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INTERNATIONAL JOURNAL OF UROLOGY
Original Article Clinical Investigation
Clinicopathological features of adrenal malignancies: Analysis of hospital-based cancer registry data in Japan
Ichiro Chihara,1 (D Yoshiyuki Nagumo,1 (D Shuya Kandori,1 (D Kosuke Kojo,1 Keisuke Sano,1
Kazuki Hamada,1 Kozaburo Tanuma,1 Haruki Tsuchiya,1 Masanobu Shiga,1 Shotaro Sakka,1
Tomokazu Kimura,1 Takashi Kawahara,1 Akio Hoshi,1 (D Hiromitsu Negoro,1 Takahiro Kojima,2
Mathis J Bryan,3 Ayako Okuyama,4 Takahiro Higashi4 and Hiroyuki Nishiyama1
1Department of Urology, University of Tsukuba, Tsukuba, Japan, 2Department of Urology, Aichi Cancer Center, Nagoya, Japan, 3International Medical Center, University of Tsukuba Affiliated Hospital, Tsukuba, Japan, and 4Center for Cancer Registries, National Cancer Center Institute for Cancer Control, Chuo-ku, Japan
Abbreviations & Acronyms
ACC = adrenal cortical carcinoma
DCCH = designated cancer care hospital
DLBCL = diffuse large B- cell lymphoma GEN = ganglioneuroblastoma HBCR = hospital-based cancer registry ICD-O-3 = International Classification of Disease for Oncology 3rd edition MPCC = malignant pheochromocytoma NE = neuroblastoma NHL = non-Hodgkin lymphoma
OS = overall survival SEER = Surveillance, Epidemiology, and End Results
UICC TNM = Union for International Cancer Control TNM
Objective: To identify the clinicopathological features of adrenal malignancies and analyze the prognoses of patients with adrenal cortical carcinoma (ACC) and malignant pheochromocytoma (MPCC).
Patients and methods: We used a hospital-based cancer registry data in Japan to extract cases of adrenal malignancies that were histologically confirmed, diagnosed, and initially treated from 2012-2015. For survival analysis, we used data from the 2008-2009 cohort to estimate 5-year overall survival (OS) by the Kaplan-Meier method.
Results: A total of 989 adrenal malignancies were identified in the 2012-2015 cohort. The most common histologies were ACC (26.4%), diffuse large B-cell lymphoma (DLBCL; 25.4%), neuroblastoma (22.2%), and MPCC (11.9%). While most ACC and MPCC patients were in their 60s, DLBCL patients accounted for 61.5% of adrenal malignancies in the over-70 cohort. Among ACC patients with clinical staging data, 46.3% of patients were stage IV. Although surgery was a chief strategy for all stages, younger patients tended to receive combination therapy, including surgery and chemotherapy or hormone therapy. In the 2008-2009 cohort, the 5-year OS rates of ACC (n = 49) and MPCC (n = 23) patients were 56.2% and 86.4% while ACC patients without surgery had 1- and 2- year OS rates of 25.0% and 12.5%.
Conclusion: In Japan, DLBCL accounted for the majority of adrenal malignancies in older patients. Despite advanced staging, ACC patients were mainly treated with surgery and their prognosis was not satisfactory. Such epidemiological data may be useful in considering initial management strategies.
Key words: adrenal cortical carcinoma, adrenal malignancies, hospital-based cancer registry, malignant pheochromocytoma, overall survival.
Correspondence
Shuya Kandori, M.D., Ph.D., Department of Urology, University of Tsukuba, 1-1-1
Tennodai, Tsukuba, Ibaraki 305- 8575, Japan.
Email: nishiuro@md.tsukuba.ac.jp
Received 5 November 2021; accepted 4 July 2022. Online publication 17 August 2022
INTRODUCTION
Adrenal malignancies are rare, with an estimated incidence of 2-10 new cases per one million persons per year.1 Among these adrenal malignances, the most common histology is adrenal cor- tical carcinoma (ACC), followed by neuroblastoma (NE) and malignant pheochromocytoma (MPCC).2 Since NE predominately occurs in childhood, the adrenal malignancies most likely to be diagnosed by non-pediatric physicians are mainly considered to be ACC and MPCC. Both are rare cancers, with incidences of 0.5-2 and 0.2-0.8 per million patients per year,3,4 and these histological subtypes carry a poor prognosis due to quick progression and frequent diagnosis at advanced stages. However, comprehensive epidemiological data on ACC and MPCC, as well as data on all adrenal malignancies, have not been fully investigated.
On the other hand, adrenal gland tumors found by chance during a physical examination or over the course of various diseases are collectively called adrenal incidentalomas.5 The preva- lence of adrenal incidentaloma approaches 3% in middle age but increases to as much as 10% in the elderly.6 Of the adrenal incidentalomas with a pathological diagnosis, adrenal
malignancies account for only 10%7,8 but rapid developments in diagnostic imaging techniques, such as abdominal ultra- sonography, computed tomography, and magnetic resonance imaging, have increased chances to find these rare tumors.2,9
Until recently, large, population-based studies on the clini- copathological features of adrenal malignancies have been limited, especially in Japan, although each malignancy type has been studied individually. Herein, to delineate the clinico- pathological features of adrenal malignancies in Japan, partic- ularly ACC and MPCC, we retrospectively analyzed new diagnoses of adrenal malignancy from 2008 to 2009 and 2012 to 2015 using a hospital-based cancer registry (HBCR) from Japan’s nationwide designated cancer care hospitals (DCCHs) and other core cancer care hospitals.
PATIENTS AND METHODS
Data sources
In Japan, HBCR data comes from a network of DCCHs supervised by the Ministry of Health, Labour and Welfare. As previously described,10 HBCR data from these hospitals, including patient characteristics, stage information, and/or first-course of treatment, are submitted annually to the National Cancer Center for analysis and distribution as the National Cancer Statistics Report. These data from the HBCR cover at least 70% of all cancers but this coverage may vary by cancer type or patient age.11
Patient information for newly diagnosed cases are routinely collected by DCCHs and cancer registrars record the details of diagnosed cancer cases based on standardized criteria. We thus used HBCR data from Japan’s DCCHs and other core cancer care hospitals to analyze clinicopathological features of adrenal malignancies that were diagnosed. At the planning phase of this study, the cohort in years 2012-2015 was the latest cohort to capture the recent clinicopathological features of adrenal malignancies; however, for survival data, the 2008 -2009 patient cohort was the most recent. The 2008-2009 cohort data from 251 DCCHs had patient survival informa- tion for 5 years after diagnosis and these data were obtained from hospitals that had a >90% follow-up rate for all cancer patients.
Hospital-based cancer registry data include patient demo- graphics, tumor characteristics, and the first course of treat- ment (e.g., surgery), defined as a treatment planned to improve the prognosis at initial diagnosis. “Surgery” was defined as open or laparoscopic surgery while “hormone ther- apy” generally included mitotane. The staging information was based on the 6th UICC TNM Classification in the 2008- 2009 cohort and the 7th UICC TNM Classification was used in the 2012-2015 cohort.
Identification of cases with malignant tumors of the adrenal glands
We identified eligible patients from the HBCR data by using the following inclusion criteria: (i) newly diagnosed with adrenal malignancies (C74.0, C74.1, and C74.9) in the years 2008-2009 or 2012-2015; (ii) received the first course of treatment at a DCCH or other core cancer care hospital; and
(iii) had a histologically confirmed tumor with International Classification of Disease for Oncology 3rd edition (ICD-O-3) histology codes. In cases of MPCC, with the update of the World Health Organization classification of adrenal tumors in 2017, pheochromocytoma is basically defined as having malignant potential and the term “metastatic pheochromocy- toma/paraganglioma” is used to replace “malignant pheochro- mocytoma/paraganglioma.”12 However, in the 2008-2009 and 2012-2015 HBCR data, the tumors histologically diag- nosed with MPCC were registered as “MPCC” with or with- out their metastases.
Statistical analyses
The overall survival (OS) rate was analyzed by the Kaplan- Meier method using JMP version 14.0 (SAS Institute).
Ethical considerations
The study protocol and data processing were approved by the University of Tsukuba Hospital Institutional Review Board (H29-013). In rare disease research for which the number of cases is <10, patient privacy is of paramount importance as data could be linked to individuals. We have therefore reported the proportion of those cases in the present study in accordance with guidelines of the Japanese Ministry of Health, Labour and Welfare.
RESULTS
Clinicopathological features of patients with adrenal malignancies
As shown in Figure 1a, among 1130 cases who were regis- tered as adrenal malignancies and received initial treatment, a total of 989 patients (87.5%) were histologically diagnosed while 121 cases (10.7%) were diagnosed by imaging modalities.
Table 1 summarizes the clinicopathological features of 989 patients with histologically diagnosed adrenal malignancies. Among all cases, the median age of all patients was 60 years (range 0-89 years), with peaks at 0-9 years and 60-79 years. (Figure S1) The proportion of males (54.1%) was slightly higher than females (45.9%). Although the clinical staging was unknown in 52.2% of the cases, these unknowns include some cases, such as NE, MPCC, ganglioneuroblastoma (GNE), and sarcoma, for which the HBCR has not estab- lished staging criteria. However, among cases with known clinical stages, stage IV was the most common (27.7%).
The most common histology was ACC, n = 261 (26.4%), followed by diffuse large B-cell lymphoma (DLBCL), n = 251 (25.4%), NE, n = 220 (22.2%), MPCC, n = 118 (11.9%), GNE, n = 23 (2.3%), and others, n = 116 (11.7%). The others included histological subtypes such as lymphoma other than DLBCL (n = 25), not otherwise specified (n = 25), and sarcoma (n = 21). Although the lymphoma groups other than DLBCL and sarcoma had sufficient sample sizes for further analysis, we categorized these as “others” since each group consisted of many types of cases with unique ICD-O-3 codes.
(a)
(b)
All patients from HBCR data diagnosed in 2012-2015
All patients from HBCR data diagnosed in 2008-2009
· Extracted adrenal malignancies (C74.0, C74.1, and C74.9)
· Extracted adrenal malignancies (C74.0, C74.1, and C74.9)
· Extracted the patients received first-course cancer treatment
· Extracted the patients received first-course cancer treatment
Malignant tumors of the adrenal gland N=1130
Malignant tumors of the adrenal gland N=258
· Extracted the patients with histological diagnosis
· Extracted the patients with histological diagnosis
Malignant tumors of the adrenal gland N=989
Malignant tumors of the adrenal gland N=230
| TABLE 1 Patient characteristics for all adrenal malignancies in the 2012-2015 cohort | |||||||
|---|---|---|---|---|---|---|---|
| Characteristic | No. of patients (%) | ||||||
| ALL | ACC | DLBCL | NE | MPCC | GNE | Others | |
| Total no. | 989 | 261 (26.4) | 251 (25.4) | 220 (22.2) | 118 (11.9) | 23 (2.3) | 116 (11.7) |
| Age | |||||||
| Median (range) | 60 (0-89) | 59 (1-86) | 71 (36-89) | 1 (0-67) | 60 (4-85) | 3 (1-79) | 70 (0-89) |
| Sex | |||||||
| Male | 535 (54.1) | 110 (42.1) | 168 (66.9) | 113 (51.4) | 56 (47.5) | 13 (56.5) | 75 (64.7) |
| Female | 454 (45.9) | 151 (57.9) | 83 (33.1) | 107 (48.6) | 62 (52.5) | 10 (43.5) | 41 (35.3) |
| Clinical stage | |||||||
| I | 75 (7.6) | 34 (13.0) | 29 (11.6) | N/A | N/A | N/A | N/A |
| II | 79 (8.0) | 41 (15.7) | 28 (11.2) | N/A | N/A | N/A | N/A |
| III | 45 (4.6) | 19 (7.3) | 23 (9.2) | N/A | N/A | N/A | N/A |
| IV | 274 (27.7) | 81 (31.0) | 130 (51.8) | N/A | N/A | N/A | N/A |
| Unknown | 516 (52.2) | 86 (33.0) | 41 (16.3) | N/A | N/A | N/A | N/A |
Note: Clinical stage of cases without available information were shown as not applicable (N/A). Abbreviations: ACC, adrenal cortical carcinoma; DLBCL, diffuse large B-cell lymphoma; GNE, ganglioneuroblastoma; MPCC, malignant pheochromocytoma/paraganglioma; NE, neuroblastoma.
In the ACC group, the proportion of females (57.9%) was slightly higher than males (42.1%) and a similar tendency was observed in the MPCC group. Among ACC cases with clinical staging data, 46.3% (81/175) of patients with ACC were stage IV. In the DLBCL group, the proportion of males (66.9%) was higher than females (33.1%) whereas, in other groups, there were no significant differences between males and females. Stage IV (51.8%) was the most common while the proportions of stages I-III were lower.
Figure 2 shows the age distribution stratified by histological subtypes. Most patients with NE and GNE were less than 10 years old with median ages of 1 and 3 years, respectively, while patients with ACC and MPCC were usually in their 60s, with median ages of 59 and 60 years. Most patients with DLBCL were in their 70s, with a median age of 71 years, and elderly patients aged over 80 years accounted for 17.1% of
analyzed cases. With regard to adrenal malignancies in the 70+ population, DLBCL accounted for the highest percentage (61.5%) while ACC and MPCC were lower (27.9% and 9.7%).
Initial treatments of ACC patients
As shown in Table 1, there was no available clinical staging information except for ACC and DLBCL patients. Although urologists have the opportunity to treat ACC patients, DLBCL patients are generally treated by non-urologist physi- cians. Furthermore, as there are significant differences in the initial treatment between ACC and DLBCL patients, further analysis of the initial treatment stratified by clinical stages was performed only in ACC patients.
As shown in Figure 3, more than half of patients at stages I-III underwent surgery only (70.6%, 56.1%, and 63.2%,
Adrenal cortical carcinoma (8370)
200
Diffuse large B-cell lymphoma (9680)
Neuroblastoma (9500)
Number of patients
150
Malignant pheochromocytoma (8700)
Ganglioneuroblastoma (9490)
100
50
0
0- 9
10-19
20-29
30-39
40-49
50-59
60-69
70-79
80-
Age
(a)
Distribution by clinical stage
(b)
Distribution by age
100%
100%
90%
90%
80%
Others
80%
Others
70%
No treatment
70%
No treatment
60%
Radiation only
60%
Radiation only
50%
Hormone therapy only
50%
Hormone therapy only
40%
“Chemotherapy only
40%
Chemotherapy only
30%
“Chemotherapy+hormone therapy
30%
Chemotherapy+hormone therapy
20%
Surgery+hormone therapy
20%
Surgery+hormone therapy
10%
Surgery+chemotherapy
10%
Surgery+chemotherapy
0%
Surgery only
0%
Surgery only
stage (n=34)
stage II (n=41)
stage III stage IV (n=19)
0-19
20-39 40-59 60-79
80-
(n=81)
(n=14) (n=41) (n=81) (n=112) (n=13)
respectively). On the other hand, the proportions of patients at those stages who underwent surgery combined with hor- mone or chemotherapy were 26.4%, 31.7%, and 31.6%, respectively. In stage IV, the patterns of treatment were diverse and the most common were surgery (surgery only [28.4%] or combined with chemotherapy [12.3%] or hormone therapy [3.7%]), followed by chemotherapy only (11.1%), hormonal therapy only (9.9%), and no treatment (6.2%). Radiotherapy was not common at any stage.
In terms of the initial treatment stratified by age, patients in their 80s received surgery at a high rate (70%) while, in con- trast, the proportion of patients who underwent combination surgery and hormone or chemotherapy was highest in the 0-19 age group and gradually decreased with age. The proportion of untreated patients was low throughout all ages; elderly patients received treatment at rates similar to younger patients.
Survival analysis of ACC and MPCC patients
As shown in Figure 1b, among 258 cases that were registered as adrenal malignancies and received initial treatment, a total
of 230 patients (89.1%) were histologically diagnosed. Table 2 summarizes the characteristics of these patients. In the 2008-2009 cohort, age and gender distributions of patients were similar to those in the 2012-2015 cohort.
Since the number of patients with MPCC was small in this cohort, OS analysis stratified by surgical treatment was only conducted for ACC patients. The 5-year OS rates of patients with ACC and MPCC were 56.2% and 86.4% (Figure 4), while, as shown in Figure 5, the 3- and 5-year OS rates of ACC patients who underwent surgery (n = 40) were 75.0% and 67.5%. In contrast, the 1- and 2-year OS rates of patients who did not receive surgery were 25.0% and 12.5%. Other histological subtypes with a sufficient number of cases for analysis were DLBCL and NE. The 5-year OS rates of patients with DLBCL and NE were 31.8% and 68.4%, respectively (Figure S2).
DISCUSSION
To our knowledge, there is only one large-scale, population- based report of adrenal malignancies.2 This previous study
| No. of patients (%) | |||||||
|---|---|---|---|---|---|---|---|
| Characteristic | ALL | ACC | DLBCL | NE | MPCC | GNE | Others |
| Total no. | 230 | 49 (21.3) | 44 (19.1) | 75 (32.6) | 23 (10.0) | 10 (4.3) | 51 (9.6) |
| Age | |||||||
| Median (range) | 45 (0-85) | 55 (2-78) | 72 (49-85) | 1 (0-54) | 51 (27-77) | 2 (1-35) | 60.5 (35-84) |
| Sex | |||||||
| Male | 131 (57.0) | 22 (44.9) | 28 (63.6) | 41 (54.7) | 12 (52.2) | 6 (60.0) | 18 (81.8) |
| Female | 99 (43.0) | 27 (55.1) | 16 (36.4) | 34 (45.3) | 11 (47.8) | 4 (40.0) | 4 (18.2) |
Note: Clinical staging data were not shown due to limited information available. Abbreviations: ACC, adrenal cortical carcinoma; DLBCL, diffuse large B-cell lym- phoma; GNE, ganglioneuroblastoma; MPCC, malignant pheochromocytoma/paraganglioma; NE, neuroblastoma.
(a)
Overall survival
1.0
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
Months
No. at risk 49
41
37
31
29
28
(b)
1.0
Overall survival
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
Months
No. at risk
23
21
20
19
19
18
Overall survival
1.0
0.8
0.6
0.4
Surgery (n=40)
0.2
No Surgery (n=[7-9])
0.0
0
12 24 36 48 60
No. at risk
Months
Surgery
40
37
35
30
28
27
No Surgery [7-9] [1-3] [1-3]
investigated 4695 primary adrenal malignancies from 1973 to 2013 in the United States using the Surveillance, Epidemiol- ogy, and End Results (SEER) database and reported 5 histo- logical groups and age-adjusted incidence, distribution trends, and cancer-specific survival for each group. In the present large-scale and population-based study of 989 cases using HBCR, we revealed, for the first time in Japan, similar clini- copathological features, including histological subtypes and age distribution, in Japanese patients with adrenal malignan- cies. We also found several relevant findings regarding the patterns of initial treatment for ACC patients. Furthermore, although the number of cases was small, our analysis of the survival rates of ACC and MPCC patients found that the
prognosis of ACC patients was poor but that of MPCC patients was relatively good.
In the present study, the most common histological sub- type was ACC (26.4%) followed by DLBCL (25.4%), NE (22.2%), and MPCC (11.9%) (Table 1). Chandrasekar et al. reported five histological subtypes using SEER and the pro- portion of ACC, NE, pheochromocytoma and paraganglioma, non-Hodgkin lymphoma (NHL), and sarcoma diagnoses were 43.8%, 39.7%, 10.9%, 4.3%, and 1.3%, respectively.2 Com- pared to those proportions, the proportions of ACC and NE in the present study were lower (26.4% and 22.2%). On the other hand, our proportion of malignant lymphoma (25.4%) was higher than the SEER study (4.3%), although histologi- cal subtypes other than DLBCL were included as NHL in the SEER. This difference in the proportion of malignant lymphoma may be based on differences in the registry sys- tem between the HBCR and the SEER. For cases of malig- nant lymphoma in the SEER, the primary site is registered only when the specific organ location of the tumor is clear and two primary sites are not be used.13 In contrast, the HBCR dictates that, if a tumor whose primary site is initially registered as an adrenal gland is diagnosed as malignant lymphoma, it will subsequently be registered as malignant lymphoma of the adrenal gland. Therefore, the proportion of malignant lymphomas of the adrenal gland in the HBCR may be higher than that of the SEER. On the other hand, previous reports demonstrated that DLBCL was a predomi- nant disease in the elderly, with an onset age of 60- 70 years,14,15 in line with the present study where most DLBCL patients were in their 60s and 70s. Kojo et al. reported DLBCL as the most common testicular malignancy
in Japanese men aged ≥60 years, especially in the 70s, from their HBCR analysis.16 Likewise, our present data also demonstrated that DLBCL comprised the majority of adrenal malignancies for men over 70 years of age although the can- cer types were different. It is necessary to suspect DLBCL and consult with a hematologist when adrenal malignancies are found in elderly patients.
In terms of treatment for ACC, surgery alone was the pre- ferred strategy (about half of all treatments) but, after taking into account combinations with hormone or chemotherapy, surgery was performed in 70% of all ACC patients. This trend reflects that complete surgical resection is the only curative treatment for resectable cases.17 On the other hand, the proportion of patients who received combination therapy, including surgery and hormone or chemotherapy, was higher in younger patients than elderly patients (Figure 3), likely because of the high ACC recurrence rate that makes postop- erative adjuvant radiation or mitotane therapies useful.18,19 The proportion of patients who underwent surgery combined with hormone or chemotherapy was highest in the 0-19 age group and gradually decreased as age increased. This finding suggests that younger patients receive more aggressive multi- disciplinary treatment in consideration of both therapeutic effect and life expectancy.
In stage IV patients (in addition to surgical treatment), hor- mone therapy alone, chemotherapy alone, and combination therapy also accounted for the majority; however, detailed drug setting or administration data was unfortunately unavail- able for this cohort. Mitotane is the only hormone drug approved in locally advanced inoperable and metastatic patients but randomized, controlled prospective trials are lacking. Currently, based on the results of the FIRM-ACT study, combination therapy with chemotherapy and mitotane (etoposide, doxorubicin, cisplatin, and mitotane) is often used.2º In current daily practice, pembrolizumab can be used for MSI-High (microsatellite instability-high) malignancies at any primary site.21 Since previous studies reported that ACC was associated with Lynch syndrome, in which malignancies are characterized by MSI-High tumors,22,23 some patients with ACC might benefit from pembrolizumab.
Regarding the prognosis of our ACC patients, the 5-year OS rate was 56.2% (Figure 4a) while Chandrasekar et al.2 reported a 5-year OS rate of 30% with no differences in age or sex between our cohort and theirs. Previous studies have reported 5-year OS rates of 16%-38%24-26 in ACC patients, similar to Chandrasekar et al. The present study showed rela- tively good OS but further analysis is necessary to increase prognostic accuracy for ACC patients since our present data did not include detailed information about patient characteris- tics and had a small sample size. Patients with inoperable tumors had extremely poor prognoses, with 1-year OS rates of 12.5% (Figure S2). This is in line with a report by Tran et al. that found in Stage IV patients had 1-year survival rates of 54% when surgery was performed but 16% when no sur- gery was performed.27 Our present study thus confirms that the only currently curative option for ACC is surgery and inoperability results in extremely poor outcomes Since there are few effective treatment options for these ACC patients with unresectable disease, genomic diagnostics that lead to
the use of potential treatments (such as pembrolizumab) should be considered.
On the other hand, the 5-year OS rates of DLBCL, MPCC, and NE patients were 31.8%, 86.4%, and 68.4%, respec- tively. The 5-year OS rates of MPCC and NE patients were better than those of ACC and DLBCL patients. A similar trend was seen in studies from the United States using SEER: the 5-year OS rates in non-Hodgkin’s lymphoma, MPCC and NE patients were 30%, 64%, and 71%, respectively. How- ever, further analyses of these patients to remedy information gaps and increase sample sizes are needed just as in ACC patients.
Our study has several limitations due to the availability of retrospective data in the HBCR. First, this study includes only data from DCCHs and other core cancer care hospitals that play a central role in cancer care and may not reflect medical treatment in Japanese general hospitals. Second, there was no detailed, individual patient information, such as clini- cal status or comorbidities, in addition to other details on chemotherapy regimens, patient surgeries, chemotherapy, or hormone therapy. Third, the pathological diagnoses did not undergo a central review. Fourth, the definition of MPCC in the present study was different from current daily practice. Finally, different temporal cohorts were used for histological distribution and life prognosis.
In conclusion, this study provides the first, crucial large- scale data showing the clinicopathological trends of adrenal malignancies in Japan, with DLBCL accounting for the majority of adrenal malignancies in older patients. Further- more, despite advanced staging, ACC patients were mainly treated with surgery and their prognoses were not satisfac- tory. These epidemiological data may be useful in consider- ing initial management strategies when adrenal malignancies are suspected.
AUTHOR CONTRIBUTIONS
Ichiro Chihara: Conceptualization; data curation; formal analysis; methodology; project administration; supervision; writing - original draft; writing - review and editing. Yoshiyuki Nagumo: Conceptualization; data curation; for- mal analysis; project administration; supervision; writing - original draft; writing - review and editing. Kosuke Kojo: Data curation; formal analysis. Keisuke Sano: Resources; validation. Kazuki Hamada: Resources; validation. Kozaburo Tanuma: Validation; visualization. Haruki Tsu- chiya: Validation. Masanobu Shiga: Data curation; valida- tion. Shotaro Sakka: Validation. Tomokazu Kimura: Investigation; validation. Takashi Kawahara: Supervision; validation. Akio Hoshi: Resources; validation. Hiromitsu Negoro: Supervision; validation. Takahiro Kojima: Fund- ing acquisition; validation. Mathis J. Bryan: Validation; writing - original draft; writing - review and editing. Ayako Okuyama: Conceptualization; data curation; formal analysis; investigation; resources; validation; writing - original draft; writing - review and editing. Takahiro Higashi: Conceptu- alization; data curation; supervision; validation. Hiroyuki Nishiyama: Conceptualization; funding acquisition; resources; supervision.
CONFLICT OF INTEREST
None declared.
APPROVAL OF THE RESEARCH PROTOCOL BY AN INSTITUTIONAL REVIEWER BOARD
The study protocol and data processing were approved by the University of Tsukuba Hospital Institutional Review Board (H29-013). This study was exempted from certain require- ments for studies involving human participants according to institutional ethical standards and the Helsinki Declaration or comparable ethical standards due to the retrospective nature of its design.
INFORMED CONSENT
N/A.
REGISTRY AND THE REGISTRATION NO. OF THE STUDY/TRIAL
N/A.
ANIMAL STUDIES
N/A.
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Supporting information
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1 Figure S2