World Journal of Surgery
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ORIGINAL SCIENTIFIC REPORT
Comparative Performance of the 7th and 8th Editions of the American Joint Committee on Cancer Staging Manual for Adrenocortical Carcinoma
Sarah B. Fisher1 . Mouhammed A. Habra2 . Yi-Ju Chiang1 . Si-Yuan Wu1 . Paul H. Graham1 . Elizabeth G. Grubbs1 . Jeffrey E. Lee1 . Nancy D. Perrier1
@ Société Internationale de Chirurgie 2019
Abstract
Background The American Joint Committee on Cancer 8th edition staging manual for adrenocortical carcinoma (ACC) redefines T stage to include large vessel invasion (T4, previously undescribed) and restricts stage IV to those with distant metastases. We evaluated the prognostic power of the 8th edition.
Methods Patients with ACC treated between January 1, 2000, and December 31, 2015, were identified. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard models.
Results Of 290 patients evaluated, the change in T stage nomenclature impacted 13 (4.5%) who were previously categorized as T3; 61 had large vessel involvement but were already T4 based on invasion of adjacent organs. The restriction of stage IV to patients with distant metastases downstaged 41 (14.1%; T4NoMo or T3-4N1Mo) to stage III. In the 7th edition, the hazard ratio (HR) for death was similar between patients with stage II and III disease, with 5-year OS 66.7%, 54.4%, 57.2%, and 14.0% (stages I, II, III, and IV, respectively). In the 8th edition, stages I and II remain unchanged, with 5-year OS for stage III and IV 44.1% and 9.2%, respectively. The c-index for the 7th and 8th editions was similar (83.4 and 82.7, respectively).
Conclusions While 8th edition changes impact a relatively small proportion of ACC patients, they represent progress toward a common staging system that accurately reflects prognosis. In the 8th edition, the inclusion of patients with T4 tumors or nodal disease as stage III rather than IV results in improved stratification between stages II and III.
This work was presented by a trainee as an oral podium presentation at the IAES Meeting/World Congress of Surgery in Krakow, Poland August 11-15, 2019.
☒ Nancy D. Perrier NPerrier@mdanderson.org
1 Department of Surgical Oncology, Unit 1484, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
2 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Introduction
With an annual incidence of 0.7-2.0 cases per million individuals worldwide, adrenocortical carcinoma (ACC) is a rare malignancy [1-3]. Unfortunately it is also aggres- sive, with limited therapeutic efficacy and five-year overall survival (OS) for all patients between 16 and 38% [4]. When possible, complete surgical resection offers the only opportunity for cure, but locoregional and distant recur- rence are common and five-year OS after curative-intent resection remains a disappointing 39-55% [5].
Staging represents a universal language that describes groups of patients with the same disease, facilitating communication between clinicians, informing prognosis, and enabling stratification among clinical trials. The rarity
of ACC combined with its aggressive nature makes the development of a relevant staging schema difficult, but understanding the nuances of disease presentation and prognosis remains important.
The original Tumor, Node, Metastasis (TNM) Interna- tional Union Against Cancer (IUCC) staging classification for ACC in 2004 was based on work by MacFarlane [6]. This system separated patients into stage I or II by dichotomizing tumor size at 5 cm in the absence of infil- tration into surrounding adipose tissue or nodal involve- ment (stage III if one factor present, stage IV if both present), and the absence of invasion into adjacent organs or distant metastases (stage IV if present). This system was criticized for inadequate separation between stages II and III as shown first by a multi-institutional German ACC registry study [7]. In this study of 416 patients 5-year disease-specific survival was 82%, 58%, 55%, and 18% for stages I, II, III, and IV, respectively, based on the 2004 IUCC classification. Comparisons between stages I and II (p= 0.13) and stages II and III (p =0.16) did not demonstrate a statistically significant difference. The authors noted a difference in survival between patients with stage IV disease without distant metastases (n = 27) as compared to those with distant metastases (n = 122, HR 0.44, 95% CI 0.25-0.78, p = 0.004) and proposed the European Network for the Study of Adrenal Tumors (ENSAT) 2008 classification. In the ENSAT 2008 system stage IV is reserved for patients with distant metastases. Patients with nodal metastases or primary tumor involve- ment of adjacent adipose or viscera are classified into stage III. Shortly thereafter Lughezzani et al. [4] used data from 16 North American Surveillance, Epidemiology, and End Results (SEER) registries to compare the ENSAT 2008 changes to the original UICC 2004 staging system. In this analysis of 573 patients, 59 patients migrated from stage IV to stage III, resulting in finer separation between stage II and stage III patients. Five-year cancer-specific mortality
by stage for the ENSAT 2008 proposed changes was 73.9%, 63.8%, 44.1%, and 6.9% for stages I, II, III, and IV, respectively.
These changes were incorporated into the 8th edition of the AJCC staging manual for ACC (Fig. 1a, b). The current study is the first to our knowledge to examine the prog- nostic value of the AJCC 8th edition staging system.
Materials and method
Following institutional review board approval, and in accordance with the Health Insurance Portability and Accountability Act of 1996, patients undergoing either medical or surgical treatment for ACC between January 1, 2000 and December 31, 2015 were identified from a prospectively maintained tumor registry of all patients with ACC treated at MD Anderson Cancer Center. Pediatric patients under the age of 16 were excluded. Patients who sought evaluation for a second opinion and did not receive any therapy at the primary institution were excluded. Demographics, clinicopathologic factors, stage, and can- cer-related outcomes were obtained from chart review. Recurrence-free survival was defined as the time (in months) from curative-intent resection to the first radio- graphic or pathologic evidence of local or distant recur- rence. Overall survival was defined as the time (in months) from the date of diagnosis to the date of death or last known contact. Overall survival was evaluated with Kaplan-Meier survival curves and Cox proportional hazard models. Factors associated with OS were identified by univariate analysis, and further evaluated with multivariate analysis. The prognostic power of the 7th and 8th AJCC staging editions was compared using concordance indices (c-index). All analyses were performed using SAS 9.4 (Cary, NC), with statistical significance defined at p < 0.05.
A
7th Edition
ENSAT/8th Edition
I
T1 NO MO
No change
I
T1 NO MO
II
T2 NO MO
No change
II T2 NO MO
III
T3 NO MO
No change
III
T3-4 NO MO
T1-2 N1 MO
Tany N1 M0
IV
T4 NO MO
Downstaged to III
T3-4 N1 MO
Tany Nany M1
No change
IV
Tany Nany M1
B
| T category | T Criteria (Changed in 8th) |
| 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 |
Fig. 1 Schema of the changes between the American Joint Committee on Cancer (AJCC) 7th edition and the European Network for the Study of Adrenal Tumors (ENSAT)/AJCC 8th edition staging systems for adrenocortical carcinoma (a) with the corresponding T category definitions with 8th edition changes noted in red/underlined (b)
Results
Patient characteristics
The demographic and clinical characteristics of 290 patients with ACC are summarized in Table 1. The most common presentation involved symptoms related to over- production of hormones (n = 133, 45.9%), with cortisol excess most frequently observed (n = 103, 35.5%). Abdominal pain was the next most common presentation (n = 77, 26.6%), and 58 patients presented with incidental tumors (20.0%); the method of presentation was unknown for 22 patients (7.6%). Adrenalectomy (with or without concomitant organ resection) was performed for 227 patients, including 34 patients with metastatic disease. Mitotane was used frequently, including for 17 patients in a neoadjuvant setting, and in 92 patients as adjuvant therapy (40.5% of patients undergoing resection).
The median follow-up for the entire cohort was 29.8 months (range 0.5-190.4 months). Median RFS was 24.5 months. Of the 198 patients with nonmetastatic dis- ease at presentation, 158 later experienced recurrence (ei- ther locoregional or distant, 79.8%). Of these, 50 (31.6%) underwent additional resection and had improved OS as compared to the 108 patients managed with medical or supportive therapy only (88.0 months versus 32.3 months, p < 0.001). During the study period 195 patients died of their disease; the median overall survival for all patients was 34.0 months.
Staging: T stage
Although 74 patients had documented evidence of renal vein or vena cava tumor thrombus, only 13 patients (4.5% of the entire cohort) had a change in T category with the 8th edition. The remainder were already categorized as T4 based on concomitant extension to surrounding organs. By definition, a change from T3 to T4 does not alter clinical stage in the 8th edition. On univariate analysis, lower T stage was associated with a slight improvement in OS (T1 HR 0.5 95% CI 0.2-1.2, T2 HR 0.5 95% CI 0.3-0.6, T3 HR 0.5 95% CI 0.4-0.7, p < 0.001). The median tumor size at diagnosis was 11.9 cm (range 2.5 cm to 27 cm). Increasing tumor size (based on either radiographic assessment or pathologic assessment) was not associated with OS in the entire cohort as well as in only those with nonmetastatic disease (p > 0.05 for each).
Staging: N stage
Forty-seven patients had clinical N1 disease (16.2%). Patients with isolated nodal disease (TanyN1M0 n = 18) had
| n (%) or median (range) | |
|---|---|
| Age (years) | 48.5 (16.9-87.1) |
| Female sex | 174 (60.0) |
| Race | |
| White | 240 (82.8) |
| Hispanic | 30 (10.3) |
| Black | 10 (3.5) |
| Asian | 6 (2.0) |
| Other | 4 (1.4) |
| Tumor hormone secretion | |
| Nonfunctional | 135 (46.6) |
| Cortisol | 103 (35.5) |
| Aldosterone | 21 (7.2) |
| Sex hormones | 35 (12.1) |
| Multiple hormones | 34 (11.7) |
| Unknown | 22 (7.6) |
| Tumor size (cm)* | 11.0 (2.5-28.0) |
| Metastatic at presentation | 93 (32.1) |
| Vascular involvement (renal vein or IVC) | 74 (25.5) |
| Upstaged to T4 due to vascular involvement | 13 (4.5) |
| Surgical approach | |
| No operation | 63 (21.7) |
| Unknown | 1 (0.3) |
| Laparoscopic/robotic | 25 (8.6) |
| Laparoscopic/robotic converted to open | 12 (4.1) |
| Open | 189 (65.2) |
| Concomitant organ/vascular resection | 84 (30.0) |
| Lymph nodes pathologically assessed | 45 (15.5) |
| Lymph node positive disease ** | 16 (35.6) |
| Resection Margins* | |
| R0 | 135 (59.5) |
| R1 | 42 (18.5) |
| R2 | 13 (5.7) |
| Unknown | 37 (16.3) |
| Ki-67 index *** | 20 (1.0-79.0) |
| Mitotane (administered at any point in therapy) | 230 (79.3) |
R0 microscopic negative margin; R1 microscopic positive margin; R2 gross positive margin
*Based on resected tumors only (n = 227)
** Based on those with lymph nodes pathologically assessed (n = 45) *** Based on those with reported values (n = 53)
improved median survival as compared to those with dis- tant metastases (TanyN0M1 n = 93; 34.7 months versus 10.3 months, p = 0.006). On univariate analysis, lymph node positive disease (N1) was associated with decreased OS (HR 2.85, 95% CI 2.0-4.0, p < 0.001).
Staging: overall survival
Using 8th edition staging, 41 patients were downstaged to stage III (Fig. 2). Of these, 29 were staged as TANOM0 and 12 were staged as T3 4N1Mo. These 41 patients had a median OS of 31.0 months (IQR 22.4-51.2 months), and a 5-year OS of 24.9%. Overall survival stratified by stage for both the 7th and 8th editions is shown in Fig. 3. In the 7th edition, the hazard ratio (HR) for death was similar between patients with stage II and III disease, with over- lapping survival curves (Fig. 3) and similar 5-year OS (54.4% vs. 57.2% respectively, Table 2). The addition of TANoMo and T3-4N1Mo patients to stage III in the 8th edition lowers the 5-year OS for stage III to 44.1% and results in less overlap between stages II and III. The
c-index for both staging systems is similar (83.4 for the 7th, 82.7 for the 8th).
Other prognostic factors for overall survival
On univariate analysis, increasing patient age, right-sided tumors, T stage, N stage, presence of distant metastases, positive resection margins, and tumor hormone production and/or specifically cortisol production correlated with poorer overall survival (p < 0.05). Clinically relevant factors that can be incorporated into staging at the time of presentation were selected for a multivariate model for OS (Table 3).
Fig. 2 Changes in stage between the American Joint Committee on Cancer 7th and 8th editions for adrenocortical carcinoma; the red box represents stage migration
| Changes in Stage between the AJCC 7th and 8th editions (n=290) | |||||
|---|---|---|---|---|---|
| AJCC 7th edition | AJCC 8th edition | ||||
| I | II | III | IV | Total | |
| I | 7 | 0 | 0 | 0 | 7 |
| I | 0 | 89 | 0 | 0 | 89 |
| III | 0 | 0 | 60 | 0 | 60 |
| IV | 0 | 0 | 41 | 93 | 134 |
| Total | 7 | 89 | 101 | 93 | 290 |
A
1.0
AJCC 7th (p value <0.001)
B
1.0
AJCC 8th (p value <0.001)
1
1
0.9
2
0.9
2
3
3
0.8
4
0.8
4
0.7
0.7
Survival (%)
0.6
Survival (%)
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Time (Years)
Time (Years)
I
7
7
6
5
3
3
2
1
1
0
0
0
0
0
0
0
I
7
7
6
5
3
3
2
1
1
0
0
0
0
0
0
0
Il
89
79
67
49
41
37
26
21
18
15
11
8
5
2
2
2
II
89
79
67
49
41
37
26
21
18
15
11
8
5
2
2
2
III
60
54
43
40
29
23
19
15
12
6
6
6
4
2
0
0
III
101
90
70
54
38
29
23
18
15
8
7
7
4
2
0
0
IV
134
72
47
25
16
11
8
6
5
4
1
1
0
0
0
0
IV
93
36
20
11
7
5
4
3
2
2
0
0
0
0
0
0
| Stage | N | Hazard ratio for death | 95% CI | 5-Year overall survival (%) |
|---|---|---|---|---|
| AJCC 7th edition | ||||
| I | 7 | Reference | 66.7 | |
| II | 89 | 1.3 | 0.4-4.2 | 54.4 |
| III | 60 | 1.2 | 0.4-3.9 | 57.2 |
| IV | 134 | 4.0 | 1.3-12.7 | 14.0 |
| AJCC 8th edition | ||||
| I | 7 | reference | 66.7 | |
| II | 89 | 1.3 | 0.4-4.2 | 54.4 |
| III | 101 | 1.6 | 0.5-7.9 | 44.1 |
| IV | 93 | 5.7 | 1.8-18.2 | 9.2 |
CI confidence interval; AJCC American Joint Committee on Cancer
| Clinical factor | HR | 95% CI | p value | |
|---|---|---|---|---|
| Age (years) | 1.02 | 1.01 | 1.03 | < 0.001 |
| Cortisol production | 1.47 | 1.08 | 2.00 | 0.015 |
| T stage (Ref T1) | 1.92 | 0.359 | ||
| T2 | 0.77 | 0.31 | 2.01 | |
| T3 | 0.78 | 0.30 | 2.67 | |
| T4 | 1.04 | 0.41 | ||
| N1 disease | 2.02 | 1.37 | 2.96 | < 0.001 |
| M1 disease | 3.55 | 2.48 | 5.09 | < 0.001 |
HR hazard ratio; CI confidence interval; Ref reference value; N1 node positive; M1 distant metastatic disease
Discussion
The current study uses a single-institution study population to evaluate the changes made in the 8th edition of the AJCC staging system for ACC. Although the changes impact only a small proportion of patients, the resulting separation between stages II, III, and IV is improved and represents a step forward in the evolution of an accurate and meaningful staging system for patients with ACC.
To be effective, a staging system must be based on widely reproducible criteria, hence the traditional T, N, and M classifications used by the AJCC. In addition to stage [1, 8-13] multiple prognostic factors have been proposed for ACC, including patient age [1, 8-10, 14, 15], tumor functional status [11, 16-20], selection for surgical therapy and operative approach [9, 10, 21-24], perioperative blood transfusion [25]; pathologic factors such as mitotic rate, ki-
67 index, Weiss score, Helsinki score, and/or grade [8, 9, 15, 18, 26-29], lymphovascular invasion [5], capsular invasion [17], and margin status [1, 12, 20, 30, 31]; and receipt of additional therapies such as mitotane [32], chemotherapy [8-10, 20], and/or radiation therapy [9, 20, 33, 34]. Conditional disease-free survival [35] and disease-free interval [36] have also been proposed as lon- gitudinal prognostic factors, but by definition are not available at the time of presentation. Genomic characteri- zation, although not examined in the current study, likely represents a future avenue of potential staging criteria [37].
To bridge the gap between traditional staging criteria and other potential prognostic factors, nomograms have been developed, although to our knowledge none have been externally validated. One group used 751 patients from the SEER database to develop a nomogram in which older age at diagnosis, diagnosis prior to 2002, higher tumor grade, distant disease (as compared to regional or local disease), nonsurgical therapy, and chemotherapy use were associated with decreased OS at 1, 3, and 5 years [8]. The use of factors subject to selection bias (i.e. selection for chemotherapy) potentially compromises its utility in the preoperative or adjuvant setting. A different group looking specifically at patients undergoing curative-intent resection developed a nomogram for RFS using tumor size > 12 cm, nodal disease, stage ≥ 3, cortisol production, and capsular invasion; with tumor size, nodal disease, and positive margins in the nomogram for OS [17]. Nomograms are particularly useful for evaluating prognosis, but stage remains most helpful in communicating disease status and associated prognosis among clinicians, comparing large groups of patients for research purposes, and/or facilitating selection criteria in clinical trials.
Increasing patient age is an accepted negative prognostic factor and represents a variable that can be easily
assimilated into a traditional staging system, and may provide better stratification at earlier stages. Asare and colleagues [14] used the SEER database to combine patients with T1 and T2 disease in the absence of nodal or distant metastases (N0M0), and instead stratified them based on age ≤ 55 years (stage I) or age >55 years (stage II). This improved 5-year OS for patients with stage I disease to 70%, as compared to 53% for stage II, whereas 5-year OS for both the AJCC 7th edition staging system and the ENSAT classification was the same at 68% and 61%, respectively. Although the data in the current study support the use of age as a prognostic factor, further evaluation and external validation are required to identify optimal dichotomization of age for future staging systems.
Another potentially easy to assimilate factor is tumor hormone production-whether that should be representa- tive of any hormone, or more specifically cortisol, remains to be determined. In the current study both tumor hormone production and specifically cortisol production were asso- ciated with poorer prognosis. One international retrospec- tive series of patients undergoing curative-intent resection demonstrated poorer recurrence-free and overall survival for patients with hypercortisolism after adjusting for sex, age, tumor stage, and mitotane use (RFS hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.04-2.62, p = 0.02; OS HR 1.55, 95% CI 1.15-2.09, p = 0.004) [16]. Another retrospective study that included patients with metastatic disease as well associated any tumor hormone production with poorer OS after accounting for age and stage (HR 1.4, 95% CI 1.06-1.86, p = 0.02); the most common hormone excess in this group was cortisol [38].
Still others have proposed a redefined staging system in which T2 and T3 are redefined using the presence or absence (respectively) of lymphovascular invasion (LVI). In this multi-institutional retrospective examination of 140 patients, LVI was associated with a poorer disease-specific survival (HR 2.81, 95% CI 1.46-5.41, p = 0.002). Although the authors encourage further evaluation of LVI as a prognostic factor for ACC, interpathologist variability in the identification and assessment of LVI, as observed in other malignancies [39], represents a potential difficulty in incorporating this into a national staging system.
Instead of adding new factors into a staging system, an alternative method of improving prognostication may be to improve the accuracy of assessment of the existing factors. As demonstrated in the current study and by others, lym- phadenectomy is not routinely performed in patients with ACC in the USA [40, 41]. Yet N stage remains a backbone of AJCC staging. Information gleaned from lymph node dissection is thus relevant for accurate staging, and may also be therapeutic. One multi-institutional group com- paring 32 patients with planned lymphadenectomy at the time of curative-intent resection versus 88 patients without
lymphadenectomy (as determined by the operative report) showed improved OS for the lymphadenectomy group (5- year OS 76% vs. 59%, p = 0.041) [42]. In the current study only 15% of patients had lymph nodes pathologically assessed, but of those, one-third had nodal metastases. Future studies should evaluate the accuracy of clinical N staging as compared to pathologic staging, and surgeons should consider lymphadenectomy at the time of curative- intent resection.
The current study has several limitations. Although all patients in this study were treated at a single institution, they varied in timing of presentation and as a result not all clinicopathologic factors were routinely assessed or recorded. In addition, the long duration of the study period contributed to variability in recording of factors such as grade, Weiss score, and/or ki-67 measurements and limits the ability to assess their prognostic value. These tumor- specific factors may be excellent candidates to incorporate into future staging systems; standardized pathologic reporting systems are encouraged. Although the single-in- stitution nature of the study allows for the strength of multidisciplinary assessment and treatment planning, the long study period may harbor variability due to evolution in treatment patterns over time. In contrast, one particular strength that should be noted is the inclusion of patients with nonsurgical disease referred for treatment of ACC at all stages, which is particularly important when assessing a staging system.
The current study represents a large single-institution validation of the newly adopted AJCC 8th edition staging system for ACC. Similar to the German ACC registry study [7], patients in the current study with isolated nodal metastases have better OS than patients with distant metastases, supporting their inclusion into stage III rather than IV as proposed by the ENSAT and adopted by the 8th edition AJCC. The resulting stage migration allows better separation between stages II, III, and IV. Future staging systems may consider incorporating age or tumor hormone production, but further work is needed.
Funding This work is not supported by a specific funding source.
Compliance with ethical standards
Conflict of interest The authors have no financial disclosures or competing interests.
References
1. Bilimoria KY, Shen WT, Elaraj D et al (2008) Adrenocortical carcinoma in the United States: treatment utilization and prog- nostic factors. Cancer 113:3130-3136
2. Fassnacht M, Kroiss M, Allolio B (2013) Update in adrenocor- tical carcinoma. J Clin Endocrinol Metab 98:4551-4564
3. Schteingart DE, Doherty GM, Gauger PG et al (2005) Manage- ment of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 12:667-680
4. Lughezzani G, Sun M, Perrotte P et al (2010) The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer- staging system: a North American validation. Eur J Cancer 46:713-719 (Oxford, England: 1990)
5. Poorman CE, Ethun CG, Postlewait LM et al (2018) A novel T-stage classification system for adrenocortical carcinoma: pro- posal from the US Adrenocortical Carcinoma Study Group. Ann Surg Oncol 25:520-527
6. Macfarlane DA (1958) Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 23:155-186
7. Fassnacht M, Johanssen S, Quinkler M et al (2009) Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115:243-250
8. Li Y, Bian X, Ouyang J et al (2018) Nomograms to predict overall survival and cancer-specific survival in patients with adrenocortical carcinoma. Cancer Manag Res 10:6949-6959
9. Tella SH, Kommalapati A, Yaturu S et al (2018) Predictors of survival in Adrenocortical Carcinoma: an analysis from the National Cancer Database (NCDB). J Clin Endocrinol Metab 103:3566-3573
10. Wang S, Chen SS, Gao WC et al (2017) Prognostic factors of adrenocortical carcinoma: an analysis of the surveillance epi- demiology and end results (SEER) database. Asian Pac J Cancer Preven APJCP 18:2817-2823
11. Else T, Williams AR, Sabolch A et al (2014) Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 99:455-461
12. Scollo C, Russo M, Trovato MA et al (2016) Prognostic factors for adrenocortical carcinoma outcomes. Front Endocrinol 7:99
13. Vanbrugghe C, Lowery AJ, Golffier C et al (2016) Adrenocor- tical carcinoma surgery-surgical extent and approach. Langen- beck’s Arch Surg 401:991-997
14. Asare EA, Wang TS, Winchester DP et al (2014) A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage I/II disease. Surgery 156:1378-1385 (dis- cussion 1385-1376)
15. Xiao WJ, Zhu Y, Dai B et al (2015) Conditional survival among patients with adrenal cortical carcinoma determined using a national population-based surveillance, epidemiology, and end results registry. Oncotarget 6:44955-44962
16. Berruti A, Fassnacht M, Haak H et al (2014) Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol 65:832-838
17. Kim Y, Margonis GA, Prescott JD et al (2016) Nomograms to predict recurrence-free and overall survival after curative resec- tion of adrenocortical carcinoma. JAMA surgery 151:365-373
18. Libe R, Borget I, Ronchi CL et al (2015) Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol 26:2119-2125
19. Margonis GA, Kim Y, Tran TB et al (2016) Outcomes after resection of cortisol-secreting adrenocortical carcinoma. Am J Surg 211:1106-1113
20. Tran TB, Postlewait LM, Maithel SK et al (2016) Actual 10-year survivors following resection of adrenocortical carcinoma. J Surg Oncol 114:971-976
21. Livhits M, Li N, Yeh MW et al (2014) Surgery is associated with improved survival for adrenocortical cancer, even in metastatic disease. Surgery 156:1531-1540 (discussion 1540-1531)
22. Wu K, Liu Z, Liang J et al (2018) Laparoscopic versus open adrenalectomy for localized (stage 1/2) adrenocortical carcinoma: experience at a single, high-volumecenter. Surgery 164:1325-1329
23. Zheng GY, Li HZ, Deng JH et al (2018) Open adrenalectomy versus laparoscopic adrenalectomy for adrenocortical carcinoma: a retrospective comparative study on short-term oncologic prognosis. OncoTargets Ther 11:1625-1632
24. Simon G, Pattou F, Mirallie E et al (2017) Surgery for recurrent adrenocortical carcinoma: a multicenter retrospective study. Surgery 161:249-256
25. Poorman CE, Postlewait LM, Ethun CG et al (2017) Blood transfusion and survival for resected adrenocortical carcinoma: a study from the United States Adrenocortical Carcinoma Group. The American surgeon 83:761-768
26. Beuschlein F, Weigel J, Saeger W et al (2015) Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab 100:841-849
27. Choi YM, Kwon H, Jeon MJ et al (2016) Clinicopathological features associated with the prognosis of patients with adrenal cortical carcinoma: usefulness of the Ki-67 index. Medicine 95:e3736
28. Duregon E, Cappellesso R, Maffeis V et al (2017) Validation of the prognostic role of the “Helsinki Score” in 225 cases of adrenocortical carcinoma. Hum Pathol 62:1-7
29. Pennanen M, Heiskanen I, Sane T et al (2015) Helsinki score-a novel model for prediction of metastases in adrenocortical car- cinomas. Hum Pathol 46:404-410
30. Anderson KL Jr, Adam MA, Thomas SM et al (2018) Impact of micro- and macroscopically positive surgical margins on survival after resection of adrenocortical carcinoma. Ann Surg Oncol 25:1425-1431
31. Margonis GA, Kim Y, Prescott JD et al (2016) Adrenocortical carcinoma: impact of surgical margin status on long-term out- comes. Ann Surg Oncol 23:134-141
32. Berruti A, Grisanti S, Pulzer A et al (2017) Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab 102:1358-1365
33. Nelson DW, Chang SC, Bandera BC et al (2018) Adjuvant radiation is associated with improved survival for select patients with non-metastatic adrenocortical carcinoma. Ann Surg Oncol 25:2060-2066
34. Viani GA, Viana BS (2019) Adjuvant radiotherapy after surgical resection for adrenocortical carcinoma: a systematic review of observational studies and meta-analysis. J Cancer Res Ther 15:S20-s26
35. Kim Y, Margonis GA, Prescott JD et al (2017) Curative surgical resection of adrenocortical carcinoma: determining long-term outcome based on conditional disease-free probability. Ann Surg 265:197-204
36. Glenn JA, Else T, Hughes DT et al (2019) Longitudinal patterns of recurrence in patients with adrenocortical carcinoma. Surgery 165:186-195
37. Zheng S, Cherniack AD, Dewal N et al (2016) Comprehensive pan-genomic characterization of adrenocortical carcinoma. Can- cer Cell 29:723-736
38. Ayala-Ramirez M, Jasim S, Feng L et al (2013) Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol 169:891-899
39. Harris EI, Lewin DN, Wang HL et al (2008) Lymphovascular invasion in colorectal cancer: an interobserver variability study. Am J Surg Pathol 32:1816-1821
40. Alanee S, Dynda D, Holland B (2015) Prevalence and prognostic value of lymph node dissection in treating adrenocortical carci- noma: a national experience. Anticancer Res 35:5575-5579
41. Nilubol N, Patel D, Kebebew E (2016) Does lymphadenectomy improve survival in patients with adrenocortical carcinoma? A population-based study. World J Surg 40:697-705. https://doi. org/10.1007/s00268-015-3283-2
42. Gerry JM, Tran TB, Postlewait LM et al (2016) Lymphadenec- tomy for adrenocortical carcinoma: Is there a therapeutic benefit? Ann Surg Oncol 23:708-713
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