Antonio Finelli, Princess Margaret Hospital, 3rd Floor Rm 130, 610 University Ave, Toronto, ON, Canada M5G 2M9. e-mail: email@example.com
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Adrenal-sparing approaches should be utilized when performing radical nephrectomy unless there are specific concerns for adrenal involvement. Although current literature demonstrates 10-year cancer control equivalence with adrenal-sparing approaches, such approaches remain under-used. Furthermore, we have yet to clearly define the long-term consequences of an iatrogenic solitary adrenal gland on overall patient health.
In our study, we demonstrate worse overall survival in patients undergoing ipsilateral adrenalectomy with radical nephrectomy for renal cell carcinoma. We provide some of the only data demonstrating an association between adrenalectomy and long-term survival, and further emphasize the importance of adrenal-sparing approaches when performing radical nephrectomy.
• To assess the impact of ipsilateral adrenalectomy on overall survival, we performed a population-level analysis. Ipsilateral adrenal-gland-sparing approaches during radical nephrectomy (RN) remain under-utilized and the long-term consequences of an iatrogenic solitary adrenal gland are poorly understood.
PATIENTS AND METHODS
• Using the Ontario Cancer Registry we identified 1651 patients in the province of Ontario, Canada, with pT1a renal cell carcinoma who underwent RN between 1995 and 2004.
• We linked individual patient information with pathological data from abstracted pathology reports and determined whether the ipsilateral adrenal gland was removed at the time of RN.
• We utilized univariable and multivariable (adjusting for age, gender, tumour size and tumour grade) Cox proportional hazard models and Kaplan–Meier curves to assess predictors of overall and cancer-specific survival.
• The overall rate of ipsilateral adrenalectomy at the time of RN was 30%.
• Median follow-up for the cohort was 109 months.
• Adrenal removal was associated with worse overall survival: 10-year mortality 26% compared with 20% for those in whom the adrenal gland was left in situ.
• Factors predictive of worse overall survival on multivariable analysis were increasing age (hazard ratio [HR] 1.07 per year, CI 1.06–1.08), high grade tumours (HR 1.38, 1.00–1.90) and having undergone ipsilateral adrenalectomy (HR 1.23, 1.00–1.50).
• Ipsilateral adrenalectomy was not predictive of cancer-specific survival (HR 1.18, 0.78–1.79).
• We demonstrated a significant association between ipsilateral adrenalectomy and overall survival.
• Our findings further support the importance of adrenal-sparing approaches at the time of RN.
Current data suggest that adrenal-sparing approaches should be utilized when performing radical nephrectomy (RN) unless there are specific concerns for adrenal involvement indicated by high risk tumour characteristics (>7 cm [1–3], upper pole location [4–6]) or concerning radiographic findings [7–10]. The indications for ipsilateral adrenalectomy for small renal masses (T1a tumours) are even fewer, and the majority of adrenal glands in this scenario should be left in situ.
Although current literature demonstrates 10-year oncological equivalence when adrenal-sparing approaches are utilized [11,12], we have yet to clearly define the long-term consequences of an iatrogenic solitary adrenal gland on overall patient health. Although rendering a patient to a solitary adrenal does not appear to have a clinically relevant impact in the days immediately following surgery , it remains important to define the lasting consequences in these patients. We sought to evaluate the impact of ipsilateral adrenalectomy on overall survival (OS) through analysis of a large population-based cohort.
PATIENTS AND METHODS
We performed a retrospective, population-based analysis using administrative databases. Patients were identified through the Ontario Cancer Registry, which captures patients in the province of Ontario with a pathological cancer diagnosis. The registry has a case ascertainment rate of greater than 95% [14,15]. We utilized CCP (prior to January 2002) and CCI (starting in 2002) codes to identify all patients undergoing RN (see the Appendix) during the 10-year period between 1995 and 2004 and confirmed this with data from pathology reports (n= 5733). Patients undergoing partial nephrectomy were excluded (n= 575). The population was further refined sequentially to exclude patients with tumours greater than 4 cm (n= 3280), venous thrombus (n= 82), fat invasion (n= 112) or tumour involvement of the adrenal gland (n= 0). Finally, we excluded patients who died within 90 days of their surgery to eliminate the impact of significant complications and peri-operative mortality (n= 33). The final cohort (n= 1651) consisted of patients undergoing RN for the treatment of T1a tumours. Only patients with pathologically confirmed RCC were included (see the Appendix). Patients with urothelial carcinomas of the renal pelvis or ureter were excluded based on specific International Classification of Diseases ICD-9 (189.1, 189.2) and ICD-10 diagnostic codes (C65.9, C66.9). The final cohort consisted of 1651 patients. The Ontario Cancer Registry contained demographic information including patient age and sex. Additional information was available on vital status and last contact date. Cause of death was determined from the listed cause of death on death certificates.
All patients were linked to individual pathology reports with unique identifiers. Trained abstracters reviewed individual pathology reports for each case and extracted data using standardized forms. Abstracters specifically noted whether the adrenal gland was present in the pathology specimen. In cases where the adrenal gland was not mentioned, we assumed that it was left in situ (n= 504). Further data were collected regarding pathology (size, grade), tumour location (lower, mid or upper pole) and tumour side.
Descriptive statistics were obtained for the entire cohort. We analysed rates of OS and cancer-specific survival (CSS) across our two main patient groups: (i) adrenal gland left in situ and (ii) adrenal gland removed.
We determined variables significantly associated with survival. We analysed OS as our primary outcome and CSS as a secondary outcome using univariable and multivariable Cox proportional hazard models and Kaplan–Meier curve analysis. We identified clinically relevant and statistically important variables (P < 0.20 in univariable analysis) to be included in our multivariable model. All analyses were performed using SAS version 9.2.
In the province of Ontario between 1995 and 2004, 1651 patients undergoing RN had a final pathological diagnosis of T1a RCC. The mean age of patients was 60.6 years (23–94 years) and 55.4% were male. Mean tumour size was 2.99 ± 0.8 cm. Median follow-up for the cohort was 109 months (3–191 months). We identified 490 patients (30%) who underwent concurrent ipsilateral adrenalectomy, while the adrenal gland was left in situ in 1161 patients (70%). The groups were similar but some differences did exist (Table 1). Patients in the adrenalectomy group were older and more likely to have larger or higher grade tumours. Five-year OS was 85.5% (n= 419) in the adrenalectomy group compared with 88.5% (n= 1027) in the non-adrenalectomy group (P= 0.09). Ten-year OS was 74.1% (n= 163) in the adrenalectomy group compared with 79.8% (n= 926) in the non-adrenalectomy group (P < 0.01). Five-year CSS was 94.7% (n= 464) in the adrenalectomy group compared with 95.9% (n= 1114) in the non-adrenalectomy group (P= 0.25). Ten-year CCS was 93.3% (n= 457) in the adrenalectomy group compared with 94.5% (n= 1097) in the non-adrenalectomy group (P= 0.33) (Table 1).
Table 1. Patient characteristics
Adrenal not removed
Median follow-up, months (interquartile range)
Age, years (mean) ±sd
60.3 ± 2.9
61.4 ± 12.0
Tumour size (mean) ±sd
2.99 ± 0.8
3.21 ± 0.7
Overall survival (5 year)
Overall survival (10 year)
Cancer-specific survival (5 year)
Cancer-specific survival (10 year)
PREDICTORS OF OS
We assessed significant predictors of OS with a Cox proportional hazard model. Factors predictive of worse OS on univariable analysis included increasing age (hazard ratio [HR] 1.07 per year, 95% CI 1.06–1.08), high grade tumours (HR 1.68, 95% CI 1.22–2.31) and having undergone ipsilateral adrenalectomy (HR 1.28, 95% CI 1.05–1.57). Predictors of worse OS on multivariable analysis were increasing age (HR 1.07, 95% CI 1.06–1.08), high grade tumours (HR 1.38, 95% CI 1.00–1.90) and having undergone ipsilateral adrenalectomy (HR 1.23, 95% CI 1.00–1.50). Variables not found to be significant predictors of overall mortality included gender, tumour size, tumour location and tumour side (Table 2). Kaplan–Meier curves were created to demonstrate OS stratified by whether or not adrenalectomy was performed (Fig. 1a).
Table 2. Univariable and multivariable Cox proportional hazard model (overall survival)
Bold indicates significant results.
Age (continuous), per year
Dimension (continuous), per cm
PREDICTORS OF CSS
We assessed significant predictors of CSS with a Cox proportional hazard model. Factors predictive of worse CSS on univariable analysis included increasing age (HR 1.05, 95% CI 1.03–1.07), high grade tumours (HR 2.56, 95% CI 1.41–4.62) and left-sided tumours (HR 1.65, 95% CI 1.11–2.46). Factors predictive of worse CSS on multivariable analysis were increasing age (HR 1.05, 95% CI 1.03–1.07) and high grade tumours (HR 2.17, 95% CI 1.19–3.94). Variables not predictive of CSS included adrenal removal, gender, tumour location and tumour side (data not shown). Kaplan–Meier curves were created to demonstrate CSS stratified by whether or not adrenalectomy was performed at the time of RN (Fig. 1b).
Herein we report improved OS in patients undergoing adrenal-sparing RN as opposed to those undergoing concomitant adrenalectomy. The data suggest that adrenalectomy may adversely impact patients' overall health and wellbeing, resulting in long-term consequences. This is supported by the fact that adrenalectomy status was associated with OS but not CSS. These findings are further highlighted by our study design in which we limited our cohort to patients with T1a RCC who are almost universally candidates for adrenal-sparing approaches and for whom CSS is excellent.
Prior studies have demonstrated oncological equivalence for adrenal-sparing RN in appropriately selected patients based on either low risk tumour characteristics or radiographic findings [10,11]. Despite this, studies continue to report a slow adoption of adrenal-sparing approaches to RN . This may be due to the fact that few short-term consequences of ipsilateral adrenalectomy have been identified . Although it may be unnecessary from an oncological standpoint to remove the adrenal gland, the long-term health consequences on the patient are not well understood and require further investigation.
Potential exists for an increased risk of adrenal insufficiency and other serious long-term sequelae in patients with a solitary adrenal gland. Although individuals with adrenal insufficiency often present with non-specific symptoms (fatigue, anorexia, gastrointestinal discomfort), it can progress to more serious problems such as electrolyte imbalances, altered consciousness and refractory hypotension . Additionally, an intact adrenal-cortical response is essential to the body's ability to compensate in acute illness . Adrenal crisis can be life-threatening and occurs in as many as 42% of patients with adrenal insufficiency [19,20].
Although there are few reports of adrenal insufficiency directly attributable to unilateral adrenalectomy, other studies have demonstrated early alterations in cortisol response following unilateral adrenalectomy . Furthermore, we have a poor ability to preoperatively identify those who will suffer from clinically significant adrenal insufficiency following surgery . Patients undergoing RN with adrenalectomy are particularly prone to long-term adrenal-related treatment dilemmas because the contralateral gland remains at increased risk for developing metastasis, especially with higher risk tumours. In a recently published series, over 4000 nephrectomies were performed for RCC with a recurrence rate in the contralateral adrenal of 2.6% . This is consistent with previously reported autopsy studies identifying a 2.5% rate of contralateral adrenal metastasis . For these patients in whom an ipsilateral adrenalectomy has already been performed, definitive treatment would result in adrenal insufficiency. Moreover, the rate of adrenal insufficiency in patients with metastatic disease involving the adrenal gland has been reported to be in the range of 20% .
These patients are also susceptible to the consequences of non-malignant adrenal processes. The prevalence rates of incidental adrenal lesions range from 4% to 6% and increase significantly with age . Such developments in patients with a solitary adrenal gland further complicate the clinical scenario and decision-making process. The adrenal gland remains vulnerable to multiple causes of primary adrenal insufficiency. Although often bilateral, these causes of adrenal insufficiency can be seen unilaterally and may disproportionately impact patients with a solitary adrenal. The prevalence of primary adrenal insufficiency in western cultures is 50 in 1 000 000 and population studies identify significantly increased incidence in elderly patients . Additionally, patients with undiagnosed adrenal insufficiency may only manifest themselves during times of physiological stress. This knowledge provides a framework and mechanistic background for which to assess the long-term consequences of adrenalectomy on OS.
We must consider certain limitations when examining the results of our study. We acknowledge the retrospective nature of our database. We are limited in our ability to capture certain patient details (i.e. radiographic findings, comorbidities) and intraoperative events that may influence treatment decisions and eventual outcome. We attempted to address these concerns by limiting our cohort to a specific population (T1a tumours) that is ideal for evaluating our question of interest and also by controlling for confounding factors in the multivariable analysis. Additionally, we determined tumour characteristics and rates of adrenalectomy from pathology reports, as opposed to operative reports. If the adrenal gland was not mentioned, we assumed that it was not removed. While this also limits the potential accuracy of some of our clinical information, it is a conservative approach. Despite these limitations, our data provide us with long-term follow-up from a large, pathologically well characterized population-based cohort.
In summary, our findings demonstrate a modest yet significant association between ipsilateral adrenalectomy and OS. With longer follow-up, the adverse effects may be further amplified. Research is needed to elucidate the physiological impact, if indeed this relationship is causal. However, these findings further support the value of adrenal-sparing approaches at the time of RN.
Findings from our population-based analysis demonstrate worse OS in patients undergoing ipsilateral adrenalectomy with RN for RCC. We provide some of the only data demonstrating an association between adrenalectomy and long-term survival. Our results further emphasize the importance of adrenal-sparing approaches when performing RN, although further research is still needed to confirm these findings.
CONFLICT OF INTEREST
Relevant CCP and CCI procedure codes, and ICD-9 and ICD-10 diagnosis codes