Original Article Clinical Investigation
Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan
Shotaro Nakanishi,1 (D Yumi Fukushima,2 Junichi Inokuchi,3 Tomoaki Hakariya,4 Hiroaki Kakinoki,5
Hideki Enokida,6 Katsuaki Chikui,7 Hirofumi Matsuoka,8 [D Toshitaka Shin,9 D Shoichiro Mukai,10 [D Tomomi Kamba,2 Masatoshi Eto,3 Ryoichi Imamura,4 Mitsuru Noguchi,5 Tsukasa Igawa,
Nobuhiro Haga,8 Toshiyuki Kamoto,1º [D Naohiro Fujimoto11 (D and Seiichi Saito1
1Department of Urology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan, 2Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan, 3Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 4Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, 5Department of Urology, Faculty of Medicine, Saga University, Saga, Japan, ‘Department of Urology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan, 7Department of Urology, Kurume University School of Medicine, Kurume, Japan, 8Department of Urology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan, 9Department of Urology, Faculty of Medicine, Oita University, Yufu-Shi, Japan, 1ºDepartment of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan, and 11Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Abbreviations & Acronyms
ACC = adrenocortical carcinoma DHEA-S = dehydroepiandrosterone- sulfate ECOG PS = Eastern Cooperative Oncology Group Performance Status Scale ENSAT = European Network for the Study of Adrenal Tumors TNM = tumor-node- metastasis
Correspondence
Shotaro Nakanishi M.D., Ph.D., Department of Urology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903- 0215, Japan.
Email: shotaro@med.u-ryukyu. ac.jp
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Received 7 June 2023; accepted 20 December 2023. Online publication 9 January 2024
Objective: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan’s data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals.
Methods: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival.
Results: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits.
Conclusion: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.
Key words: adjuvant treatment, adrenocortical carcinoma, surgical role.
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare disease, with an annual incidence of approximately 0.7-2 cases per million people.1 The prevalence rate is higher in women aged 40-50 years. Most cases of ACC are sporadic, although there are some congenital and familial forms of the disease.2 ACC is suspected when the tumor size exceeds 4 cm, because ACC tumors are larger than benign adrenal masses. ACC accounts for 2% of adrenal tumors measuring 4 cm or less, 6% of tumors that measure from 4.1 to 6 cm, and 25% of tumors greater >6 cm.3 Surgical resection is the mainstay of treatment for the localized disease.4 Although most
patients with ACC present with a resectable disease, the recurrence rate is high. Therefore, adjuvant mitotane therapy has been reported to significantly prolong recurrence-free sur- vival in a study using multivariate analysis.5 Although patients with European Network for the Study of Adrenal Tumors (ENSAT) stage IV have poor prognosis, cytoreduc- tive adrenalectomy significantly improves overall survival.6 However, due to the limited treatment methods available at present, a novel approach for ACC is urgently required.
Because ACC is derived from endocrine organs, hormone- secreting tumors account for approximately 60% of all ACC cases. However, symptoms caused by hormone over-secretion are present in approximately 40% of all cases of ACC.7 Patients with hormone-secreting ACC present with manifesta- tions of virilization, feminization, Cushing syndrome, or rarely hyperaldosteronism, whereas nonfunctioning ACC is usually diagnosed incidentally.
Despite being a rare cancer, comprehensive reports on ACC from Japan are limited. Therefore, it is essential to review Japan’s data on ACC. In this study, we aim to assess data on 46 patients-with ACCs-across 10 Japanese univer- sity hospitals.
METHODS
We retrospectively analyzed the medical records of patients with ACC, who underwent treatment across 10 university hospitals in the Kyushu and Okinawa districts between Janu- ary 2009 and May 2019. This study was approved by the Ethics Committee of the University of the Ryukyus and each Institution (Approval No. 1442) and each hospital.
The diagnosis and therapeutic care of the ACC patients were based on the General Rule for Clinical and Pathological Studies on Adrenal Tumor8 and the guidelines of the ENSAT group.4 The staging system was based on the tumor-node- metastasis (TNM) system for ACC of the American Joint Committee on Cancer/International Union Against Cancer, which has been available since 2009.9 Stage I was defined by the presence of a tumor with a diameter of <5 cm (T1N0M0); stage II was defined by the presence of a tumor with a diameter of >5 cm (T2N0M0); stage III was defined by any size with local invasion but not invading adjacent organs, or tumor greater than 5 cm in size and regional lymph node metastasis (T1-2N1M0 or T3N0M0); stage IV was defined by the presence of distant metastasis or any size that invades adjacent organs or large blood vessels (T4N0M0 or T3-4N1M0 or any T any N M1). Recurrence of disease was based on clinical, laboratory, and radiological evidence and did not require histological confirmation.
Plasma hormone hypersecretion should be suspected in adrenal tumors, especially when a patient presents with clini- cal symptoms. The reference values for the adrenocortical hormone levels were as follows: adrenocorticotropic hor- mone: 9-52 pg/mL; testosterone: male, 2.0-7.5 ng/ml and female, 0.1-0.5 ng/ml; cortisol: 2.7-15.5 µg/dL; aldosterone: 30-160 pg/mL; dehydroepiandrosterone-sulfate (DHEA-S): male, age range: 20-29; 165-542 µg/dL, 30-39; 120- 441 µg/dL, 40-49; 83-396 µg/dL, 50-59; 62-282 µg/dL, more than 60; 14-224 µg/dL, female, age range: 20-29; 85-
299 µg/dL, 30-39; 54-203 µg/dL, 40-49; 25-195 µg/dL, 50 -59; 11-116 µg/dL, more than 60; 50-100 µg/dL. Therefore, we defined an abnormal level of hormone as follows: adreno- corticotropic hormone ≤5 pg/mL; testosterone ≥10 ng/ml; cortisol ≥20 µg/dL; aldosterone ≥150 pg/mL; and DHEA-S: It was defined as being above the upper limit of normal for age and gender. 10-12
Statistical analyses were performed using JMP version 15 (SAS Institute Inc., Cary, NC, USA). Survival time was cal- culated from the time of diagnosis to the date of death. The relationship between categorical variables and overall survival was analyzed using the Kaplan-Meier method, and statistical significance was calculated using the log-rank test. Statistical significance was set at p < 0.05.
RESULTS
Backgrounds of the patients
We enrolled 46 patients with ACC (Table 1). The diagnosis of ACC was based on resected specimens of adrenalectomy in 34 cases and metastasectomy in two cases, while the remaining 10 cases were diagnosed by needle biopsy (one case), autopsy (two cases), and imaging testing (seven cases). We presented details of seven cases diagnosed with imaging. The median size of the primary tumor in these cases was 75 mm (50-105). Among them, three cases underwent fluoro- deoxyglucose positron emission tomography, which showed high uptake, while five cases were diagnosed by computed tomography and magnetic resonance imaging.
Of the 34 patients, six were diagnosed with benign tumors and underwent surgery. Fifteen patients underwent laparo- scopic surgery, with 12 having confirmed negative surgical margins and three with unknown margin. On the other hand, 18 patients underwent open surgery. Surgical margins were negative in 10 cases, positive in two cases, and unknown in the remaining six cases. The median tumor diameter in cases treated with laparoscopic surgery was 52 mm, while it was 82.5 mm in cases treated with open surgery (p = 0.0015) (data not shown).
The opportunities for diagnosis included clinical symptoms in 20 patients (43%) and incidental in 25 (54%). Thirty (65%) patients were female. The median age at diagnosis was 60.5 years. Approximately 85% of the patients had an East- ern Cooperative Oncology Group Performance Status Scale (ECOG PS) <2. Among the comorbidities, hypertension was the most common in 24 patients (52%). The tumor staging was as follows: 3 (7%) stage I, 19 (42%) stage II, 7 (15%) stage III, and 14 (29%) stage IV. The most common site of metastasis was the lungs in six cases (13%), followed by liver in five cases (11%). The Weiss score was calculated for 28 tumor sections. Weiss scores 3-5 corresponded to 65% of the cases (Table 1). The Ki-67 proliferation index (PI) was examined in 26 patients, of whom, 14 patients (54%) had more than 10% of the PI.
Treatment for the ACC patients
Thirty-four patients (74%) underwent adrenalectomy. Of these, 18 patients (53%) underwent open surgery and 15
| No. or median | % or range | |
|---|---|---|
| Age (years): median, range | 60.5 | (16-83) |
| Men/Women | 16/30 | 35%/65% |
| BMI, median, range | 22.5 | (14.8-38) |
| PS | ||
| 0 | 27 | 59% |
| 1 | 12 | 26% |
| 2 | 1 | 2% |
| Unknown | 6 | 13% |
| Tumor laterality | ||
| Right | 14 | 30% |
| Left | 28 | 61% |
| Unknown | 4 | 9% |
| Tumor size, median, | 73.5 | (11-200) |
| range (mm) | ||
| Comorbidities | ||
| Diabetes | 8 | 17% |
| Hypertension | 24 | 52% |
| Hyperlipidemia | 8 | 17% |
| Opportunity for discovery | ||
| Symptomatic | 20 | 43% |
| Asymptomatic | 25 | 54% |
| Unknown | 1 | 3% |
| Diagnostic methods | ||
| Adrenalectomy | 34 | 74% |
| Metastasectomy | 2 | 4% |
| Needle biopsy | 1 | 3% |
| Autopsy | 2 | 4% |
| Imaging test | 7 | 15% |
| Clinical T stage | ||
| 1 | 6 | 13% |
| 2 | 22 | 48% |
| 3 | 7 | 15% |
| 4 | 9 | 20% |
| Unknown | 2 | 4% |
| N stage | ||
| 0 | 32 | 70% |
| 1 | 10 | 21% |
| Unknown | 4 | 9% |
| M stage | ||
| 0 | 31 | 67% |
| 1 | 13 | 28% |
| Unknown | 2 | 5% |
| Metastatic sites | ||
| Lung | 6 | 13% |
| Liver | 5 | 11% |
| Lymph nodes | 2 | 4% |
| Bone | 1 | 2% |
| Others | 6 | 13% |
| AJCC 7th staging | ||
| I | 3 | 7% |
| II | 19 | 41% |
| III | 8 | 17% |
| IV | 14 | 30% |
| Unknown | 2 | 5% |
| Weiss criteria (N = 28) | ||
| 3 | 5 | 18% |
| 4 | 8 | 29% |
| 5 | 5 | 18% |
| 6 | 3 | 11% |
| 7 | 4 | 14% |
| 8 | 2 | 7% |
| 9 | 1 | 3% |
| No. or median | % or range | |
|---|---|---|
| Ki-67 index (N = 26) More than 10% | 14 | 54% |
| Pathological T stage (N = 34) | ||
| 1 | 3 | 9% |
| 2 | 12 | 35% |
| 3 | 5 | 15% |
| 4 | 1 | 3% |
| Unknown | 13 | 38% |
(44%) underwent laparoscopic surgery. The procedures involved adrenalectomy alone in 26 patients (76%), adrenal- ectomy with dissection of regional lymph nodes in three patients (9%), and adrenalectomy with combined resection of the surrounding organs and metastasectomy in five patients (15%). The median operating time was 230 min (IQR: 206.5 -319), and the blood loss was 320 mL (29-1455).
Only one patient (3%) received neoadjuvant chemotherapy, which consisted of mitotane plus etoposide, doxorubicin, and cisplatin (EDP). EDP is a chemotherapy that combines etopo- side, doxorubicin, and cisplatin. The doses and administration of these medications were as follows: etoposide: 100 mg per square meter of body-surface area on days 2 to 4, doxorubi- cin: 40 mg per square meter on Day 1, and cisplatin: 40 mg per square meter on Days 3 and 4. Adjuvant chemotherapy was administered to 19 patients (59%). Seventeen patients received mitotane, one received mitotane plus EDP, and the other had incomplete information (Table 2). Of 19 patients
| TABLE 2 Treatment for the ACC patients. | ||
| Surgical methods (adrenalectomy n = 34) | ||
| Open surgery | 18 | 53% |
| Laparoscopic surgery | 15 | 44% |
| Unknown | 1 | 3% |
| Resection | ||
| Adrenalectomy alone | 26 | 76% |
| Added lymph node resection | 3 | 9% |
| Added surrounding organ | 5 | 15% |
| resection and metastasectomy | ||
| Operative time | 230 | [206.5-319] |
| Blood loss | 320 | [29-1455] |
| Neoadjuvant chemotherapy | ||
| Received | 1 | 3% |
| Mitotane plus EDP | 1 | |
| Not received | 28 | 87.5% |
| Unknown | 3 | 9.5% |
| Adjuvant chemotherapy | ||
| Received | 19 | 59% |
| Mitotane only | 17 | |
| Mitotane plus EDP | 1 | |
| Unknown | 1 | |
| Not received | 13 | 41% |
who had adjuvant therapy, Ki-67 PI was examined in 12; half of these patients were classified as high risk (Ki-67 PI exceeding 10%), while the other half were categorized as low risk.
Outcome of the patients with ACC
The median follow-up time was 31 months, with correspond- ing five- and 10-year overall survival rates of 59% and 53%, respectively (Figure 1a). Notably, overall survival differed sig- nificantly among TNM system for ACC of the American Joint Committee on Cancer/International Union Against Cancer stages (p = 0.0044; Figure 1b). Specifically, the median overall survival for patients with stage IV disease was 12 months. We classified cases with Weiss scores between 3 and 5 as lower and 6 and 9 as higher, but no significant difference in overall survival was observed between the two groups (p = 0.4684; Figure 2a). The value of Ki-67 PI was divided into high and low groups at a cutoff value of 10%. However, no significant difference in overall survival was observed between the two groups (p = 0.1612; Figure 2b). Hormone secretion was not significantly associated with the prognosis (data not shown). Regarding the effects of treatments on the overall survival, adjuvant therapy had no significant impact on overall survival of postoperative patients at stages I-III (p = 0.4023; Figure 3). In contrast, primary tumor resection was significantly associ- ated with prolonged overall survival in patients with stage IV disease (p = 0.0262; Figure 4). The ECOG PS of all these cases was 0 or 1; therefore, the ECOG PS did not differentiate between the presence or absence of primary tumor resection. Details of five cases with primary tumor resection were described below.
The first case involved a 73-year-old woman with liver metastasis who underwent primary tumor removal, followed by radiation for liver metastases. She died 23 months after diagnosis. The second patient was a 71-year-old woman who had pulmonary metastasis. The primary tumor was removed laparoscopically, and at the same time, the lung metastases were removed thoracoscopically. Remarkably, she survived for 44 months after diagnosis. The third case was a 43-year-old woman with liver metastasis. She under- went laparotomy to remove both the primary and the meta- static liver tumor. She survived for 6 months after diagnosis. The fourth case involved a 71-year-old man who had liver metastases, and the metastatic lesions were removed simultaneously with the primary tumor. He sur- vived for 61 months after diagnosis. The fifth case involved a 73-year-old woman with bone metastasis, where only the primary tumor was removed. She survived for 18 months after diagnosis. In three of the five cases, the metastatic tumor was removed concurrently with the primary tumor. In addition, one patient underwent radiotherapy for metastatic lesions. These findings suggest a potential impact of local- ized treatment at metastatic lesions.
Serum hormone level in ACC patients
Plasma hormone levels in patients with ACC are shown in Table 3 and Figure 5. Plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured in 39, 33, 17, and 29 patients, respectively. Among the cases evalu- ated for plasma hormones, 23%, 42%, 29%, and 62% showed higher levels than the upper normal limits, respectively.
(a)
1.0
(b) 1.0
Stage I (n=3)
0.8
Percent survival
Percent survival
0.8
Stage III (n=8)
0.6
0.6
Stage II (n=19)
0.4
0.4
Stage IV (n=14)
0.2
0.2
P = 0.0044
0.0
0.0
0
50
100
150
200
0
50
100
150
200
months
months
46
27
15
9
5
4
3
3
I:
3
2
2
1
II:
19
16
9
5
3
2
1
1
III:
8
3
1
1
IV:
14
4
2
(a)
1.0
(b) 1.0
P = 0.4684
P=0.1612
Percent survival
0.8
Lower Weiss score (n=18)
Percent survival
0.8
Lower Ki-67 PI (n=12)
0.6
0.6
0.4
Higher Weiss score (n=10)
0.4
Higher Ki-67 PI (n=14)
0.2
0.2
0.0
20
40
60
80
100
120
0.0
0
0
20
40
60
80
100
120
months
months
L:
18
13
8
7
4
L:
12
9
5
5
3
H:
10
6
4
2
1
1
H:
14
7
5
2
1
1
1.0
Percent survival
Adjuvant therapy (n=19)
0.8
0.6
No adjuvant therapy (n=13)
0.4
0.2
P= 0.4023
0.0
0
50
100
150
200
months
Adjuvant:
19
16
9
5
2
2
2
No:
13
10
6
4
3
2
DISCUSSION
Five-year survival rates of ACC patients with stages I to II, III, and IV are 60% to 80%, 30% to 50%, and less than 25%, respectively.4,13 In our study, the 5-year survival rates according to the stage were 100%, 70%, 67%, and 31%, respectively. Notably, the prognosis of patients across all stages seemed to improve. Aggressive removal of the primary tumor, even at stage IV, and even in the event of recurrence, along with surgical treatment and radiation therapy, poten- tially contributed to these overall prognosis improvements. The patient who underwent metastasectomy six times was confirmed to be alive after a 35-month observation period. In patients with metastatic disease, many institutions empirically select resection of the primary tumor as part of the treatment
1.0
0.8
Percent survival
Resection of primary tumor (n=5)
0.6
0.4
No resection of primary tumor (n=9)
0.2
P = 0.0262
0.0
0
5
10
15
20
25
30
35
40
45
Resection
5
5
4
4
3
2
2
2
months
2
1
No resection
9
4
2
1
1
1
| TABLE 3 Values of plasma hormone in the ACC patients. | ||||
|---|---|---|---|---|
| Number of patients | Median | Interquartile range | Normal range | |
| ACTH (pg/mL) | 36 | 7.2 | (2.0, 18.8) | 9-52 |
| Testosterone | 17 | 3.2 | (1.0, 10.7) | |
| (ng/ml) | ||||
| Male | 6 | 3.4 | (1.9, 41.7) | 2.0-7.5 |
| Female | 11 | 1.8 | (0.8, 11.1) | 0.1-0.5 |
| Cortisol (µg/dL) | 39 | 13.8 | (10.1, 19) | 2.7-15.5 |
| Aldosterone | 33 | 122 | (85.5, 266) | 30-160 |
| (pg/mL) | ||||
| DHEA-S (µg/dL) | 29 | 267 | (92.5, 1269) | |
| Male | 11 | 267 | (116, 1520) | |
| Female | 18 | 281.5 | (76, 1174.5) | |
cortisol
aldosterone
high =low
high low
DHEA-S
testosterone
high low
high low
in the absence of efficient systemic therapies. Srougi et al. pooled 339 patients with metastatic ACC, with and without primary tumor extirpation. Their findings indicate a signifi- cantly favorable prognosis in the group that underwent pri- mary tumor extirpation.º In this study, the prognosis was significantly better in patients who underwent primary tumor resection, although the number of patients was small. There- fore, the decision regarding resection of the primary tumor in ACC patients with metastasis should be carefully considered on a case-by-case basis.
Surgical resection of the ACC is considered the primary treatment for localized diseases.4 Laparoscopic surgery is the standard treatment for benign adrenal tumors. However, no consensus regarding the optimal resection technique for ACC exists. Using a systematic review and meta-analysis approach, Nakanishi et al. compared open vs laparoscopic surgery for ACC and reported that open surgery had a lower positive resection margin rate and better 3-year overall and recurrence-free survival rates.14 However, they concluded that laparoscopic surgery was more effective in selected cases because of a significantly shorter hospital stay.14 Delman et al. compared open vs laparoscopic surgery for ACC and reported that the overall survival was the same for both.15
Additionally, Cavallaro et al. recommended open surgery for tumors larger than 8 cm.16 In the laparoscopic surgery group of the present study, 29% of patients were classified as T1, 64% as T2, 7% as T3, and no T4 cases were observed, while in the open surgery group, 6% were classified as T1, 71% as T2, 6% as T3, and 18% as T4. Although no significant dif- ference was observed in the ENSAT stages between the lapa- roscopic and open surgery groups, more T4 cases tended to be treated with open surgery. Consistent with previous reports, our results showed that laparoscopic surgery was per- formed in selected cases.
Adjuvant mitotane therapy is recommended for patients after complete surgical resection who have either stage III or stage IV disease or high-grade disease of any stage (Ki- 67 PI >10%).17 Pathologists generally classify the malignant potential of ACC as high or low grade according to the mitotic count, whereas ENSAT treatment algorithms often rely on the Ki-67 PI. Tumors with a Ki-67 PI of 10% or less are considered low risk, whereas those with a PI of more than 10% are considered high risk.18,19 For example, there is no evidence supporting adjuvant mitotane recom- mendation for patients with stage I-III and Ki-67 PI <10% after R0 resection (ADIUVO trial, ClinicalTrials.gov
identifier: 777244). There are currently ongoing clinical tri- als (ADIUVO-2 trial, ClinicalTrials.gov identifier: NCT03583710) for adjuvant treatment of high-risk cases (stage I-III and Ki-67 PI >10%) of ACC with mitotane alone and mitotane plus cisplatin and etoposide, with the results expected around 2025.
EDP plus mitotane (EDP-M) is currently the standard che- motherapy regimen in the first-line treatment of advanced ACC.20 In a randomized phase-III First International Ran- domized Trial in Locally Advanced and Metastatic (FIRM- ACT) study, the overall survival of patients with advanced ACC treated with EDP-M tended to be prolonged, but no sig- nificant difference was observed when compared with strepto- zotocin and mitotane (Sz-M) therapy. Nevertheless, EDP-M significantly prolonged the time of tumor progression com- pared with Sz-M.4 Despite the advantage of EDP-M, the mean survival rate of patients with advanced ACC is still frustrating. Currently, immunotherapy has revolutionized can- cer treatment, exhibiting promising anti-tumor activity in dif- ferent solid tumors, including ACC. In a phase II study of pembrolizumab that enrolled 39 patients with advanced ACC, the clinical activity of 200 mg pembrolizumab every 3 weeks was assessed regardless of the prior therapy received. This study reported an objective response rate of 23%, a disease control rate of 52%, and a median overall survival of 24.9 months.21 Future clinical results are highly anticipated.
Functional tumors account for approximately 60% of all ACC cases.1 However, symptoms caused by hormone over- secretion are evoked in around 40% of all cases of ACC. Due to the retrospective nature of this study, hormone mea- surement items and the number of cases measured varied and were small, making it difficult to comment on their relation- ship with symptoms or the amount of hormone secretion. Based on these results, we strongly recommend performing hormone measurements without fail when diagnosing an adrenal tumor.
Our study has several limitations. Firstly, it was a retro- spective analysis of ACC patients treated across 10 university hospitals. Secondly, histological confirmation was not con- ducted in 7 (15%) of 46 cases. Thirdly, each hospital had a slightly different treatment strategy, which may have affected the prognostic outcomes. Nevertheless, considering that ACC is a rare cancer, the present report provides real-world data on its clinicopathological characteristics.
In conclusion, the present study revealed that patients with metastatic ACC had the poorest prognosis, whereas resection of the primary tumor for metastatic ACC was sig- nificantly associated with prolonged overall survival. In con- trast, adjuvant mitotane did not have a significant effect on overall survival. We anticipate that the findings of this study will contribute to future medical treatment of ACC in Japan.
AUTHOR CONTRIBUTIONS
Shotaro Nakanishi: Conceptualization; Data curation; For- mal analysis; Writing-original draft. Yumi Fukushima: Data curation; Resources; Writing-review & editing. Juni- chi Inokuchi: Data curation; Resources; Writing-review &
editing. Tomoaki Hakariya: Data curation; Writing-review & editing; Resources. Hiroaki Kakinoki: Data curation; Resources; Writing-review & editing. Hideki Enokida: Data curation; Resources; Writing-review & editing. Kat- suaki Chikui: Data curation; Resources; Writing-review & editing. Hirofumi Matsuoka: Data curation; Resources; Writing-review & editing. Toshitaka Shin: Data curation; Resources; Writing-review & editing. Shoichiro Mukai: Data curation; Resources; Writing-review & editing. Tomomi Kamba: Data curation; Resources; Writing-review & editing. Masatoshi Eto: Data curation; Resources; Writing -review & editing. Ryoichi Imamura: Data curation; Resources; Writing-review & editing. Mitsuru Noguchi: Data curation; Resources; Writing-review & editing. Tsu- kasa Igawa: Data curation; Resources; Writing-review & editing. Nobuhiro Haga: Data curation; Resources; Writing -review & editing. Toshiyuki Kamoto: Data curation; Resources; Writing-review & editing. Naohiro Fujimoto: Data curation; Resources; Writing-review & editing. Seiichi Saito: Conceptualization; Writing-review & editing; Supervision.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
APPROVAL OF THE RESEARCH PROTOCOL BY AN INSTITUTIONAL REVIEW BOARD
This study was approved by the Ethics Committee of the University of the Ryukyus and each university hospital (Approval No. 1442).
INFORMED CONSENT
N/A.
REGISTRY AND THE REGISTRATION NO. OF THE STUDY/TRIAL
N/A.
ANIMAL STUDIES
N/A.
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