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JSR Surgical Research
Association for Academic Surgery
High perioperative morbidity and mortality in patients with malignant nonfunctional adrenal tumors
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Andrea R. Marcadis, MD,* Gustavo A. Rubio, MD, Zahra F. Khan, MD, Josefina C. Farra, MD, and John I. Lew, MD, FACS
Division of Endocrine Surgery, DeWitt Daughtry Family Department of Surgery, Leonard M Miller School of Medicine, University of Miami, Miami, Florida
ARTICLE INFO
Article history:
Received 13 February 2017 Received in revised form 28 April 2017
Accepted 25 May 2017 Available online xxx
Keywords:
Adrenal adenoma Adrenocortical carcinoma
Nonfunctional
Outcomes
ABSTRACT
Background: Both functional (hormone hypersecreting) and nonfunctional (non- hypersecreting) adrenal tumors can have benign or malignant pathology. This study compares perioperative in-hospital outcomes after adrenalectomy in patients with benign versus malignant nonfunctional primary adrenal tumors.
Methods: A retrospective cross-sectional analysis was performed using the Nationwide Inpatient Sample database (2006-2011) to identify patients who underwent unilateral open or laparoscopic adrenalectomy for nonfunctional primary adrenal tumors. Patients were subdivided by benign and malignant final pathology. Demographics, comorbidities, and perioperative complications were compared between groups using bivariate and multivariate logistic regression.
Results: Of 23,297 patients, 89.7% (n = 20,897) had benign tumors, whereas 10.3% (n = 2400) had malignant tumors. Those with malignant tumors had higher Charlson Comorbidity Index scores and were more likely to undergo adrenalectomy at high volume centers. For both laparoscopic and open approach, patients with malignant nonfunctional tumors had higher rates of intraoperative complications including vascular and splenic injury (P < 0.01), as well as postoperative complications including hematoma, shock, acute kidney injury, venous thromboembolism, and pneumothorax (P < 0.01). In addition, the malignant group had higher rates of blood transfusions, longer hospital stay, and higher in-hospital mortality (P < 0.05) than benign counterparts. On risk-adjusted multivariate analysis, malignant nonfunctional primary adrenal tumors were independently associated with increased risk of complications following adrenalectomy.
Conclusions: Patients with malignant nonfunctional primary adrenal tumors have higher perioperative morbidity and mortality compared to patients with benign nonfunctional adrenal tumors. Such patients should be medically optimized before adrenalectomy, and surgeons must remain vigilant in preventing perioperative complications.
@ 2017 Elsevier Inc. All rights reserved.
* Corresponding author. Division of Endocrine Surgery, DeWitt Daughtry Family Department of Surgery, Leonard M Miller School of Medicine, University of Miami, 1120 NW 14th Street (M-875), Clinical Research Building, 4th Floor, Miami, FL 33136. Tel .: +305 243 4211x3; fax: +305 243 4221.
Introduction
With the increasing use of abdominal imaging studies, adre- nal tumors are more commonly identified within the general population.1,2 Adrenal tumors can be classified by functional (hormone hypersecreting) or nonfunctional (non- hypersecreting) status, and whether they are benign or ma- lignant. Both functional and nonfunctional adrenal tumors can have either benign or malignant behavior. Diagnostic evaluation of adrenal tumors involves assessment of func- tional status, as well as reviewing imaging studies for tumor size and for any findings suspicious for malignancy.1,2 While there is general agreement for the role of adrenalectomy in the management of functional adrenal tumors, the recom- mendations for surgical resection in patients with nonfunc- tional adrenal tumors still vary.1
The National Institutes of Health, the American Associa- tion for Clinical Endocrinologists, and the American Associa- tion of Endocrine Surgeons recommend adrenalectomy for tumors that are either hormonally functional, greater than 4- 6 cm, or those that have imaging findings suspicious for ma- lignancy, including irregular borders, heterogeneity, hemor- rhage, central necrosis, and calcifications.1,3 Since adrenal malignancy is clinically elusive unless it invades nearby structures or has metastasized, many patients with suspi- cious nonfunctional adrenal tumors undergo surgical resec- tion for diagnostic as well as therapeutic purposes.3 Although adrenal carcinoma is rare, its consequences are significant, and many patients present with advanced disease. 4,5 Depending on the stage of the disease, 5-y survival has been reported to be between 13% and 81%.6-8
The previous studies have shown that underlying adrenal pathology can affect operative outcomes. A recent retrospec- tive study of the Nationwide Inpatient Sample (NIS) database showed that patients with benign adrenal masses (functional and nonfunctional combined) were more likely to experience major perioperative complications with adrenalectomy than those with malignant adrenal tumors.9 This outcome was attributed to the higher rate of functional tumors (including pheochromocytomas, cortisol secreting, and aldosterone secreting tumors) with their associated hemodynamic alter- ations, in the benign pathology group.9
The current study, therefore, examines only patients with nonfunctional adrenal tumors, and compares those with benign and malignant pathology with regard to their periop- erative in-hospital outcomes after adrenalectomy.
Methods
A retrospective cross-sectional analysis was performed using the NIS database (2006-2011) to identify patients who under- went unilateral adrenalectomy for nonfunctional adrenal tu- mors. A tumor was considered to be nonfunctional if it did not release excess catecholamines, aldosterone, or cortisol. Therefore, patients with International Classification of Dis- eases, Ninth Revision (ICD-9) codes for Conn’s syndrome, Cushing’s syndrome, hyperaldosteronism, pheochromocy- toma, or malignant hypertension were excluded. Patients
with nonfunctional adrenal tumors were further stratified into benign and malignant groups based on the final pathol- ogy. Within the malignant group, only patients with primary adrenal cancer were included, and those with metastasis to the adrenal gland from a separate primary tumor were excluded. Additionally, patients who underwent adrenalec- tomy with an admitting diagnosis of traumatic injury to the adrenal gland were excluded.
Patient demographics, socioeconomic and clinical factors, comorbidities, hospital characteristics, intraoperative com- plications, and in-hospital postoperative complications were examined. Variables available from NIS included age, sex, race, comorbidities, and admission status (elective versus nonelective). A modified version of the Charlson Comorbidity Index10 was calculated for each patient and compared be- tween groups. Hospital-level data from the NIS included hospital location and teaching status. Hospital adrenalectomy volume was calculated using NIS unique hospital identifiers assigned to each case. Hospitals were then stratified into quartiles by annual adrenalectomy volume.
When comparing intraoperative and postoperative com- plications, groups were subdivided by operative approach (open versus laparoscopic). For postoperative variables, length of stay and in-hospital mortality data were reported in the NIS. Other postoperative complications were identified using ICD-9 codes largely based on a previously published model.11 ICD-9 codes that were used to query the database for di- agnoses, procedures, and complications are listed in Appendix A.
Statistical analysis was performed using SPSS (IBM, version 21; SPSS, Inc, Chicago, IL). Data were compared using two- tailed chi-square and t-tests as appropriate, as well as with risk-adjusted multivariate logistic regression. A P value < 0.05 was considered statistically significant. This study used dei- dentified patient data and was exempt from Institutional Re- view Board approval.
Results
There were 23,297 patients who underwent unilateral adre- nalectomy for nonfunctional primary adrenal tumors identi- fied in the NIS database between 2006 and 2011 and met study inclusion criteria. Of these patients, 89.7% (n = 20,897) had benign pathology, whereas the remaining 10.3% (n = 2400) had malignant tumors.
Patients with malignant nonfunctional primary adrenal tumors were younger than those with benign tumors (Table 1). While women were the predominant sex in both the malig- nant and benign groups, there was a significantly higher percentage of men in the malignant as compared to the benign group (Table 1). There were also significant differences with regard to race and ethnicity between groups.
While patients with benign nonfunctional adrenal tumors were more likely to be obese and had higher rates of hyper- tension, diabetes mellitus, and chronic lung disease, patients with malignant nonfunctional primary adrenal tumors were more likely to have renal failure, peripheral arterial disease, liver disease, and coagulopathy. Moreover, patients with
| Demographic/ comorbidity | Benign (%) (89.7%; n = 20,897) | Malignant (%) (10.3%; n = 2400) | P value |
|---|---|---|---|
| Mean age, y (SD) | 53.9 (15.1) | 49.1 (20.7) | <0.01 |
| Sex | |||
| Female | 61.8 | 53.1 | <0.01 |
| Male | 38.2 | 46.9 | |
| Race/ethnicity | |||
| White | 72.2 | 75.9 | <0.01 |
| Black | 13.2 | 8.9 | |
| Hispanic | 8.1 | 9.0 | |
| Asian | 2.4 | 2.5 | |
| Native American | 0.7 | 0.5 | |
| Other | 3.4 | 3.2 | |
| Comorbidities | |||
| Hypertension | 65.0 | 51.4 | <0.01 |
| Diabetes mellitus | 23.4 | 17.2 | <0.01 |
| Chronic lung disease | 16.5 | 12.4 | <0.01 |
| Obesity | 13.5 | 9.9 | <0.01 |
| Congestive heart failure | 3.7 | 3.6 | 0.87 |
| Renal failure | 3.7 | 4.6 | 0.02 |
| Peripheral arterial disease | 2.7 | 3.6 | <0.01 |
| Liver disease | 1.7 | 3.1 | <0.01 |
| Coagulopathy | 1.2 | 3.8 | <0.01 |
| Charlson Comorbidity Index | |||
| 0 | 57.2 | 41.5 | <0.01 |
| 1 | 26.1 | 16.7 | |
| ≥2 | 16.7 | 41.8 | |
| Hospital location/ teaching status | |||
| Urban, teaching | 72.2 | 79.5 | <0.01 |
| Urban, nonteaching | 24.1 | 16.4 | |
| Rural | 3.7 | 4.2 | |
| Hospital annual adrenalectomy volume (quartile) | |||
| 4th (<4/y) | 26.4 | 21.0 | <0.01 |
| 3rd (4-10/y) | 27.1 | 21.3 | |
| 2nd (10-26/y) | 23.3 | 29.0 | |
| 1st (>26/y) | 23.2 | 28.7 | |
| SD = standard deviation. | |||
malignant nonfunctional primary adrenal tumors had signif- icantly higher Charlson Comorbidity Index scores as compared to those with benign nonfunctional adrenal tumors.
There were significant differences seen in hospital loca- tion and teaching status between groups (Table 1). While the majority of patients in both groups underwent adrenalec- tomy at urban teaching hospitals, this percentage was significantly higher in patients with malignant as compared to benign tumors, with a significantly higher percentage of patients in the benign group being treated at urban nonteaching centers. Additionally, patients with malignant tumors were more likely to undergo adrenalectomy at hos- pitals in the two highest quartiles for adrenalectomy volume (Table 1).
Patients with malignant nonfunctional primary adrenal tumors more often underwent open (compared to laparo- scopic) adrenalectomy than patients in the benign group (91.2% versus 83.3%, P < 0.01). This group also had a higher rate of adrenalectomy during a nonelective admission (17.7% versus 10.7%, P < 0.01) compared to the benign group. Patients with malignant tumors experienced higher rates of intra- operative vascular and splenic injuries regardless of the operative approach (Table 2). There was no difference be- tween the benign and malignant cohorts with regard to liver injury in either approach.
In both operative approaches, patients with malignant nonfunctional primary adrenal tumors had higher rates of postoperative complications including hematoma, adreno- cortical insufficiency, venous thromboembolism, pneumo- thorax, shock, cardiac complications and had overall higher rates of blood transfusion than their benign coun- terparts (Table 2). In patients undergoing open adrenalec- tomy, those with malignant tumors had higher rates of postoperative acute kidney injury; however, this difference was not appreciated in those who underwent laparo- scopic approach (Table 2). In both operative approaches, there was no difference in postoperative wound complica- tions between the benign and malignant groups, except for an increased rate of percutaneous abdominal drain place- ment in patients who underwent open adrenalectomy for malignancy.
While patients undergoing laparoscopic resection had a shorter mean hospital stay compared to those undergoing open adrenalectomy, in both approaches, patients with ma- lignant tumors had significantly longer mean hospital stay than their benign counterparts. In those who underwent open adrenalectomy, there was a significantly higher rate of in- hospital death in patients in the malignant as compared to the benign group. This difference in mortality between groups was not observed with patients who underwent laparoscopic resection.
On risk-adjusted multivariate analysis, there were several factors that were independently associated with an increased rate of complications, including coagulopathy, renal failure, congestive heart failure, obesity, increased Charlson Comorbidity Index score, emergent admission, liver disease, open surgical approach, male sex, chronic lung disease, and older age (Table 3). Malignant primary adrenal tumors were also independent risk factors for perioperative complications. Additionally, adrenalectomy performed at high volume adrenal hospitals was indepen- dently associated with a decreased risk of perioperative complications.
| Table 2 - Postoperative complications of patients with benign versus malignant nonfunctional adrenal tumors. | ||||||
|---|---|---|---|---|---|---|
| Complication | Open adrenalectomy | Laparoscopic adrenalectomy | ||||
| Benign (%) (88.8%; n = 17,396) | Malignant (%) (11.2%; n = 2188) | P value | Benign (%) (94.3%; n = 3501) | Malignant (%) (5.7%; n = 212) | P value | |
| Intraoperative technical complications | ||||||
| Vascular injury | 4.0 | 8.8 | <0.01 | 3.0 | 14.6 | <0.01 |
| Spleen injury | 2.3 | 8.7 | <0.01 | 0.8 | 10.4 | <0.01 |
| Liver injury | 0.3 | 0.5 | 0.09 | 0.3 | 0.0 | 0.44 |
| Pancreatic injury | 0.0 | 0.2 | <0.01 | 0.3 | 0.0 | 0.44 |
| Postoperative complications | ||||||
| Blood transfusion | 7.2 | 21.4 | <0.01 | 5.4 | 16.0 | <0.01 |
| Acute kidney injury | 2.7 | 5.6 | <0.01 | 1.6 | 0.0 | 0.06 |
| Hematoma | 2.1 | 5.3 | <0.01 | 1.6 | 4.7 | <0.01 |
| Adrenocortical insufficiency | 2.6 | 4.5 | <0.01 | 2.5 | 11.8 | <0.01 |
| Venous thromboembolism (DVT, PE) | 0.6 | 2.3 | <0.01 | 0.7 | 2.4 | <0.01 |
| Pneumothorax | 1.0 | 2.1 | <0.01 | 0.6 | 2.4 | <0.01 |
| Shock | 0.6 | 2.1 | <0.01 | 0.4 | 2.4 | <0.01 |
| Cardiac complications | 0.9 | 2.0 | <0.01 | 0.8 | 2.4 | 0.02 |
| Pneumonia | 1.4 | 1.2 | 0.45 | 0.8 | 0.0 | 0.18 |
| Wound complications | ||||||
| Infection | 0.7 | 0.7 | 0.87 | 0.0 | 0.0 | d |
| Dehiscence | 0.2 | 0.3 | 0.52 | 0.0 | 0.0 | d |
| Peritoneal abscess | 0.3 | 0.2 | 0.41 | 0.0 | 0.0 | d |
| Seroma | 0.1 | 0.0 | 0.26 | 0.1 | 0.0 | 0.58 |
| Percutaneous abdominal drainage | 0.4 | 0.9 | <0.01 | 0.1 | 0.0 | 0.58 |
| Length of stay, d (SD) | 4.3 (6.6) | 7.2 (8.5) | <0.01 | 3.4 (5.2) | 5.8 (6.9) | <0.01 |
| In-hospital death | 0.3 | 1.8 | <0.01 | 0.7 | 0.0 | 0.23 |
DVT = deep vein thrombosis; PE = pulmonary embolism; SD = standard deviation.
Discussion
In this retrospective analysis, the majority of patients un- dergoing unilateral adrenalectomy for a nonfunctional pri- mary adrenal tumor have benign final pathology. These results are consistent with the literature and are expected when considering the rarity of adrenocortical carcinoma (approximately 1-2 cases per million people in the United States),2,12,13 compared to the more common benign adrenal adenomas.1
In the current study, patients with malignant nonfunc- tional primary adrenal tumors were younger, on average, than those with benign tumors. This is in concordance with the literature, which reveals adrenocortical carcinoma to be most common in children younger than 5 y and adults aged 30-40 y.6 Additionally, while a majority of patients in both groups were women, men composed a higher percentage of the ma- lignant as compared to the benign group. This also corre- sponds with the previous studies which show that while adrenal tumors overall are more common in women,14 the
incidence of adrenocortical carcinoma in women is only marginally higher than in men.12
Patients with malignant nonfunctional primary adrenal tumors had higher overall rates of medical comorbidities, as measured by the Charlson Comorbidity Index.10 This may, in part, explain their higher perioperative complication rates. Some of these comorbidities, such as higher rates of liver disease and coagulopathy, may be explained by the common metastasis of adrenocortical carcinoma to the liver,15 as well as concomitant use of chemotherapy and other immuno- suppressive agents in cancer patients. Interestingly, patients with benign nonfunctional adrenal tumors had higher rates of certain comorbidities including hypertension, diabetes mellitus, chronic lung disease, and obesity, which could, in part, be explained by the association between chronic adre- nal stress and stimulation from these underlying conditions leading to the development of adrenal tumors. Obesity, dia- betes, and hypertension, for example, have previously been shown to be associated with clinically silent adrenal masses on autopsy.16
| Table 3 - Multivariate analysis revealing factors independently associated with any examined perioperative complication. | ||
|---|---|---|
| Any complication | OR (95% CI) | P value |
| Coagulopathy | 5.03 (3.89-6.49) | <0.01 |
| Primary adrenal cancer | 2.95 (2.65-3.28) | <0.01 |
| Renal failure | 2.25 (1.91-2.66) | <0.01 |
| Congestive heart failure | 1.86 (1.57-2.21) | <0.01 |
| Obesity | 1.71 (1.55-1.90) | <0.01 |
| Charlson Comorbidity Index ≥ 2 (versus 0) | 1.69 (1.53-1.85) | <0.01 |
| Emergent (versus elective) | 1.64 (1.47-1.82) | <0.01 |
| Liver disease | 1.60 (1.26-2.02) | <0.01 |
| Open adrenalectomy (versus laparoscopic) | 1.28 (1.15-1.43) | <0.01 |
| Male sex (versus female) | 1.14 (1.06-1.23) | <0.01 |
| Chronic lung disease | 1.14 (1.03-1.26) | <0.01 |
| Older age (per y) | 1.01 (1.01-1.02) | <0.01 |
| Top quartile for hospital annual adrenalectomy volume (versus lowest quartile) | 0.85 (0.75-0.96) | <0.01 |
CI = confidence interval; OR = odds ratio.
Open adrenalectomy was the more common operative approach for both benign and malignant nonfunctional pri- mary adrenal tumors. This finding is expected, as patients with nonfunctional adrenal tumors often undergo adrenal- ectomy for large tumors, or tumors with known or suspected malignancy, in which open surgery is indicated.17,18 There was a higher percentage of patients with benign as compared to malignant nonfunctional tumors that underwent laparo- scopic adrenalectomy, as expected.17 Laparoscopic adrenal- ectomy remains controversial for resection of most adrenocortical carcinomas and may be associated with higher recurrence rates and worse overall survival.17,19,20 Nonethe- less, open adrenalectomy has been reported to be associated with longer hospital stays and increased short-term compli- cation rates.18 The results of the current study demonstrate that, regardless of operative approach (laparoscopic or open), patients in the malignant group experienced higher rates of perioperative complications compared to patients with benign tumors.
The higher rates of intraoperative complications such as vascular and splenic injuries seen in the malignant as compared to the benign group may be secondary to the ten- dency of adrenal malignancies to invade blood vessels and nearby organs, causing a more difficult operative dissection. This proclivity for vascular invasion by malignant adrenal tumors as well as the risk of hemorrhage from necrotizing malignant tumors21 may also explain the higher rate of adrenalectomy during emergent hospital admissions for ma- lignant as compared to benign nonfunctional adrenal tumors.
Patients in the malignant cohort had significantly higher rates of postoperative complications including acute kidney injury, hematoma, pneumothorax, and shock, as well as higher overall rates of blood transfusion compared to their
benign counterparts. These higher rates of postoperative complications can be attributed to the aggressive and invasive nature of malignant adrenal tumors. The higher rate of venous thromboembolism in malignant compared to benign nonfunctional adrenal tumors may be related to the ability of such malignant tumors to invade the venous system, causing thrombosis in the adrenal vein and the inferior vena cava, as well as by the hypercoagulable state frequently encountered in malignancy. The reason for the higher rate of adrenocor- tical insufficiency after adrenalectomy in patients with ma- lignant nonfunctional adrenal tumors is unclear but may be related to the chemotherapy (e.g., mitotane) and radiotherapy treatments that these patients receive.22,23 The overall higher complication rate in patients undergoing adrenalectomy for malignant nonfunctional adrenal tumors may, in turn, explain their longer hospital stays and higher in-hospital mortality than their benign counterparts.
A majority of patients in this study underwent adrenalec- tomy at urban teaching hospitals. Patients with malignant tumors underwent adrenalectomy at the highest volume hospitals more frequently than those with benign tumors, and this may reflect referral patterns for these more complicated cases. In the multivariate analysis, adrenalectomy performed at the highest volume hospitals was independently associated with lower risk of perioperative complications. The previous studies have also shown improved adrenalectomy outcomes at higher volume centers.11,24,25 However, despite being associated with lower perioperative complication rates, one study found that treatment at high volume centers did not improve long-term survival for patients with adrenocortical carcinoma.26
This current study, to the authors’ knowledge, represents the largest retrospective analysis comparing outcomes after adrenalectomy in patients with benign and malignant nonfunctional primary adrenal tumors. A recent study per- formed using the same database comparing outcomes after adrenalectomy in benign compared to malignant adrenal tu- mors overall (including both functional and nonfunctional tumors in each group) revealed a higher perioperative complication rate in the benign as compared to the malignant group.9 This finding was attributed to the higher percentage of patients in the benign group with hormonally functional tu- mors, which more commonly cause perioperative shifts in blood pressure and heart rate, and, with cortisol secreting tumors, postoperative adrenal insufficiency.9 The authors’ current study, however, excludes patients diagnosed with functional tumors and demonstrates the opposite effect, with a higher complication rate in the malignant compared to the benign group. This higher complication rate associated with malignant tumors was observed in both open and laparo- scopic approaches. Furthermore, with multivariate analysis adjusting for differences in demographics, comorbidities, and hospital characteristics between groups, nonfunctional pri- mary adrenal cancer was independently associated with higher relative risk of perioperative complications compared to benign adrenal tumors.
There are certain limitations of this study. There is an inherent risk of coding errors leading to missed or inaccurate diagnoses in this administrative database. This can also result in overestimation or underestimation of complication rates.
Moreover, there is no postdischarge data so the current analysis does not include complications occurring after hos- pital discharge or rates of readmission. In addition, the NIS database does not include data to indicate cases of laparo- scopic converted to open adrenalectomy. Therefore, certain cases coded as laparoscopic may have been converted to open, and this may influence complication rates reported in the laparoscopic cohort. Nonetheless, multivariate analysis showed that malignancy and open adrenalectomy were independently associated with increased perioperative complication rates. Therefore, the finding that more patients in the malignant cohort underwent open compared to lapa- roscopic adrenalectomy is not the only reason for the higher complication rate in the malignant group.
In conclusion, this study reveals higher in-hospital morbidity and mortality in patients with malignant as compared to benign nonfunctional primary adrenal tumors. These findings reinforce the importance of careful perioper- ative management in patients undergoing adrenalectomy for known or suspected nonfunctional adrenal malignancy. Such patients should be preoperatively counseled and medically optimized for adrenalectomy, and surgeons should remain vigilant in minimizing perioperative complications.
Acknowledgment
Authors’ contributions: A.R.M., M.D., is responsible for manuscript composition and data analysis. G.A.R., M.D., is responsible for data compilation and analysis, and manu- script review. Z.F.K., M.D., and J.C.F., M.D., contributed to manuscript review. J.I.L., M.D., contributed to data analysis, manuscript composition, and review.
Disclosure
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jss.2017.05.116.
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