EnM ENDOCRINOLOGY AND METABOLISM
Check for updates
Original Article
The Modified S-GRAS Scoring System for Prognosis in Korean with Adrenocortical Carcinoma
Sun Kyung Baek1,*, Seung Hun Lee2,*, Seung Shin Park3,4, Chang Ho Ahn5,6, Sung Hye Kong3,5, Won Woong Kim7, Yu-Mi Lee7, Su Jin Kim8, Dong Eun Song9, Tae-Yon Sung7, Kyu Eun Lee8, Jung Hee Kim3,4, Kyeong Cheon Jung10, Jung-Min Koh2
1Department of Internal Medicine, Kyung Hee University Hospital; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine; 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine; 4Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, Seoul; 5Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam; ‘Lunit; 7Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine; 8Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine; ‘Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine; 10Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
Background: Adrenocortical carcinomas (ACCs) are rare tumors with aggressive but varied prognosis. Stage, Grade, Resection sta- tus, Age, Symptoms (S-GRAS) score, based on clinical and pathological factors, was found to best stratify the prognosis of Europe- an ACC patients. This study assessed the prognostic performance of modified S-GRAS (mS-GRAS) scores including modified grade (mG) by integrating mitotic counts into the Ki67 index (original grade), in Korean ACC patients.
Methods: Patients who underwent surgery for ACC between January 1996 and December 2022 at three medical centers in Korea were retrospectively analyzed. mS-GRAS scores were calculated based on tumor stage, mG (Ki67 index or mitotic counts), resec- tion status, age, and symptoms. Patients were divided into four groups (0-1, 2-3, 4-5, and 6-9 points) based on total mS-GRAS score. The associations of each variable and mS-GRAS score with recurrence and survival were evaluated using Cox regression analysis, Harrell’s concordance index (C-index), and the Kaplan-Meier method.
Results: Data on mS-GRAS components were available for 114 of the 153 patients who underwent surgery for ACC. These 114 pa- tients had recurrence and death rates of 61.4% and 48.2%, respectively. mS-GRAS score was a significantly better predictor of re- currence (C-index=0.829) and death (C-index=0.747) than each component (P<0.05), except for resection status. mS-GRAS scores correlated with shorter progression-free survival (P=8.34E-24) and overall survival (P=2.72E-13).
Conclusion: mS-GRAS scores showed better prognostic performance than tumor stage and grade in Asian patients who underwent surgery for ACC.
Keywords: Adrenocortical carcinoma; Prognosis; Survival analysis; Recurrence
Received: 6 July 2024, Revised: 25 July 2024, Accepted: 16 August 2024
Corresponding author: Jung Hee Kim
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-4839, Fax: +82-2-764-2199, E-mail: jhee1@snu.ac.kr
Copyright @ 2024 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Com- mons Attribution Non-Commercial License (https://creativecommons.org/ licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu- tion, and reproduction in any medium, provided the original work is properly cited.
*These authors contributed equally to this work.
INTRODUCTION
Adrenocortical carcinomas (ACCs) are very rare malignancies with the incidence of 0.7 to 2.0 per million per year [1,2] and about 1.0 per million per year in Korea [3]. Prognosis of ACC vary widely by 5-year overall survival (OS) rates range from 10% to 60% [4,5], despite generally poor prognosis due to the aggressive behavior and tendency to recur of these tumors. A reg- istry-based nationwide survey of 204 patients in Korea showed that the 5-year OS and disease-specific survival (DSS) rates were 64.5% and 70.6%, respectively [6]. Surgery remains the only cu- rative modality in the treatment of ACC. However, more than 50% ACC underwent initial complete resection will still develop disease recurrence or metastasis [7], and 15% die within 2 years [5]. So, reliable determination of patient prognosis after resection is critical to guide the frequency of follow-up examinations and adjuvant treatment, as well as to more accurately counsel patients regarding their long-term outcomes.
Recently, several clinical parameters, histopathological, path- ological, and surgical related factors were found to be correlated with the prognosis of ACC patients [8,9]. The European Net- work for the Study of Adrenal Tumours (ENSAT) staging sys- tem is widely used as the standard prognostic factor in ACC [5,8,10]. Five-year survival is 60%-80% for tumors limited to adrenal, 35%-50% for locally advanced disease, and much lower in case of metastasis [8]. Other prognostic factors include resection status [11-13], Ki67 proliferation index [14], and mi- totic counts [8,15,16]. The European Society of Endocrinology- ENSAT guidelines have stratified the risk of recurrence based on tumor stage, resection status, and Ki-67 index (or mitotic counts). Although older age and hypercortisolism are associated with poorer OS [17-19], their prognostic value remains uncer- tain [20,21].
Although individual clinical and histopathological prognostic markers are limited in predicting patient prognosis, their combi- nations may have better prognostic accuracy in patients with ACC. The prognostic value of the GRAS components, includ- ing tumor grade (G; Weiss score >6 and/or Ki67 index ≥20%), resection status (R), age (A), and tumor- or hormone-related symptoms (S), was initially evaluated in 444 patients with ad- vanced ACC [22]. Stage, Grade, Resection status, Age, Symp- toms (S-GRAS) scores, a modified form of the GRAS classifi- cation that includes ENSAT stage and focuses on Ki67 index for grading, allowed better stratification than its individual clinical and histopathological characteristics in 107 patients [23]. Re- cently, S-GRAS scores showed a prognostic performance supe-
rior to that of tumor stage and Ki67 index in predicting progres- sion-free survival (PFS) and DSS in 942 European patients with ACC [24]. Less is known, however, about the prognostic per- formance of S-GRAS scores in Asian patients who undergo sur- gery for ACC. Understanding the clinical characteristics and prognostic stratification of ACC in Asian patients is essential for their proper management. The present study therefore investi- gated the prognostic utility of modified S-GRAS (mS-GRAS) scores, which incorporate a modified grade by integrating mi- totic counts with the Ki67 index, in Korean patients undergoing adrenalectomy for ACC, prompted by the limited availability of Ki67 index data.
METHODS
Patients and data collection
This retrospective, multicenter study included patients who un- derwent surgery for ACC at three tertiary hospitals in Korea, Asan Medical Center (AMC), Seoul National University Hospi- tal (SNUH), and Seoul National University Bundang Hospital (SNUBH), and was part of the Korean Adrenal Disorder Study (KADS; clinicaltrial.gov No. 06229405). Patients aged ≥18 years diagnosed with or treated for histologically confirmed ACC at these three tertiary hospitals between January 1, 1996 and December 31, 2022 and available for follow-up were re- cruited. Only conventional subtype of ACC included [25]. The study protocol conformed to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Boards of AMC (No. 2022-1496), SNUH (No. 2204-155-1320), and SNUBH (No. B-2207-769-401), which waived requirements for written informed consent owing to the retrospective nature of this study.
Data recorded from patient records included age, sex, age at diagnosis, body mass index, tumor size, modality of tumor di- agnosis (e.g., incidental; symptom-related, either to the tumor mass or hormone secretions; or other/unknown), ENSAT stage, treatment (surgery, adjuvant mitotane, or palliative mitotane), and date of adrenalectomy. Other factors included resection sta- tus (with R0 indicating complete resection, RX indicating un- known resection status, R1 indicating the removal of all macro- scopic disease, accompanied by microscopic residual disease, and R2 indicating macroscopic residual disease); mitotic counts; Ki67 index; date of disease recurrence after primary surgery; and date of last visit or death. Symptoms were defined as hor- mone-related if they were associated with excess adrenal hormone(s) (e.g., glucocorticoids, mineralocorticoids, or andro-
EnM
gen), tumor-related if they were associated with a mass effect (e.g., abdominal pain), or systemic cancer-related (e.g., fatigue or weight loss).
S-GRAS scores of patients undergoing adrenalectomy were calculated as described [23,24]: ENSAT stage (S; stage 1 or 2=0 points; stage 3=1 point; stage 4=2 points), grade based on Ki67 index (G; 0%-9%=0 point; 10%-19%=1 point; ≥20%=2 points), resection status of the primary tumor (R0=0 points; RX=1 point; R1=2 points; R2=3 points), age at diagnosis (A; <50 years=0 point; ≥50 years=1 point), and hormone, tumor, or systemic cancer-related symptoms at presentation (S; no=0 point; yes=1 point). If Ki67 index was not available, it could be replaced by mitotic count [8]. Modified G based on mitotic counts in patients without information on Ki67 index was scored as 0 points for ≤5 mitoses/50 high powered fields (HPF), 1 point for 6-20 mitoses/50 HPF, and 2 points for >20 mitoses/50 HPF [25]. mS-GRAS scores ranged from 0 to 9 and were categorized into four groups, consisting of patients with mS-GRAS scores of 0-1, 2-3, 4-5, and 6-9 points [23,24].
Endpoints
PFS and OS were determined by retrospective review of medi- cal records at each institution. PFS was defined as the time from primary tumor resection to the first radiological evidence of re- lapse or death from any cause, and OS was defined as the time from diagnosis of ACC until death from any cause.
Statistical analysis
Continuous variables are presented as the median (interquartile range [IQR]) and categorical variables are presented as the number (percentage). The prognostic effects of total mS-GRAS score, its individual components, and groups of mS-GRAS scores for PFS and OS were evaluated by univariable Cox re- gression analysis, with results reported as hazard ratios (HRs), 95% confidence intervals (CIs), and P values. The discrimina- tive performances of total mS-GRAS score and groups of mS- GRAS scores were compared with the performances of single components of mS-GRAS scores using Harrell’s Concordance index (C-index) [26]. Harrell’s C-index is defined as the propor- tion of patient pairs in which the predicted and observed surviv- al outcomes are in agreement with respect to rank, with a higher C-index indicative of better model discrimination. PFS and OS for each of the groups of mS-GRAS score groups were deter- mined by the Kaplan-Meier method and compared by log-rank tests. All statistical analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria),
with P values <0.05 defined as statistically significant.
RESULTS
Clinical characteristics of patients with available mS- GRAS data
Of the 153 patients who underwent adrenalectomy for ACC be- tween January 1996 and December 2022 at three medical cen- ters in Korea, 114 (74.5%) had available mS-GRAS data (Table
| Table 1. Characteristics of Patients with ACC Included in mS- GRASª Analysis (n=114) | ||
|---|---|---|
| Variable | Available | Value |
| Women | 114 (100.0) | 67 (58.8) |
| Age at diagnosis, yr | 114 (100.0) | 51.0 (41.0-62.0) |
| ≥50 | 114 (100.0) | 61 (53.5) |
| BMI, kg/m2 | 105 (92.1) | 23.6 (22.0-25.9) |
| Size, cm | 111 (97.4) | 7.9 (5.5-11.0) |
| Symptom | 111 (97.4) | 55 (48.2) |
| ENSAT stage | 114 (100.0) | |
| 1 | 13 (11.4) | |
| 2 | 54 (47.4) | |
| 3 | 17 (14.9) | |
| 4 | 30 (26.3) | |
| Ki67 index or mitotic count | ||
| Ki67 index | 79 (69.3) | 10.0 (4.0-18.5) |
| Mitotic counts/50 HPF | 96 (84.2) | 20.0 (5.0-46.5) |
| Additional treatmentb | 114 (100.0) | 61 (53.5) |
| Adjuvant mitotane | 114 (100.0) | 35 (30.7) |
| Mitotane dose, mg | 32 (94.1) | 2,000 (1,500-3,000) |
| Mitotane level, mg/L | 9 (26.5) | 11.8 (7.1-13.5) |
| Mitotane blood level > 14 mg/L | 9 (26.5) | 6 (66.7) |
| Resection status | 114 (100.0) | |
| R0 | 70 (61.4) | |
| RX | 7 (6.1) | |
| R1 | 7 (6.1) | |
| R2 | 30 (26.3) | |
Values are expressed as number (%) or median (interquartile range). ACC, adrenocortical carcinoma; mS-GRAS, modified Stage, Grade, Resection status, Age, Symptom; BMI, body mass index; ENSAT, Eu- ropean Network for the Study of Adrenal Tumour; HPF, high powered field.
amS-GRAS components: ENSAT stage (S), modified grading (mG), re- section status (R), age (A), and tumor- or hormone-related symptoms (S); bAdditional treatment included the adjuvant treatment with mitotane, additional operation, and other chemotherapy/radiation.
1). These patients were followed-up for a median 58.8 months (range, 1.4 to 204.6). Of these 114 patients, 60 (52.6%) were aged ≥50 years, and 54 (47.4%) had symptoms. Thirteen (11.4%), 54 (47.4%), 17 (14.9%), and 30 (26.3%) patients had ENSAT stages 1, 2, 3, and 4 disease, respectively. Thirty-five (30.7%) patients received adjuvant mitotane, at a median dose of 2,000 mg. Blood levels of mitotane were measured in nine (26.5%) of these 35 patients, with six (66.7%) of these nine hav-
ing mitotane levels over 14 mg/L. Relapse occurred in 70 (60.5%) of the 114 patients, at a median 23.0 months (IQR, 12.1 to 39.1) (data not shown). Locoregional recurrence occurred in nine (7.9%) patients, distant metastases in 45 (39.5%), and both in 16 (14.0%). Fifty-five (48.2%) patients died at a median 120.0 months (IQR, 67.9 to not reached).
The proportions of women, symptomatic patients, and patients with ENSAT stage 1 were higher, whereas the proportion of pa-
| Scores | Variable | No.(%) | No. of relapse (%) | HR (95% CI) | P value | Harrell's C-index (95% CI) | P value® | P valued |
|---|---|---|---|---|---|---|---|---|
| S | ENSAT stage | 114 (100.0) | 70 (61.4) | 0.782 (0.716-0.833)e | 0.037e | 0.115 | ||
| 0 | 1-2 | 67 (58.8) | 33 (49.3) | Ref | ||||
| 1 | 3 | 17 (14.9) | 7 (41.2) | 1.12 (0.49-2.56) | 0.786 | |||
| 2 | 4 | 30 (26.3) | 30 (100.0) | NA | 0.994 | |||
| Modified G | Ki67 index (%) or mitotic count, mitoses/50 HPF | 114 (100.0) | 70 (61.4) | 0.644 (0.558-0.715)e | <0.001e | <0.001e | ||
| 0 | 0-9 or ≤5 | 44 (38.6) | 21 (47.7) | Ref | ||||
| 1 | 10-19 or 6-20 | 33 (28.9) | 21 (63.6) | 1.67 (0.91-3.07) | 0.097 | |||
| 2 | ≥20 or>20 | 37 (32.5) | 28 (75.7) | 2.99 (1.67-5.35)e | <0.001e | |||
| R | Resection status | 114 (100.0) | 70 (61.4) | 0.814 (0.755-0.867)e | 0.333 | 0.832 | ||
| 0 | R0 | 70 (61.4) | 30 (42.9) | Ref | ||||
| 1 | RX | 7 (6.1) | 6 (85.7) | 3.29 (1.35-8.03)e | 0.009€ | |||
| 2 | R1 | 7 (6.1) | 4 (57.1) | 2.15 (0.76-6.14) | 0.151 | |||
| 3 | R2 | 30 (26.4) | 30 (100.0) | NA | 0.995 | |||
| A | Age, yr | 114 (100.0) | 70 (61.4) | 0.526 (0.480-0.583) | <0.001e | <0.001e | ||
| 0 | <50 | 54 (47.4) | 35 (64.8) | Ref | ||||
| 1 | ≥50 | 60 (52.6) | 35 (58.3) | 0.89 (055-1.42) | 0.614 | |||
| S | Symptom | 114 (100.0) | 70 (61.4) | 0.628 (0.563-0.691)e | <0.001e | <0.001e | ||
| 0 | No | 60 (52.6) | 28 (46.7) | Ref | ||||
| 1 | Yes | 54 (47.4) | 42 (77.8) | 2.26 (1.40-3.65)e | 0.001e | |||
| mS-GRAS | 114 (100.0) | 70 (61.4) | 1.90 (1.65-2.18)e | <0.001e | 0.829 (0.759-0.880)e | Ref | ||
| mS-GRAS group | 114 (100.0) | 70 (61.4) | 0.815 (0.751-0.864)e | Ref | ||||
| 0-1 | 28 (24.6) | 10 (35.7) | Ref | |||||
| 2-3 | 43 (37.7) | 22 (51.2) | 1.84 (0.87-3.90) | 0.109 | ||||
| 4-5 | 11 (9.6) | 7 (63.6) | 3.18 (1.19-8.48) | 0.021e | ||||
| 6-9 | 32 (28.1) | 31 (96.9) | 69.51 (25.99-185.86)e | <0.001e |
PFS, progression-free survival; HR, hazard ratio; mS-GRAS, modified Stage, Grade, Resection status, Age, Symptom; CI, confidence interval; ENSAT, European Network for the Study of Adrenal Tumour; HPF, high powered field; R0, complete resection; RX, uncertain resection; R1, microscopic incom- plete resection; R2, macroscopic incomplete resection.
amS-GRAS components: ENSAT stage (S), modified grading (modified G), resection status (R), age (A), and tumor- or hormone-related symptoms (S); bPatients subjected to mS-GRAS analysis who underwent adrenalectomy and had data for all variables included in modified S-GRAS scores; “P values comparing Harrell’s C-index of the variable with that of the mS-GRAS score; dP values comparing Harrell’s C-index of the variable with that of the S- GRAS groups; eSignificant results (P<0.05).
tients with ENSAT stage 3 were lower in the 114 patients with available mS-GRAS data than in the 39 without available mS- GRAS data (Supplemental Table S1). In addition, patients with available mS-GRAS data were younger in age and had larger sized tumors than those without available mS-GRAS data.
Prognostic performance of total mS-GRAS score, its individ- ual components, and categories of mS-GRAS scores on PFS ENSAT stage 4 (vs. ENSAT stage 1-2), modified G2 (vs. modi- fied G0), RX and R2 (vs. R0), and symptoms (vs. no symptoms) were associated with PFS, whereas age was not (Table 2). Eval- uation of all 153 patients with ACC who underwent adrenalec- tomy showed that ENSAT stage 3 and 4 (vs. ENSAT stage 1-2), RX and R2 (vs. R0), and symptoms (vs. no symptoms) were as- sociated with relapse, whereas age was not (Supplemental Table S2).
Discrimination statistics using Harrell’s C-index showed that total mS-GRAS score (C-index=0.829; 95% CI, 0.759 to 0.880) was superior to each of its components (P<0.05 each), except for R (P=0.333), in predicting relapse (Table 2). Groups of mS- GRAS scores (C-index=0.815; 95% CI, 0.751 to 0.864) also showed better prognostic performance for relapse than each of its components (P<0.05 each), except for ENSAT stage (P= 0.115) and R (P=0.832) (Table 2). Compared with patients in the mS-GRAS 0-1 group, the HRs of the mS-GRAS 6-9, 4-5, and 2-3 groups for relapse were 69.51 (95% CI, 25.99 to 185.86;
P<0.001), 3.18 (95% CI, 1.19 to 8.48; P=0.021), and 1.84 (95% CI, 0.87 to 3.90; P=0.109), respectively. Groups of mS-GRAS score also correlated significantly with shorter PFS (P=8.34E-24) (Fig. 1).
Prognostic performance of total S-GRAS score, its original grading components, and categories of S-GRAS scores on PFS
In 79 patients with available Ki67 index as original grading component of S-GRAS to investigate the prognostic perfor- mance of original S-GRAS score, S-GRAS score (C-in- dex=0.805; 95% CI, 0.720 to 0.870) and groups of S-GRAS scores (C-index=0.803; 95% CI, 0.717 to 0.864) showed better prognostic performance for relapse than grading compartment using Ki67 index of original S-GRAS score (C-index=0.648; 95% CI, 0.552 to 0.731; P<0.001 each) (Supplemental Table S3).
Prognostic performance of total mS-GRAS score, its individual components, and categories of mS-GRAS scores on OS
ENSAT stage 4 (vs. ENSAT stages 1-2), modified G2 (vs. mod- ified G0), and RX and R2 (vs. R0) were all associated with OS, whereas age and symptom were not (Table 3). In all 153 pa- tients with ACC who underwent adrenalectomy showed that
1.00
1.00
Modified S-GRAS score
Progression-free survival probability
Modified S-GRAS score
0-1
0-1
2-3
2-3
4-5
0.75
4-5
Overall survival probability
6-9
0.75
L
6-9
L
*+m
0.50
1
0.50
1
0.25
P=8.34E-24
0.25
P=2.72E-13
0.00
A
0.00
B
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
0
12
24
36
48
60
72
84
96
108
120
132
144
56
.68
1
180 19
22 1922 4
Observation periods (mo)
Observation periods (mo)
Number at risk
Number at risk
0-1
28
24
20
18
13
11
8
6
3
2
2
2
2
2
1
0
0-1
28
28
26
25
24
19
18
18
16
12
9
8
4
3
3
2
1
0
0
0
2-3
43
30
22
17
15
12
9
7
4
4
2
2
1
1
0
0
2-3 43
40
38
34
31
27
26
22
20
19
18
14
11
6
5
3
3
1
0
0
4-5
11
7
5
2
1
1
0
0
0
0
0
0
0
0
0
0
4-5
11
11
9
8
7
6
5
4
2
2
1
1
0
0
0
0
0
0
0
0
6-9
32
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6-9
32
20
12
8
5
4
3
3
2
2
2
1
1
0
0
0
0
0
0
0
EnM Baek SK, et al.
| Scores | Variable | No. (%) | No. of death (%) | HR (95% CI) | P value | Harrell's C-index (95% CI) | P value® | P valued |
|---|---|---|---|---|---|---|---|---|
| S | ENSAT stage | 114 (100.0) | 55 (48.2) | 0.700 (0.627-0.754)e | 0.047e | 0.050€ | ||
| 0 | 1-2 | 67 (58.2) | 22 (32.8) | Ref | ||||
| 1 | 3 | 17 (14.9) | 8 (47.1) | 2.36 (0.62-8.94) | 0.205 | |||
| 2 | 4 | 30 (26.3) | 25 (83.3) | 8.23 (2.47-27.50)e | 0.001e | |||
| Modified G | Ki67 index (%) or mitotic count, mitoses/50 HPF | 114 (100.0) | 55 (48.2) | 0.634 (0.553-0.694)e | 0.001e | 0.004e | ||
| 0 | 0-9 or ≤5 | 44 (38.6) | 14 (31.8) | Ref | ||||
| 1 | 10-19 or 6-20 | 33 (28.9) | 14 (42.4) | 1.41 (0.67-2.96) | 0.365 | |||
| 2 | ≥20 or>20 | 37 (32.5) | 27 (73.0) | 3.44 (1.79-6.58)e | <0.001e | |||
| R | Resection status | 114 (100.0) | 55 (48.2) | 0.713 (0.636-0.769)e | 0.148 | 0.141 | ||
| 0 | R0 | 70 (61.4) | 21 (30.0) | Ref | ||||
| 1 | RX | 7 (6.1) | 5 (71.4) | 2.91 (1.09-7.75)e | 0.033e | |||
| 2 | R1 | 7 (6.1) | 4 (57.1) | 2.39 (0.82-6.96) | 0.112 | |||
| 3 | R2 | 30 (26.4) | 25 (83.3) | 6.33 (3.48-11.50)e | <0.001e | |||
| A | Age, yr | 114 (100.0) | 55 (48.2) | 0.545 (0.490-0.612) | <0.001e | <0.001e | ||
| 0 | <50 | 54 (47.4) | 22 (40.7) | Ref | ||||
| 1 | ≥50 | 60 (52.6) | 33 (55.0) | 1.56 (0.91-2.69) | 0.106 | |||
| S | Symptom | 114 (100.0) | 55 (48.2) | 0.551 (0.484-0.613) | <0.001e | <0.001e | ||
| 0 | No | 60 (52.6) | 27 (45.0) | Ref | ||||
| 1 | Yes | 54 (47.4) | 28 (51.9) | 1.32 (0.78-2.25) | 0.298 | |||
| mS-GRAS | 114 (100.0) | 55 (48.2) | 1.37 (1.25-1.50)e | <0.001e | 0.747 (0.684-0.805)e | Ref | ||
| mS-GRAS group | 114 (100.0) | 55 (48.2) | 0.746 (0.673-0.795)e | Ref | ||||
| 0-1 | 28 (24.6) | 5 (17.9) | Ref | |||||
| 2-3 | 43 (37.7) | 17 (39.5) | 2.32 (0.85-6.28) | 0.099 | ||||
| 4-5 | 11 (9.6) | 5 (45.5) | 3.22 (0.93-11.15) | 0.065 | ||||
| 6-9 | 32 (28.1) | 28 (87.5) | 13.14 (5.01-34.50)e | <0.001e |
OS, overall survival; HR, hazard ratio; mS-GRAS, modified Stage, Grade, Resection status, Age, Symptom; CI, confidence interval; ENSAT, European Network for the Study of Adrenal Tumour; HPF, high powered field; R0, complete resection; RX, uncertain resection; R1, microscopic incomplete resec- tion; R2, macroscopic incomplete resection.
amS-GRAS components: ENSAT stage (S), modified grading (modified G), resection status (R), age (A), and tumor- or hormone-related symptoms (S); bPatients subjected to mS-GRAS analysis who underwent adrenalectomy and had data for all variables included in mS-GRAS scores; “P values compar- ing Harrell’s C-index of the variable with that of the mS-GRAS score; dP values comparing Harrell’s C-index of the variable with that of the S-GRAS groups; eSignificant results (P<0.05).
ENSAT stages 3 and 4 (vs. ENSAT stages 1-2), R2 (vs. RO), and symptoms (vs. no symptoms) were also associated with death, whereas age was not (Supplemental Table S2).
Discrimination statistics using Harrell’s C-index showed that total mS-GRAS score (C-index=0.747; 95% CI, 0.684 to 0.805) was superior to each of its components (P<0.05 each), except R (P=0.148), in predicting death (Table 3). Group of mS-GRAS score (C-index=0.746; 95% CI, 0.673 to 0.795) also showed
better prognostic performance than each of its components (P<0.05 each), except R (P=0.141), in predicting death (Table 3). Compared with patients in the mS-GRAS 0-1 group, the HRs of the mS-GRAS 6-9, 4-5, and 2-3 groups for death were 13.14 (95% CI, 5.01 to 34.50; P<0.001), 3.22 (95% CI, 0.93 to 11.15; P=0.065), and 2.32 (95% CI, 0.85 to 6.28; P=0.099), re- spectively. Groups of mS-GRAS scores correlated significantly with shorter OS (P=2.72E-13) (Fig. 1).
Prognostic performance of total S-GRAS score, its original grading components, and categories of S-GRAS scores on OS
Compared with grading (C-index=0.629; 95% CI, 0.534 to 0.714), S-GRAS score (C-index=0.727; 95% CI, 0.633 to 0.798; P=0.024) and S-GRAS group (C-index=0.740; 95% CI, 0.640 to 0.802; P=0.035) showed better prognostic performance for death in the 79 patients with available K67 index data (Supple- mental Table S4).
DISCUSSION
To our knowledge, this study is the first to validate the prognos- tic performance of mS-GRAS score-a minimally modified ver- sion of the S-GRAS scoring system, based on clinical and histo- pathological characteristics, for both PFS and OS in Asian pa- tients with ACC. The mS-GRAS score was found to be superior to ENSAT staging, grading, age, and symptoms, but not to re- section status, in predicting OS and PFS in Asian patients with ACC. Grouping of mS-GRAS scores was also superior to grad- ing, age, and symptoms in the prognosis discrimination of both PFS and OS. These findings indicated that the mS-GRAS scor- ing system might be useful in predicting post-surgical prognosis in patients with ACC.
Several clinical and histopathological characteristics have been associated with the prognosis of ACC patients following surgery. ENSAT stage, reflecting the extent of the tumor, was found to be the most important prognostic factor [5,8,10]. Other major prognostic factors include resection status [11-13], Ki67 index [8,14-16], and mitotic counts [8,27]. Guidelines have therefore stratified the risk of recurrence based on tumor stage, resection status, and Ki-67 index (or mitotic count) [8], with a recent study reporting that the prognostic performance of S- GRAS was superior to that of tumor stage, resection status, and Ki67 index in predicting PFS and DSS in European patients with ACC [24]. Furthermore, a single-center study involving 51 patients in China showed that groups of S-GRAS scores were predictive of cancer-specific survival (CSS) [28]. That study, however, found that of the parameters used to calculate S- GRAS score, only ENSAT stage was significantly associated with CSS. Therefore, to our knowledge, the present study is the first to validate the superior prognostic performance of the mS- GRAS score, compared with ENSAT staging and grading (Ki- 67 index or mitotic counts), for both PFS and OS in Asian pa- tients with ACC.
In agreement with the results of previous studies showing that
adequate resection status, including locoregional lymph node dissection and tumor thrombus embolectomy, improved both diagnostic accuracy and therapeutic outcome [8,29,30], resec- tion status was significantly associated with PFS and OS in the present study. In addition, S-GRAS score was superior to resec- tion status in predicting PFS and DSS [24]. The present study showed that Harrell’s C-index of mS-GRAS score was numeri- cally higher than that of resection status, but the difference was not statistically significant. Although R1 status has been associ- ated with a poorer prognosis than RX [24], R1 status was not significantly associated with PFS and OS in the present study. It is difficult to exactly quantify the impact of resection status on the risk of relapse and death due to lack of accurate reporting and frequent RX reports [9]. In the present study, the small number of patients with R1 status (seven of 114, 6.1%) and the potential misclassification of R2 as RX status due to the inclu- sion of patients with ACC beginning in 1996 may explain the lack of statistical significance between the prognostic perfor- mances of mS-GRAS score and resection status.
Hypercortisolism was also reported to be prognostic of clini- cal outcomes in patients with ACC [17-19]. Because advanced age was reported to be a prognostic factor [31], age was includ- ed in the mS-GRAS scoring system. Nevertheless, the present study found that mS-GRAS scores were superior to symptoms and age in predicting both PFS and OS. The presence of symp- toms was associated with relapse but not with death in the 114 patients with mS-GRAS scores. By contrast, the presence of symptoms was associated with both relapse and death in the 153 patients who underwent adrenalectomy. In both groups, howev- er, advanced age was not associated with relapse or death, in agreement with a study showing that age was the only factor in S-GRAS scores not associated with PFS and DSS [24]. And a registry-based nationwide survey of 204 patients in Korea showing that age was not associated with mortality [6]. The cut- off value of 50 years was derived from the median age of study subjects in the ENSAT study [22]. Taken together, these find- ings suggest the need for additional studies assessing whether advanced age is a prognostic factor in patients with ACC.
In this study, approximately 65% of patients who underwent adrenalectomy experienced relapse and 90% of the patients who experienced relapse showed recurrence of distant metastases. Mitotane is the mainstay of adjuvant therapy in ACC, with ret- rospective studies showing that mitotane treatment was associ- ated with significantly longer PFS and OS [32]. The utility of adjuvant mitotane for all patients with ACC is unclear, as stud- ies have reported conflicting results; mitotane administration is
EnM
cumbersome, requiring complex hormone replacement, the need for careful monitoring, and the potential toxicity of this re- agent; and the lack of reliable markers predicting response to treatment [33,34]. Currently, adjuvant mitotane is proposed for patients considered at high risk of recurrence (Ki67 index ≥ 10%, RX-R1, and/or ENSAT stage 3-4) [8,9,16]. S-GRAS scores of 4-5 have been associated with longer PFS in mitotane- treated patients [24]. Furthermore, an open-label, parallel, ran- domized, phase 3 (ADIUVO) trial found that adjuvant mitotane might not be indicated in patients with low to intermediate risk of recurrence (R0, ENSAT stage I-III, and Ki-67 ≤10%) [34]. These findings suggested that S-GRAS score can be used to stratify patients more likely to benefit from adjuvant mitotane.
The present study had several limitations, including its retro- spective design. In addition, because Ki-67 indices were ob- tained for only 79 (51.6%) of the 153 patients who underwent adrenalectomy, a modified grading was used, consisting of mi- totic counts and Ki-67 indices. Total S-GRAS score and S- GRAS score groups by original grading using only the Ki-67 index were associated with PFS and OS. Third, we could not analyze the potential use of mS-GRAS score to stratify patients more likely to benefit from adjuvant mitotane.
In conclusion, the present study found that the prognostic per- formance of the mS-GRAS scoring system was superior to that of tumor stage and proliferation activity, including Ki67 index or mitotic count, in Korean patients who underwent surgery for ACC. The S-GRAS scoring system may be useful in predicting the prognosis of Asian patients who undergo surgery for ACC.
CONFLICTS OF INTEREST
Chang Ho Ahn in Lunit as a medical director and has a stock option in the firm. Jung Hee Kim is a deputy editor of the jour- nal. But she was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
ACKNOWLEDGMENTS
We thanked Sookkyeong Seo for the data collection. This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare of the Republic of Korea (Project No. HI22C0049, HI21C0032).
AUTHOR CONTRIBUTIONS
Conception or design: S.H.L., J.H.K. Acquisition, analysis, or interpretation of data: S.K.B., S.H.L., S.S.P., C.H.A., S.H.K., W.W.K., Y.M.L., S.J.K., D.E.S., T.Y.S., K.E.L., J.H.K., K.C.J., J.M.K. Drafting the work or revising: S.K.B., S.H.L., J.H.K. Fi- nal approval of the manuscript: S.K.B., S.H.L., S.S.P., C.H.A., S.H.K., W.W.K., Y.M.L., S.J.K., D.E.S., T.Y.S., K.E.L., J.H.K., K.C.J., J.M.K.
ORCID
Sun Kyung Baek https://orcid.org/0000-0002-1080-7241 Seung Hun Lee https://orcid.org/0000-0003-0496-247X Jung Hee Kim https://orcid.org/0000-0003-1932-0234
REFERENCES
1. Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Ex- tent of disease at presentation and outcome for adrenocorti- cal carcinoma: have we made progress? World J Surg 2006; 30:872-8.
2. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, Dieleman J, Kerstens MN, Links TP, et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer 2013;49:2579-86.
3. National Cancer Center. Annual report of cancer statistics in Korea in 2019 [Internet]. Goyang: National Cancer Center; 2021 [cited 2024 Sep 5]. Available from: http://ncc.re.kr/ cancerStatsList.ncc?searchKey=total&search Value=&page Num=1.
4. Else T, Williams AR, Sabolch A, Jolly S, Miller BS, Ham- mer GD. Adjuvant therapies and patient and tumor charac- teristics associated with survival of adult patients with adre- nocortical carcinoma. J Clin Endocrinol Metab 2014;99: 455-61.
5. Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willen- berg HS, Beuschlein F, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classifica- tion for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 2009;115:243-50.
6. Lim JS, Lee SE, Kim JH, Kim JH. Characteristics of adre- nocortical carcinoma in South Korea: a registry-based na- tionwide survey. Endocr Connect 2020;9:519-29.
7. Calabrese A, Basile V, Puglisi S, Perotti P, Pia A, Saba L, et al. Adjuvant mitotane therapy is beneficial in non-metastatic
mS-GRAS Score for Prognosis of ACC in Asians
EnM
adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 2019;180:387-96.
8. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Net- work for the Study of Adrenal Tumors. Eur J Endocrinol 2018;179:G1-46.
9. Terzolo M, Fassnacht M. Endocrine tumours: our experi- ence with the management of patients with non-metastatic adrenocortical carcinoma. Eur J Endocrinol 2022;187:R27- 40.
10. Lughezzani G, Sun M, Perrotte P, Jeldres C, Alasker A, Is- barn H, et al. The European Network for the Study of Adre- nal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur J Cancer 2010;46:713-9.
11. Erdogan I, Deutschbein T, Jurowich C, Kroiss M, Ronchi C, Quinkler M, et al. The role of surgery in the management of recurrent adrenocortical carcinoma. J Clin Endocrinol Metab 2013;98:181-91.
12. Johanssen S, Hahner S, Saeger W, Quinkler M, Beuschlein F, Dralle H, et al. Deficits in the management of patients with adrenocortical carcinoma in Germany. Dtsch Arztebl Int 2010;107:885-91.
13. Margonis GA, Kim Y, Prescott JD, Tran TB, Postlewait LM, Maithel SK, et al. Adrenocortical carcinoma: impact of sur- gical margin status on long-term outcomes. Ann Surg Oncol 2016;23:134-41.
14. Beuschlein F, Weigel J, Saeger W, Kroiss M, Wild V, Daf- fara F, et al. Major prognostic role of Ki67 in localized adre- nocortical carcinoma after complete resection. J Clin Endo- crinol Metab 2015;100:841-9.
15. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev 2014;35:282-326.
16. Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Foucha- rdiere C, Haak HR, et al. Adrenocortical carcinomas and ma- lignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:1476-90.
17. Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, 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 Endo- crinol Metab 2006;91:2650-5.
18. Berruti A, Fassnacht M, Haak H, Else T, Baudin E, Sperone P, et al. Prognostic role of overt hypercortisolism in com- pletely operated patients with adrenocortical cancer. Eur Urol 2014;65:832-8.
19. Vanbrabant T, Fassnacht M, Assie G, Dekkers OM. Influ- ence of hormonal functional status on survival in adrenocor- tical carcinoma: systematic review and meta-analysis. Eur J Endocrinol 2018;179:429-36.
20. Assie G, Antoni G, Tissier F, Caillou B, Abiven G, Gicquel C, et al. Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 2007;92:148-54.
21. Margonis GA, Kim Y, Tran TB, Postlewait LM, Maithel SK, Wang TS, et al. Outcomes after resection of cortisol-secret- ing adrenocortical carcinoma. Am J Surg 2016;211:1106-13.
22. Libe R, Borget I, Ronchi CL, Zaggia B, Kroiss M, Kerkhofs T, et al. Prognostic factors in stage III-IV adrenocortical car- cinomas (ACC): an European Network for the Study of Ad- renal Tumor (ENSAT) study. Ann Oncol 2015;26:2119-25.
23. Lippert J, Appenzeller S, Liang R, Sbiera S, Kircher S, Alt- ieri B, et al. Targeted molecular analysis in adrenocortical carcinomas: a strategy toward improved personalized prog- nostication. J Clin Endocrinol Metab 2018;103:4511-23.
24. Elhassan YS, Altieri B, Berhane S, Cosentini D, Calabrese A, Haissaguerre M, et al. S-GRAS score for prognostic classi- fication of adrenocortical carcinoma: an international, multi- center ENSAT study. Eur J Endocrinol 2021;186:25-36.
25. Mete O, Erickson LA, Juhlin CC, de Krijger RR, Sasano H, Volante M, et al. Overview of the 2022 WHO classification of adrenal cortical tumors. Endocr Pathol 2022;33:155-96.
26. Harrell FE Jr, Califf RM, Pryor DB, Lee KL, Rosati RA. Evaluating the yield of medical tests. JAMA 1982;247: 2543-6.
27. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13:202-6.
28. Lin W, Dai J, Xie J, Liu J, Sun F, Huang X, et al. S-GRAS score performs better than a model from SEER for patients with adrenocortical carcinoma. Endocr Connect 2022;11: e220114.
29. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin Endocrinol Metab 2013;98:4551-64.
30. Reibetanz J, Jurowich C, Erdogan I, Nies C, Rayes N, Dralle H, et al. Impact of lymphadenectomy on the oncologic out- come of patients with adrenocortical carcinoma. Ann Surg 2012;255:363-9.
31. Asare EA, Wang TS, Winchester DP, Mallin K, Kebebew E,
EnM
Sturgeon C. A novel staging system for adrenocortical carci- noma better predicts survival in patients with stage I/II dis- ease. Surgery 2014;156:1378-86.
32. Tang Y, Liu Z, Zou Z, Liang J, Lu Y, Zhu Y. Benefits of adju- vant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis. Biomed Res Int 2018; 2018:9362108.
33. Bedrose S, Daher M, Altameemi L, Habra MA. Adjuvant
therapy in adrenocortical carcinoma: reflections and future directions. Cancers (Basel) 2020;12:508.
34. Terzolo M, Fassnacht M, Perotti P, Libe R, Kastelan D, Lac- roix A, et al. Adjuvant mitotane versus surveillance in low- grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study. Lancet Diabetes Endocrinol 2023;11:720-30.
EnM
mS-GRAS Score for Prognosis of ACC in Asians
| Supplemental Table S1. Characteristics of ACC Patients withª (n=114) and without (n=39) Available mS-GRASb Data | |||
|---|---|---|---|
| Variable | Patients with available mS-GRAS data (n=114) | Patients without available mS-GRAS data (n=39) | P value |
| Women | 67 (58.8)ª | 14 (35.9)d | 0.022ª |
| Age at diagnosis, yr | 51.0 (41.0-62.0)ª | 46.0 (34.0-53.5)ª | 0.038ª |
| ≥50 | 61 (53.5) | 14 (35.9) | 0.087 |
| BMI, kg/m2 | 23.6 (22.0-25.9) | 23.9 (21.2-25.2) | 0.239 |
| Size, cm | 7.9 (5.5-11.0)ª | 10.0 (8.5-14.5)ª | 0.001ª |
| Symptom | 55 (48.2)ª | 29 (74.4)d | 0.008ª |
| ENSAT stage | 0.048ª | ||
| 1 | 13 (11.4)ª | 1 (2.6)d | |
| 2 | 54 (47.4)d | 16 (41.0)d | |
| 3 | 17 (14.9)ª | 13 (33.3)ª | |
| 4 | 30 (26.3)d | 9 (23.1)d | |
| Additional treatment® | 61 (53.5) | 14 (35.9) | 0.113 |
| Adjuvant mitotane | 35 (30.7) | 7 (17.9) | 0.123 |
| Mitotane dose, mg | 2,000 (1,500-3,000) | 2,000 (2,000-2,000) | 0.538 |
| Mitotane level, mg/L | 11.8 (7.1-13.5) | 15.5 (11.8-16.9) | 0.371 |
| Mitotane blood level > 14 mg/L | 6 (17.1) | 2 (14.3) | >0.999 |
| Resection status | >0.999 | ||
| R0 | 70 (61.4) | 27 (69.2) | |
| RX | 7 (6.1) | 1 (2.6) | |
| R1 | 7 (6.1) | 1 (2.6) | |
| R2 | 30 (26.3) | 10 (25.6) | |
Values are expressed as number (%) or median (interquartile range).
ACC, adrenocortical carcinoma; mS-GRAS, modified Stage, Grade, Resection status, Age, Symptom; BMI, body mass index; ENSAT, European Net- work for the Study of Adrenal Tumour; R0, complete resection; RX, uncertain resection; R1, microscopic incomplete resection; R2, macroscopic incom- plete resection.
“Patients who underwent adrenalectomy and had data on all components of mS-GRAS scores; bmS-GRAS components: ENSAT stage (S), modified grading (mG), resection status (R), age (A), and tumor- or hormone-related symptoms (S); “Additional treatment included the adjuvant treatment with mitotane, additional operation, and other chemotherapy/radiation; dSignificant results (P<0.05).
EnM
| Scores | Variable | PFS | OS | ||||||
|---|---|---|---|---|---|---|---|---|---|
| No. (%) | No. of relapse (%) | HR (95% CI) | P value | No. (%) | No. of death (%) | HR (95% CI) | P value | ||
| S | ENSAT stage | 153 (100.0) | 100 (65.4) | 153 (100.0) | 100 (65.4) | ||||
| 0 | 1-2 | 84 (54.9) | 44 (52.4) | Ref | Ref | 14 (9.2) | 3 (21.4) | Ref | Ref |
| 1 | 3 | 30 (19.6) | 17 (56.7) | 4.64 (1.36-15.87)b | 0.015b | 30 (19.6) | 17 (56.7) | 3.82 (1.13-12.93)b | 0.032b |
| 2 | 4 | 39 (25.5) | 39 (100.0) | NA | NA | 39 (25.5) | 39 (100.0) | 9.91 (3.02-32.49)b | <0.001b |
| R | Resection status | 153 (100.0) | 100 (65.4) | 153 (100.0) | 85 (55.6) | ||||
| 0 | R0 | 97 (63.4) | 48 (49.5) | Ref | Ref | 97 (63.4) | 39 (40.2) | Ref | Ref |
| 1 | RX | 8 (5.2) | 7 (87.5) | 2.75 (1.23-6.15)b | 0.014b | 8 (5.2) | 6 (75.0) | 2.14 (0.90-5.09) | 0.086 |
| 2 | R1 | 8 (5.2) | 5 (62.5) | 1.77 (0.70-4.47) | 0.225 | 8 (5.2) | 5 (62.5) | 1.87 (0.74-4.75) | 0.188 |
| 3 | R2 | 40 (26.2) | 40 (100.0) | 47.14 (24.85-89.42)b | <0.001b | 40 (26.2) | 35 (87.5) | 5.29 (3.27-8.57)b | <0.001b |
| A | Age, yr | 153 (100.0) | 100 (65.4) | 153 (100.0) | 85 (55.6) | ||||
| 0 | <50 | 78 (51.0) | 54 (69.2) | Ref | Ref | 78 (51.0) | 41 (52.6) | Ref | Ref |
| 1 | ≥50 | 75 (49.0) | 46 (61.3) | 0.89 (0.60-1.32) | 0.551 | 75 (49.0) | 44 (58.7) | 1.32 (0.85-2.02) | 0.212 |
| S | Symptom | 153 (100.0) | 100 (65.4) | 153 (100.0) | 85 (55.6) | ||||
| 0 | No | 69 (45.1) | 34 (49.3) | Ref | Ref | 69 (45.1) | 33 (47.8) | Ref | Ref |
| 1 | Yes | 84 (54.9) | 66 (78.6) | 2.04 (1.35-63.09)b | 0.001b | 84 (54.9) | 52 (61.9) | 1.56 (1.01-2.43)b | 0.046b |
PFS, progression-free survival; OS, overall survival; HR, hazard ratio; mS-GRAS, modified Stage, Grade, Resection status, Age, Symptom; CI, confi- dence interval; ENSAT, European Network for the Study of Adrenal Tumour; NA, not applicable; R0, complete resection; RX, uncertain resection; R1, microscopic incomplete resection; R2, macroscopic incomplete resection.
ªmS-GRAS components: ENSAT stage (S), modified grading (G), resection status (R), age (A), and tumor- or hormone-related symptoms (S); bSignifi- cant results (P<0.05).
EnM
| Scores | Variable | No. (%) | No. of relapse (%) | HR (95% CI) | P value | Harrell's C-index (95% CI) | P value® | P valued |
|---|---|---|---|---|---|---|---|---|
| G | Ki67 index, % | 79 (100.0) | 46 (58.2) | 0.648 (0.552-0.731)e | <0.001e | <0.001e | ||
| 0 | 0-9 | 36 (45.6) | 17 (27.8) | Ref | ||||
| 1 | 10-19 | 23 (29.1) | 14 (60.9) | 1.62 (0.80-3.30) | 0.180 | |||
| 2 | ≥20 | 20 (25.3) | 15 (75.0) | 2.99 (1.48-6.10)e | 0.003e | |||
| S-GRAS | 79 (100.0) | 46 (58.2) | 1.76 (1.50-2.06)e | <0.001e | 0.805 (0.720-0.870)e | Ref | ||
| S-GRAS group | 79 (100.0) | 46 (58.2) | 0.803 (0.717-0.864)e | Ref | ||||
| 0-1 | 23 (29.1) | 9 (39.1) | Ref | |||||
| 2-3 | 29 (36.7) | 13 (44.8) | 1.30 (0.55-3.06) | 0.546 | ||||
| 4-5 | 7 (8.9) | 4 (57.1) | 1.99 (0.60-6.53) | 0.259 | ||||
| 6-9 | 20 (25.3) | 20 (100.0) | 136.86 (26.83-698.14)e | <0.001e |
PFS, progression-free survival; HR, hazard ratio; S-GRAS, Stage, Grade, Resection status, Age, Symptom; CI, confidence interval. ªS-GRAS components: European Network for the Study of Adrenal Tumour (ENSAT) stage (S), grading (G), resection status (R), age (A), and tumor- or hormone-related symptoms (S); “Patients subjected to S-GRAS analysis who underwent adrenalectomy and had available Ki-67 indices for S-GRAS scores; “P values comparing Harrell’s C-index of grading with that of S-GRAS score; dP values comparing Harrell’s C-index of grading with that of S- GRAS groups; eSignificant results (P<0.05).
EnM
| Scores | Variable | No. (%) | No. of death (%) | HR (95% CI) | P value | Harrell's C-index (95% CI) | P value® | P valued |
|---|---|---|---|---|---|---|---|---|
| G | Ki67 index, % | 79 (100.0) | 32 (40.5) | 0.629 (0.534-0.714)e | 0.024e | 0.035e | ||
| 0 | 0-9 | 36 (45.6) | 10 (27.8) | Ref | ||||
| 1 | 10-19 | 23 (29.1) | 10 (60.9) | 1.75 (0.73-4.22) | 0.209 | |||
| 2 | ≥20 | 20 (25.3) | 12 (75.0) | 3.25 (1.39-7.59)e | 0.006e | |||
| S-GRAS | 79 (100.0) | 32 (40.5) | 1.76 (1.50-2.06)e | <0.001e | 0.727 (0.633-0.798)e | Ref | ||
| S-GRAS group | 79 (100.0) | 32 (40.5) | 0.740 (0.640-0.802)e | Ref | ||||
| 0-1 | 23 (29.1) | 4 (17.4) | Ref | |||||
| 2-3 | 29 (36.7) | 10 (34.5) | 2.11 (0.66-6.72) | 0.209 | ||||
| 4-5 | 7 (8.9) | 2 (28.6) | 1.80 (0.33-9.85) | 0.498 | ||||
| 6-9 | 20 (25.3) | 16 (80.0) | 10.14 (3.35-30.67)e | <0.001e |
OS, overall survival; HR, hazard ratio; S-GRAS, Stage, Grade, Resection status, Age, Symptom; CI, confidence interval. ªS-GRAS components: European Network for the Study of Adrenal Tumour (ENSAT) stage (S), grading (G), resection status (R), age (A), and tumor- or hormone-related symptoms (S); “Patients subjected to S-GRAS analysis who underwent adrenalectomy and had available Ki-67 indices for S-GRAS scores; “P values comparing Harrell’s C-index of grading with that of S-GRAS score; dP values comparing Harrell’s C-index of grading with that of S- GRAS groups; eSignificant results (P<0.05).