World Journal of Surgery
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ORIGINAL SCIENTIFIC REPORT
Adrenal Surgery for Synchronously Metastatic Adrenocortical Carcinoma: A Population-Based Analysis
Kan Wu1 . Zhihong Liu1 . Xiang Li1 . Yiping Lu1
Accepted: 5 January 2021 /Published online: 22 January 2021 @ Société Internationale de Chirurgie 2021
Abstract
Background Metastatic adrenocortical carcinoma (ACC) is an aggressive cancer with poor prognosis, with limited treatment options. The survival benefit of adrenal surgery in patients with synchronous metastatic disease has not been well explored.
Methods Patients with ACC with synchronous metastases were identified from the Surveillance, Epidemiology, and End Results database (2010-2016). The effect of adrenal surgery on different patterns of distant metastases was assessed. The overall survival was estimated by the Kaplan-Meier method. Multivariable Cox regression analysis was performed to identify prognostic factors associated with survival outcome.
Results A total of 202 patients with synchronous metastatic ACC were identified from the SEER database, 76 (37.6%) patients underwent adrenal surgery. Compared to nonsurgical patients, patients who underwent adrenal surgery had a better survival (median overall survival: 4 vs. 13 months, P < 0.001). In sub-analyses, except for patients with liver metastases (P = 0.670), adrenalectomy could consistently confer a significant survival benefit in patients with lung metastases (P = 0.003), bone metastases (P = 0.020), and multiple metastases (P = 0.002). Cox regression analysis revealed that in addition to adrenalectomy [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45-0.92; P = 0.017], metastasectomy (HR = 0.48, 95% CI 0.26-0.86; P = 0.013), and chemotherapy (HR = 0.59, 95% CI 0.42-0.82; P = 0.002) were also associated with improved survival.
Conclusions Our findings support the view that adrenal surgery may be associated with improved survival in patients with synchronous metastatic ACC (except for patients with liver metastases), and the metastatic sites have significant prognostic implications on survival outcomes with adrenal surgery.
Kan Wu and Zhihong Liu have contributed equally to this work.
☒ Xiang Li xiangli.87@163.com
☒ Yiping Lu
1 Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu 610041, Sichuan, China
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine neo- plasm with an estimated incidence of 0.7-2/1,000,000 individuals annually [1]. More than 50% of patients with ACC may have adrenal hormone excess, such as hyper- cortisolism, aldosteronism, or mixed Cushing and virilizing syndromes, leading to more mortality associated with hormonal hypersecretion [2]. Approximately one-third of patients already present with synchronous metastases at the time of initial diagnosis with a poor prognosis [3]. The
5-year survival rate is less than 15% for metastatic ACC patients [4].
Currently, the mainstay of treatment in metastatic ACC is the mitotane plus chemotherapy regimen, based on the FIRM-ACT study [5]. It was considered to be a promising treatment choice, but did not show a significant effect on survival outcome. Furthermore, the administration of this cytotoxic therapy often comes with diverse adverse effects. Given the lack of effective treatment alternatives, surgical intervention is commonly recommended and remains still the only potentially curative treatment option for pro- longing survival in patients with a metastatic disease if technically possible [4, 6].
Many publications revealed that patients with metastatic disease could reach a better survival from an aggressive surgical approach that could be safely done, with moderate complications and perioperative mortality [7-10]. But these studies are limited by the small number of syn- chronous metastases, large differences in indications for surgery, and various conflicting conclusions. Synchronous and metachronous metastases should be treated as two distinct clinical entities, with different disease behaviors [9, 11]. Owing to the rarity of this disease, the role of adrenal surgery for treatment of synchronous metastatic ACC has been poorly explored.
Surgical resection of the primary tumor aims to elimi- nate a large percentage of the tumor burden, palliate local symptoms, and reduce hormone production [6]. But adrenal surgery has not been usually considered as a treatment option for patients with synchronous metastatic ACC because of their dismal prognosis. Previous studies sug- gested that operative intervention, especially R0 resection, might improve survival in patients with stage IV ACC [9, 11, 12], but the small sample sizes limited their gen- eralization. Recently, a population-based investigation by Wang et al. indicated that primary site surgery was asso- ciated with improved survival for patients with syn- chronous metastatic ACC [13]. But they failed to consider the different metastatic sites among metastatic ACC patients, which are important factors for surgical decision- making and survival outcomes [14].
Given this background, this study sought to evaluate the role of adrenal surgery on different patterns of distant metastases in patients with ACC using a large population- based database.
Methods
Study population
We obtained data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)
database which collects and publishes survival outcomes for approximately 28% of the American population. We identified patients diagnosed with metastatic ACC from 2010 to 2016, because the information about distant metastases (lung, liver, bone, and brain) are available after 2010.
Inclusion criteria included the following: (1) patients with a primary site labeled as codes: C740: Cortex of adrenal gland and C749: Adrenal gland, NOS, and the histology code: 8370: Adrenal cortical carcinoma (ac- cording to the International Classification of Disease for Oncology, 3rd edition); (2) patients had distant metastases at initial diagnosis (M1 disease); (3) patients diagnosed with a unilateral tumor, and positive histology; and (4) patients older than 18 years of age. Patients with more than one primary malignancy were excluded. Patients with unknown survival months or unknown surgical information were excluded from the cohort.
Adrenal surgery
Surgical resection of the primary tumors included radical adrenalectomy (labeled with codes 40, total surgical removal of primary site; and 60, radical surgery), and debulking surgery (including local tumor excision, and partial surgical removal of primary site, as well as labeled with “debulking”).
Demographic and clinical variables
Study variables included patient age, sex, race, marital status, laterality, year of diagnosis, tumor size, sites of metastases (such as the lung, liver, bone, and brain), treatment modality (surgery, radiotherapy, or chemother- apy), survival time, and survival status.
Age at diagnosis was classified into two groups: < 65, and ≥65 years. Tumor size was categorized as <10.0 and 10.0 cm, whereas tumors > 30.0 cm were treated as the coding errors. Multiple metastases were defined as two or more involved organs Surgery of metastatic site was cat- egorized into yes, no, and unknown. Radiation therapy was yes, and no/unknown. Chemotherapy was yes, and no/un- known. Survival outcome was analyzed as overall survival (OS).
Statistical analysis
Baseline characteristics are described using categorical variables, or continuous variables. Comparisons were per- formed by the T tests, Chi-square, and Fisher exact tests, as appropriate. Survival time was estimated using the Kaplan- Meier method and compared by using the log-rank test. Cox proportional hazards model was applied to identify
independent factors associated with survival and expressed as hazard ratio (HR) with 95% confidence interval (CI).
All statistical analyses were performed with SPSS software version 22.0 (IBM, Armonk, NY) and R software (version 3.5.1; R Foundation). All tests were two-sided, and P value of <0.05 was determined as statistical significance.
Results
Patient characteristics
Overall, 202 patients with synchronous metastatic ACC were identified from the SEER database between 2010 and 2016. A total of 76 (37.6%) patients underwent surgical resection for the primary sites, while 126 (62.4%) cases did not receive surgical treatment. The majority of patients were females (59.4%), white race (81.7%), married (53.0%), and treated with chemotherapy (61.9%). The distribution of metastases location was assessed, 25.2% of patients had isolated lung metastases, 18.3% of patients had isolated liver metastases, 6.4% of patients had isolated bone metastases, and 37.6% of patients presented with multiple metastases.
The baseline demographic and clinicopathological characteristics of the entire patients and the subgroups according to undergo adrenal surgery or not are presented in Table 1. Patients with younger age or larger tumor tended to receive adrenal surgery. Likewise, the excision of metastatic lesions was more performed in patients who underwent adrenalectomy.
Surgical outcomes
Among the 202 patients finally recruited, 157 (77.7%) patients died during the follow-up period (median time: 5 months). As shown in Fig. 1, compared to nonsurgical patients, patients undergoing adrenal surgery had a better survival (median OS: 4 vs. 13 months, P < 0.001). Among the patients who underwent adrenal surgery, a total of 66 (86.8%) patients underwent radical adrenalectomy, while 10 (13.2%) patients received debulking surgery. The 3-year OS rate was 24.9% for patients who underwent radical surgery versus 27.0% for patients who received debulking procedure (P = 0.514, Fig. 1).
In sub-analyses, except for patients with liver metas- tases, the effect of adrenal surgery on the survival out- comes of metastatic ACC patients was consistently favorable across all prespecified subgroups (all HR < 1.0, Fig. 2). Adrenal surgery could confer a significant survival benefit in patients with lung metastases (median OS: 36 vs. 4 months, HR = 0.34, 95% CI 0.16-0.72; P = 0.003), bone
metastases (median OS: not reached vs. 6 months, HR = 0.11, 95% CI 0.01-0.98; P = 0.020), and multiple metastases (median OS: 16 vs. 4 months, HR = 0.43, 95% CI 0.24-0.76; P = 0.002, Fig. 3). However, no benefit from adrenal surgery was observed in patients with liver metastases (median OS: 5 vs. 7 months, HR = 1.16, 95% CI 0.57-2.38; P = 0.670).
The systemic therapy of metastatic disease was then examined. Figure 4 displayed the Kaplan-Meier curves of OS after adrenal surgery according to the different com- bination therapies. The median OS was 39 months for patients who underwent adrenal surgery and metastasec- tomy versus 11 months for patients who underwent adrenal surgery alone (P = 0.029). Likewise, adrenal surgery con- ferred a survival benefit in patients who received adrenal surgery combined with chemotherapy versus adrenalec- tomy alone (median OS: 21 vs. 4 months, P < 0.001). However, no statistically significant survival advantage was observed in patients treated with adrenalectomy and radiation therapy (P = 0.135).
Table 2 shows the results of univariate and multivariate analysis of prognostic factors associated with survival outcomes of synchronous metastatic ACC patients. In univariate analysis, adrenal surgery (P < 0.001), surgery of metastatic site (P < 0.001), and administration of chemotherapy (P < 0.001) were associated with improved survival. Whereas, age older than 65 years (P < 0.001), liver metastases (P = 0.038), and multiple metastases (P = 0.029) were associated with worse survival. In the multivariable Cox analysis, adrenal surgery (HR = 0.64, 95% CI 0.45-0.92; P = 0.017), age older than 65 years (HR = 1.53, 95% CI 1.09-2.15; P = 0.014), surgical excision of metastatic lesion (HR = 0.48, 95% CI 0.26-0.86; P = 0.013), and administration of chemother- apy (HR = 0.59, 95% CI 0.42-0.82; P = 0.002) remained independent predictors of survival (Table 2).
Discussion
In this study, we found that adrenal surgery might bring survival advantage for patients with synchronous meta- static ACC, except for patients with liver metastases, suggesting the metastatic site could be used as an important variable for the association of surgical outcomes. Further- more, our study indicated that in addition to adrenalec- tomy, surgical resection of metastatic lesions and administration of chemotherapy were also of value for the treatment of metastatic ACC.
The benefits of adrenal surgery on survival outcomes for patients with synchronous metastatic ACC are still con- troversial. Due to the poor prognosis of this highly aggressive cancer and insufficient evidence, few
| Patient characteristics | Overall | Adrenal surgery | P value | |
|---|---|---|---|---|
| No | Yes | |||
| Number of patients | 202 | 126 (62.4) | 76 (37.6) | |
| Age, years (mean ± SD) | 55.1 ± 15.4 | 55.8 ± 15.6 | 53.8 ± 14.9 | 0.372 |
| <65 | 144 (71.3) | 83 (65.9) | 61 (80.3) | 0.029 |
| ≥65 | 58 (28.7) | 43 (34.1) | 15 (19.7) | |
| Sex, n (%) | 0.220 | |||
| Female | 120 (59.4) | 79 (62.7) | 41 (53.9) | |
| Male | 82 (40.6) | 47 (37.3) | 35 (46.1) | |
| Race, n (%) | 0.976 | |||
| White | 165 (81.7) | 103 (81.7) | 62 (81.6) | |
| Other/unknown | 37 (18.3) | 23 (18.3) | 14 (18.4) | |
| Marital status, n (%) | 0.714 | |||
| Married | 107 (53.0) | 68 (54.0) | 39 (51.3) | |
| Single/unknown | 95 (47.0) | 58 (46.0) | 37 (48.7) | |
| Laterality, n (%) | 0.217 | |||
| Left | 103 (51.0) | 60 (47.6) | 43 (56.6) | |
| Right | 99 (49.0) | 66 (52.4) | 33 (43.4) | |
| Tumor size, cm (mean ± SD) | 11.9 ± 5.7 | 10.9 ± 4.4 | 13.5 ± 7.0 | 0.007 |
| <10 | 67 (33.2) | 49 (38.9) | 18 (23.7) | 0.018 |
| ≥10 | 107 (53.0) | 57 (45.2) | 50 (65.8) | |
| Unknown | 28 (13.8) | 20 (15.9) | 8 (10.5) | |
| Site of metastasis, n (%) | 0.450 | |||
| Lung only | 51 (25.2) | 32 (25.4) | 19 (25.0) | |
| Liver only | 37 (18.3) | 20 (15.9) | 17 (22.4) | |
| Bone only | 13 (6.4) | 7 (5.6) | 6 (7.9) | |
| Multiple | 76 (37.6) | 53 (42.1) | 23 (30.3) | |
| Other/unknown | 25 (12.4) | 14 (11.1) | 11 (14.5) | |
| Surgery of metastatic site, n (%) | <0.001 | |||
| No/unknown | 174 (86.1) | 122 (96.8) | 52 (68.4) | |
| Yes | 28 (13.9) | 4 (3.2) | 24 (31.6) | |
| Radiation, n (%) | 0.904 | |||
| No/unknown | 163 (80.7) | 102 (81.0) | 61 (80.3) | |
| Yes | 39 (19.3) | 24 (19.0) | 15 (19.7) | |
| Chemotherapy, n (%) | 0.137 | |||
| No/unknown | 77 (38.1) | 53 (42.1) | 24 (31.6) | |
| Yes | 125 (61.9) | 73 (57.9) | 52 (68.4) | |
| Vital status, n (%) | 0.005 | |||
| Alive | 45 (22.3) | 20 (15.9) | 25 (32.9) | |
| Dead | 157 (77.7) | 106 (84.1) | 51 (67.1) | |
SD standard deviation
institutions provide radical or debulking surgery for patients with metastatic disease. However, several studies showed that radical adrenalectomy in conjunction with complete metastasectomy had a favorable survival in well- selected patients with distant metastases at initial presen- tation [11, 12, 15, 16]. These results have been
acknowledged by international consensus guidelines that suggest adrenal tumor resection can be performed in patients with limited metastatic lesions if iR0 resection seems feasible at metastatic sites, but against the routine use of adrenalectomy in cases with extensive and unre- sectable metastatic diseases [6, 17]. In contrast, an analysis
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| Fig. 2 Treatment effect of adrenalectomy on median overall survival in all | Median survival (months) | ||||
|---|---|---|---|---|---|
| Subgroup | Adrenalectomy | Non-surgery | Hazard Ratio (95% CI) | ||
| prespecified subgroups | All patients | 13 | 4 | 0.49 (0.34-0.68) | |
| Age, years | |||||
| < 65 | 16 | 6 | 0.52 (0.34-0.77) | ||
| ≥ 65 | 7 | 2 | 0.54 (0.29-1.02) | ||
| Sex | |||||
| Female | 18 | 4 | 0.48 (0.30-0.75) | ||
| Male | 11 | 6 | 0.55 (0.33-0.92) | ||
| Tumor size, cm | |||||
| < 10 | 7 | 6 | 0.53 (0.27-1.07) | ||
| ≥ 10 | 18 | 4 | 0.49 (0.31-0.78) | ||
| Site of metastasis | |||||
| Lung only | 36 | 4 | 0.34 (0.16-0.72) | ||
| Liver only | 5 | 7 | 1.16 (0.57-2.38) | ||
| Bone only | NR | 6 | H | 0.11 (0.01-0.98) | |
| Multiple | 16 | 4 | 0.43 (0.24-0.76) | ||
| Other/Unknown | 6 | 5 | 0.70 (0.28-1.71) | ||
| Radiation | |||||
| No/Unknown | 11 | 4 | 0.55 (0.38-0.79) | ||
| Yes | 30 | 5 | T | 0.23 (0.09-0.63) | |
| Chemotherapy | |||||
| No/Unknown | 3 | 2 | 0.75 (0.45-1.27) | ||
| Yes | 21 | 6 | F | 0.41 (0.26-0.65) | |
| .2 0.4 0.6 0.8 1 <--- Adrenalectomy Better -- | 1.2 -- Non-surgery Better --- > | ||||
of the Dutch Adrenal Network found that patients with synchronous metastases who underwent adrenalectomy had a better median survival than patients who did not undergo surgical resection (16.6 vs. 1.8 months, P < 0.001), even in the presence of distant metastases [9]. This result was
consistent with our findings, and we further assessed the effects of adrenal surgery on different patterns of distant metastases in patients with ACC, and found that adrenalectomy could not confer a survival benefit in patients with liver metastases, highlighting the potential
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Fig. 3 Kaplan-Meier survival curves by adrenalectomy for patients with isolated lung metastases (a), isolated liver metastases (b), isolated bone metastases (c), multiple metastases (d)
effect of metastatic site on survival outcome with adrenal surgery.
From a clinical standpoint, our study displayed a sur- vival benefit from adrenalectomy with a very encouraging result, presenting a chance to prolong survival for patients with synchronous metastatic ACC. Nonetheless, there are many elusive issues on this topic. For one, how to identify the reliable clinical or genetic factors that can be used to help select patients to undergo adrenalectomy or not. A handful of studies suggested that aggressive surgical approach should be carefully performed in patients with older age [16], high Ki-67 index [18], liver metastases, or multifocal diseases [10] after multidisciplinary discussion because of their worse prognosis. Likewise, our findings indicated that older age, liver metastases, and multiple metastases were associated with poor survival. More importantly, we found that adrenal surgery did not provide a significant survival benefit for patients with liver metas- tases. But these outcomes could not fully tailor surgical treatment in metastatic ACC with heterogeneous tumor biology. Future studies should focus on identifying
suitable candidates who may benefit more from adrenalectomy [19].
Recently, a meta-analysis focused on the operative management of metastatic ACC and provided pooled data from 13 retrospective studies. Metastasectomy could be safely done and associated with prolonged survival of patients with distant metastases [20]. This result is con- sistent with our data showing similar survival benefit from resection of distant metastases. In addition, we confirmed that patients with metastatic ACC who underwent adrenalectomy and metastasectomy had a better prognosis than cases who underwent adrenal surgery alone. Of note, subsequent disease recurrences are quite common in patients who received aggressive surgical intervention [21]. Therefore, the additional systemic treatment seems rea- sonable, and is urgently needed to establish, to prevent disease progression and prolong survival.
The effect of adjuvant or neoadjuvant chemotherapy on survival outcome of patients with advanced ACC remains a subject of debate. Many reports based on single-arm studies have led to different therapeutic regimens and are limited by inherent selection bias [17]. The final standard
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chemotherapy regimen for advanced ACC cannot be given by current guidelines. Several previous studies showed that additional chemotherapy had no significant impact on survival outcomes of advanced ACC patients, whether before or after surgery [7, 10]. Conversely, a US study by Mayo Clinic and MD Anderson Cancer Center showed that neoadjuvant chemotherapy may be associated with the improved survival after operative intervention in patients with synchronous metastatic diseases [12]. In terms of our study, we found that the administration of chemotherapy is an independent factor associated with survival improve- ment. Furthermore, we found that adrenal surgery com- bined with chemotherapy for synchronous metastatic ACC patients might be superior to adrenalectomy alone on sur- vival. But there is no direct evidence to support the use of neoadjuvant chemotherapy for synchronous metastatic ACC in our study, due to lack of sufficient information on the type of chemotherapy in the SEER database. In view of the efficacy of the comprehensive experience, we suggest that neoadjuvant treatment may have a survival advantages and should be tested in future clinical trials for advanced ACC.
Palliative radiation therapy and debulking surgery are commonly used to alleviate local symptoms of patients with metastatic cancer, especially for cases with bone metastases [8, 22]. However, a retrospective analysis from the German ACC Registry found that incomplete resection for metachronous metastatic ACC did not confer any sur- vival advantage, compared with patients who received nonsurgical therapy [23]. In addition, in a review of 27 patients undergoing surgery for stage IV ACC, Benzon et al. reported the median survival of patients undergoing R0 resection improved when compared to patients who received R2 resection (860 vs. 390 days; P = 0.02) [12]. But contrary to the previous results, we found that patients who underwent radical adrenalectomy and patients under- going debulking procedure had similar survival outcomes, and were better than cases who had not undergone any surgical treatment. Consequently, debulking surgery or additional localized therapies might be another option for the selected cases with large tumor burdens, severe symptoms, and poor clinical conditions [6, 17].
There are several limitations in this study. First, despite this study is based on the SEER database, the sample size is still small and also limited by the inherent bias of a
| Variable | Overall survival median (mo) | Univariate | Multivariate | ||
|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | ||
| Adrenal surgery | |||||
| No | 4 | Reference | Reference | ||
| Yes | 13 | 0.49 (0.34-0.68) | <0.001 | 0.64 (0.45-0.92) | 0.017 |
| Age, years | |||||
| <65 | 8 | Reference | Reference | ||
| ≥65 | 3 | 1.83 (1.31-2.56) | <0.001 | 1.53 (1.09-2.15) | 0.014 |
| Sex | |||||
| Female | 6 | Reference | |||
| Male | 6 | 0.99 (0.72-1.37) | 0.971 | ||
| Race | |||||
| White | 6 | Reference | |||
| Other | 8 | 0.86 (0.56-1.32) | 0.479 | ||
| Marital status | |||||
| Married | 8 | Reference | |||
| Single | 4 | 1.34 (0.97-1.86) | 0.073 | ||
| Laterality | |||||
| Left | 6 | Reference | |||
| Right | 6 | 0.97 (0.71-1.32) | 0.834 | ||
| Tumor size, cm | |||||
| <10 | 6 | Reference | |||
| ≥10 | 7 | 0.73 (0.52-1.04) | 0.079 | ||
| Site of metastasis | |||||
| Lung only | 8 | Reference | Reference | ||
| Liver only | 5 | 1.68 (1.03-2.73) | 0.038 | 1.36 (0.83-2.22) | 0.221 |
| Bone only | 13 | 0.85 (0.38-1.91) | 0.686 | 0.95 (0.42-2.14) | 0.900 |
| Multiple | 6 | 1.59 (1.05-2.41) | 0.029 | 1.39 (0.91-2.12) | 0.125 |
| Other/unknown | 6 | 1.73 (1.00-2.98) | 0.050 | 1.58 (0.91-2.74) | 0.102 |
| Surgery of metastatic | site | ||||
| No | 6 | Reference | Reference | ||
| Yes | 39 | 0.36 (0.21-0.62) | <0.001 | 0.48 (0.26-0.86) | 0.013 |
| Radiation | |||||
| No/unknown | 6 | Reference | |||
| Yes | 7 | 0.81 (0.53-1.22) | 0.309 | ||
| Chemotherapy | |||||
| No/unknown | 3 | Reference | Reference | ||
| Yes | 9 | 0.48 (0.35-0.67) | <0.001 | 0.59 (0.42-0.82) | 0.002 |
ACC: adrenocortical carcinoma; HR: hazard ratio; 95% CI: 95% confidence interval Variables with P ≤ 0.05 in univariate analysis were included in the multivariate Cox regression
retrospective study. Secondly, detailed information on patient performance status, postoperative complications, metastasectomy (complete or incomplete resection), and medical treatment is unavailable in the SEER database. Third, several prognostic parameters such as the Ki-67 index [18], surgical margin status [12], and hormonal
functional status [24] are not recorded, but these have been proven to be independent prognostic factors for metastatic ACC patients. Finally, we only examined the effect of surgical resection on patients with synchronous metastases, because we could not obtain information on whether the
patients experienced recurrences or metachronous metas- tases after surgery.
Conclusions
Our study suggests that adrenal surgery may be associated with improved survival in patients with synchronous metastatic ACC (except for patients with liver metastases), and sites of distant metastases have a significant impact on survival outcomes with adrenal surgery. Given a retro- spective fashion of this study, larger prospective clinical studies are warranted to validate the role of adrenalectomy in synchronous metastatic ACC.
Funding This work was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University.
Compliance with ethical standards
Conflict of interest All authors in the study declare no conflict of interests.
Ethical approval The authors are in compliance with all applicable ethical standards.
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