on the clinical scenario. Some tumours, both benign and malignant, might secrete multiple hormones or precursors, and additional tests might be required. Additional confirmatory testing might also be needed. All patients with an adrenal mass should be ruled out for pheochromocytoma in addition to the above tests. Abbreviations: x, present; - , absent; ACTH, adrenocorticotropic hormone; BMP, basic metabolic panel; DHEA-S, dehydroepiandrosterone-sulphate; DST, 1 mg overnight dexamethasone suppression test; UFC, urine free cortisol.
posterior musculature. Bleeding is minimized as a result of the increased insufflation pressure. Some clinicians suggest pain is decreased and return of gastrointestinal function is faster with this approach than for the laparo- scopic approach. The posterior retroperitoneoscopic approach is particularly useful for bilateral adrenalec- tomy, as patients do not have to be repositioned during the operation. The posterior approach obviates the need for extensive lysis of intra-abdominal adhesions in patients who have previously undergone upper abdominal surgery. The disadvantages of this approach include anaesthetic considerations associated with prone positioning, but do not generally include cardiovascular compromise.86 Adrenal glands situated anteriorly on the kidney and near the renal hilum can be problematic.87 Table 3 and Figures 2 and 3 demonstrate situations that are amenable to the transperitoneal and retroperitoneal approaches.
Robotic
Robot-assisted minimally invasive procedures can be per- formed for any of the above approaches. The advantages of using a robot include increased dexterity for some of the instruments used. Whether this approach has advantages other than for improved access to adrenal glands situ- ated at an anterior position or those near the renal hilum is unclear.88-94
Open
Open adrenalectomy is the preferred approach for very large adrenal tumours and known or suspected ACCs. The classic anterior approach enables full access to all organs of the peritoneal cavity and chest if necessary. The patient is positioned supine on the table. Incisions can be made in the midline or subcostal depending on preoperative factors and the need for multivisceral resection.
Posterior
Although now virtually replaced by the posterior retro- peritoneal approach, the open posterior approach was favoured by many surgeons in the past. Despite providing direct access to the gland, adequate visualization can be difficult with the open posterior approach, and no access to intraperitoneal organs is realistically available. Other disadvantages include possible injury and chronic pain as a result of damage of the neurovascular bundle of the eleventh or twelfth rib or diaphragmatic injury.
Thoracoabdominal
Although not often required, the thoracoabdominal approach can be useful in patients with large adrenal tumours or those involving the retrohepatic vena cava where visualization will be difficult as a result of the body type or previous abdominal surgery. The patient is placed in a semi-lateral decubitus position on a beanbag with an axillary roll.95 The ipsilateral arm is held in place paral- lel over the contralateral arm. The pelvis remains flat. An incision is made 2 cm inferior to the ipsilateral scapula and carried from lateral to medial along the eighth intercostal space and then inferiorly along the upper midline of the abdomen to the umbilicus. The diaphragm is incised to enable access to the chest and abdomen with excellent visualization of the retroperitoneal structures. Recovery can be delayed as a result of pulmonary issues or recov- ery of gastrointestinal function, and chronic pain from injury of the neurovascular bundle of the rib can occur.
Partial adrenalectomy
Removal of a portion of the adrenal gland (Figures 4 and 5) to enable the preservation of at least 30% of the structure for residual function6 has been described most often in the setting of patients with bilateral phaeo- chromocytoma and multiple endocrine neoplasia type 2 or von Hipple-Lindau syndromes.97,98 The goal is to prevent Addisonian crisis, which has been reported in up to 15% of patients undergoing bilateral total adrenalec- tomy. A review of six studies including 203 patients who underwent bilateral adrenalectomy reported an incidence of Addisonian crisis of 9%.99 Partial adrenalectomy for bilateral hereditary phaeochromocytoma is based on the assumptions that malignancy is infrequent, recurrence rates are acceptable and that only 10-35% of patients require steroid supplementation.100 Long-term follow-up is essential, as most recurrences are reported 10 years or more after the initial resection.101,102
Partial adrenalectomy has been used in patients with aldosterone or cortisol-secreting adenomas. Intra- operative ultrasonography is useful to ensure complete resection of the adenoma. Biochemical cure is almost certain in patients with single adenomas, whereas in the case of erroneous excision of a nodule in the setting of bilateral hyperplasia, a complete unilateral total adrenal- ectomy would not cure the patient.97,103-106 Experience with partial adrenalectomy for Cushing-related adenomas
| Table 3 | Characteristics amenable to LTPA and PRA | ||
|---|---|---|
| Characteristic | LTPA | PRA |
| Size of benign tumour (cm) | <10 | <7-8 |
| BMI (kg/m2) | Any BMI | <45 |
| Anterior or posterior to kidney | Any position | Adrenal gland posterior to kidney |
| Adrenal:kidney position | Any position | Adrenal gland away from renal hilum |
| Twelfth rib:kidney position | Rib lies over lower third of kidney | Rib lies over upper two-thirds of kidney |
| Subcutaneous adipose depth (cm) | >5-6 | <5-6 |
| Perinephric adipose | Thick | Thin |
| Previous upper abdominal surgery | No | Yes |
| Stage 3 or 4 renal insufficiency | Yes | No |
Abbreviations: LTPA, laparoscopic transperitoneal adrenalectomy; PRA, laparoscopic posterior retroperitoneal adrenalectomy.
a
Left adrenal
b
Renal hilum
Left adrenal gland
a
b
Left adrenal gland
Left adrenal gland
Left kidney
44.8 mm from skin to retroperitoneum at tip of twelfth rib
is limited. However, the popularity of this procedure is growing, and it can be performed as long as any possi- bility of malignancy is ruled out on the basis of size and imaging characteristics. A cure rate of 99.4% has been reported in a series of 170 patients with Cushing-related adenomas who underwent a partial adrenalectomy.107
Operative management of ACC
The first operation is the best and usually only chance for long-term local control of malignancy with the goal of a complete (R0) resection in the absence of penetration of
the tumour capsule.108-110 One study examined the effect of hospital volume (that is, the number of operations performed per year) on patient outcome, and concluded that patients undergoing surgery at high-volume centres experienced a better oncological outcome than those at low-volume centres.111 Complete removal of the tumour can require multivisceral resection. The decision to take this operative approach should occur preoperatively, rather than after handling the tumour during surgery.
For any lesion suspected to be ACC, additional pre- operative imaging beyond that used to characterize the adrenal mass should be obtained to evaluate for distant metastatic disease and to assign a preliminary stage to the tumour (Table 4), as the operative approach might be changed or surgery delayed or cancelled depending on the findings. At a minimum, a chest CT should be obtained. Although FDG or 11C-metomidate PET can be helpful to examine the rest of the body and characterize lesions, small or necrotic metastases could be missed. Despite their rarity, we have observed an increase in brain metastases in patients with ACC, and a CT scan of the head could also be included. If direct tumour invasion of the aorta, vena cava or renal veins (with or without intravenous tumour thrombus) is suspected, MRI with venography or MRI with angiography can be helpful. The use of MRI also provides critical information about liver metastases and their relationship to the intrahepatic vessels if liver resec- tion is considered. Additional evaluation of the vessels can be made by direct arteriogram or venography or intra- vascular ultrasonography; however, these procedures are rarely necessary.
Laparoscopic versus open resection
Controversy surrounds the issue of whether laparoscopic adrenalectomy is appropriate for patients with ACC. This type of cancer can invade through the tumour capsule and microscopic evidence of the tumour is frequently present at the surface of the adrenal gland. Application of pressure (however light) to the tumour should be avoided if pos- sible. Tumours should not be divided into smaller pieces before extraction to enable a full pathological review after the surgery. Some surgeons compromise by initiation of adrenalectomies laparoscopically to assess for evidence of intraperitoneal metastasis or invasion of the adrenal gland into other organs and then conversion to an open approach if necessary; however, this direct exploration of the tumour violates oncological principles of resection. A recurring argument is that in ‘expert’ hands, laparo- scopic adrenalectomy might be appropriate for certain malignant adrenal tumours; however, no consensus defi- nition exists of what constitutes adequate expertise.112 In addition, adequate expertise does not necessarily trans- late to expertise for biologically aggressive, often invasive, large adrenal cancers. Indeed, most ACCs are removed by less experienced adrenal surgeons.113
Published data that compares the efficacy of laparo- scopic adrenalectomy and open adrenalectomy for ACC are both limited and hampered by referral bias. Initial recommendations published after the first International Adrenal Cancer Symposium in 2003 stated that there
was no role for laparoscopic removal of a known or probable ACC, but controversy existed about the role of laparoscopic removal of indeterminate lesions.114 Recom- mendations by the American Association of Clini- cal Endocrinologists and the American Association of Endocrine Surgeons published in 2009 advocate for open adrenalectomy by an experienced surgeon as the pro- cedure of choice if ACC is suspected.5 Conversely, the European Society of Endocrine Surgeons and the Euro- pean Society for Medical Oncology suggest laparoscopic adrenalectomy can be performed for European Network for the Study of Adrenal Tumours (ENS@T) stage 1 or 2 tumours <8-10 cm if an RO resection is performed and the surrounding periadrenal tissue is removed.115,116 Neither guideline addresses the differentiation of stage 1-2 ACCs from microscopic or unappreciated stage 3 ACC preoperatively, which occurs in 25% of patients.
At least seven studies have been published since 2010 that specifically address the topic of laparoscopic adrenal- ectomy versus open adrenalectomy for ACC. Studies published by researchers from the MD Anderson Cancer Center, Houston, TX, USA, report higher local recurrence and peritoneal carcinomatosis in patients who underwent laparoscopic adrenalectomy than in those who under- went open adrenalectomy.117,118 Similarly, in a study by the French group of Leboulleux and co-workers, perito- neal carcinomatosis occurred in 60% of patients under- going laparoscopic adrenalectomy compared with 25% of patients undergoing open adrenalectomy.119
By contrast, two similarly designed studies from Italy using some of the same patients reported comparable recurrence-free survival for laparoscopic adrenalectomy and open adrenalectomy in patients with stage 1 and 2 disease.120,121 However, patients who had R2 resections, tumour capsule violation, conversion from laparoscopic to open surgery, and those found to have stage 3 tumours on final pathology were excluded from the study. This exclusion limits the analysis to patients with true stage 1 or stage 2 disease that cannot be determined definitively before surgery.
A case-control study by the German ACC Registry Group reported no difference in overall or disease- free survival, tumour capsule violation or peritoneal carcinomatosis among 117 patients undergoing open adrenalectomy and 35 patients undergoing laparoscopic adrenalectomy for stage 1-3 ACCs <10 cm.122 However, three times as many patients in the open adrenalectomy group had stage 3 disease. In addition, no data regard- ing margin status was available for 37% of the patients, calling into question the researchers’ ability to evaluate the completeness of the resection.
Surgical studies should differentiate between local or peritoneal recurrence and distant recurrence as an indication of quality of resection, as the type of opera- tive approach probably has less influence on the develop- ment of distant metastases than does the presence of local or peritoneal recurrence. In our experience, peritoneal recurrence as the first site of recurrence is associated with the shortest survival of all sites of recurrence. A retro- spective study from our centre reviewed 88 patients with
Right adrenal gland
Left adrenal gland
Adrenal nodule
ACC, 17 of whom underwent laparoscopic adrenal- ectomy. Although overall recurrence rates at any site were similar, and despite smaller tumours in the laparo- scopic adrenalectomy group (median 7.0 cm) than in the open adrenalectomy group (median 12.3 cm), the laparo- scopic adrenalectomy group had an appreciably shorter disease-free interval than the open adrenalectomy group (median 9.2 months versus 19.2 months). The laparo- scopic adrenalectomy group contained more R1 or R2 resections or notation of intraoperative tumour spill than the open adrenalectomy group (50% versus 18%).123 These results were confirmed in an extended follow-up study of 110 patients undergoing open adrenalectomy and 46 patients undergoing laparoscopic adrenalectomy. After laparoscopic adrenalectomy, 30% had positive margins or intraoperative tumour spill compared with 16% of patients who underwent open adrenalectomy, despite larger tumours and more stage 3 tumours in the open adrenalectomy group. Time to visible tumour-bed recurrence or peritoneal recurrence in patients with stage 2 ACC was shorter in those who underwent laparo- scopic adrenalectomy than in those who underwent open adrenalectomy. Overall survival for patients with stage 2 ACC was markedly longer in those undergoing open adrenalectomy than in those undergoing laparo- scopic adrenalectomy, including a subgroup that com- pared only patients with R0 resections.124 Thus, the existing literature is inconclusive regarding laparoscopic adrenalectomy versus open adrenalectomy for ACC. Until such time as conclusive data are available, an open approach is recommended for all adrenocortical tumours that cannot be classified as benign before surgery.
Poor initial surgical treatment, either laparoscopic or open, can rarely be corrected, whether by reoperation, radiotherapy or chemotherapy. Extirpation of the pri- mary tumour in the setting of synchronous metastatic disease at the time of presentation is associated with poor outcome, and survival is generally not improved with surgery. In highly selected cases, surgery with the intent of an R0 resection of the primary tumour and any
a
Harmonic scalpel
b
Harmonic scalpel
Inferior phrenic vein
Adrenal tumour
Right adrenal vein Aortic branch
Aortic arterial branch Left adrenal vein
Inferior phrenic artery
Adrenal tumour
Renal arterial branch
Inferior vena cava
Renal arterial branch
Right renal vein
Left renal vein
| Table 4 | ENS@T staging system for ACC | |||
|---|---|---|---|
| Stage | Tumour (T) | Node (N) | Distant metastasis (M) |
| I | T1 | N0 | M0 |
| II | T2 | N0 | M0 |
| III | T1-2 T3-4 | N1 NO-1 | M0 M0 |
| IV | T1-4 | NO-1 | M1 |
T1, tumour size ≤5cm; T2, tumour size >5cm; T3, infiltration of tumour into surrounding tissue; T4, invasion of tumour into adjacent organs or tumour thrombus within the renal vein or vena cava. N0, negative lymph nodes; N1, positive lymph node(s). M0, no distant metastasis; M1, distant metastasis. Abbreviations: ACC, adrenocortical carcinoma; ENS@T, European Network for the Study of Adrenal Tumors.
metastatic disease (often few in number and contained within a single organ system) can be pursued. In patients with known metastatic disease and tumour thrombus in the vena cava, we often pursue resection of the primary tumour and thrombus even if all sites of metastatic disease cannot be removed, as the tumour thrombus can occlude the vena cava, leading to severe swelling of the lower extremities and a very poor quality of life prior to death. Some of these patients can survive for >3 years. Resection of the primary tumour without complete resection of metastatic disease is sometimes performed in an attempt to improve the symptoms of hormone excess, most often cortisol and aldosterone, which can become extremely dif- ficult to manage. Although removal of 90% of the tumour has been described for other neuroendocrine malignan- cies, these tumours often grow slowly and patients display lengthy survival times. Whether quality of life with regard to recovery from extensive surgery and any complica- tions from surgery and control of hormone levels is truly improved for a long enough time to justify the patients undergoing the procedure is unclear. Hormone levels often return to high levels soon after surgery and patients
can rarely be completely free from medical management of hormone excess unless an R0 resection is performed.
Lymphadenectomy
The role of lymph-node dissection in the treatment of ACC remains unknown; no consensus exists in the field. Nevertheless, knowledge of the nodal status often leads to changes in treatment strategies. In one retrospective study, locoregional lymphadenectomy was reported to improve outcome, although some of this improvement can probably be attributed to upstaging and subsequent increased aggressiveness of the treatment.125 Limitations of this study included unclear reporting of the exact nodal basins that were cleared. Although outcome improved as more nodes were removed, this increase in retrieved nodes was probably attributable to nodes retrieved as part of more aggressive multivisceral resections.126 These findings reinforce the need for wide and aggressive resec- tions while leaving the role of prophylactic nodal dis- section unknown.126 Brennan and colleagues have called for improved standardization of operative management of ACCs.127
Management of invasive tumours
Extirpation of large ACCs can be extremely challenging for even the most experienced surgeon. A partial hepa- tectomy might be required in some patients to achieve an R0 en-bloc resection. If needed, the liver can be com- pletely mobilized from the inferior vena cava, affording superb visualization and access to the inferior vena cava.
Tumour thrombus is not a contraindication to resec- tion. A classification scheme for intracaval tumour thrombus from ACC is shown in Figure 6.128 In most cases, venotomy and simple closure suffices for removal of the tumour; however, in certain cases, resection of a portion of the vena cava might be required if access to the
REVIEWS
Right level I
Left level Ia
Left level Ib
Level II
Level IIIa
Level IIIb
Level IV
intrahepatic inferior vena cava is limited. A ringed poly- tetrafluoroethylene graft can then be used to reconstruct the vena cava. Vascular control of the vena cava can also be achieved in the chest using a median sternotomy or by a thoracoabdominal approach. In rare circumstances veno-venous bypass or cardiopulmonary bypass might be useful.
The need for resection of portions of arteries or their branches is a general, but not absolute, contraindication to surgery for ACC. The celiac axis and takeoff of the superior mesenteric artery are often partially encased with the tumour and each patient should be considered individually.
En-bloc resection of a tumour with an accompanying portion of the diaphragm might be required to achieve negative margins. Smaller diaphragmatic defects might be closed primarily, whereas prosthetic materials are used for closure of larger defects.
Reoperations
Patients with recurrent ACC should be managed using a multidisciplinary approach, which will vary accord- ing to the extent of disease and life expectancy. Various techniques can be used to manage metastatic sites of
disease. These approaches include conventional surgery, external-beam radiation, chemotherapy, radiofrequency ablation and embolization (coil embolization and chemo- embolization). The extent and speed of disease progres- sion guide the decision for reoperation in the setting of recurrence. The number of organs involved at the time of the first metastasis and length of disease-free recurrence are predictors of survival.129-134
Decisions about resection must be individualized and probably have no effect on eventual death as a result of the disease, but survival might be extended in some patients. In our experience, patients with local recurrence who have undergone laparoscopic adrenalectomy are more likely to have a tumour that is too small to be detected by imaging elsewhere in the peritoneal cavity compared with those having undergone open adrenalectomy. Therefore, the type of initial operative resection is important to the decision- making process for reoperation. Some groups have noted that tumour grade influences outcome.129,133 This finding might influence the decision for reoperation as patients with low-grade tumours generally have a slower speed of disease progression than those with high-grade tumours and reoperation might be more beneficial in patients with low-grade tumours. We often monitor patients for several months during systemic therapy in the setting of ques- tionably resectable tumours or recurrences to assess for tumour responsiveness and speed of disease progression. If progression is not rapid, resection might proceed with greater benefit, whereas patients with marked progression of disease do not undergo reoperation.
Postoperative considerations
Complications are generally infrequent in expert hands; however, they can occur regardless of which operative approach is used and can lead to mortality or serious long lasting morbidity.113,135,136 The potential for serious mor- bidity and mortality should be carefully considered when evaluating patients with ACC for reoperation with regard to expected long-term quality of life after an often com- plex surgery versus expected length of survival. Among the complications associated with adrenalectomy in general are wound infection, intra-abdominal abscess, bleeding, damage to surrounding structures, incisional hernia, cardiovascular and thromboembolic compli- cations, anaesthetic reactions and tumour recurrence. Specific to complex adrenal resections, complications can include (but are not limited to) pneumothorax, pan- creatitis or pancreatic leak, renal insufficiency or failure, and chyle leak. Hernias are most likely to occur in the setting of hypercortisolism. In addition, flank incisions can lead to abdominal wall laxity as a result of muscle denervation. Pancreatic leak can occur after pancreatic resection, and injury to the spleen might necessitate splenectomy. Hepatic resection might lead to biliary leak, hepatic insufficiency, or frank liver failure depending on the extent of resection. Empyema, biliary-pleural fistula, or tumour seeding might complicate resections that involve entry into the thoracic cavity.
Glucocorticoid insufficiency should be anticipated in patients with hypercortisolism that was identified
before the surgery. Adequate supplementation should be initiated in the perioperative period and continued after resection. Recovery time for patients with a normal contralateral adrenal function and normal hypothalamic- pituitary-adrenal axis function undergoing complete tumour resection varies widely.137,138 Additional con- siderations in patients having undergone surgery for hypercortisolism include the need for physical therapy, the need for assistance with cognitive or psychiatric disorders and an evaluation of their cardiovascular risk.139
Conclusions
Surgical treatment of adrenocortical tumours has evolved substantially over the past few decades. This improve- ment is coupled with an increased understanding of the biochemical nature of the different tumours. Multiple
surgical approaches to the adrenal gland exist, and clini- cians must understand the indications, advantages and disadvantages of each. In addition, patients with adrenal cancer should be managed by a multidisciplinary team.
Review criteria
A MEDLINE search of English-language papers was conducted using keywords that included “adrenal”, “adrenalectomy”, “adrenocortical cancer”, “Cushing syndrome”, “Cushing disease” and “aldosterone”. The terms of this literature search were identified in the title, abstract or medical subject heading. References within identified reports were also examined to identify additional articles of interest. Criteria for exclusion were articles published before 1980, and a concerted effort was made to cite the most recent literature.
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Author contributions
B.S.M. researched data for the article, contributed to discussion of the content and wrote the article. G.M.D. reviewed/edited the manuscript before submission.