Medicine OPEN
Prognostic factors and treatment outcomes in patients with adrenal cortical carcinoma A registry-based study
Tao Chen, MMª, Dongyang Zeng, MMª, Guang Zhou, MMª, Linghui Qin, MMª, Xiaoyuan Qian, MDa,*[D
Abstract
Adrenal cortical carcinoma (ACC) is rare in clinical practice, and its prognosis and treatment have not been systematically studied. This study aimed to investigate the prognostic factors and impact of treatment strategies on overall survival (OS) and cancer- specific survival (CSS) in patients with ACC, using Surveillance, Epidemiology, and End Results registry data. Patient’s data for ACC pathologically diagnosed between 2000 and 2021 were identified from Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method was used to assess OS and CSS. While Cox proportional hazards regression analysis was used to evaluate the risk predictors of OS and CSS, the effects of surgery, chemotherapy, and radiotherapy on OS and CSS were also assessed using directed acyclic graphs-guided multivariate Cox regression model. A total of 444 patients with ACC were enrolled. The median OS and CSS in this cohort were 25 and 30 months, respectively. The OS at 1, 2, and 5 years were 62.7%, 50.2%, and 31.5%, respectively, while the CSS at 1, 2, and 5 years were 66.6%, 54.8%, and 37.2%, respectively. Patients with ≥ 53 years old, pathological grade III/IV, clinical stage III/IV, T3/4, N1, M1, and none receiving the therapy of surgery or radiation had worse survival. Old age, worse clinical stages, poor pathological grade, distant metastasis, no surgical treatment, and no radiation therapy were risk predictors of OS and CSS. In addition, receiving surgery or radiation therapy improved OS and CSS in the directed acyclic graph-guided multivariate Cox regression model. ACC has malignant behavior and a relatively poor prognosis. Old age, poor pathological grades, late clinical stages, and advanced tumor node metastasis classification indicate poor survival. While surgical resection of tumor lesions is one of the effective treatments, which can improve the outcome of patients with ACC, radiation therapy may be a palliative and beneficial treatment for patients with advanced disease.
Abbreviations: ACC = adrenal cortical carcinoma, CI = confidence interval, CSS = cancer-specific survival, DAG = directed acyclic graphs, HR = hazard ratio, IQR = interquartile range, OS = overall survival, RT = radiation therapy, SEER = Surveillance, Epidemiology, and End Results, TNM = tumor node metastasis.
Keywords: adrenal cortical carcinoma, clinical characteristics, prognosis, treatment strategies
1. Introduction
Adrenal cortical carcinoma (ACC) is a rare malignant tumor, originating from renal epithelial gland.[1] Based on big data analyses, the annual incidence of ACC has been between 0.7 and 2 per 1,000,000 population over the last decade.[1,2] ACC has different clinical features, such as excessive secretion of adrenal hormones (60%), cancerous pain (30-40%), inciden- tal detection on imaging studies (10-15%),[3] and unfavorable clinical outcomes.[1,4] Owing to the lack of special symptoms, signs, and tumor markers in the early stages of ACCs, which
has aggressive biological characteristics, most patients are diag- nosed at an advanced clinical stage, which may contribute to adverse survival.[5] Systematic understanding of the clinicopath- ological features and prognosis of ACC is relatively limited. A few studies revealed that patients with large size and late NM stage had decreased survival.[6] There is no standard treatment, and surgical removal of the tumor lesion is the main treatment strategy. There is a high recurrence rate after radical or palli- ative resection and the impact of comprehensive treatment on survival is relatively limited.[7]
TC and DZ contributed equally to this work.
This research was supported by a grant from the Natural Science Foundation of Hubei Province (No. 2023AFB866).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
As the data from the SEER registry were de-identified and public, institutional review board approval was waived, and informed consent was not required for this study.
Supplemental Digital Content is available for this article.
a Department of Urology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
* Correspondence: Xiaoyuan Qian, Department of Urology, Xiangyang Central
Hospital, Affiliated Hospital of Hubei University of Arts and Science, 136 Jingzhou
Street, Xiangcheng, Xiangyang City 441021, Hubei, China (e-mail: 932488575@ qq.com).
Copyright @ 2025 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is
permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
How to cite this article: Chen T, Zeng D, Zhou G, Qin L, Qian X. Prognostic factors and treatment outcomes in patients with adrenal cortical carcinoma: A registry-based study. Medicine 2025;104:30(e42831).
Received: 17 December 2024 / Received in final form: 23 February 2025 / Accepted: 26 May 2025
http://dx.doi.org/10.1097/MD.0000000000042831
Due to the lack of large-scale samples, studies on the treat- ment and prognostic factors of ACC have focused on case series reports and small sample studies.[7,8] Although a recent study discovered that relevant prognostic factors affect the cancer- specific survival of patients with malignant adrenal tumors,[9] the prognostic value of different strategies and risk factors affecting the survival of patients with ACC remains unclear. The role of surgery, especially radiation therapy (RT) and che- motherapy, in treatment needs further research. Hence, in this study, we used the Surveillance, Epidemiology, and End Results (SEER) database to explore the risk factors that affect the sur- vival of patients with ACC. Additionally, different directed acyclic graphs (DAG)-guided-Cox regression models were con- ducted, and the values of surgery, RT, and chemotherapy during the treatment of patients were investigated.
2. Materials and methods
2.1. Data extraction
All clinical and follow-up data were downloaded from the SEER database, covering approximately 35% of the entire U.S. population.[10] By linking to https://seer.cancer.gov/seerstat/, SEER*Stat 8.4.1.2 software was run to retrieve the “Incidence- SEER Research Plus Data, 17 Registries, Nov 2021 Sub” database and obtain information on patients, who had been diagnosed with pathological features as ACC between 2000 and 2021, from the SEER database. According to the third edition of the International Classification of Tumor Diseases (ICD-O- 3), patient data in morphology code 8370/3: ACC were down- loaded. Eligible inclusion and exclusion criteria were follows: (1) complete follow-up information of patients was available; (2) the tumor was verified by pleomorphism; (3) the time of diagnosis and therapy was between 2000 and 2021; (4) bilat- eral tumors were excluded; (5) cases lacking complete clinico- pathological information related to the study were not included. A total of 444 patients with ACC who met these criteria were recruited and 1334 cases that did not meet the inclusion criteria were excluded.
2.2. Patient information
Using the “case listing session” option, patients’ demographic information about age, sex, race, survival status, and survival time after treatment was extracted. Clinicopathological fea- tures, such as tumor size, laterality, tumor stage, tumor node metastasis (TNM) classification, and pathological grade, were also collected from the database. The pathological grades were divided into grade I (highly differentiated), grade II (moderately differentiated), grade III (poorly differentiated), and grade IV (undifferentiated). The patients were classified by the seventh edition of TNM. In addition, we obtained information on treat- ment strategies such as, surgery, RT, or chemotherapy. Overall survival (OS) was deemed the primary endpoint, which was cal- culated as the survival time from the date of definite diagnosis to the date of death from any cause or last follow-up. Cancer- specific survival (CSS) was seen as the secondary endpoint, being defined as the survival time from the date of definite diagnosis to the date of death which resulted in ACC.
2.3. Statistical analysis
We used the R statistical package v 3.6.3 (The R Foundation for Statistical Computing, Vienna, Austria) for statistical anal- yses. The optimal cutoff value of age, which was 53 years, was obtained, using receiver operating characteristic curves. Continuous non-normally distributed variables are displayed as median and interquartile range (IQR), while continuous variables with a normal distribution are presented as mean ± standard
deviation. Categorical variables were presented as numbers and percentages. Survival curves were visualized using the Kaplan- Meier method and differences between survival curves were compared using log-rank tests. The Cox proportional hazards regression model was performed to estimate in univariate and multivariate analyses, the predictors of OS and CSS, which were adjusted for other significant prognostic factors. A DAG diagram consists of directed vectors and factors affecting the prognosis of ACC. A pairwise causal relationship of variables is pointed at by a directed arrow. In graph theory, a directed graph is a DAG if it cannot start from a dependent variable and return to that point by several edges. In this way, the intermediate vari- ables can be excluded and the collinearity between variables can be solved. Therefore, DAG-directed regression models were constructed to identify the influence of surgery, chemotherapy, and RT on OS and CSS.[11] Reported P values (two-sided) were considered statistically significant when the value was <. 05.
3. Results
3.1. Patient characteristics
A total of 444 patients with ACC were included in this study and their underlying characteristics are presented in Table S1, Supplemental Digital Content, https://links.lww.com/MD/P219. The median age of the cohort was 56 years (IQR, 45-65 years). The median tumor size at primary diagnosis was 11 cm, and its IQR was 8.0 to 15.4cm. Based on the TNM stage classifica- tion, 23 (5.18%) patients were in T1, 187 (42.1%) in T2, 196 (21.6%) in T3, and 100 (22.5%) in T4. Lymph node metas- tasis was identified in 100 (22.5%) patients. Meanwhile, 164 (36.9%) patients had distant metastases at the time of confirma- tion. According to the AJCC 7th edition of ACC, there were 20 (4.5%) patients in stage I, 139 (31.3%) in stage II, 65 (14.6%) in stage III, and 208 (46.8%) in stage IV. Pathological grad- ing showed that 9 (2.03%), 17 (3.83%), 36 (8.11%), and 23 (5.18%) of all cases were in stages I, II, III, and IV, respectively. Moreover, most patients (76.8%) with ACC received surgical therapy and only a few patients (16.4%) received RT. Half of the (48.0%) received chemotherapy.
3.2. Impact of clinical characteristics and treatment methods on prognosis
The median OS and CSS of all patients were 25.0 months (95% confidence interval [CI]: 20.0-30.0) and 30.0 months (95% CI: 25.0-38.0), respectively. The OS rates at 1, 2, and 5 years were 24.4%, 15.1%, and 2.3%, respectively. CSS rates at 1, 2, and 5 years were 27.0%, 17.9%, and 2.8%, respectively. Young patients had longer survival than older age (median OS: 35 vs 17 months, P < . 001; CSS: 38 vs 23 months, P < . 031) (Figures S1A and S2A, Supplemental Digital Content, https://links.lww.com/ MD/P220). Survival rates were related to pathological grading. The median OS of grades I, II, III, and IV were 81, 66, 11, and 83 months, respectively (total P = . 030) (Figure S1B, Supplemental Digital Content, https://links.lww.com/MD/P220), while CSS were not reached, 66, 19, and 1 not reached (total P = . 016) (Figure S2B, Supplemental Digital Content, https://links.lww. com/MD/P220). Likewise, high-stage tumors adversely affected the survival of ACCs. The median OS for stages I, II, III, and IV was 67 months, 89 months, 27 months, and 8 months, respec- tively (total P <. 001; I vs IV, P < . 001; II vs III, P < . 001; II vs IV, P < . 001; Ill vs IV, P < . 001) (Figure S1C, Supplemental Digital Content, https://links.lww.com/MD/P220) when CSS was not reached, not reached, 40 months, and 9 months (total P < . 001; I vs IV, P < . 001; II vs III, P = . 001; II vs IV, P < . 001; Ill vs IV, P < . 001) (Figure S2C, Supplemental Digital Content, https://links.lww.com/MD/P220). The survival rates were also influenced by T staging, the median survival of T1, T2, T3,
A
Strata ++ Surgery + No
B
Strata ++ Radiation + No
C
Chemotherapy + Yes + No
1.00-
1.00-
1.00-
Overall survival
0.75
Overall survival
0.75
Overall survival
0.75
0.50
0.50
0.50
0.25
p<0.001++ +++++
0.25
0.25
p < 0.001
0.00
0.00
0.00
0
30
60
90
120
0
30
60
90
0
30
60
90
Months after surgery
Months after surgery
120
Months after surgery
120
Number at risk
Number at risk
Number at risk
Strata
Surgery
174
69
32
10
0
Strata
Radiation
40
22
14
4
0
Strata
Yes
158
44
17
6
0
No
99
6
2
0
0
No
233
53
20
6
0
No
115
31
17
4
0
0
30
60
90
120
0
30
60
90
120
0
30
Months after surgery
Months after surgery
Months after surgery
60
90
120
D
E
F
Strata + Surgery + No
Strata
Radiation
No
Chemotherapy + Yes + No
1.00
Cancer-specific survival
1.00-
Cancer-specific survival
Cancer-specific survival
1.00-
0.75
0.75
0.75
0.50
0.50
0.50
0.25
p < 0.001
0.25
p < 0,001
0.25
0.00
0.00
0.00
0
30
Months after surgery
60
90
120
0
30
60
90
0
Months after surgery
120
Months after surgery
30
60
90
120
Number at risk
Number at risk
Number at risk
Strata
Surgery
174
69
32
10
0
Strata
Radiation
40
22
14
4
0
Strata
Yes
158
44
17
6
0
No
99
6
2
0
0
No
233
53
20
6
0
No
115
31
17
4
0
0
30
Months after surgery
60
90
120
0
30
Months after surgery
60
90
120
0
30
Months after surgery
60
90
120
and T4 for OS was 58, 53, 21, and 10 months, respectively (total P <. 001; T1 vs T3, P =. 008; T1 vs T4, P <. 001; T2 vs T3, P <. 001; T2 vs T4, P <. 001; T3 vs T4, P =. 011) (Figure S1D, Supplemental Digital Content, https://links.lww.com/MD/ P220), while the median survival for CSS was 67, 89, 22, and 12 months, respectively (total P <. 001; T1 vs T3, P = . 023; T1 vs T4, P <. 001; T2 vs T3, P <. 013; T2 vs T4, P <. 003; T3 vs T4, P = . 017) (Figure S2D, Supplemental Digital Content, https:// links.lww.com/MD/P220). Lymph node or distant metastasis can lead to shorter survival rates. The median OS times of NO and N1 were 32, and 6 months, respectively (total P <. 001) (Figure S1E, Supplemental Digital Content, https://links.lww. com/MD/P220). For CSS, 38 months and 7 months corre- sponded to the median survival of NO, and N1 (P <. 001) (Figure S2E, Supplemental Digital Content, https://links.lww.com/MD/ P220). In contrast to patients with distant metastases, patients without distant metastases showed longer OS (median OS: 53 vs 7 months, P < . 001) (Figure S1F, Supplemental Digital Content, https://links.lww.com/MD/P220) and better CSS (median CSS: 74 vs 7 months, P < . 001) (Figure S2F, Supplemental Digital Content, https://links.lww.com/MD/P220). Patients who under- went surgery had a longer survival (median OS: 38 vs 4 months, P < . 001; median CSS: 50 vs 5 months, P < . 001) (Figures S1G and S2G, Supplemental Digital Content, https://links.lww.com/ MD/P220). Interestingly, patients who were treated with che- motherapy displayed lower OS and CSS than those who were not (median OS: 22 months and 30 months, P = . 025; median CSS: 26 months and 42 months, P = . 006) (Figures S1H and S2H, Supplemental Digital Content, https://links.lww.com/MD/ P220). Moreover, patients who received RT had higher survival
times (median OS: 64 vs 20 months, P < . 001; median CSS: 75 vs 27 months, P <. 001) (Figures S1I and S2I, Supplemental Digital Content, https://links.lww.com/MD/P220).
As the majority of patients undergoing RT and chemother- apy were in stages III and IV, these cases were in the subgroup analysis. Patients who underwent surgery had higher survival than patients who did not undergo surgery (median OS: 21 vs 4 months, P <. 001; median CSS: 27 vs 4 months, P <. 001) (Fig. 1A, D). Patients who received radiation had longer survival (median OS: 38 vs 9 months, P <. 001; median CSS: 45 vs 10 months, P < . 001) (Fig. 1B, E). No significant difference in OS and CSS rates were detected between the chemotherapy patients and non-chemotherapy patients (median OS: 14 vs 7 months, P = . 610; median CSS: 15 vs 11 months, P = . 770) (Fig. 1C, F).
3.3. Risk factors for OS and CSS in patients with ACCs
To explore the risk factors for OS and CSS in ACC patients, a Cox regression model was applied. Univariate Cox regression analysis indicated that OS and CSS were affected by tumor size, clinical stage, pathological grade, TNM stage, surgery, RT, and chemotherapy (P < . 05). All significant variables were included in the multivariate Cox regression model for further analysis. In multivariate analysis, venerable age (OS: Hazard ratio [HR]: 1.014, 95% CI: 1.006-1.023; P <. 001; CSS: HR: 1.010, 95% CI: 1.001-1.019; P = . 032), poor pathological grade (III vs I: OS: HR: 3.684, 95% CI: 1.370-9.911; P = . 010; CSS: HR: 5.321, 95% CI: 1.566-18.075; P = . 007), distant metastases (OS: HR: 1.757, 95% CI: 1.123-2.750; P = . 014; CSS: HR: 1.852, 95% CI: 1.137-3.016; P < . 013), no-surgery
(OS: HR: 2.809, 95% CI: 1.947-4.052; P = . 014; CSS: HR: 3.197, 95% CI: 2.160-4.732; P < . 013), and no radiation (OS: HR: 1.671, 95% CI: 1.157-2.412; P = . 006; CSS: HR: 1.554, 95% CI: 1.050-2.301; P = . 028) remained independent prog- nostic factors for OS and CSS. The results of the analyses are presented in Tables 1 and 2.
3.4. Influence of surgery, chemotherapy, and RT on OS and CSS
Different DAGs were constructed to identify the mediating and confounding variables that directly affected survival prognosis (OS and CSS) and all confounding variables were included in
the Cox regression model. When surgery was included as the primary exposure factor in the regression model directed by DAG (Figure S3, Supplemental Digital Content, https://links. lww.com/MD/P220), surgery was an independent risk fac- tor for OS (HR: 3.051, 95% CI: 2.142-4.364; P <. 001) and CSS (HR: 3.400, 95% CI: 2.332-4.959; P <. 001) (Table 3). While RT was deemed as the main exposure variable (Figure S4, Supplemental Digital Content, https://links.lww.com/MD/ P220), the findings showed that RT was associated with OS (HR: 1.670, 95% CI: 1.184-2.44; P = . 004) and CSS (HR: 1.569, 95% CI: 1.066-2.309; P = . 022) (Table 4). However, chemotherapy seen as an exposure factor was enrolled into the Cox regression model (Figure S5, Supplemental Digital Content, https://links.lww.com/MD/P220), chemotherapy
| Characteristics | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age (years) | 1.014 (1.006-1.022) | <. 001 | 1.014 (1.006-1.023) | .001 |
| Sex | ||||
| Female | Reference | Reference | ||
| Male | 1.198 (0.955-1.503) | .119 | ||
| Race | ||||
| Black | Reference | Reference | ||
| White | 1.598 (1.014-2.518) | .044 | 1.092 (0.677-1.764) | .718 |
| Other* | 1.514 (0.826-2.776) | .180 | 1.126 (0.603-2.104) | .710 |
| Tumor stage | ||||
| I | Reference | Reference | ||
| II | 0.949 (0.487-1.850) | .878 | 0.837 (0.206-3.406) | .804 |
| III | 1.834 (0.923-3.646) | .084 | 1.152 (0.283-4.69) | .843 |
| IV | 4.557 (2.405-8.637) | <. 001 | 2.162 (0.527-8.868) | .284 |
| SEER stage | ||||
| Local | Reference | |||
| Regional | 2.062 (1.484-2.866) | <. 001 | ||
| Distant | 5.173 (3.920-6.826) | <. 001 | ||
| Laterality | ||||
| Left | Reference | Reference | ||
| Right | 1.025 (0.820-1.281) | .831 | ||
| Tumor size (cm) | 1.001 (1.000-1.001) | .0164 | 1.000 (1.000-1.001) | .481 |
| Pathologic grade | ||||
| Grade I | Reference | Reference | ||
| Grade II | 1.209 (0.420-3.480) | .725 | 1.873 (0.628-5.588) | .260 |
| Grade III | 2.588 (1.001-6.695) | .0498 | 3.684 (1.37-9.911) | .010 |
| Grade IV | 1.070 (0.377-3.039) | .898 | 1.843 (0.626-5.424) | .267 |
| T stage | ||||
| T1 | Reference | Reference | ||
| T2 | 1.144 (0.642-2.038) | .648 | 1.030 (0.303-3.501) | 962 |
| T3 | 2.418 (1.192-3.872) | .011 | 1.596 (0.473-5.379) | .451 |
| T4 | 3.234 (1.803-5.802) | <. 001 | 1.029 (0.31-3.42) | 962 |
| TX | 3.511 (1.849-6.666) | <. 001 | 0.535 (0.149-1.924) | .339 |
| N stage | ||||
| N0 | Reference | Reference | ||
| N1 | 2.554 (1.852-3.523) | <. 001 | 1.070 (0.744-1.54) | .714 |
| NX | 2.943 (2.005-4.320) | <. 001 | 1.356 (0.893-2.059) | .153 |
| M stage | ||||
| M0 | Reference | Reference | ||
| M1 | 1.400 (3.231-5.085) | <. 001 | 1.757 (1.123-2.75) | .014 |
| Surgery | ||||
| Yes | Reference | Reference | ||
| No | 5.109 (3.969-6.578) | <. 001 | 2.809 (1.947-4.052) | <. 001 |
| Radiotherapy | ||||
| Yes | Reference | Reference | ||
| No/Unknown | 2.076 (1.472-2.927) | <. 001 | 1.671 (1.157-2.412) | .006 |
| Chemotherapy | ||||
| Yes | Reference | Reference | ||
| No/Unknown | 0.779 (0.623-0.973) | .028 | 1.218 (0.934-1.589) | .146 |
ACC = adrenal cortical carcinoma, CI = confidence interval, HR = hazard ratio, OS = overall survival.
* Other included American Indian/Alaskan Native and Asian/Pacific Islander.
| Characteristics | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age (years) | 1.009 (1.001-1.018) | .027 | 1.01 (1.001-1.019) | .032 |
| Sex | ||||
| Female | Reference | |||
| Male | 1.229 (0.962-1.570) | .098 | ||
| Race | ||||
| Black | Reference | |||
| White | 1.496 (0.925-2.418) | .101 | ||
| Other* | 1.434 (0.752-2.734) | .274 | ||
| Tumor stage | ||||
| I | Reference | Reference | ||
| II | 0.808 (0.396-1.646) | .556 | 0.878 (0.21-3.671) | .858 |
| III | 1.659 (0.799-3.446) | .175 | 1.229 (0.296-5.095) | .777 |
| IV | 4.412 (2.249-8.658) | <. 001 | 2.34 (0.558-9.819) | .245 |
| SEER stage | ||||
| Local | Reference | |||
| Regional | 2.095 (1.448-3.031) | <. 001 | ||
| Distant | 5.853 (4.312-7.946) | <. 001 | ||
| Laterality | ||||
| Left | Reference | |||
| Right | 1.026 (0.806-1.307) | .833 | ||
| Tumor size (cm) | 1.001 (1.000-1.001) | .021 | 1.0002 (0.9997-1.001) | .417 |
| Pathologic grade | ||||
| Grade I | Reference | Reference | ||
| Grade II | 2.852 (0.356-22.810) | .323 | 2.69 (0.718-10.084) | .142 |
| Grade III | 9.675 (1.340-69.870) | .024 | 5.321 (1.566-18.075) | .007 |
| Grade IV | 11.597 (1.600-84.130) | .015 | 2.614 (0.702-9.736) | .152 |
| T stage | ||||
| T1 | Reference | Reference | ||
| T2 | 1.025 (0.560-1.877) | .936 | 0.869 (0.252-2.996) | .823 |
| T3 | 1.969 (1.062-3.648) | .031 | 1.391 (0.41-4.726) | .597 |
| T4 | 2.999 (1.613-6.223) | <. 001 | 0.867 (0.258-2.915) | .818 |
| N stage | ||||
| N0 | Reference | Reference | ||
| N1 | 2.607 (1.852-3.670) | <. 001 | 1.015 (0.692-1.488) | .941 |
| Nx | 2.794 (1.837-4.249) | <. 001 | 1.255 (0.796-1.979) | .328 |
| M stage | ||||
| M0 | Reference | Reference | ||
| M1 | 4.681 (3.642-6.015) | <. 001 | 1.852 (1.137-3.016) | .013 |
| Surgery | ||||
| Yes | Reference | Reference | ||
| No | 5.534 (4.232-7.236) | <. 001 | 3.197 (2.1602-4.732) | <. 001 |
| Radiotherapy | ||||
| Yes | Reference | Reference | ||
| No/unknown | 1.957 (1.359-2.820) | <. 001 | 1.554 (1.05-2.301) | .028 |
| Chemotherapy | ||||
| Yes | Reference | Reference | ||
| No/unknown | 0.717 (0.563-0.913) | .007 | 1.220 (0.916-1.624) | .175 |
ACC = adrenal cortical carcinoma, CI = confidence interval, CSS = cancer-specific survival, HR = hazard ratio.
* Other included American Indian/Alaskan Native and Asian/Pacific Islander.
was not associated with OS (HR: 1.236, 95% CI: 0.954- 1.602; P = . 109) and CSS (HR: 1.228, 95% CI: 0.926-1.602; P = . 154) (Table 5).
4. Discussion
ACC is a rare malignancy with poor prognosis and aggressive behavior.[12,13] Even after surgical resection, the median sur- vival time is not more than 12 months, and the 5-year survival rate is 16% to 45%.[2,14] Owing to the rarity of ACC and the lack of large case reports and clinical randomized controlled trials, clinicians often have little knowledge about this tumor. The diagnosis and treatment of ACC are limited.[6] Limited chemotherapy options, limited efficacy of chemotherapy, and limited efficacy and safety of RT jointly create a treatment
dilemma for ACC.[15] Currently, there is no standard treat- ment for ACC, and the effectiveness of various treatments, including surgery, RT, chemotherapy, and immunotherapy, needs to be further investigated. Therefore, early diagnosis and appropriate treatment strategies are of great significance for improving the prognosis of ACC. Here, we used the SEER database to discover the clinical features of ACC and identify independent risk factors affecting patient’ survival. Moreover, we illustrated the influence of different treatment strategies on the prognosis of ACC patients. Our findings indicate that ACC presents a malignant behavior and that surgical treat- ment plays an important role in improving the prognosis of patients. Patients with ACC may benefit from RT. However, chemotherapy was not associated with the survival of patients with ACC at any stage.
| Variables | OS | CSS | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Surgery | ||||
| Yes | Reference | Reference | ||
| No | 3.051 (2.142-4.346) | <. 001 | 3.4 (2.332-4.959) | <. 001 |
| Age (years) | 1.017 (1.008-1.025) | <. 001 | 1.012 (1.003-1.021) | .008 |
| Tumor size (mm) | 1.0002 (0.9997-1.001) | .497 | 1.0002 (0.9997-1.001) | .398 |
| Pathologic grade | ||||
| Grade I | Reference | Reference | ||
| Grade II | 1.774 (0.604-5.214) | .297 | 2.497 (0.673-9.268) | .172 |
| Grade III | 3.601 (1.368-9.479) | .009 | 5.108 (1.521-17.152) | .008 |
| Grade IV | 1.769 (0.615-5.094) | .29 | 2.423 (0.657-8.933) | .184 |
| T stage | ||||
| T1 | Reference | Reference | ||
| T2 | 0.945 (0.526-1.698) | .851 | 0.823 (0.445-1.521) | .534 |
| T3 | 1.789 (0.985-3.25) | .056 | 1.631 (0.872-3.051) | .126 |
| T4 | 1.419 (0.76-2.648) | .272 | 1.183 (0.6134-2.282) | .616 |
| N stage | ||||
| N0 | Reference | Reference | ||
| N1 | 1.121 (0.782-1.606) | .535 | 1.084 (0.74-1.59) | .679 |
| Nx | 1.452 (0.954-2.21) | .082 | 1.377 (0.869-2.18) | .173 |
| M stage | ||||
| M0 | Reference | Reference | ||
| M1 | 2.658 (1.979-3.57) | <. 001 | 2.896 (2.108-3.979) | <. 001 |
ACC = adrenal cortical carcinoma, CI = confidence interval, CSS = cancer-specific survival, DAG = directed acyclic graphs, HR = hazard ratio, OS = overall survival.
| Variables | OS | CSS | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Radiotherapy | ||||
| Yes | Reference | Reference | ||
| No/unknown | 1.67 (1.184-2.44) | .004 | 1.569 (1.066-2.309) | .022 |
| Surgery | ||||
| Yes | Reference | Reference | ||
| No | 2.791 (1.953-3.99) | <. 001 | 3.134 (2.139-4.593) | <. 001 |
| Age (years) | 1.016 (1.007-1.024) | <. 001 | 1.011 (1.002-1.02) | .013 |
| Tumor size (mm) | 1.0003 (0.9997-1.001) | .349 | 1.0003 (0.9997-1.001) | .301 |
| Pathologic grade | ||||
| Grade I | Reference | Reference | ||
| Grade II | 1.828 (0.623-5.366) | .272 | 2.539 (0.685-9.419) | .163 |
| Grade III | 3.86 (1.464-10.18) | .006 | 5.388 (1.603-18.111) | .006 |
| Grade IV | 1.83 (0.636-5.269) | .263 | 2.476 (0.672-9.123) | .173 |
| T stage | ||||
| T1 | Reference | Reference | ||
| T2 | 0.984 (0.548-1.766) | .956 | 0.854 (0.462-1.579) | .614 |
| T3 | 1.941 (1.067-3.534) | .03 | 1.751 (0.934-3.282) | .081 |
| T4 | 1.461 (0.783-2.725) | .234 | 1.221 (0.633-2.354) | .552 |
| N stage | ||||
| N0 | Reference | Reference | ||
| N1 | 1.079 (0.752-1.546) | .681 | 1.049 (0.715-1.539) | .808 |
| Nx | 1.439 (0.945-2.192) | .09 | 1.363 (0.861-2.159) | .186 |
| M stage | ||||
| M0 | Reference | Reference | ||
| M1 | 2.716 (2.016-3.658) | <. 001 | 2.947 (2.14-4.059) | <. 001 |
ACC = adrenal cortical carcinoma, CI = confidence interval, CSS = cancer-specific survival, DAG = directed acyclic graphs, HR = hazard ratio, OS = overall survival.
Patients with ACC would benefit greatly from surgical resec- tion and radiation therapy. In this study, we found that patients with ACC who underwent surgery or radiation therapy had lon- ger survival times than those who did not. Stratified analysis demonstrated that patients with advanced ACC could benefit from surgery or radiation therapy. Despite the lack of specific treatments, it is unquestionable that surgical resection is the
primary treatment for ACC. Surgery is the best choice for cura- tive treatment of localized ACC.[12,16] Patients who undergo sur- gery can achieve a longer survival.[17] Although there is a lack of data to support the effectiveness of surgical treatment for meta- static ACC, debulking surgery has been recommended by some scholars.[18] In more advanced patients, cytoreductive surgery can help control hormones and may allow the initiation of systemic
| Variables | OS | CSS | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Chemotherapy | ||||
| Yes | Reference | Reference | ||
| No/unknown | 1.236 (0.954-1.602) | .109 | 1.228 (0.926-1.628) | .154 |
| Surgery | ||||
| Yes | Reference | Reference | ||
| No | 3.026 (2.127-4.304) | <. 001 | 3.38 (2.322-4.921) | <. 001 |
| Age (years) | 1.015 (1.006-1.023) | .001 | 1.01 (1.001-1.019) | .027 |
| Tumor size (mm) | 1.0002 (0.9996-1.001) | .542 | 1.0002 (0.9997-1.001) | .429 |
| Pathologic grade | ||||
| Grade I | Reference | Reference | ||
| Grade II | 1.802 (0.613-5.295) | .284 | 2.53 (0.681-9.392) | .165 |
| Grade III | 3.66 (1.39-9.635) | .009 | 5.17 (1.54-17.359) | .008 |
| Grade IV | 1.745 (0.606-5.023) | .302 | 2.382 (0.646-8.778) | .192 |
| T stage | ||||
| T1 | Reference | Reference | ||
| T2 | 0.938 (0.522-1.684) | .829 | 0.815 (0.441-1.508) | .515 |
| T3 | 1.769 (0.974-3.214) | .061 | 1.612 (0.862-3.017) | .135 |
| T4 | 1.433 (0.767-2.675) | .259 | 1.192 (0.618-2.3) | .6 |
| N stage | ||||
| N0 | Reference | Reference | ||
| N1 | 1.151 (0.801-1.652) | .447 | 1.111 (0.757-1.632) | .591 |
| Nx | 1.412 (0.927-2.153) | .108 | 1.343 (0.848-2.129) | .209 |
| M stage | ||||
| M0 | Reference | Reference | ||
| M1 | 2.886 (2.112-3.944) | <. 001 | 3.14 (2.242-4.39) | <. 001 |
ACC = adrenal cortical carcinoma, CI = confidence interval, CSS = cancer-specific survival, DAG = directed acyclic graphs, HR = hazard ratio, OS = overall survival.
therapy,[12] and surgery is associated with better outcomes.[19] These results are consistent with our findings. Although the long-term effect of cytoreductive surgery is limited because dis- tant metastasis of the tumor will gradually progress, it can help some patients with distant metastasis achieve hormonal control and relieve symptoms.[20] When there is a tumor thrombus in the vena cava, tumor resection is also feasible when the technology is feasible and conditions are allowed. The resection of a tumor thrombus can greatly relieve the pain of patients and reduce the possibility of rapid death due to tumor thrombus.[21]
The role of radiation therapy (RT) in the treatment of ACC has become increasingly prominent. In the early days, the poten- tial role of RT in improving the survival of patients with ACC was ignored by earlier reports that prematurely denied the efficacy of this treatment strategy. On the basis of unreliable documentation, several scholars have pointed out that ACC is a radiotherapy-insensitive malignancy. Some studies have denied the role of radiation therapy in studies based on small sample sizes.[20] A growing number of studies have confirmed that RT is effective in the management of ACC and have acknowledged the modality’s potential role in ACC treatment.[11] Until now, almost all studies with large sample sizes have discovered that adjuvant RT can decrease the risk of local recurrence and improve OS.[22- 25] Kimpel et al reported that RT was associated with beneficial effects on outcomes in patients with advanced ACC when used at an adequate dosage.[26] In this retrospective study, we also identified that patients with ACC who received RT had longer OS and CSS and would benefit from RT.
The overall efficacy of the drug therapy was poor. In this study, we identified that patients with ACC undergoing che- motherapy did not have longer survival, and chemotherapy was not associated with their outcomes. Chemotherapy is still an important choice for salvage treatment of advanced ACC despite suboptimal efficacy. Notably, mitotane is a com- monly used drug in the treatment of ACC, which can improve the prognosis of advanced patients to a certain extent. Its killing effect on tumor cells occur through the cleavage of
intracellular mitochondria, which triggers apoptosis and alleviates the symptoms associated with excessive hormone secretion by blocking 5a-reductase.[27,28] However, the high incidence of adverse events and low response rate limit the use of chemotherapy.
This study had several limitations, that should be acknowl- edged. First, inherent selection bias, which is retrospective in nature, was unavoidable. Second, because the specific treat- ment plan and time of chemotherapy and RT are not clear, the specific effects of RT dose and location on tumor prognosis require further investigation. Finally, recurrence-free survival, another prognostic indicator, was unavailable in the SEER database. Fourth, although we used data from the SEER data- base in this study, the number of cases included was still small. Further studies with larger sample sizes are required to con- firm our findings. However, these shortcomings were unavoid- able. However, this study is of great value in helping clinicians understand the prognosis of ACC and develop appropriate treatment strategies.
5. Conclusion
ACC is a rare malignancy of the adrenal gland with aggressive biological behavior. Older age, poor pathological grade, higher clinical stage, and advanced TNM classification may result in an enormously detrimental outcome. Surgical resection of tumor lesions remains a necessary therapeutic strategy. Meanwhile, RT is beneficial to ACC patients, especially metastatic ACC, and should be applied in the treatment of ACC. However, the value of chemotherapy in patients with ACC remains unclear. The significance of various treatments for ACC needs to be further confirmed by more studies with larger sample sizes.
Acknowledgments
We would like to thank The SEER Program for providing data.
Author contributions
Conceptualization: Dongyang Zeng, Tao Chen.
Data curation: Dongyang Zeng, Tao Chen, Xiaoyuan Qian, Guang Zhou, Linghui Qin.
Formal analysis: Guang Zhou.
Funding acquisition: Xiaoyuan Qian.
Methodology: Xiaoyuan Qian.
Supervision: Linghui Qin.
Validation: Linghui Qin, Xiaoyuan Qian.
Visualization: Dongyang Zeng, Xiaoyuan Qian.
Writing - original draft: Xiaoyuan Qian, Linghui Qin.
Writing - review & editing: Guang Zhou, Xiaoyuan Qian.
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