Since the 1960s, routine ipsilateral adrenalectomy (IA) has been considered an integral step in the removal of renal tumors as a part of a radical nephrectomy. However, recent data from the past decade have narrowed the indications for adrenalectomy and called into question the need for adrenalectomy at all in the treatment of renal cell carcinoma (RCC).
We sought to identify the role of adrenalectomy in the treatment of RCC. Specifically, we wanted to answer the following questions: What is the incidence of ipsilateral adrenal involvement by cancer? How reliable is preoperative imaging? What is the rate of ipsilateral and contralateral metachronous recurrence? And finally, what are the potential noncancer sequelae from unnecessary removal of the adrenal gland?
A systematic literature search of Embase, PubMed, Cochrane, and Ovid Medline was performed to identify studies evaluating the role of adrenalectomy during RCC surgery. Only articles published in English from the years 2000–2015 were included. Case reports, articles about primary adrenal tumors, letters to the editor, and surgical technique papers were excluded.
We found little evidence to suggest that routine IA is associated with a higher risk of short-term surgical or medical complications. We did not find evidence that IA is associated with improved cancer control. Tomographic preoperative imaging of the adrenal gland demonstrating no cancer involvement is rarely wrong (<1% of the time), and the few adrenal lesions missed on imaging can often be identified intraoperatively. Some evidence indicates that IA may be associated with worse long-term survival. Adrenalectomy rates have been decreasing in recent years, reflecting a changing practice pattern.
IA at the time of kidney surgery for a renal mass should be performed only if radiographic or intraoperative evidence indicates adrenal gland involvement.
We sought to define the role of adrenalectomy in patients with kidney cancer. Although there are not high-quality studies to answer this question definitively, we conclude that the adrenal gland should be spared unless there is clinical evidence of adrenal involvement.
Keywords: Adrenalectomy, Kidney cancer, Renal cell cancer, Radical nephrectomy.
It has been nearly a half century since the radical nephrectomy (RN) was standardized by the work of Robson and colleagues . This classic urologic work represented an important milestone in the attempt to create uniformity in the surgical management of renal cell carcinoma (RCC). The approach of Robson et al, which followed the prevailing belief that more radical surgery would translate into improved oncologic outcomes, was also necessitated in part by the difficulty in accurately defining the size and spread of the primary tumor. This difficulty justified the wide excision of normal tissue along with the tumor, including the ipsilateral adrenal gland, and has been a part of a worldwide practice and clinical guidelines . However, with the development of high-resolution imaging, more accurate preoperative clinical staging of renal tumors has become possible, and the need for all of the components of the RN for all renal masses has come under scrutiny including ipsilateral adrenalectomy (IA).
When Robson et al first described the RN , preoperative imaging quality was poor compared with standards today, and the typical presenting tumor was large, symptomatic, and often locally invasive. Therefore it followed that wide local excision of a kidney tumor and its surrounding tissue would likely offer a superior oncologic outcome compared with a simple nephrectomy. But surprisingly, even in these early cohorts, the survival outcomes were not statistically superior to simple nephrectomy alone . Nevertheless, within a decade another publication on a small cohort of patients with renal tumors (n = 58) found the incidence of ipsilateral adrenal involvement to be 10%, which seemed to justify its removal because of the relatively frequent involvement of the adrenal gland, the ease of IA, and the low perceived morbidity .
With the increased use of magnetic resonance imaging (MRI) and computed tomography (CT) abdominal imaging, there has been a clear migration among newly diagnosed kidney cancer patients toward lower stages  and . With this stage migration to smaller, lower risk tumors, the reported incidence of ipsilateral adrenal involvement is now closer to 1–4% , , , , , , and . In response to the dropping incidence of ipsilateral adrenal metastasis, some authors have suggested that routine IA may be indicated only in specific circumstances where the risk of adrenal involvement is higher, such as large or upper pole tumors or an abnormal adrenal gland on CT scan , , and . However, with improved cross-sectional imaging quality, other authors advocate never performing an IA in the absence of radiographic or intraoperative evidence of adrenal gland involvement , , , , and . In this review, we sought to identify when IA is supported by evidence in patients with RCC.
2. Evidence acquisition
To identify studies evaluating the role of adrenalectomy during RCC surgery, a systematic literature search of the Embase, PubMed, Cochrane, and Ovid Medline databases was performed. Search terms included adrenalectomy, renal cell cancer, renal cancer, kidney cancer, nephrectomy, and partial nephrectomy. References identified from other reviews were also examined for inclusion. Only articles published in English from 2000–2015 were searched to capture more recent data and trends. This search identified 1055 articles, and after removing duplicates (n = 260), 795 articles remained. Case reports (n = 212), articles about primary adrenal tumors (n = 98), letters to the editor/replies (n = 40), and papers comparing surgical techniques (n = 37) were excluded, leaving 408 papers that we reviewed by title and/or abstract to determine if the content would be appropriate for inclusion in the review. We also reviewed papers prior to 2000 that were repeatedly referred to in later publications.
2.1. Outcomes evaluated
The outcomes of interest were complications (perioperative and risk of long-term adrenal insufficiency), cancer control (incidence of ipsilateral adrenal involvement/improved staging, incidence of metachronous adrenal involvement, and cancer-specific survival [CSS]), overall survival (OS), and trends in the use of IA.
3. Evidence synthesis
The rationale for routine IA has the following theoretical advantages: improved cancer control, more accurate staging, avoidance of a subsequent operation if a asynchronous metastasis develops, and perceived low morbidity when coupled with a nephrectomy. Included articles were evaluated for their contribution of evidence on these topics. We did not identify any high-quality randomized controlled trials. One small randomized trial of 40 patients was clearly underpowered to detect any cancer or survival difference and may have been underpowered to detect any hormonal differences as well . Several systematic reviews , , and  were identified as well as clinical guidelines . Because of the general lack of high-quality level 1 evidence, these systematic reviews  and  only included a few articles for review  and . Most of the original research studies we identified were single-institution cohort studies comparing outcomes in patients who underwent IA during renal surgery with either RN or partial nephrectomy (PN) alone. A smaller minority of studies were either multi-institutional or population-based studies.
3.1.1. Perioperative complications
We did not identify any large studies that specifically addressed the risk of increased complications of IA when performed in conjunction with either PN or RN. In a small 40-patient randomized study, no significant differences were found in operative time, estimated blood loss, hospital stay, and postoperative complications . However, this study was small and the complication rate low enough for this type of surgery that the study was clearly underpowered to answer this question. There is a prime opportunity for investigation into this question; however, the study would have to be large to detect a very small potential difference in perioperative outcomes.
3.1.2. Risk of adrenal insufficiency
In their small randomized study of 20 patients having an adrenalectomy versus 20 with adrenal-sparing surgery, Hellstrom and colleagues noted no significant differences in postoperative adrenal hormones except for a slight transient higher cortisol level for those who did not have the adrenal gland removed . Unfortunately, the numbers were small and the follow-up was short, so it remains uncertain whether this lack of difference is because there truly is no difference or whether the study was merely underpowered. Other retrospective studies also failed to find a difference in the risk of adrenal insufficiency .
We were unable to identify any long-term studies measuring the risk of adrenal insufficiency in adult patients treated for RCC. We did find one study of patients treated as children for Wilms tumor or neuroblastoma with a subset of them having either an adrenalectomy or partial adrenalectomy . With a median follow-up of 27 yr of the survivors of these tumors, the researchers found no higher rates of adrenal insufficiency compared with controls. However, these data are not likely applicable to adult RCC patients because it is possible in younger children that the contralateral adrenal gland may be able to compensate as we see with kidney removal in young children. Because this study looked only at the small subset of survivors, that cohort may have done exceptionally well and may not be representative of all patients who had their adrenal gland removed as children.
We did find several reports indicating a 2–10% risk of a contralateral adrenal metastasis depending on the risk factors , , , and . If the ipsilateral adrenal gland had been removed at the initial treatment, there would be a sizable group of patients facing adrenal insufficiency versus leaving in untreated cancer versus attempting a partial adrenalectomy.
Finally, there are several reports of postoperative adrenal insufficiency after a unilateral adrenalectomy as part of kidney surgery , , , , , and . Although this risk appears to be relatively low, we seem to be unable to predict who is at risk for adrenal insufficiency after a unilateral adrenalectomy . Overall, there are not high-quality studies to answer this question, we suspect the risk of adrenal insufficiency is low after a unilateral adrenalectomy.
3.2. Cancer control
3.2.1. Incidence of ipsilateral adrenal involvement/Improved cancer staging
The incidence of cancer in the ipsilateral adrenal gland during surgery for renal cancer is clearly low and becoming even more uncommon. From early estimates of approximately 10% , most studies now are well below 5% and many <1% , , , , , , and . Pooled estimates from a recent meta-analysis of 21 studies including 11 000 patients found an incidence rate of 4.5% . In the case of small renal masses (<7 cm), which represent an increasingly larger proportion of all newly diagnosed RCCs, the incidence of ipsilateral adrenal involvement with RCC is even lower with only 0.1% in a series of 2065 , 0.5% in a series of 2513 , and 0.7% in a series of 3743 patients in Canada . Even in the subset of patients who clearly have a higher risk of adrenal involvement  and  such as higher grade, higher stage, renal vein invasion, and/or larger or upper pole tumors, the incidence is still <10% . In addition to these 8000 patients from the three studies mentioned earlier, a review by O’Malley et al confirmed the low incidence rates of ipsilateral adrenal involvement from 16 additional recent publications from around the world in >7000 patients .
Some have wondered if there any evidence that IA should be performed to improve cancer staging for patients whose imaging does not demonstrate adrenal involvement. We found very little evidence that cancer staging can be improved by the use of routine IA. One older study reported that on final surgical pathology, of the 30 patients with bilateral adrenal gland involvement with RCC, 7 had normal CT scans preoperatively, suggesting that CT may miss a substantial number of adrenal metastases . However, this study had >1000 patients, and although the authors do not comment on the preoperative imaging of the rest of the cohort, if only 50% had imaging, the negative predictive value (NPV) of a normal adrenal gland on CT would still be about 99% for no adrenal involvement with cancer. Pooled estimates from a 2012 meta-analysis of many of the studies listed in Table 1 found a NPV of a preoperative CT to be 98.5% . From multiple other studies from around the world, the NPV of preoperative CT imaging is approaching 100% (Table 1). In other words, if preoperative contrast-enhanced CT or MRI imaging does not demonstrate an adrenal abnormality, these data would suggest there is <1 chance in 100 that the adrenal gland will be involved with cancer. This has been a very consistent finding in multiple institutions worldwide, suggesting that many radiologists and urologists have the skills to identify normal glands on imaging and that these patients can safely forgo adrenalectomy. With such a high NPV, we conclude that the adrenal gland can be spared if the preoperative imaging is normal even in patients with tumors that are large, located in the upper pole , or demonstrate renal vascular invasion. We note that several authors comment that in the rare instance that preoperative imaging was negative and cancer was indeed found involving the adrenal gland, there was evidence of that involvement intraoperatively  and  adding to the reassurance that a surgeon is extremely unlikely to leave cancer behind if both imaging and intraoperative findings are normal.
|Study||No. of patients||Negative predictive value, %||Positive predictive value, %|
|Lane et al ||2065||NR||12.5|
|Weight et al ||1541||99*||NR|
|Siemer et al ||1110||99*||NR|
|Antonelli et al ||914||96||73|
|Kuczyk et al ||819||99.7||NR|
|Tsui et al ||511||99.4||50|
|Moudouni et al ||210||98||80|
|Autorino et al ||192||99.4||35|
|Kutikov et al ||179||100||33.3|
|Kobayashi et al  and ||165||99.4||NR|
|Gabr et al ||159||NR||13.6|
|Leibovitch et al ||158||100||40|
|Gill et al ||157||100||26|
|Blakely et al ||117||100||62.5|
|Kletscher et al ||100||100||50|
* Calculated negative predictive value based on reported false-negative computed tomography scans, but denominator of patients who had negative imaging and negative adrenal pathology is assumed.
NR = not reported.
Although we believe an abnormal adrenal gland should be removed when treating a patient with RCC, it may not be cancer, particularly in smaller renal masses. Adrenal incidentalomas are a common problem, and they may occur with a renal mass. Many studies find that the positive predictive value of an abnormal adrenal gland on CT is only ≥50% (12–15%) for patients with kidney tumors <7 cm (Table 1). In other words, of patients with small renal masses and concerning adrenal findings (such as a mass or thickening) on the preoperative CT scan, nearly 85% have a benign adenoma on surgical removal. Therefore even some of these patients with preoperative adrenal masses or thickening in a solitary gland could potentially be biopsied and have their adrenal gland spared if benign pathology is identified, particularly if the tumor characteristics suggest a low risk of adrenal involvement .
3.2.2. Incidence of metachronous adrenal recurrence and treatment outcomes
Some have argued that even if IA does not find a high incidence of ipsilateral adrenal involvement, another potential reason for IA is that it may remove microscopic metastasis and prevent the need for a second surgery. We looked for evidence of subsequent ipsilateral adrenal metastasis in patients who underwent adrenal-sparing surgery to estimate the number of patients who would have avoided another operation. We tried to compare the outcomes in patients who had ipsilateral involvement at the time of the original surgery versus those who had metachronous ipsilateral adrenal involvement in follow-up only. We also looked for studies that reported the risk of contralateral metachronous adrenal involvement.
3.2.3. Subsequent ipsilateral adrenal gland involvement
We found the rate of subsequent ipsilateral metachronous adrenal gland involvement to be very low (Table 2), ranging from 0% to 1.7%. Therefore the number needed to treat to prevent one ipsilateral metachronous recurrence would be nearly 100 patients. Furthermore, it appears that a solitary ipsilateral adrenal recurrence can be treated. The morbidity of a laparoscopic adrenalectomy is low, and the relatively good cancer outcomes with a solitary adrenal metachronous metastasis from RCC add to this rationale. Many authors have reported that median survival after adrenal gland removal for a metachronous metastasis from RCC is among the highest of all metastatic cancers . Although most patients with recurrence of RCC to the adrenal gland will die of cancer, several authors have reported median survival between 3 and 7 yr after a solitary adrenal gland metastasectomy , , , and . These survival rates are comparable with those with synchronous adrenal gland involvement , , , , , , , and . In a similar fashion, 5-yr survival rates are not high for those with adrenal and distant or lymph node metastases (5–10%), but there clearly are reports of long-term survival (>5 yr), particularly for those with solitary adrenal metastasis , , , , , and . Therefore it does not appear that an opportunity for so-called rescue will be missed in many patients by forgoing an IA.
|Study||Patients with spared ipsilateral/contralateral adrenal gland, n||Median follow-up, yr||Metachronous ipsilateral adrenal involvement, n (%)||Metachronous contralateral adrenal involvement, n (%)|
|Weight et al ||2477/4011||8.2||45/2477 (1.7)||105/3099 (2.6)|
|Lane et al ||2017||5.5||13/2017 (0.7)||5/2066 (0.2)|
|Antonelli et al ||265/1164||4.2||2/265 (0.75)||14/1164 (1.2)|
|Siemer et al ||500||NR||0/500 (0)||NR|
|Kessler et al ||350||5.2||NR||5/350 (1.4)|
|Wunderlich et al ||272||Autopsy study||NR||15/272 (5.5)|
|Kobayashi et al ||228||5.8||0/228 (0)||NR|
|Bazzi et al ||190/NR||4.2||0/190 (0)||NR|
NR = not reported.
3.2.4. Subsequent contralateral adrenal gland involvement
Although once believed to be rare, with only 60 reported cases in the literature until 2003 , metachronous contralateral adrenal gland metastasis from RCC is more common than previously believed , , and . When direct invasion from large upper pole tumors is excluded, accumulating data suggest the risk of hematogenous spread to the adrenal gland is nearly equal between the ipsilateral and contralateral adrenal gland (Table 2). In a large single-institution cohort that did not undergo either an ipsilateral or contralateral adrenalectomy at the time of original RCC surgery, the 10-yr risk of an ipsilateral and contralateral adrenal metastasis was 2.3% and 2.9%, respectively. Several autopsy studies have also found a similar risk of both ipsilateral and contralateral adrenal metastases  and . These data call into question the argument that an IA should be performed to prevent a subsequent recurrence; for if the risk of a subsequent recurrence is equal between the two glands, either they should both be removed, or a coin should be flipped, or neither should be removed.
3.2.5. Cancer-specific survival
We were unable to find any evidence that routine IA improves CSS , , , , , , , , , , , , , and . All the retrospective studies we examined found no CSS advantage to adrenalectomy including pooled estimates of >11 000 patients in a 2012 meta-analysis (hazard ratio: 0.89; 95% confidence interval, 0.67–1.19; p = 0.43) . Because there are no randomized trials, these cohorts are subject to confounding bias. In other words, those who underwent adrenalectomy in most of these cohorts had worse cancer characteristics at baseline and that led to the adrenalectomy. Many of the studies tried to control for these factors, but the risk of bias was significant. Nevertheless, with the accumulating data that suggest a more limited and focused operation in the case of RCC that offers similar cancer-specific outcomes in a meta-analysis of PN versus RN , there is little reason to believe the cancer operation would be compromised by leaving the ipsilateral adrenal gland in place.
3.2.6. Cytoreductive nephrectomy and adrenal involvement
We were unable to identify any studies addressing the utility of removing the ipsilateral adrenal gland as part of a cytoreductive procedure. However, given the leading role surgery plays in the control of RCC, as well as the growing data suggesting there may be a limited role for metastasectomy in RCC  and , we would recommend removing any ipsilateral adrenal gland that appears to be involved radiographically or intraoperatively.
3.3. Overall survival
We were unable to find any evidence that routine IA improves OS, and most studies find equivalent OS in those having an adrenalectomy and adrenal-sparing surgery , , and . These studies also have a potential confounding bias because in general, contemporary surgical series selectively perform adrenalectomy in higher risk cases. We did identify a retrospective population-based cohort study that evaluated the effect of adrenalectomy on OS in 1651 patients undergoing RN for small renal masses . This cohort is appealing because the cancer-specific risk of death should be low (<5%) , which may allow insight into the effect of removing an adrenal gland without as much concern that the cancer outcomes may drive the OS outcomes. The non–cancer-related deaths in this study were nearly six times more common than the cancer-related deaths. With a median follow-up of 9.1 yr, these authors found no difference in CSS but observed a worse OS for those who had the adrenal gland removed (HR: 1.23; 95% CI, 1.0–1.5; p = 0.046) . After 10 yr they observed a 5% OS benefit for those who did not have their adrenal gland removed versus those who did (79.8% vs 74.1%, respectively).
3.4. Trends in ipsilateral adrenalectomy
We identified only a few studies commenting on the trends in IA for patients with RCC , , and . These studies demonstrate that despite declining use of adrenalectomy, as many as 20–40% of patients are still having their adrenal glands removed  and . It appears this is likely a persistent educational gap because in high-volume renal surgery centers, IA rates are approximately 1–2%  and . In a recent case-control study in the United States, kidney cancer surgeons who use older or outdated techniques for the treatment of kidney tumors, such as open RN for a renal mass <4 cm, are much more likely to also remove the adrenal gland .
Overall the quality of published evidence is low, with a significant risk of bias, to guide us when to perform an IA in patients with RCC. However, there may be little rationale for randomized studies because the level 2 evidence so consistently shows the same result: IA has no measurable advantage and may be associated with long-term harms. Therefore, we must form conclusions based on the quality of evidence we have. We conclude that IA does not improve cancer outcomes. No subset of patients should routinely undergo IA when preoperative imaging is normal because the NPV is >99%. Rates of IA are dropping, particularly at high-volume kidney cancer centers, but a subset of surgeons has been slow to adopt adrenal-sparing techniques, which may provide an opportunity for an educational intervention.
Author contributions: Christopher J. Weight had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Weight, Thompson.
Acquisition of data: Weight.
Analysis and interpretation of data: Weight, Mulders, Pantuck, Thompson.
Drafting of the manuscript: Weight.
Critical revision of the manuscript for important intellectual content: Weight, Mulders, Pantuck, Thompson.
Statistical analysis: Weight.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Weight, Mulders, Pantuck, Thompson.
Other (specify): None.
Financial disclosures: Christopher J. Weight certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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a Department of Urology, University of Minnesota, Minneapolis, MN, USA
b Radbount University, Nijmegen Medical Centre, Nijmegen, The Netherlands
c University of California at Los Angles, Los Angeles, CA, USA
d Mayo Clinic, Rochester, MN, USA
Corresponding author. Department of Urology, University of Minnesota, 420 Delaware St. SE, MMC 394, Minneapolis, MN 55455, USA. Tel. +1 612 925 7486; Fax: +1 612 626 0428.
© 2015 European Association of Urology, Published by Elsevier B.V.