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Clinical-Kidney cancer Rethinking the definition of stage III disease in adrenocortical carcinoma: Assessing the impact of clinical lymph node positive disease
Benjamin J. Lichtbroun, M.D.a,c,*, Helen Gao, B.S.a,c, Kevin Chua, M.D.a,c, John Pfail, M.D.a,c, Rachel Passarelli, M.D.ª,c, Hiren V. Patel, M.D., Ph.D.a,b,c, Sammy Elsamra, M.D.”, Eric A. Singer, M.D., M.A., M.S., F.A.C.S., F.A.S.C.O.ª, Vignesh T. Packiam, M.D.ª,
David Golombos, M.D.ª, Thomas L. Jang, M.D., M.P.H.ª, Saum Ghodoussipour, M.D.ª, Arnav Srivastava, M.D., M.P.H.a,b,e
a Section of Urologic Oncology, Division of Urology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson University Hospital, New Brunswick, NJ
b Department of Urology, University of California, San Francisco, CA
” Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ d Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
e Division of Dow Health Services Research, Department of Urology, University of Michigan, Ann Arbor, MI
Received 4 August 2024; received in revised form 22 December 2024; accepted 12 January 2025
Abstract
Introduction: Stage III adrenocortical carcinoma encompasses both lymph node positive (TanyN1M0) and negative (T3-4N0M0) dis- ease. Given the disease’s rarity, the current staging paradigm’s estimates of survival are supported by limited evidence. Consequently, we examined the impact of clinical lymph node positivity on survival outcomes in the context of the current staging of advanced adrenocortical carcinoma.
Methods: We identified patients with clinical stage III and IV disease from the National Cancer Database. Kaplan-Meier methods and Cox proportional hazards models estimated overall survival for stage III lymph node negative, stage III lymph node positive, and stage IV disease.
Results: We identified 917 patients with adrenocortical carcinoma - 322 (35.1%) stage III lymph node negative, 67 (7.3%) stage III lymph node positive, and 528 (57.6%) stage IV. 3-year overall survival for patients with stage III lymph node negative, stage III lymph node positive, and stage IV disease was 48.6%, 29.4%, and 15.6%, respectively. On univariable analysis, patients with stage III lymph node positive disease were associated with worse survival than those with stage III lymph node negative disease (HR 1.72, 95% CI 1.26-2.37, P < 0.001); however, this relationship did not maintain significance in multivariable analysis (HR 1.27, 95% CI 0.88-1.83, P = 0.21).
Conclusion: Our study finds that patients with clinical stage III lymph node positive adrenocortical carcinoma may have worse survival outcomes than stage III patients without lymph node involvement. The results of this study suggest the need for an updated, more nuanced staging paradigm, which differentiates stage III disease by lymph node positivity. @ 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords: Adrenocortical carcinoma; Cancer staging; Lymph node positivity; Adjuvant therapy
| 1. Introduction Adrenocortical carcinoma is a rare malignancy, with only approximately 600 incident cases diagnosed annually in the United States [1]. Patients often have nonspecific | |
|---|---|
| Funding: The work from the Cancer Institute of New Jersey is supported | |
| by a grant from the National Cancer Institute: P30CA072720 and Arnav Srivastava is supported by a training grant from the National Cancer Insti- tute: T32CA180984. | |
| *Corresponding author. | |
| E-mail address: blichtbr@rwjms.rutgers.edu (B.J. Lichtbroun). | symptoms and roughly a quarter of patients may present |
with advanced disease [2]. Given this, patients with stage III and IV disease have reported 5-year overall survival rates of 24-50% and 0-17%, respectively [2-4].
The American Joint Committee on Cancer (AJCC) has 2 definitions of stage III adrenocortical carcinoma: 1) lymph-node negative disease (T3-4N0M0) or 2) lymph- node positive disease (TanyN1M0). Patients with stage IV disease must have metastatic spread (TanyNanyM1) [5]. Even among those with surgically resectable disease, 70% of patients may have a recurrence within 28 months, implying aggressive tumor biology [6]. Characterizing which patients are at higher risk for poor oncologic out- comes may help define roles for adjuvant treatment, closer surveillance schedules, and clinical trial enrolment. Though a paucity of such literature exists, owing to the disease’s rarity, prior literature suggests that lymph node involvement portends a worse prognosis. Importantly, this represents an opportunity for more precise stratification within the AJCC staging system, to improve alignment of stage and tumor risk [4,7,8].
In this study, we assessed survival outcomes in patients with clinical stage III lymph node negative, clinical stage III lymph node positive, and clinical stage IV disease. We hypothesize that patients with clinical stage III lymph node positive adrenocortical carcinoma will have inferior
survival compared to those with clinical stage III lymph node negative disease. Instead, those patients with stage III node positive disease will exhibit survival patterns similar to patients with stage IV disease (i.e., those with metasta- sis). Consequently, we should consider an updated staging classification that differentiates between stage III lymph node positive and lymph node negative disease.
2. Methods
2.1. Study population and outcomes
The National Cancer Database (NCDB) is a joint project of the Commission on Cancer (CoC) of the American Col- lege of Surgeons and the American Cancer Society. The CoC’s NCDB and the hospitals participating in the CoC’s NCDB are the source of de-identified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions by the authors. There are over 1,500 accredited hospitals that are required to report new cancer diagnoses to the NCDB. The NCDB captures >70% of new cancer cases reported each year. Information regarding patient demographics, cancer staging, tumor characteristics, surgical treatment, and patient prognosis is recorded [9].
NCDB 2004-2018 N = 157,596
All ACC population N = 4311
Missing treatment information N = 1484
All ACC patients N = 2827
Missing staging information N = 1046
All stage ACC patients N = 1781
Stage I and II patients N = 743
Stage III and IV patients N = 1038
Clinical Stage III and IV patients N = 917
Not clinically staged N = 121
cStage III LN- N = 322 (35.1%)
cStage III LN+ N = 67 (7.3%)
cStage IV N = 528 (57.6%)
| Demographics | cStage III LN (-) | cStage III LN (+) | cStage IV | |||
|---|---|---|---|---|---|---|
| Variable | Count | Percentage/SD | Count | Percentage/SD | Count | Percentage/SD |
| Total | 322 | 67 | 528 | |||
| Lymph node dissection* | ||||||
| LN dissected | 81 | 25.2% | 36 | 53.7% | 72 | 13.6% |
| LN not dissected/unknown | 241 | 74.8% | 31 | 46.3% | 456 | 86.4% |
| Tumor grade | ||||||
| 1 | 8 | 2.5% | 1 | 1.5% | 9 | 1.7% |
| 2 | 10 | 3.1% | 2 | 3.0% | 8 | 1.5% |
| 3 | 38 | 11.8% | 5 | 7.5% | 56 | 10.6% |
| 4 | 21 | 6.5% | 1 | 1.5% | 22 | 4.2% |
| Cell type undetermined | 245 | 76.1% | 58 | 86.6% | 433 | 82.0% |
| Received surgery* | ||||||
| Yes | 244 | 75.8% | 39 | 58.2% | 143 | 27.1% |
| No | 78 | 24.2% | 28 | 41.8% | 385 | 72.9% |
| Systemic therapy* | ||||||
| Yes | 181 | 56.2% | 29 | 43.3% | 191 | 36.2% |
| No | 141 | 43.8% | 38 | 56.7% | 337 | 63.8% |
| Chemotherapy* | ||||||
| None | 179 | 55.6% | 29 | 43.3% | 190 | 36.0% |
| Neoadjuvant | 6 | 1.9% | 2 | 3.0% | 20 | 3.8% |
| Adjuvant | 118 | 36.6% | 23 | 34.3% | 113 | 21.4% |
| Unknown/Unknown sequence | 19 | 5.9% | 13 | 19.4% | 205 | 38.8% |
| Age, y | 54.0 | 17.5 | 58.1 | 15.2 | 54.2 | 16.4 |
| Sex | ||||||
| Female | 183 | 56.8% | 37 | 55.2% | 322 | 61.0% |
| Male | 139 | 43.2% | 30 | 44.8% | 206 | 39.0% |
| Race | ||||||
| White | 267 | 82.9% | 60 | 89.6% | 445 | 84.3% |
| Black | 42 | 13.0% | 4 | 6.0% | 58 | 11.0% |
| Native American | 2 | 0.6% | 1 | 1.5% | 0 | 0.0% |
| Asian | 7 | 2.2% | 1 | 1.5% | 11 | 2.1% |
| Other | 4 | 1.2% | 1 | 1.5% | 14 | 2.7% |
| Charlson comorbidity index | ||||||
| 0 | 233 | 72.4% | 50 | 74.6% | 389 | 73.7% |
| 1 | 63 | 19.6% | 9 | 13.4% | 98 | 18.6% |
| 2 | 17 | 5.3% | 3 | 4.5% | 28 | 5.3% |
| 3 | 9 | 2.8% | 5 | 7.5% | 13 | 2.5% |
| Distance from treatment center, mi* | ||||||
| ≤6.4 | 68 | 21.1% | 14 | 20.9% | 151 | 28.6% |
| >6.4-16.2 | 67 | 20.8% | 20 | 29.9% | 139 | 26.3% |
| >16.2-31 | 51 | 15.8% | 12 | 17.9% | 71 | 13.4% |
| >31 | 105 | 32.6% | 14 | 20.9% | 137 | 25.9% |
| N/A | 31 | 9.6% | 7 | 10.4% | 30 | 5.7% |
| Annual income* | ||||||
| ≥$63,333 | 85 | 26.4% | 21 | 31.3% | 188 | 35.6% |
| $50,354-$63,332 | 84 | 26.1% | 20 | 29.9% | 116 | 22.0% |
| $40,227-$50,353 | 70 | 21.7% | 14 | 20.9% | 87 | 16.5% |
| <$40,227 | 48 | 14.9% | 5 | 7.5% | 101 | 19.1% |
| N/A | 35 | 10.9% | 7 | 10.4% | 36 | 6.8% |
| Regional education* | ||||||
| <6.3% | 76 | 23.6% | 12 | 17.9% | 135 | 25.6% |
| 6.3%-10.8% | 70 | 21.7% | 23 | 34.3% | 135 | 25.6% |
| 10.9%-17.5% | 81 | 25.2% | 8 | 11.9% | 104 | 19.7% |
| ≥17.6% | 60 | 18.6% | 17 | 25.4% | 118 | 22.3% |
| N/A | 35 | 10.9% | 7 | 10.4% | 36 | 6.8% |
| Insurance status | ||||||
| Private | 171 | 53.1% | 28 | 41.8% | 256 | 48.5% |
| Not Insured | 17 | 5.3% | 5 | 7.5% | 33 | 6.3% |
| Medicaid | 29 | 9.0% | 7 | 10.4% | 59 | 11.2% |
| Medicare | 83 | 25.8% | 27 | 40.3% | 153 | 29.0% |
(continued)
| Demographics | cStage III LN (-) | cStage III LN (+) | cStage IV | |||
|---|---|---|---|---|---|---|
| Variable | Count | Percentage/SD | Count | Percentage/SD | Count | Percentage/SD |
| Other government | 13 | 4.0% | 0 | 0.0% | 7 | 1.3% |
| Insurance status unknown | 9 | 2.8% | 0 | 0.0% | 20 | 3.8% |
| Hospital type | ||||||
| Academic/Research program | 156 | 48.4% | 31 | 46.3% | 216 | 40.9% |
| Community cancer program | 7 | 2.2% | 3 | 4.5% | 22 | 4.2% |
| Comprehensive community cancer program | 55 | 17.1% | 13 | 19.4% | 129 | 24.4% |
| Integrated network cancer program | 42 | 13.0% | 10 | 14.9% | 62 | 11.7% |
| N/A | 62 | 19.3% | 10 | 14.9% | 99 | 18.8% |
Abbreviations: LN = lymph node; Regional Education = the number of adults age 25 or older in the patient’s zip code who did not graduate from high school.
* significant difference in proportions/medians.
From the NCDB we captured 4,311 patients with adre- nocortical carcinoma from 2010 to 2017. We included only those with complete treatment and clinical staging data (N=1,781) (Fig. 1). Only those with clinical stage III or IV disease were included (N=917). Only 109 patients with stage III or IV disease and complete pathologic data were found in the NCDB.
Our primary outcome was overall survival. The primary exposure was presence of clinical lymph node positive dis- ease in patients with stage III adrenocortical carcinoma. We adjusted multivariable models for age, receipt of surgery, receipt of systemic therapy and Charlson Comorbidity Index.
2.2. Data analysis
Patients from the NCDB were stratified into 3 groups by clinical staging: 1) those with lymph node negative stage III disease (cT3-4N0M0); 2) those with lymph node posi- tive stage III disease (cTanyN1M0); and 3) those with stage IV metastatic disease (cTanyN0- 1M1). Patient characteris- tics were enumerated. Kaplan-Meier survival estimates and Cox proportional hazards regression models assessed over- all survival between stage III (lymph node positive and lymph node negative) and stage IV disease. Survival esti- mates and 95% confidence intervals (95% CIs) were calcu- lated from survival functions at 12, 24, and 36 months. In an effort to assess the impact of treatment on survival, Kaplan-Meier survival estimates were assessed between those who did and did not receive treatment of any kind in stage III lymph node positive disease as well as stage IV disease. All data analyses were conducted using R Statisti- cal Software (version 4.3.0; R Foundation for Statistical Computing, Vienna, Austria).
3. Results
Final analysis included 917 patients from 2010 to 2017, 322 (35.1%) patients with lymph node negative stage III
disease, 67 (7.3%) patients with lymph node positive stage III disease, and 528 (57.6%) with stage IV disease. Demo- graphic information for each cohort is described in Table 1. Table 2 Median follow-up was 11.07 months (IQR 3.75- 30.06). The mean age of the stage III lymph node positive group was 58.1 years (SD 15.2) compared to 54.0 (SD 17.5) and 54.2 (SD 16.4) for the stage III lymph node nega- tive and stage IV groups, respectively. A greater percentage of patients with stage III lymph node negative (75.8%) dis- ease received surgery, compared with stage III lymph node positive (58.2%), and stage IV (27.1%) disease. Similarly, patients deemed stage III lymph node negative (56.2), underwent systemic therapy more commonly than those with stage III node positive (43.3%) or stage IV (36.2%) disease.
The 3-year overall survival of patients with stage III lymph node negative, stage III lymph node positive, and stage IV disease was 48.6%, 29.4%, and 15.6%, respec- tively (Fig. 2). The 3-year overall survival for patients with stage III lymph node positive disease was 33.0% for those who did receive treatment (systemic therapy or surgery), compared to 27.4% for those who did not (Fig. 3). Simi- larly, among stage IV patients, 3-year overall survival was higher among those receiving treatment (29.8% vs. 10.2%, Fig. 4).
Among patients with stage III adrenocortical carcinoma, lymph node positive disease was associated with poorer survival (HR 1.72, 95% CI 1.26-2.37, P < 0.001. This rela- tionship did not maintain significance on multivariable analysis (HR 1.27, 95% CI 0.88-1.83, P=0.21). Not under- going surgery, was associated with an increased risk of death (Multivariable HR 2.29, 95% CI 1.67-3.13, P < 0.001).
4. Discussion
Patients with advanced adrenocortical carcinoma have poor oncologic outcomes. In this retrospective study, we find that among patients with clinical stage III disease,
| cStage III | Univariable Model n = (389) | Multivariable Model n = (286) | ||||
|---|---|---|---|---|---|---|
| Variable | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Positive LN | ||||||
| No | Reference | Reference | Reference | Reference | Reference | Reference |
| Yes | 1.72 | 1.26-2.37 | < 0.001 | 1.27 | 0.88-1.83 | 0.21 |
| Lymph node dissection* | ||||||
| LN dissected | Reference | Reference | Reference | Reference | Reference | Reference |
| LN not dissected/unknown | 1.06 | 0.80-1.39 | 0.70 | 1.18 | 0.82-1.70 | 0.37 |
| Tumor grade | ||||||
| 1 | Reference | Reference | Reference | - | - | - |
| 2 | 0.43 | 0.10-1.78 | 0.24 | - | - | - |
| 3 | 1.46 | 0.57-3.78 | 0.43 | - | - | - |
| 4 | 0.89 | 0.30-2.66 | 0.83 | - | - | - |
| Cell type undetermined | 1.43 | 0.59-3.48 | 0.43 | - | - | - |
| Received surgery | ||||||
| Yes | Reference | Reference | Reference | Reference | Reference | Reference |
| No | 1.83 | 1.40-2.41 | < 0.001 | 2.29 | 1.67-3.13 | < 0.001 |
| Systemic therapy | ||||||
| No | Reference | Reference | Reference | Reference | Reference | Reference |
| Yes | 1.29 | 1.00-1.67 | 0.046 | 1.16 | 0.85-1.58 | 0.35 |
| Age | 1.02 | 1.02-1.03 | < 0.001 | 1.03 | 1.02-1.05 | < 0.001 |
| Sex | ||||||
| Female | Reference | Reference | Reference | Reference | Reference | Reference |
| Male | 1.02 | 0.79-1.31 | 0.88 | 0.88 | 0.65-1.17 | 0.37 |
| Race | ||||||
| White | Reference | Reference | Reference | Reference | Reference | Reference |
| Black | 1.03 | 0.70-1.52 | 0.88 | 0.94 | 0.59-1.51 | 0.81 |
| Native American | 1.12 | 0.28-4.51 | 0.87 | 1.92 | 0.47-7.84 | 0.37 |
| Asian | 0.72 | 0.27-1.94 | 0.51 | 0.61 | 0.19-1.92 | 0.40 |
| Other | 1.76 | 0.65-4.76 | 0.26 | 0.95 | 0.23-3.91 | 0.94 |
| Charlson comorbidity index | ||||||
| 0 | Reference | Reference | Reference | Reference | Reference | Reference |
| 1 | 1.10 | 0.80-1.52 | 0.55 | 0.93 | 0.65-1.34 | 0.70 |
| 2 | 0.83 | 0.44-1.58 | 0.58 | 0.75 | 0.39-1.44 | 0.39 |
| 3 | 1.68 | 0.86-3.29 | 0.13 | 1.10 | 0.54-2.24 | 0.78 |
| Insurance status | ||||||
| Private | Reference | Reference | Reference | - | - | - |
| Not Insured | 0.94 | 0.53-1.66 | 0.8237 | - | - | - |
| Medicaid | 1.03 | 0.65-1.65 | 0.8949 | - | - | - |
| Medicare | 1.74 | 1.31-2.32 | 0.0002 | - | - | - |
| Other government | 2.01 | 1.08-3.75 | 0.0271 | - | - | - |
| Insurance status unknown | 1.08 | 0.44-2.65 | 0.8619 | - | - | - |
| Hospital type | ||||||
| Academic/Research program | Reference | Reference | Reference | - | - | - |
| Community cancer program | 1.23 | 0.58-2.65 | 0.5897 | - | - | - |
| Comprehensive community cancer program | 1.39 | 1.00-1.93 | 0.0526 | - | - | - |
| Integrated network cancer program | 1.44 | 0.99-2.11 | 0.0566 | - | - | - |
| N/A | - | - | - | - | - | - |
lymph node positivity was associated with decreased over- all on univariable analysis. However, this did not maintain significance on multivariable analysis. Further, older patients and those not undergoing surgery had increased risk of mortality.
The first TNM staging classification for adrenocorti- cal carcinoma was published in 2004, which had a broad definition of stage IV disease including both metastatic (TanyNanyM1) as well as locally advanced disease (T3-
4N1M0 and T4N0M0). Prior studies have examined this previous staging classification for adrenocortical carci- noma as a reflection of measured survival outcomes. An earlier study of 416 patients with adrenocortical carci- noma of all stages found that those with positive lymph nodes, confirmed on final pathology, had worse disease- specific survival compared to those with negative nodes (HR 2.5, 95% CI, 1.2-5.7) [8]. Based off of these and earlier data, the previous TNM classification was
Classification + cStage III LN- + cStage III LN+ + cStage IV
100
74.1%
75
Overall Survival
53.6%
57%
48.6%
50
33.3%
36.2%
29.4%
25
23.3%
15.6%
0
p < 0.0001
0
12
24
36
Time (months)
Classification
Number at risk
cStage III LN-
322
231
164
120
cStage III LN+
67
32
18
14
cStage IV
528
176
102
53
0
12
24
36
Time (months)
cStage III LN+ Treatment + No Treatment + Treatment
100
67%
75
Overall Survival
50
37.7%
33%
44.8%
25
30.8%
27.4%
0
p = 0.11
0
12
24
36
cStage III LN+ Treatment
Time (months)
Number at risk
No Treatment
41
16
10
8
Treatment
26
16
8
6
0
12
24
36
Time (months)
cStage IV Treatment + No Treatment + Treatment
100
75
61.3%
Overall Survival
50
43.6%
29.8%
25
26.8%
15.6%
10.2%
0
p < 0.0001
0
12
24
36
Time (months)
cStage IV Treatment
Number at risk
No Treatment
387
92
49
25
Treatment
141
84
53
28
0
12
24
36
Time (months)
changed, reflecting its current form [8]. Further, Libe et al. [4] retrospectively reviewed patients with advanced adrenocortical carcinoma (stage III-IV) in a granular European registry. Survival probability of patients with node positive disease, but not venous invasion, was found to overlap with stage IV disease. They also inves- tigated the prognostic role of the number of involved disease sites, considering both the primary involved adrenal gland and regional lymph nodes as unique organs disease sites. In dose dependent fashion, patients with more disease sites (i.e., metastatic site, lymph node involvement, or primary tumor) had increasingly poor survival. Aligning with other studies, the authors advo- cated for a staging classification which would include a subclassification of stage IV disease that would qualify patients with lymph node involvement as having stage IVa adrenocortical carcinoma [4,10-12].
The current guidelines recommend performing locore- gional lymphadenectomy during adrenalectomy for adreno- cortical carcinoma [13,14]. Our data suggests, at least, an important prognostic role for lymphadenectomy given the implications on survival. Prior series have demonstrated a relationship between lymphadenectomy and improved sur- vival [7,15]. Further, extent of node dissection may also contribute to improved oncologic outcomes. A retrospec- tive study of 283 patients undergoing adrenalectomy found that patients with at least 5 lymph nodes removed had improved recurrence-free survival [16]. These studies
suggest a therapeutic benefit of lymphadenectomy during adrenalectomy. However, improved classification of patients as lymph node positive or negative may account for much of the observed benefit (i.e., the Will Rogers Phe- nomenon).
Staging classification in adrenocortical carcinoma has natural implications for adjuvant therapy in patients with advanced tumors. Current National Comprehensive Cancer Network guidelines, propose adjuvant chemotherapy or radiotherapy as an option for patients at risk of local recur- rence (i.e., positive margins, rupture capsule, large tumor size, high grade disease) [13]. However, there is little pro- spective evidence supporting adjuvant therapy in this set- ting [13]. The recently published ADIUVO trial, examined the use of adjuvant Mitotane in patients at low or intermedi- ate risk for progression, as it was deemed unethical to ran- domize high risk patients to observation. In the ADIUVO trial, low or intermediate risk was defined as patients who had a complete resection with negative surgical margins, stage I-III, and Ki67<10%. In a study of 91 patients, the authors found that there were no differences in 5- year overall survival or 5-year recurrence free survival between the adjuvant mitotane group and observation alone after surgery [17]. A recent 13-institution retro- spective study by the US Adrenocortical Carcinoma Group found that when adjusting for stage and tumor and treatment-related factors, adjuvant mitotane after resection of adrenocortical carcinoma also did not
improve overall survival or recurrence free survival [18]. In our study, the difference in rates of systemic therapy between the populations may have played a role in the differences in overall survival.
Our study has several limitations beyond its retrospec- tive design [19]. Our study, despite using a large database, is limited by sample size due to the rarity of adrenocortical carcinoma. This may, in part, explain the lack of statistical significance in the multivariable analysis. Further, our anal- ysis was restricted to clinical node status as opposed to pathologic node status, as only 109 patients had complete pathologic data. While clinical node status offers important prognostic value and informs treatment decisions, decisions such as adjuvant therapy are typically based on final patho- logic staging. Another limitation is the heterogeneity of treatment protocols among patients. The NCDB has limited data granularity and does not include variables including chemotherapy agent and tumor metabolic activity. Given that the data is pooled from >1,500 hospitals, there is no centralized radiographic or pathologic review, which intro- duces biases in terms of staging and grading classification. The NCDB also only has information regarding overall sur- vival and not outcomes such as cancer-specific survival and recurrence-free survival. Lastly, due to the relatively short follow-up duration, we used Kaplan-Meier estimates in order to quantify estimated long-term survival. These esti- mates can be imprecise due to the small sample size of our population. Future research is needed with a larger sample size and prospectively collected data in order to further inform the prognostic implications of having lymph node positive disease.
Despite these limitations, our data suggests that clinical lymph node status offers important clinical nuance in patients with stage III adrenocortical carcinoma. In a uni- variable analysis, we observe that lymph node positive dis- ease is statistically associated with poorer overall survival. However, this did not maintain statistical significance on multivariable analysis. As a result, current staging may not reflect these differential survival outcomes - building a case for reclassification of advanced adrenocortical carci- noma.
5. Conclusion
Stage III adrenocortical carcinoma encompasses both clinically localized, lymph node positive, disease (TanyN1M0) as well as lymph node negative disease (T3- 4N0M0). Our study suggests differential survival between stage III patients with and without lymph node involve- ment. Our study builds on the body of literature demonstrat- ing that lymph node positive disease confers worse oncologic outcomes. With the results of our study building on the prior data on advanced adrenocortical carcinoma, consideration should be given for reclassification of stage III adrenocortical carcinoma to reflect these differential sur- vival outcomes.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
CRediT authorship contribution statement
Benjamin J. Lichtbroun: Writing - original draft, Supervision, Resources, Project administration, Project administration, Investigation, Data curation, Conceptualiza- tion. Helen Gao: Software, Methodology, Formal analysis, Data curation. Kevin Chua: Writing - review & editing, Methodology, Investigation. John Pfail: Writing - review & editing, Methodology, Investigation. Rachel Passarelli: Writing - review & editing, Methodology, Investigation. Hiren V. Patel: Writing - review & editing, Methodology, Investigation. Sammy Elsamra: Writing - review & edit- ing, Methodology, Investigation. Eric A. Singer: Writing - review & editing, Writing - original draft, Methodology, Investigation, Conceptualization. Vignesh T. Packiam: Writing - review & editing, Methodology, Investigation. David Golombos: Writing - review & editing, Methodol- ogy, Investigation. Saum Ghodoussipour: Writing - review & editing, Writing - original draft, Visualization, Supervision, Resources, Project administration, Methodol- ogy, Investigation, Funding acquisition, Conceptualization. Arnav Srivastava: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investiga- tion, Funding acquisition, Formal analysis, Data curation, Conceptualization.
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