ORIGINAL ARTICLE
Check for updates
The clinical utility of ‘GRAS’ parameters in stage I-III adrenocortical carcinomas: long-term data from a high-volume institution
Jiayu Liang1 . Zhihong Liu1 . Liang Zhou1 . Yongquan Tang2 . Chuan Zhou1 . Kan Wu1 . Fuxun Zhang1 . Fan Zhang1 . Xin Wei1 . Yiping Lu DD1 . Yuchun Zhu1
Received: 26 July 2019 / Accepted: 15 November 2019 @ Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Background Adrenocortical carcinoma (ACC) is a rare cancer with poor survival. We sought to identify prognostic factors and assess its clinical utility in postoperative management of nonmetastatic ACC.
Methods We included 65 patients who underwent adrenalectomy and clinicopathological diagnosed as European Network for the Study of Adrenal Tumors (ENSAT) stage I-III ACC in our center from 2009 to 2017. Potential clinicopathological parameters were selected. The prognostic correlation, including overall survival (OS) and recurrence-free survival (RFS), was analyzed using Kaplan-Meier method and univariate and multivariate Cox model.
Results The 2-year and 5-year post-surgery survival rate were 54.6% (95%CI: 42.5-70.1%) and 33.5% (95%CI: 22.3-50.6%), respectively. 46 (70.8%) cases were symptomatic ACC. Tumor-related or hormone-related symptom was identified as independent prognostic factor in OS (HR =5.5, 95%CI: 1.87-16.16) and RFS (HR =3.62, 95%CI: 1.28-10.24). Higher tumor grade (Weiss score > 6 or Ki67 index ≥ 20%) was independently associated with poor OS (HR = 4.73, 95%CI: 2.15-10.43). R status (R1/R2/Rx) was independently correlated with worse RFS (HR =2.56, 95% CI:1.21-5.43). Accordingly, patients with higher GRAS (Grade, R status, age, and symptoms) score were more likely to have poor prognosis (OS: HR = 2.7, 95%CI: 1.43-5.11 and RFS: HR = 3.31, 95%CI: 1.68-6.52, respectively).
Conclusions Symptoms, higher tumor grade and positive/unknown R status were independent risk factors in stage I-III ACC. Comprehensive consideration of GRAS parameters may optimize the prognostic assessment for postoperative patients.
Keywords Adrenocortical carcinoma · Prognosis . ENSAT · GRAS . Risk assessment
Introduction
Adrenocortical carcinoma (ACC) is a rare and deadly endocrine malignancy with an estimated 0.7-2.0 cases per million inhabitants [1, 2]. Compete surgical resection is the
These authors contributed equally: Jiayu Liang, Zhihong Liu
☒ Yiping Lu yipinglu@163.com
☒ Yuchun Zhu
1 Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China
2 Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
only chance for cure for ACC, especially towards patients with resectable tumor in European Network for the Study of Adrenal Tumors (ENSAT) stage I-III. However, more than 50% ACC underwent initial complete resection will still develop disease recurrence or metastasis [3]. For these patients, additional operation, adjuvant treatment with mitotane, and other chemotherapy/radiation are the sug- gested therapeutic choices but with limited antitumor effects in general [4-6]. As a result, the prognosis of ACC is poor worldwide.
In recent years, several clinical parameters, pathological index/scores, and surgical related factors were found to be correlated with the survival of ACC patients. For example, some studies suggest that age, tumor stage, and hormone secretion are clinical prognostic factors during follow-up [7-9]. Histopathological index and score, especially Ki67 index and Weiss score, also exert an impact on prognosis [10, 11]. Meanwhile, for patients who underwent radical
resection surgery, resection (R) status is another influencing factor associated with dose dependent compromised survi- val [12, 13]. However, while these studies indeed provide initial consideration toward risk assessment for ACC, they are usually either difficult to apply in clinical practice, or are often just consider one aspect of elements that could affect prognosis. For this reason, identifying clinical available prognostic factors and synthetically considering their clin- ical significance would be more practical in guiding post- operation management of these patients.
In a study from Libé et al. researchers successfully revealed the remarkable prognostic value of combined ‘GRAS’ parameters (grade, R status, age, and symptoms) in patients in ENSAT stage III and stage IV, providing novel supplemental reference to decision-making for advanced ACC [14]. Given the accessibility of GRAS parameters in clinical work, it would also be of great importance to explore their prognostic value in all ACC patients who underwent radical adrenalectomy. In this study, we respectively collected ACC cases diagnosed as ENSAT stage I-III from our institution. The prognosis of patients diagnosed incidentally were compared with that of symp- tomatic presented patients. Different tumor grade and resection status were also examined to identify their effects on overall survival (OS) or recurrence-free survival (RFS). Finally, for the first time, we proposed that the integrated GRAS parameters could be helpful in distinguishing ACC patients at early stage with different prognostic risks in addition to current ENSAT system.
Methods
Patient cohort and data collection
From 1 January 2009 to 31 December 2017, patients that underwent resection for tumors in our institution and clin- icopathologically confirmed as ENSAT stage I-III ACC were retrospectively analyzed. Cases with available clinical and follow-up data were enrolled in this study. Clinical records were extracted, including age, gender, symptoms, hormone secretions, tumor size, Ki67 index, tumor grade, ENSAT stage, and R status.
Symptoms were defined as “no” for incidental ACC and “yes” for signs- or symptoms-related ACC (i.e. tumor mass associated pain and endocrine hypertension). Hormone secretion were defined as “no” for negative hormone detection results and “yes” for positive hormone secretion (i.e. cortisol). Tumor size was categorized as <7.5 or ≥7.5 cm. According to a report from Beuchlein et al. [15], patients in our cohort were also distinguished into three different subgroups (Ki<10%, between 10-20% and ≥20%) to check the prognostic effects of Ki67 index. Tumor
grade was scored based on the pathological evaluation (Grade I for Weiss score ≤6 and Ki67 index <20%; Grade II for Weiss score >6 or Ki67 index ≥ 20%). R status was depended on surgical evaluation (R0: complete resection; R1: microscopically positive margin; R2: macroscopically positive margin; Rx: resection status unknown). GRAS score was defined as GRAS 1: ≤1 risk factor in GRAS parameters; GRAS 2: 2 risk factors in GRAS parameters; GRAS 3: ≥3 risk factors in GRAS parameters.
OS was defined as time from primary resection of ACC to death due to any cause. Surviving patients were censored at the timepoint of last follow-up. RFS was defined as time from primary resection of ACC to first recurrence (i.e. local recurrence, peritoneal carcinomatosis, or distant metas- tases), based on clinical, radiographic, and laboratory evi- dence. Under the ethical guidelines as required by Declaration of Helsinki, this research protocol was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee.
Statistical analysis
Statistical analyses were performed using the R system (version 3.4.4). Survival analyses were analyzed by Kaplan-Meier method and log-rank test. 95% confidence intervals (CI) and median survival time were estimated in Kaplan-Meier analyses. Clinicopathological categorical data were compared using Chi-Square or Fisher’s exact tests. Univariate and multivariate Cox regression analyses were performed to identify the significant risk factors. Gender, age, hormone secretion, tumor size, T stage, N stage, ENSAT stage, R status, grade, and symptoms were included in the univariate Cox proportional hazards regression. Variables with a P value < 0.05 were included in the multivariate Cox regression. A P value <0.05 was considered statistically significant.
Results
A total of 65 patients were included in the final cohort: 9 (13.9%) were ENSAT stage I, 35 (53.8%) ENSAT stage II, and 21 (32.3%) ENSAT stage III. Due to the limited cases of stage I in this cohort, patients at stage I and stage II were considered together and appropriately merged as a subgroup in the following statistical analyses. The median follow-up time was 600 days (IQR 242-893). The 2-year and 5-year survival rates were 54.6% (95%CI: 42.5-70.1%) and 33.5% (95%CI: 22.3-50.6%), respectively. Surgical details and the adjuvant treatment information were summarized in Table 1. Briefly, 63.1% of patients underwent open surgery and the other patients were treated with minimally invasive surgery (Laparoscopic or Robotic-assisted adrenalectomy).
| No of patients | Percentage | |
|---|---|---|
| Modality of diagnosis | ||
| Tumor-related symptomsª | 27 | 41.6% |
| Hormone-related symptomsb | 19 | 29.2% |
| Incidentally | 19 | 29.2% |
| Hormonal production | ||
| Cortisol | 13 | 20% |
| Others (i.e. androgens, aldosterone) | 15 | 23.1% |
| T stage | ||
| ≤5 cm | 9 | 13.8% |
| >5 cm | 37 | 56.9% |
| Infiltration into surrounding tissue | 4 | 6.2% |
| Invasion into adjacent organs | 12 | 18.5% |
| Venous tumor thrombus in vena cava or renal vein | 5 | 7.7% |
| Surgical approaches | ||
| Open | 41 | 63.1% |
| Laparoscopic | 23 | 35.4% |
| Robotic-assisted | 1 | 1.5% |
| Additional treatments | ||
| Re-operation for recurrence | 10 | 15.4% |
| Adjuvant mitotane treatment | 4 | 6.2% |
| Others | 6 | 9.2% |
| Follow-up | ||
| Median (IQR) | 600 | (242-893) |
| 2-year survival (95%CI) | 54.6% | (42.5-70.1) |
| 5-year survival (95%CI) | 33.5% | (22.3-50.6) |
ªi.e. nausea, vomiting, abdominal fullness, and backache
bi.e. Cushing syndrome, hypertension, headache, hirsutism, acne, and menopause
“Radiation therapy, radiofrequency ablation, and chemoembolization
In this cohort, only a small part of patients (n = 4) received adjuvant mitotane treatment after the operation. The other treatments include cytoreductive surgery, radiation therapy, radiofrequency ablation, and chemoembolization.
Among 65 cases, 46 (70.8%) patients presented tumor- related symptoms or hormone-related symptoms. It is interesting to note that patients diagnosed with an incidental ACC were found less likely to have an abnormal hormone secretion compared with the patients who presented with symptoms (15.8 vs 54.3%, P = 0.004). There was no sig- nificant correlation between symptoms, tumor grade, R status, and other clinicopathological parameters. The main distributions of patients with different characters are sum- marized in Table 2.
To identify the potential prognostic risks of these ACC cases, patients with different Ki67 index, symptoms, tumor grade, and R status were compared. Kaplan-Meier curves
that revealed both OS and RFS are shown in Figs. 1 and 2. Similar to the previous report [15], we found that Ki67 did provide potential prognostic value for clinical outcome. Patients with Ki67 <10%, 10-19%, and ≥20% had sig- nificantly different OS (log rank P <0.001, Fig. 1a), but not RFS (log rank P= 0.2, Fig. 1b). Meanwhile, higher grade of ACC was significantly correlated with worse OS (log rank P<0.001, Fig. 1c). And no difference of RFS was observed between grade I and grade II subgroups (log rank P= 0.7, Fig. 1d).
Notably, symptomatic ACC patients had poor OS and RFS compared with the patients diagnosed incidentally (log rank P<0.001 and P=0.005, respectively, Fig. 2a, b). Positive or unknown surgical margin status, including R1, R2, and Rx, were not related to the OS (log rank P= 0.3, Fig. 2c), but were remarkably associated with disease recurrence (log rank P = 0.005, Fig. 2d) in this ACC cohort. Furthermore, tumor grade and symptoms were found sig- nificantly correlated with the OS in the univariate analysis. ENSAT stage, symptoms, and R status were associated with RFS in the univariate model. There was no difference in survival between patients that underwent open and mini- mally invasive surgery (Table 3). In the following multi- variate model, symptom was verified as an independent risk factor both for OS (HR = 5.5, 95%CI: 1.87-16.16, P= 0.002) and RFS (HR =3.62, 95%CI: 1.28-10.24, P= 0.015). Meanwhile, tumor grade was found as another independent prognostic factor for OS (HR = 4.73, 95%CI: 2.15-10.43, P<0.001) and R status was independently associated with RFS (HR = 2.56, 95%CI:1.21-5.43, P= 0.014), respectively.
Given that the prognosis effects of GRAS parameters were previously recognized in the advanced ACC and our results also revealed a clinical significance of these factors, we fur- ther comprehensively assessed their clinical utility in stage I-III ACC. As shown in Fig. 3a and Fig. 3b, patients with a greater number of GRAS risk factors had both worse OS (log rank P<0.001) and RFS (log rank P=0.003) compared with the patients who had lower GRAS score, respectively. In addition, this prognostic difference was still significant in the pairwise comparison of patients from three different GRAS subgroups separately (Fig. 3c). Following regression analysis of ENSAT stage subgroups suggested that patients with higher GRAS score were more likely to have poor OS and RFS (Fig. 3d), especially in the earlier stage ACC subgroup (stage I/II, OS: HR = 2.7, 95%CI: 1.43-5.11 and RFS: HR = 3.31, 95%CI: 1.68-6.52, respectively).
Discussion
Identification of prognostic risks remains an urgent need for patients with ACC. Though the study of ENSAT network
| Characteristics | All | Symptoms | R status | Grade | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Yes | No | P | R1/2/X | R0 | P | II | I | P | ||
| Gender | ||||||||||
| Female | 39 | 26 | 13 | 0.37 | 13 | 26 | 0.58 | 15 | 24 | 0.34 |
| Male | 26 | 20 | 6 | 7 | 19 | 7 | 19 | |||
| Age | ||||||||||
| <50 | 47 | 34 | 13 | 0.65 | 14 | 33 | 0.78 | 16 | 31 | 0.96 |
| ≥50 | 18 | 12 | 6 | 6 | 12 | 6 | 12 | |||
| Hormone secretion | ||||||||||
| No | 37 | 21 | 16 | 0.004 | 19 | 28 | 0.92 | 13 | 24 | 0.80 |
| Yes | 28 | 25 | 3 | 11 | 17 | 9 | 19 | |||
| Tumor size(cm) | ||||||||||
| <7.5 | 35 | 26 | 9 | 0.50 | 11 | 24 | 0.91 | 10 | 25 | 0.33 |
| ≥7.5 | 30 | 20 | 10 | 9 | 21 | 12 | 18 | |||
| T stage | ||||||||||
| T1+T2 | 46 | 31 | 15 | 0.35 | 12 | 34 | 0.20 | 14 | 32 | 0.37 |
| T3 | 19 | 15 | 4 | 8 | 11 | 8 | 11 | |||
| Node stage | ||||||||||
| N0/Nx | 55 | 40 | 15 | 0.46 | 17 | 38 | 1 | 18 | 37 | 0.73 |
| N1 | 10 | 6 | 4 | 3 | 7 | 4 | 6 | |||
| ENSAT stage | ||||||||||
| I+II | 44 | 30 | 14 | 0.51 | 12 | 32 | 0.38 | 13 | 31 | 0.29 |
| III | 21 | 16 | 5 | 8 | 13 | 9 | 12 | |||
Bold values indicates statistical significant P values (P<0.05)
A
Strata + ki67: < 10%
ki67: ≥10% ~ < 20%
B
Strata + ki67: < 10%
ki67: ≥10% ~ < 20%
ki67: ≥20%
ki67: ≥20%
1.00
P < 0.001
1.00
P = 0.2
Survival probability
Survival probability
0.75
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0
400
800
1200
1600
2000
2400
2800
0
400
Overall Survival (days)
Recurrence-Free Survival (days)
800
1200
1600
2000
2400
2800
Number at risk
Number at risk
Strata
26
16
12
10
5
2
2
1
26
13
6
6
3
1
1
1
18
14
10
4
3
2
1
1
Strata
18
8
4
1
1
1
0
0
21
13
1
0
0
0
0
0
21
8
1
0
0
0
0
0
0
400
800
1200
1600
2000
2400
2800
0
400
800
1200
1600
2000
2400
2800
C
Strata
Grade: I
D
Strata
Grade: I
Grade: Il
Grade: II
Survival probability
1.00
P < 0.001
Survival probability
1.00
P = 0.7
0.75
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0
400
800
1200
1600
Overall Survival (days)
2000
2400
2800
0
400
800
1200
1600
2000
2400
2800
Recurrence-Free Survival (days)
Number at risk
Number at risk
Strata
43
29
21
13
7
4
3
2
Strata
43
20
10
7
4
2
1
1
22
14
2
1
1
0
0
0
22
9
1
0
0
0
0
0
0
400
800
1200
1600
2000
2400
2800
0
400
800
1200
1600
2000
2400
2800
A
Strata + Symptoms: No
B
Strata
Symptoms: No
Symptoms: Yes
Symptoms: Yes
Survival probability
1.00
P < 0.001
Survival probability
1.00
P = 0.005
0.75
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0
400
800
1200
1600
2000
2400
2800
0
400
800
1200
Recurrence-Free Survival (days)
1600
2000
2400
2800
Overall Survival (days)
Number at risk
Number at risk
Strata
19
13
11
8
6
3
2
2
Strata
19
12
9
6
4
2
1
1
46
30
12
6
2
1
1
0
46
17
2
1
0
0
0
0
0
400
800
1200
1600
2000
2400
2800
0
400
800
1200
1600
2000
2400
2800
C
Strata
R status: RO
D
Strata
R status: RO
R status: R1/R2/Rx
R status: R1/R2/Rx
Survival probability
1.00
P =0.3
Survival probability
1.00
P = 0.005
0.75
0.75
0.50
0.50
0.25
0.25
0.00
0.00
0
400
800
1200
1600
2000
2400
2800
0
400
800
1200
1600
2000
2400
Overall Survival (days)
Recurrence-Free Survival (days)
2800
Number at risk
Number at risk
Strata
45
29
14
9
4
2
1
0
Strata
45
22
8
5
2
1
0
0
20
14
9
5
4
2
2
2
20
7
3
2
2
1
1
1
0
400
800
1200
1600
2000
2400
2800
0
400
800
1200
1600
2000
2400
2800
| Variables | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| Hazard Ratio | 95%CI | P value | Hazard Ratio | 95%CI | P value | |
| OS | ||||||
| Gender (male) | 0.8 | 0.4-1.62 | 0.537 | |||
| Age (≥50) | 0.7 | 0.33-1.51 | 0.364 | |||
| Hormone secretion (yes) | 0.9 | 0.45-1.78 | 0.762 | |||
| Tumor Size (≥7.5) | 0.89 | 0.45-1.76 | 0.745 | |||
| T stage | 1.17 | 0.84-1.62 | 0.346 | |||
| N stage | 1.12 | 0.34-3.67 | 0.856 | |||
| Stage | 1.62 | 0.94-2.8 | 0.081 | |||
| Minimally invasive surgery | 0.9 | 0.45-1.8 | 0.765 | |||
| R status (R1/2/X) | 1.43 | 0.73-2.83 | 0.3 | |||
| Grade (II) | 4.22 | 2.04-8.73 | <0.001 | 4.73 | 2.15-10.43 | <0.001 |
| Symptoms (yes) | 5.06 | 1.76-14.58 | 0.003 | 5.5 | 1.87-16.16 | 0.002 |
| DFS | ||||||
| Gender (Male) | 0.73 | 0.34-1.59 | 0.429 | |||
| Age (≥50) | 0.85 | 0.37-1.95 | 0.708 | |||
| Hormone secretion (yes) | 1.12 | 0.53-2.36 | 0.76 | |||
| Tumor Size (≥7.5) | 1.07 | 0.5-2.26 | 0.866 | |||
| T stage | 1.42 | 0.99-2.02 | 0.054 | |||
| N stage | 0.85 | 0.2-3.6 | 0.821 | |||
| Stage | 2.04 | 1.11-3.74 | 0.021 | 1.75 | 0.93-3.32 | 0.085 |
| Minimally invasive surgery | 1.73 | 0.85-3.52 | 0.133 | |||
| R status (R1/2/X) | 2.79 | 1.33-5.88 | 0.007 | 2.56 | 1.21-5.43 | 0.014 |
| Grade (II) | 1.19 | 0.53-2.67 | 0.668 | |||
| Symptoms (yes) | 3.93 | 1.42-10.86 | 0.008 | 3.62 | 1.28-10.24 | 0.015 |
A
Strata + GRAS=1 + GRAS=2 -+ GRAS=3
Survival probability
1.00
P < 0.001
0.75
0.50
0.25
0.00
0
400
800
1200
1600
2000
2400
2800
Overall Survival (days)
Number at risk
Strata
32
20
13
10
7
4
3
2
21
18
9
4
1
0
0
0
12
5
1
0
0
0
0
0
0
400
800
1200
1600
2000
2400
2800
C
Subgroup
Hazard Ration(95%CI)
OS
GRAS 2 VS. GRAS 1
3.08(1.31-7.25)
GRAS 3 VS. GRAS 1
2.22(1.34-3.67)
GRAS 3 VS. GRAS 2
3.04(1.23-7.52)
RFS
GRAS 2 VS. GRAS 1
2.5(1.04-6)
GRAS 3 VS. GRAS 1
2.33(1.34-4.03)
GRAS 3 VS. GRAS 2
2.01(0.73-5.54)
0.50
1.0
2.0
4.0
8.0
The estimates
has provided a crucial system in prognostic stratification, there is still a lack of additional references in postoperative management of ACC patients. This study identified clinical available prognostic factors and confirmed the prognostic value of GRAS parameters in stage I-III ACC. Different from ENSAT system that is largely based on the evaluating range of tumor invasion, more factors were considered in GRAS parameters. Our data show that patients with higher GRAS score are at higher risks for tumor recurrence sur- vival and OS during their postoperative periods. We hope that this finding could be helpful in providing more infor- mation to both patients and physicians and increasing the quality of postoperative management.
GRAS parameters were firstly reported in 2015 [14]. In that retrospective study, Libé et al. identified the prognostic value of age (P<0.0001), symptoms (P<0.05), R status (P=0.001), and grade (P =0.06) in more than four hun- dred advanced ACC patients (stage III and IV) from four European countries. Following studies further validated the clinical significance of these parameters respectively. For example, through analyzing data from 13 institutions in the United States, Rossfeld et al. found that patients identified incidentally had a significant improved RFS (P=0.03), suggesting that evaluating incidentally identified or symp- tomatic ACC could be regarded as a noninvasive prognostic
B
Strata + GRAS=1 -+- GRAS=2 -+ GRAS=3
Survival probability
1.00
P = 0.003
0.75
0.50
0.25
0.00
0 400
800
1200
1600
2000
2400
2800
Recurrence-Free Survival (days)
Number at risk
Strata
32
18
9
6
4
2
1
1
21
10
2
1
0
0
0
0
12
1
0
0
0
0
0
0
0
400
800
1200
1600
2000
2400
2800
D
Subgroup
Hazard Ration(95%CI)
OS
All patients
2.76(1.67-4.56)
ENSAT stage I+II
2.7(1.43-5.11)
ENSAT stage III
2.77(1.01-7.27)
RFS
All patients
2.35(1.4-3.95)
ENSAT stage I+II
3.31(1.68-6.52)
ENSAT stage III
1.19(0.52-2.74)
0.50
1.0
2.0
4.0
The estimates
tool [16]. Another report based on the National Cancer Data Base revealed that negative, microscopically, and macro- scopically positive margin status after ACC resection was also associated with patient outcomes [13]. Furthermore, according to the European society of endocrinology clinical practice guidelines, Ki67 index was suggested to be con- sidered either at the time of initial diagnosis or when reas- sessing prognosis during follow-up [11]. Similar results were observed in our current study. Specifically, as non- invasive and clinical available parameters, symptomatic ACC, tumor grade, and R status were identified as inde- pendent prognostic factors for stage I-III patients who underwent tumor resection in our institution.
To optimize the clinical utility of GRAS parameters in ACC, we further combined these four factors and evaluated their prognostic effects in addition to ENSAT stage. Con- sidering the independent influence of symptomatic ACC, tumor grade, and R status on patient outcome was observed here, our strategy is therefore to directly assess the number of existing risk factors for each patient individually. As a result, the prognosis of patients was well distinguished according to the GRAS score. In addition, as a supplemental tool, the GRAS score indeed revealed a risk prediction potential in different subgroup of ENSAT stages, especially in the group of early stage ACC. It is important to note that
although patient age is not identified as prognostic factor in our cohort, it is still an important factor and should not be ignored. In fact, increasing age was identified to associate with poor prognosis in a 3185 patients-based multivariate analysis [17]. Moreover, our preliminary results indicated the practicability and additional prognostic value of GRAS score in postoperation ACC management. However, it is premature to conclude that GRAS score is a perfect pre- diction model in ACC due to the limited number of such a rare disease in this study.
As a kind of endocrine malignancies, hormonal hyper- secretion is commonly observed in ACC and also recog- nized as a risk factor for poor outcome. Those cortisol-, androgens- or aldosterone-related ACCs are commonly presented with hormone-secreting symptoms, such as Cushing syndrome or virilization, and diagnosed by fol- lowing discovery of an adrenal mass on imaging examine. Both Cushing’s syndrome and cortisol excess in ACC are reported to influence prognosis [18-20]. Recently, a meta- analysis [21] further confirmed the higher mortality risk of cortisol-secreting ACCs (RR: 1.71, 95% CI: 1.18-2.47). In our research, hormone secretion was associated with symptomatic ACC (P=0.004), but hormonal production was not shown prognostic effects (P = 0.762). This may be partly due to the diversity of hormonal secretion and rela- tively small proportion (12/25) of cortisol-secreting ACC in this single-center ACC cohort.
Altogether, this study provides new evidence on the prognostic value of GRAS parameters based on ACC cases from a referral center in West China. We believe that a better recognition of these noninvasive clinical indicators would largely contribute to both preoperative decision- making and postoperative patient management. Accord- ingly, patients with more GRAS risk factors could be therefore suggested a more active surveillance during their postoperation follow-up.
The retrospective nature of this study is the main lim- itation, and prospective studies are needed to further con- firm the prediction efficiency of GRAS parameters. Although it is a relatively large cohort of ACC cases from a single institution, the limited number of included patients also restricts additional evaluation of GRAS score. Parti- cularly, in this study, we have not observed an association between different R status and OS. That could be partly explained by the multidisciplinary treatments for cases with recurrence and positive R status, such as cytoreductive surgery, radiation therapy, radiofrequency ablation, and chemoembolization. However, considering the retrospective nature and small sample size, it is yet unknown whether these treatments are effective. Meanwhile, it is reported that adjuvant mitotane could prolong OS of ACC patients at high risk of recurrence and mitotane levels could also pre- dict the outcome of patients [22-24]. But due to the low
ratio (6%) of adjuvant mitotane treatment in our cohort, we are unable to assess the benefits of different postoperative therapies for patients involved in the current study.
Conclusions
For ACC patients underwent tumor resection, there is lim- ited approach to evaluate the postoperative prognostic risks. In this study, we retrospectively identified the potential prognostic factors using a large single-center cohort of ACC cases in ENSAT stage I-III. Symptomatic ACC, higher tumor grade, and positive/unknown R status were recog- nized as independent risk factors. Accordingly, GRAS parameters-based score may be helpful in outcome predic- tion and optimize the postoperative management on ACC.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical approval This work was supported by the Science and Tech- nology Foundation of the Sichuan Province (2016FZ0099 to Xin Wei and 2017SZ0123 to Zhihong Liu), and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University. The research protocol was approved by the West China Hospital of Sichuan Uni- versity Biomedical Research Ethics Committee.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. S.H. Golden, K.A. Robinson, I. Saldanha et al., Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J. Clin. Endocrinol. Metab. 94, 1853-1878 (2009)
2. T.M. Kerkhofs, R.H. Verhoeven, J.M. Van der Zwan et al., Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur. J. Cancer 49, 2579-2586 (2013)
3. S. Puglisi, P. Perotti, D. Cosentini et al., Decision-making for adrenocortical carcinoma: surgical, systemic, and endocrine management options. Expert Rev. Anticancer Ther. 18(11), 1125-1133 (2018)
4. I. Erdogan, T. Deutschbein, C. Jurowich et al., The role of surgery in the management of recurrent adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 98(1), 181-191 (2013)
5. M. Terzolo, A. Berruti, Adjunctive treatment of adrenocortical carcinoma. Curr. Opin. Endocrinol. Diabetes Obes. 15(3), 221-226 (2008)
6. M. Fassnacht, M. Terzolo, B. Allolio et al., Combination che- motherapy in advanced adrenocortical carcinoma. N. Engl. J. Med. 366(23), 2189-2197 (2012)
7. G. Abiven, J. Coste, L. Groussin et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J. Clin. Endocrinol. Metab. 91, 2650-2655 (2006)
8. M. Volante, E. Bollito, P. Sperone et al., Clinicopathological study of a series of 92 adrenocortical carcinomas: from a proposal of simplified diagnostic algorithm to prognostic stratification. Histopathology 55, 535-543 (2009)
9. A. Berruti, M. Fassnacht, H. Haak et al., Prognostic role of overt hypercortisolism in completely operated patients with adrenocor- tical cancer. Eur. Urol. 65, 832-838 (2014)
10. B.S. Miller, P.G. Gauger, G.D. Hammer et al., Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade. Langenbecks Arch. Surg. 395, 955-961 (2010)
11. M. Fassnacht, O.M. Dekkers, T. Else et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 179(4), G1-G46 (2018)
12. G.A. Margonis, Y. Kim, J.D. Prescott et al., Adrenocortical car- cinoma: impact of surgical margin status on long-term outcomes. Ann. Surg. Oncol. 23(1), 134-141 (2016)
13. K.L. Anderson Jr, M.A. Adam, S.M. Thomas et al., Impact of micro- and macroscopically positive surgical margins on survival after resection of adrenocortical carcinoma. Ann. Surg. Oncol. 25 (5), 1425-1431 (2018)
14. R. Libé, I. Borget, C.L. Ronchi et al., Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann. Oncol. 26 (10), 2119-2125 (2015)
15. F. Beuschlein, J. Weigel, W. Saeger et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resec- tion. J. Clin. Endocrinol. Metab. 100(3), 841-849 (2015)
16. K.K. Rossfeld, S.K. Maithel, J. Prescott et al., The prognostic significance of adrenocortical carcinomas identified incidentally. J. Surg. Oncol. 118(7), 1155-1162 (2018)
17. S.H. Tella, A. Kommalapati, S. Yaturu et al. Predictors of survival in adrenocortical carcinoma: an analysis from the National Cancer Database. J. Clin. Endocrinol. Metab. 103(9), 3566-3573 (2018)
18. J. Lindholm, S. Juul, J.O. Jorgensen et al., Incidence and late prognosis of Cushing’s syndrome: a population-based study. J. Clin. Endocrinol. Metab. 86, 117-123 (2001)
19. R.N. Clayton, P.W. Jones, R.C. Reulen et al., Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol. 4, 569-576 (2016)
20. O.M. Dekkers, E. Horvath-Puho, J.O. Jorgensen et al., Multi- system morbidity and mortality in Cushing’s syndrome: a cohort study. J. Clin. Endocrinol. Metab. 98, 2277-2284 (2013)
21. T. Vanbrabant, M. Fassnacht, G. Assie et al., Influence of hormonal functional status on survival in adrenocortical carcinoma: systematic review and meta-analysis. Eur. J. Endocrinol. 179(6), 429-436 (2018)
22. I. Veytsman, L. Nieman, T. Fojo, Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J. Clin. Oncol. 27(27), 4619-4629 (2009)
23. M. Terzolo, A.E. Baudin, A. Ardito et al., Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur. J. Endocrinol. 169(3), 263-270 (2013)
24. A. Calabrese, V. Basile, S. Puglisi, Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 180(6), 387-396 (2019)