ENDOCRINE SOCIETY
OXFORD
The European Network for the Study of Adrenal Tumors Staging System (2015): A United States Validation
Letizia Maria Ippolita Jannello, 1,2,3[D Reha-Baris Incesu, 1,4 iD Simone Morra, 1,5
Lukas Scheipner, 1,60D Andrea Baudo, 1,3,7 [D Mario de Angelis, 1,8 Carolin Siech, 1,9[D Zhe Tian,1 Jordan A. Goyal,1 Stefano Luzzago,2,10[D Francesco A. Mistretta,2,10 Matteo Ferro,2,10 Fred Saad,10 Shahrokh F. Shariat, 11,12,13,14[D Felix K. H. Chun,9D Alberto Briganti,8[D Derya Tilki, 4,15,16 [D Sascha Ahyai, 60D Luca Carmignani,7,17[D Nicola Longo,5 Ottavio de Cobelli, 2,10[D Gennaro Musi,2,10[D and Pierre I. Karakiewicz İD
1Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, H2X 0A9, Canada
2Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, 20141, Italy
3Department of Urology, Università degli Studi di Milano, Milan, 20122, Italy
4Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, 20251, Germany
5Department of Neurosciences, Science of Reproduction and Odontostomatology, University of Naples Federico II, Naples, 80131, Italy
6Department of Urology, Medical University of Graz, Graz, 8010, Austria
7Department of Urology, IRCCS Policlinico San Donato, Milan, 20097, Italy
8Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy
9Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, 60629, Germany
10Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, 20141, Italy
11Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, 1090, Austria
12Department of Urology, Weill Cornell Medical College, New York, NY 10065, USA
13Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
14Hourani Center of Applied Scientific Research, Al-Ahliyya Amman University, Amman, 19328, Jordan
15Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, 20251, Germany
16Department of Urology, Koc University Hospital, Istanbul, 34010, Turkey
17Department of Urology, IRCCS Ospedale Galeazzi-Sant’Ambrogio, Milan, 20157, Italy
Correspondence: Letizia Maria Ippolita Jannello, MD, Department of Urology, IEO European Institute of Oncology, IRCCS, Via Ripamonti 435, Milan, 20141, Italy. Email: letizia.jannello@unimi.it.
Abstract
Objective: To test the ability of the 2015 modified version of the European Network for the Study of Adrenal Tumors staging system (mENSAT) in predicting cancer-specific mortality (CSM), as well as overall mortality (OM) in adrenocortical carcinoma (ACC) patients of all stages, in a large- scale, and contemporary United States cohort.
Methods: We relied on the Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) to test the accuracy and calibration of the mENSAT and subsequently compared it to the 8th edition of the American Joint Committee on Cancer staging system (AJCC).
Results: In 858 ACC patients, mENSAT accuracy was 74.7% for 3-year CSM predictions and 73.8% for 3-year OM predictions. The maximum departures from ideal predictions in mENSAT were +17.2% for CSM and +11.8% for OM. Conversely, AJCC accuracy was 74.5% for 3-year CSM predictions and 73.5% for 3-year OM predictions. The maximum departures from ideal predictions in AJCC were -6.7% for CSM and -7.1% for OM.
Conclusion: The accuracy of mENSAT is virtually the same as that of AJCC in predicting CSM (74.7% vs 74.5%) and OM (73.7% vs 73.5%). However, calibration is lower for mENSAT than for AJCC. In consequence, no obvious benefit appears to be associated with the use of mENSAT relative to AJCC in US ACC patients.
Key Words: adrenocortical carcinoma, staging system, prognostic model, external validation
Abbreviations: ACC, adrenal cortical carcinoma; AJCC, American Joint Committee on Cancer staging system; CSM, cancer-specific mortality; ENSAT, European Network for the Study of Adrenal Tumors; IQR, interquartile range; mENSAT, European Network for the Study of Adrenal Tumors staging system; OM, overall mortality; SEER, Surveillance, Epidemiology, and End Results.
Adrenocortical carcinoma (ACC) is a rare solid tumor. Its clinical presentation can vary widely depending on the hor- mones produced (cortisol, aldosterone, androgen/estrogen, or none) and the stage of the disease. Based on its rarity, clini- cians rely on staging systems for the prediction of prognosis. In North America, the American Joint Committee on Cancer staging system (AJCC) is generally used for that pur- pose in ACC patients (1). The current AJCC was introduced in 2017, optimizing the prognostic differences between stages II and III. Hence, stage I and stage II were defined as tumors ≤ 5 cm in size without lymph node or distant metastases (TINOM0) and tumors > 5 cm in size without lymph node or distant metastases (T2NOM0), respectively. While stage III in- cluded patients classified as the invasion of surrounding tis- sues/organs or the vena renalis/cava without lymph node or distant metastases (T3-4NOM0) or any T stage but N1 and no distant metastasis (anyTN1M0). Finally, stage IV included only patients with metastatic disease (anyTanyNM1) (Table 1). A different European staging system has been pro- posed by the European Network for the Study of Adrenal Tumors (ENSAT) and it was validated in a historical cohort of United States ACC patients (2, 3). Since then, a modified ENSAT-staging system (mENSAT) has been introduced (4) and addressed the findings that node-positive (N1) and the number of tumor-involved organs should be used to refine the staging classification (5). Accordingly, the 2015 mENSAT focuses on modifying stage III and stage IV. Stage I and stage II were defined according to previous versions as in AJCC. Whereases, stage III was classified as the invasion of surrounding tissues/organs or the vena renalis/cava without lymph nodes or distant metastases (T3-4NOM0). Finally, stage IV was categorized into subgroups according to the number of tumor-involved organs including N1 patients (IVa: ≤2, IVb: 3, and IVc: > 3) (Table 1) (4).
mENSAT has not yet been tested for its ability to predict ei- ther cancer-specific mortality (CSM) or overall mortality (OM) using standard testing criteria in either European or United States ACC patients. These standard testing criteria for any prognostic model, including mENSAT and AJCC,
| AJCC | mENSAT | |
|---|---|---|
| Stage I | TINOM0 | TINOM0 |
| Stage II | T2NoMo | T2NOM0 |
| Stage III | anyTN1M0 T3-4NOM0 | T3-4NOM0 |
| Stage IV | anyTanyNM1 | |
| IVa | anyTN1M0, anyTanyNM1 (≤2 organs including N) | |
| IVb | anyTanyNM1 (=3 organs including N) | |
| IVc | anyTanyNM1 (>3 organs including N) |
Abbreviations: AJCC, 8th edition of the American Joint Committee on Cancer staging system; mENSAT, 2015 modified European Network for the Study of Adrenal Tumors staging system.
T1: ≤5 cm confined to the adrenal, T2: >5 cm confined to the adrenal, T3: any size, local soft tissue invasion, T4: any size, adjacent organ invasion, or major vein tumor thrombus; NO: absence of positive lymph node, N1: at least one positive lymph node; MO: absence of distant metastases, and M1: presence of distant metastases.
consist of accuracy and calibration. We addressed this knowl- edge gap and tested mENSAT within a large-scale, contem- porary United States cohort of ACC patients from within the Surveillance, Epidemiology, and End Results (SEER) data- base. Additionally, we relied on the same metrics to test the 8th edition of AJCC (1). Based on previous data, we hypothe- sized that mENSAT may perform similarly or may even out- perform AJCC (3).
Materials and Methods
Data Source and Study Population
The SEER database samples 34.6% of the United States popu- lation in terms of demographic composition and cancer inci- dence (6). Within the SEER database (2004-2020), we identified ACC patients (International Classification of Disease for Oncology [ICD-O-3] site code C74.0/C74.9; histo- logic code: “8370/3: Adrenal cortical carcinoma,” “8010/3: Carcinoma, NOS,” and “8140/3: Adenocarcinoma of the ad- renal, NOS”) aged ≥ 18 years (6). Moreover, only patients with complete data regarding vital status, stage information, and surgery status (performed vs not performed) were in- cluded. We excluded patients with tumor size <2 cm (1.3%), patients with tumor size that qualified for the defin- ition of high-end outliers (> 25.0 cm; 2.5%) to avoid bias, and autopsy or death certificate-only cases. Since SEER is en- tirely anonymous, study-specific ethics approval was waived by the institutional review board (7, 8).
Statistical Analyses
Four analytical steps were completed. First, we tabulated baseline patient and tumor characteristics. Descriptive statis- tics included frequencies and proportions for categorical var- iables. Medians and interquartile ranges (IQR) were reported for continuously coded variables. Second, CSM and OM rates were plotted according to the Kaplan-Meier methodology. Third, the predictive accuracy of the 2 different staging sys- tems was quantified at 3 years of follow-up, first for CSM and then for OM. The area under the curve (AUC) derived from the receiver operating characteristic (ROC) curve was used for both CSM and OM testing. In accuracy analyses, a value of 100% indicates perfect predictions while 50% is equivalent to a flip of a coin. Fourth, in calibration plots, we graphically depicted the relationship between predicted and observed 3-year CSM rates, and subsequently 3-year OM rates. The same methodology was applied to mENSAT and then repeated for AJCC. Accuracy test and calibration were subjected to 2000 bootstrap resamples to calculate an un- biased measure of mENSAT and AJCC abilities to discrimin- ate among stages (9).
All statistical tests were two-sided with the level of signifi- cance set at P <. 05 and were performed with R Software Environment for Statistical Computing and Graphics (R version 4.1.3; R Foundation for Statistical Computing, Vienna, Austria) (10).
Results
Descriptive Characteristics
Of all 858 ACC patients identified between 2004 and 2020, 540 (63%) were female, and 602 (70%) were Caucasian (Table 2). The median age at diagnosis was 56 years (IQR,
44-65 years). The median tumor size was 110 mm (IQR, 79- 147 mm). The median follow-up was 21 months (IQR, 7-61 months). We stratified the overall population according to the mENSAT and AJCC (Table 2). Of 314 AJCC stage III,
| N= 858 | |
|---|---|
| Age at diagnosis, years, median (IQR) | 56 (44-65) |
| Tumor size (mm), median (IQR) | 110 (79-147) |
| Sex, female, n (%) | 540 (63%) |
| Side, left, n (%) | 464 (54%) |
| Race/ethnicity, Caucasian, n (%) | 602 (70%) |
| Surgery performed, n (%) | 707 (82%) |
| mENSAT, n (%) | |
| stage I | 76 (8.9%) |
| stage II | 265 (31%) |
| stage III | 275 (32%) |
| stage IVa | 204 (24%) |
| stage IVb | 31 (3.6%) |
| stage IVc | 7 (0.8%) |
| 8th edition of AJCC, n (%) | |
| stage I | 76 (9%) |
| stage II | 265 (31%) |
| stage III | 314 (37%) |
| stage IV | 203 (24%) |
| Metastases (cor M1 patients), n (%) | |
| Bones | 12 (6%) |
| Brain | 2 (1%) |
| Liver | 44 (22%) |
| Lung | 59 (29%) |
| Multiple metastases | 86 (42%) |
Abbreviations: AJCC, 8th edition of the American Joint Committee on Cancer staging system; IQR, interquartile range; mENSAT, 2015 modified version of the European Network for the Study of Adrenal Tumors staging system.
39 harbored anyTN1M0, and were reclassified from stage III in AJCC to stage IVa in mENSAT.
Cancer-Specific Mortality and Overall Mortality Outcomes
In the overall population, the median CSM and OM rates were 36 and 28 months, respectively (Fig. 1). After stratifica- tion, according to mENSAT stages I to IVb, the 3-year CSM-free survival rates ranged from 76.6% to 24.1% and the 3-year OM-free survival rates ranged from 71.9% to 18.9% (Figs. 2A and 3A). Similarly, after stratification ac- cording to AJCC stage I to IV, the 3-year CSM-free survival rates ranged from 76.6% to 14.0% and the 3-year OM-free survival rates ranged from 71.9% to 11.4% (Figs. 2B and 3B).
Accuracy of mENSAT and AJCC in Predicting CSM and OM
After 2000 bootstrap resamples, for CSM 3-year predictions, the accuracy of mENSAT was 74.8% (95% CI, 71.3%- 78.7%) vs 74.5% (95% CI, 70.9%-78.4%) for AJCC. Similarly, after 2000 bootstrap resamples, for OM 3-year predictions, the accuracy of mENSAT was 73.8% (95% CI, 70.5%-77.6%) vs 73.5% (95% CI, 70.0%-77.3%) for AJCC.
Calibration of mENSAT and AJCC in Predicting CSM-Free Survival and OM-Free Survival
Calibration plots depicted the differences between predicted and observed CSM-free survival rates, as well as the differences between predicted and observed OM-free survival rates. In ideal predictions, predicted values equal observed values. After 2000 bootstrap resamples, mENSAT calibration in CSM predictions revealed a maximum departure from the ideal prediction value of +17.2%. Conversely, the maximum departure from the ideal predictions for AJCC was -6.7% (Fig. 4). For OM, after 2000 bootstrap resamples, mENSAT calibration revealed a maximum departure from the ideal pre- diction value of +11.8. On the other hand, the maximum de- parture from the ideal prediction for AJCC was -7.1% (Fig. 5).
A
Overall Population - All
B
Overall Population - All
1.00
1.00
+
+
+
+
Three-year CSM: 50.0% Median CSM 36 months
Three-year OM: 55.6% Median OM 28 months
0.75
0.75
Survival Probability
Survival Probability
0.50
0.50
0.25
0.25
0.00
0.00
0
6
12
18
24
30
36
42
48
54
60
0
6
12
18
24
30
36
42
48
54
60
Months
Months
Overall Population
Number at risk
Overall Population
Number at risk
All
858
675
550
464
391
338
299
272
249
237
218
All
858
675
550
464
391
338
299
272
249
237
218
0
6
12
18
24
30
Months
36
42
48
54
60
0
6
12
18
24
30
36
42
48
54
Months
60
A
mENSAT
B
8th AJCC
1.00
Three-year CSM-FS
+
+
1.00
Three-year CSM-FS
+
-Stage I: 76.6%
+
+
-Stage I: 76.6%
+
+
+
-Stage II: 69.3%
+
+
+
-Stage II: 69.3%
+
-Stage III: 46.5%
+
+
-Stage III: 49.5%
+
+
+
+
+
Stage I
-Stage IV: 14.0%
+
+
0.75
+
+
+
Stage I
-Stage IVa: 15.7%
+
+
+
+
+
+
+
+
+
+
+
Survival Probability
0.75
+ +
-Stage IVb: 24.1%
Survival Probability
Stage II
+
+
+
Stage II
+
+
-Stage IVc: NA
+
+
+
+
+
+
+
+
+
+
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0.50
Stage tH
0.50
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Stage
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p < 0.0001
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Stage IVc
Stage IVa
p
0.0001
Stage IV
+
+
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Stage IVb
+
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0.00
0.00
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6
12
18
24
30
36
42
48
54
60
0
6
12
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24
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36
42
48
54
60
Months
Months
Number at risk
Number at risk
11
76
68
60
51
42
33
27
26
24
I
mENSAT
246
227
215 138
194
181
169
147
21
17
141
138
AJCC8th
76
68
60
51
42
33
27
26
24
21
17
I
265
275
204
233
183
114
93
159
70
117
64
II
265
246
227
215
194
181
169
159
147
141
138
IVa
74
55
36
27
80 20
15
13
61
52
13
11
III
Nvb
IVc
31
7
5
2
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3
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314
262
203
154
124
101
87
75
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55
1
4
1
4
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3
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2
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TV
203
99
60
44
31
23
16
12
10
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8
0
6
12
18
24
30
Months
36
42
48
54
60
0
6
12
18
24
30
Months
36
42
48
54
60
Three-year CSM AUC: 74.7% (95% CI: 71.3 - 78.7%)
Three-year CSM AUC: 74.5% (95% CI: 70.9 - 78.4%)
A
mENSAT
B
8th AJCC
1.00
Three-year OM-FS: -Stage I: 71.9%
Three-year OM-FS:
+
+
1.00
+
+
-Stage I: 71.9%
+
+
+
+
+
-Stage II: 63.4%
+
-Stage II: 63.4%
+
-Stage III: 40.7%
+
+
+
0.75
Stage
0.75
Stage
-Stage III: 33.6%
-Stage IVa: 12.9%
Survival Probability
-Stage IV: 11.4%
+
+
+
+
+
+
Stage
+
Survival Probability
-Stage IVb: 18.9%
I
+
Stage II
+
+
+
+
Stage IVc: NA
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0.50
0.50
+
Stage III
Stage III
+ +
+
+
+
+
+
+
+
+
+
+
0.25
+
0.25
+
+
0.0001
+
+
+
+
+
+
Stage IVa
p
+
<; 0.0001
+
+
Stage IV +
+
+
+
Stage IVc
+
+
+
+
0.00
Stage IVb
0.00
+
+
+
+
+
0
6
12
18
24
30
36
42
48
54
60
0
6
12
18
24
30
36
42
48
54
60
Number at risk
Months
Number at risk
Months
I
I
mENSAT
58
AJCC8th
76
68
60
51
42
33
27
24
21
17
13
13
265
246
227
215
194
181
169
26
159
147
141
138
15
314
262
203
154
124
101
87
75
68
65
55
IVe
7
9
2
1
4
1
4
1
1
0
0
0
0
0
V
203
99
60
44
31
23
16
12
10
10
8
0
6
12
18
24
30
Months
36
42
48
54
60
0
6
12
18
24
30
Months
36
42
48
54
60
Three-year OM AUC: 73.8% (95% CI: 70.5 - 77.6%)
Three-year OM AUC: 73.5% (95% CI: 70.0 - 77.3%)
Discussion
To be effective, a staging system must be based on widely re- producible criteria. Prognostication in any malignancy is im- portant for initial treatment selection, adjuvant or salvage therapy, type and frequency of follow-up, as well as for the interest of the patients and the treating physicians. Currently, the most widely used staging systems for prognos- tication in ACC are AJCC and ENSAT. However, the later version of the ENSAT, namely the mENSAT (4), has not yet been validated in either European or United States ACC pa- tients. We hypothesized that it may outperform AJCC, as was recorded for the original ENSAT when it was compared to the 7th edition of AJCC (3). We relied on the 2004-2020 SEER database, in which 858 ACC patients were identified, and made several noteworthy observations.
First, ACC is a rare malignancy. Its annual incidence in North America is 0.7 per million, vs 1.5 per million in
Europe (11, 12). Staging systems are more important in rare malignancies than in more prevalent ones, since clinicians tend to be less familiar with the prognoses of patients harbor- ing rare malignancies. Historically, AJCC represented the sta- ging standard of care in United States ACC patients. However, a European alternative to AJCC, namely ENSAT, was intro- duced in 2008 (2). Its ability to predict CSM and OM exceeded that of AJCC (3). However, the ability of the novel mENSAT to predict CSM or OM is unknown in either United States or European patients. In the current study, we addressed this knowledge gap. Specifically, we tested mENSAT CSM and OM predictions relative to those of the 8th AJCC. We relied on standard testing metrics, namely accuracy and calibration, that were applied to CSM as well as OM predictions for both staging systems (mENSAT and AJCC) in a head-to-head fash- ion within the same patient population.
Second, within the SEER database, we identified 858 United States ACC patients. These 858 United States patients differed
A
2015 mENSAT-staging system
B
2017 8th edition AJCC-staging system
1.0
1.0
Stage I: n=76(9%)
Stage II: n=265(31%)
Stage I: n=76(9%)
0.8
Stage II: n=265(31%)
Stage III: n=275(31%)
0.8
Stage III: n=314(36%)
Stage IVa: n=204(24%)
I
Stage IV: n=203(24%)
I
Observed probability
Stage IVb: n=31(4%)
[]
Observed probability
0.6
0.6
III
III
0.4
0.4
0.2
Vb
0.2
IVa
TV
0.0
0.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
Predicted probability
Predicted probability
A
2015 mENSAT-staging system
B
2017 8th edition AJCC-staging system
1.0
1.0
Stage I: n=76(9%)
Stage I: n=76(9%)
0.8
Stage II: n=265(31%)
Stage III: n=275(31%)
0.8
Stage II: n=265(31%)
Stage III: n=314(36%)
Stage IVa: n=204(24%)
I
Stage IV: n=203(24%)
I
Observed probability
Stage IVb: n=31(4%)
Observed probability
0.6
0.6
0.4
III
0.4
0.2
IVb
0.2
IVa
V
0.0
0.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
Predicted probability
Predicted probability
from the original 444 ACC patients included in the mENSAT development cohort in several ways. First, 55% of the mENSAT development cohort were aged over 50 years, where- as in the current study of United States ACC patients, 65% were aged over 50 years. Thus, United States ACC patients were older than their European counterparts. Unfortunately, standard re- porting for age distribution was not included in the original mENSAT report. Additionally, the stage distribution also dif- fered. Specifically, the original 444 European patients exhibited a more advanced ACC stage than their United States counter- parts. In both ACC populations, ACC was more frequently di- agnosed in female individuals. Of European patients within the mENSAT development cohort, 61% were female vs 63% of United States patients within the current study. Other character- istics such as race/ethnicity, tumor laterality, and tumor size could not be compared since such variables were not reported in the European mENSAT study. Based on the presence of these differences between European and United States ACC patients, a formal validation of the mENSAT is clearly required and rep- resents the endpoint of the current study.
Third, we tested mENSAT for accuracy and calibration. Subsequently, we applied the same metrics to AJCC. For ac- curacy, mENSAT and AJCC were similar when CSM (74.7% vs 74.5%) and prediction in OM (73.7% vs 73.5%) represented the respective endpoints. When calibration repre- sented the metrics of interest, mENSAT performed worse than AJCC. Specifically, in mENSAT calibration, the maximum de- parture from the ideal prediction was +17.2% when CSM rep- resented the endpoint of interest. The maximum departure from the ideal prediction was +11.8% when OM represented the endpoint of interest. Conversely, regarding AJCC, max- imum departures from the ideal prediction were -6.7% for CSM and -7.1% for OM.
Taken together, the above observations indicate similar ac- curacy for mENSAT relative to AJCC. However, mENSAT was outperformed by AJCC in calibration. These observations provide little rationale for the use of mENSAT instead of AJCC in United States patients. However, when comparisons between the United States and European ACC patients are re- quired, especially under circumstances where mENSAT has
been used, its application in United States patients will result in CSM and OM predictions that are roughly similar to those of AJCC, with limitations as described above.
Despite its novelty, our study has some limitations. First and foremost, it shares the same constraints as all other retro- spective studies that relied on the SEER database (13, 14). Second, both the mENSAT and AJCC have been applied and tested in predominantly Caucasian populations. Specifically, in the current study, 70% of ACC patients were Caucasian. In the mENSAT development study, this propor- tion was not reported (4). The current United States validation of mENSAT therefore predominantly applies to Caucasian patients. Similarly, the validation of AJCC in the current study also applies primarily to Caucasians. The ability of both mENSAT and AJCC to specifically predict CSM and OM in African American, Hispanic, and Asian patients here remains unknown. The rarity of ACC in these specific race/ethnicity subgroups renders formal testing of either mENSAT or AJCC virtually impossible. Last but not least, despite the rela- tively large size of this ACC population, specific groups and subgroups included a small number of observations. For ex- ample, in the current study, only 7 patients fulfilled the defin- ition of mENSAT stage IVc. This proportion was higher in the original mENSAT development cohort (n =63). A similar limitation applies to stage I patients in both the current study as well as the ENSAT development cohort (2).
Conclusion
The accuracy of mENSAT is virtually the same as that of AJCC in predicting CSM (74.7% vs 74.5%) and OM (73.7% vs 73.5%). However, calibration is lower for mENSAT than for AJCC. In consequence, no apparent benefit appears to be associated with the use of mENSAT relative to AJCC in United States ACC patients.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author Contributions
Conceptualization and Methodology: L.M.I.J., R.I., S.M. Acquisition of the data: L.M.I.J., S.M. Formal analysis: L.M.I.J., Z.T. Investigation and Data Curation: L.M.I.J., L.S., A.B., M.d.A., C.S., J.A.G., S.L., F.A.M. Writing- Original Draft: L.M.I.J., S.M. Visualization: M.F., F.S., S.F.S., F.K.H.C., D.T., S.A., L.C., O.d.C., G.M., A.B. Funding acquisition: N/A; Supervision: O.d.C., G.M., P.I.K. Project administration: P.I.K.
Disclosures
The authors have nothing to disclose.
Data Availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Ethics Consent Statement
All analyses and their reporting followed the Surveillance, Epidemiology, and End Results (SEER) reporting guidelines. Due to the anonymously coded design of the SEER database, study-specific institutional review board ethics approval is not required.
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