ORIGINAL ARTICLE
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Causes of death in patients with malignant adrenal tumours: a population-based analysis
Yang Zheng1,2 . Song Ren3 . Zeyi Yan4 . Ting Hu1,2 . Yunlin Feng3 . Dong Wang2 . Shida Fan2 . Shangqing Ren2
Received: 14 July 2024 / Accepted: 11 February 2025 / Published online: 24 February 2025 @ The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE) 2025
Abstract
Objective This study aimed to characterize the causes of death and compute the risk of mortality due to each cause among patients with malignant adrenal tumours.
Methods Data from malignant adrenal tumour patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2020). With reference data from the general population, the standardized mortality ratio (SMR) was calculated to assess all causes of death for malignant adrenal tumour patients.
Results A total of 1651 patients who died from primary malignant adrenal neoplasms were included; 854 cases of adreno- cortical carcinoma (ACC)-related death, 118 cases of pheochromocytoma (PCC)-related death and 333 cases of neuroblas- toma (NB)-related death were identified for further analysis. Approximately 56.78%~87.69% of patients died from primary malignant adrenal tumours, 7.21%~13.56% died from secondary malignant neoplasms (SMNs), and 5.11%~29.66% died from noncancer diseases. The main causes of death associated with SMNs included lung and bronchial cancer and soft tis- sue cancers, including heart, kidney and renal pelvis cancers; the noncancer causes of death included mainly heart disease, septicemia, and cerebrovascular disease. Compared with chemotherapy-naïve patients, chemotherapy-treated patients had higher SMRs of SMNs, including cancers of the colon (excluding the rectum), lung, bronchus, bones and joints; soft tissues, including the heart, kidney and renal pelvis; the brain and peripheral nervous system; and leukaemia, as well as nontumor diseases, including heart disease, septicemia, and cerebrovascular disease. Patients with NB were more likely to die from SMNs, including soft-tissue malignancies of the heart, bones and joints; brain; peripheral nervous system; the female genital system, including the ovary; leukaemia, including lymphocytic leukaemia; myeloid and monocytic leukaemia; and lym- phoma, including non-Hodgkin lymphoma.
Conclusion In addition to primary cancer, SMNs and nontumor diseases were important causes of death in patients with malignant adrenal tumours. Neuroblastoma patients and chemotherapy- treated patients are more likely to die from SMNs and should monitored closely.
Keywords Malignant adrenal tumours . Causes of death . SMR · SEER
Yang Zheng, Song Ren and Zeyi Yan contributed equally to this work.
☒ Yunlin Feng fengyunlin@med.uestc.edu.cn
☒ Dong Wang wangdong19690530@163.com
☒ Shida Fan 18523636523@163.com
☒ Shangqing Ren rsq0516@163.com
1 School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China
2 Robotic Minimally Invasive Surgery Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
3 Department of Nephrology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
4 The First Clinical Medicine College of Lanzhou University, Lanzhou 730000, Gansu Province, China
Introduction
Adrenal masses are among the most frequently diagnosed human tumours, with a prevalence of 3-10% in human pop- ulations [1], but only a small proportion of adrenal tumours are malignant adrenal tumours. Several main malignant neo- plasms of the adrenal gland, including adrenocortical carci- noma (ACC) [2], malignant pheochromocytoma (PCC), and neuroblastoma (NB) [3], are rare and aggressive.
ACC, arising from the adrenal cortex, accounts for 0.05- 0.2% of all human cancers, with an estimated incidence of 0.7-2 cases per million per year [3, 4]. It is usually diag- nosed at an advanced stage, with a 5-year mortality rate of approximately 75-90% in most cases [5]. PCCs, which are derived from the adrenal medulla, are rare catecholamine- producing tumours that cause significant cardiovascular morbidity and mortality. PCC has an annual incidence of 2-8 new cases per million individuals [6, 7]. The overall 5-year mortality rate of malignant PCC is between 40% and 64% [8]. NB originates from primordial neural crest cells that can normally develop into the sympathetic nervous sys- tem, and approximately 50% of NB tumours originate in the adrenal gland [9]. It frequently occurs in children aged 0-4 years [10], with an annual incidence rate of 6 cases per million children [11]. Previous studies indicate that approxi- mately 40% of NB patients present with distant metastases at initial diagnosis [12].
In recent years, remarkable efforts have been made to identify significant prognostic factors for major malignant adrenal tumours. It has been well confirmed that tumour stage, age and surgical margin status were associated with ACC prognosis [13, 14]. Additionally, previous studies have demonstrated that primary tumour size, tumour location and genetic status were significant prognostic indicators for malignant PCC [8, 15]. However, there is a lack of popu- lation-based studies characterizing the causes of death for patients with malignant adrenal tumours. Early intervention for these conditions and their correlated risk factors could help prolong survival in these populations. Hence, the aim of this study was to comprehensively assess all causes of death for patients with malignant adrenal tumours, includ- ing ACC, PCC and NB, and further calculate their SMRs on the basis of reference data from the general population.
Methods
Data sources
Patient data were obtained from the SEER database, which covers approximately 34.6% of the overall US popula- tion, using SEER*Stat software (National Cancer Institute,
Bethesda, MD, USA, version 8.3.9.2) [16, 17]. The mortal- ity data of the general population were from the U.S. Centers for Disease Control and Prevention. The data are publicly available and therefore do not require ethical approval from the institutional review board.
Patients
Patients who were diagnosed with malignant adrenal tumours upon pathological examination of postadrenal- ectomy specimens from 2004 to 2020 as the first primary malignancy were included. The following variables were utilized: pathological information (based on the ICD-O-3/ WHO 2008 definition), staging profile (according to the SEER Summary Stage 2000), follow-up period, survival time, and all causes of death.
Study variables
The groupings for certain variables were as follows: age (0-9, 10-39, 40-49, 50-59, 60-69, 70-79, 80+), sex (male, female), year of diagnosis (2004-2006, 2009-2014, 2015-2020), race (White, Black, American Indian-Alas- kan Native, Asian or Pacific Islander), pathology (8370/3: adrenal cortical carcinoma; 9500/3: neuroblastoma, NOS; 8700/3: pheochromocytoma, malignant; 8140/3: adenocar- cinoma, NOS; 8890/3), tumour stage (localized, regional, and distant), surgical treatment (yes, no/unknown), che- motherapy (yes, no/unknown), and radiotherapy (yes, no/ unknown).
Statistical analysis
Given that there is significant heterogeneity between differ- ent malignant adrenal tumours in terms of clinical charac- teristics, prognosis and treatment, we stratified malignant adrenal tumours into three main subgroups on the basis of pathological type (ACC, PCC, and NB) and analysed detailed causes of death for patients with each subtype. The SMR is defined the ratio of the number of observed deaths to the number of expected deaths. The expected number of deaths was computed according to the total person-years of the included patients and the incidence in the general popu- lation. The SMR of all-cause death and the 95% confidence interval (95% CI) were calculated with the exact method of statistics. We also analysed the SMRs and 95% CIs for patients grouped according to tumour stage (localized, regional, and distant), survival time after diagnosis (<1 year, 1-5 years, 5-10 years, >10 years), and chemotherapy treatment (yes, no/unknown). All analyses were performed
using SEER*Stat software (version 8.3.9.2; National Can- cer Institute, Bethesda, MD, USA), and a p value<0.05 was considered to indicate statistical significance.
Results
In this study, 3457 patients with malignant adrenal tumours were identified in the SEER cohort. A total of 1319 ACC patients, 1279 NB patients and 314 PCC patients were included for further analysis. The majority of patients with malignant adrenal tumours had distant disease (n=1872), with a total mortality rate of 58.44%. The overall mortality rates of patients with localized and regional disease after diagnosis were 29.47% and 44.43%, respectively. The base- line information of the included patients with malignant adrenal tumours is shown in Table 1.
The number of new cases of malignant adrenal tumours and patients with localized disease gradually increased between 2004 and 2020, whereas increases in cases of regional and distant disease were not obvious (Fig. 1). The mortality rate among patients with malignant adrenal tumours who died from primary cancer, SMN, or noncan- cer disease substantially decreased in the first 5 years after diagnosis (Fig. 2).
Causes of death for patients with ACC
The number of new patients diagnosed with malignant ACC slightly increased from 2004 to 2020 (shown in Fig. 3). After a median follow-up of 107 months, a total of 854 patients with malignant ACC died after diagnosis, 76.81% of whom died from primary ACC, 12.18% of whom died from SMNs, and 11.01% of whom died from nontumor dis- eases. The median overall survival of patients with ACC was 21 months (95% CI: 18-24 months) (Fig. 4). A total of 776 (90.87%) and 78 (9.13%) deaths occurred during the follow-up periods of <5 years and >5 years, respectively (Supplementary Fig. 1).
The main causes of death for patients with malignant ACC are presented in Table 2. The major causes of SMN- related death in ACC patients were cancers of the respira- tory system, including the lung and bronchus; the digestive system; the urinary system, including the kidney and renal pelvis; and soft tissue, including the heart. The risk of mor- tality due to malignancies of the liver, stomach, lung and bronchus; bones and joints; and kidney and renal pelvis was significantly greater among ACC patients than among the general US population. The most common noncancer causes of death for patients with malignant ACC were heart disease, septicemia, cerebrovascular disease, nephritis, nephrotic syndrome and nephrosis. Notably, the SMRs of
diseases of the heart, septicemia, cerebrovascular disease, and other infectious and parasitic diseases, including HIV, significantly increased compared with those of the general population. For patients with ACC, the risk of mortality due to SMNs or nontumour disease each year after diagnosis are shown in Supplementary Fig. 1.
The overall mortality rates of patients with localized, regional and distant disease after diagnosis were 41.52%, 62.89% and 83.62%, respectively. Compared with the gen- eral population, there was no significantly increased risk of death from SMNs among individuals with localized and regional diseases. Patients with distant disease had a sig- nificantly greater risk of mortality from SMNs, including lung and bronchial cancers and kidney and renal pelvis neo- plasms, and nontumor diseases, including cerebrovascular disease and heart disease, than did the general population (Table 2).
Causes of death for patients with NB
The number of new patients diagnosed with NB remained stable from 2004 to 2020 (shown in Fig. 3). After a median follow-up of 95 months, a total of 1279 individuals with NB were studied, and 333 patients died. A total of 316 (94.89%) of them died from malignant cancers; of these patients, 292 (87.69%) died from primary cancer and 24 (7.21%) died from SMNs. Nontumour diseases accounted for only 5.11% of all deaths. The median overall survival was not reached (Fig. 4). A total of 295 (88.60%) and 38 (11.4%) deaths occurred within or beyond 5 years after diagnosis, respec- tively (Supplementary Fig. 2).
The main causes of death for NB patients are shown in Table 3. The main causes of death in SMNs were cancers of soft tissue, including the heart, bones and joints; the brain and peripheral nervous system; and the female genital sys- tem, including the ovary; and leukaemia, including lympho- cytic leukaemia; myeloid and monocytic leukaemia; and lymphoma, including non-Hodgkin lymphoma. Compared with the general population, patients with NB had a signifi- cantly increased risk of mortality from malignancies of the bones and joints; soft tissue, including the heart; the female genital system, including the ovary; and the brain and peripheral nervous system; and lymphomas, including non- Hodgkin lymphoma, and leukaemia, including lymphocytic leukaemia and myeloid and monocytic leukaemia. The most common noncancer causes of death in NB patients were septicemia, heart disease, accidents, effects, pneumonia and influenza. Compared with those of the general population, the SMRs of heart disease and septicemia were significantly increased in NB patients. The risk of mortality due to SMNs
| Variables | Localized | Regional | Distant | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Patients, n | Deaths, n | SMR(95%CI) | Patients, n | Deaths, n | SMR(95%CI) | Patients, n | Deaths, n | SMR(95%CI) | |
| Total | 984 | 290 | 5.46*(4.85-6.13) | 601 | 267 | 14.49*(12.8-16.34) | 1,872 | 1,094 | 60.23*(56.71-63.9) |
| Age | |||||||||
| 0-9 years | 264 | 10 | 8.51*(4.08-15.65) | 179 | 18 | 23.57*(13.97- | 938 | 312 | 104.62*(93.33- |
| 37.25) | 116.89) | ||||||||
| 10-39 years | 157 | 30 | 20.86*(14.08- | 87 | 41 | 90.04*(64.61- | 195 | 139 | 323.42"(271.89- |
| 29.78) | 122.15) | 381.88) | |||||||
| 40-49 years | 118 | 36 | 10.97*(7.68- | 53 | 27 | 36.60*(24.12- | 114 | 93 | 126.71*(102.27- |
| 15.18) | 53.26) | 155.22) | |||||||
| 50-59 years | 154 | 63 | 9.02*(6.93-11.54) | 108 | 59 | 16.43*(12.51- | 223 | 194 | 70.34*(60.79-80.96) |
| 21.19) | |||||||||
| 60-69 years | 168 | 76 | 5.56*(4.38-6.96) | 94 | 58 | 10.49*(7.97-13.56) | 202 | 171 | 60.25*(51.56-69.99) |
| 70-79 years | 83 | 44 | 2.93*(2.13-3.93) | 58 | 44 | 9.90*(7.19-13.29) | 121 | 110 | 22.43*(18.43-27.03) |
| 80+years | 40 | 31 | 2.69*(1.83-3.82) | 22 | 20 | 6.88*(4.2-10.63) | 79 | 75 | 21.32*(16.77-26.73) |
| Sex | |||||||||
| Male | 415 | 119 | 6.02*(4.98-7.2) | 287 | 125 | 12.50*(10.4-14.89) | 964 | 534 | 48.57*(44.54-52.87) |
| Female | 569 | 171 | 5.13*(4.39-5.96) | 314 | 142 | 16.86*(14.2-19.87) | 908 | 560 | 78.10*(71.77-84.85) |
| Year of diagnosis | |||||||||
| 2004-2008 | 268 | 106 | 4.29*(3.51-5.19) | 164 | 89 | 12.60*(10.12- | 525 | 348 | 55.77*(50.07-61.95) |
| 15.51) | |||||||||
| 2009-2014 | 351 | 123 | 5.82*(4.84-6.95) | 201 | 101 | 12.59*(10.25-15.3) | 650 | 417 | 59.59*(54-65.59) |
| 2015-2020 | 365 | 61 | 8.39*(6.42-10.78) | 236 | 77 | 23.05*(18.19-28.8) | 697 | 329 | 66.78*(59.76-74.4) |
| Race | |||||||||
| White | 779 | 244 | 5.53*(4.86-6.27) | 494 | 225 | 14.44*(12.62- | 1,438 | 848 | 57.44*(53.64-61.44) |
| 16.46) | |||||||||
| Black | 114 | 23 | 4.65"(2.95-6.97) | 64 | 27 | 13.33*(8.79-19.4) | 258 | 152 | 60.82*(51.54-71.3) |
| American Indian- | 4 | 1 | 48.99*(1.24- | 1 | 0 | 0(0-112.14) | 10 | 8 | 284.25"(122.72- |
| Alaska Native | 272.93) | 560.09) | |||||||
| Asian or Pacific | 87 | 22 | 5.44*(3.41-8.23) | 42 | 15 | 18.99*(10.63- | 166 | 86 | 98.41*(78.72- |
| Islander | 31.33) | 121.54) | |||||||
| Pathology | |||||||||
| 8370/3: Adrenal | 448 | 186 | 7.04*(6.07-8.13) | 291 | 183 | 18.87*(16.23- | 580 | 485 | 66.27*(60.51-72.44) |
| cortical carcinoma | 21.81) | ||||||||
| 9500/3: Neuroblas- | 206 | 7 | 6.76"(2.72-13.93) | 167 | 20 | 26.32#(16.08- | 906 | 306 | 105.83*(94.31- |
| toma, NOS | 40.65) | 118.38) | |||||||
| 8700/3: Pheo- | 160 | 29 | 1.90*(1.27-2.73) | 59 | 19 | 3.74*(2.25-5.84) | 95 | 70 | 18.17*(14.17-22.96) |
| chromocytoma, | |||||||||
| malignant | |||||||||
| 8140/3: Adenocar- | 5 | 5 | 77.38#(25.13- | 2 | 2 | 9.18*(1.11-33.16) | 26 | 25 | 69.18*(44.77- |
| cinoma, NOS | 180.59) | 102.12) | |||||||
| 8890/3: Leiomyo- | 15 | 9 | 4.54*(2.07-8.61) | 9 | 7 | 13.67*(5.49-28.16) | 6 | 6 | 26.40*(9.69-57.45) |
| sarcoma, NOS | |||||||||
| Surgical treatment | |||||||||
| No/unknown | 133 | 52 | 9.39#(7.02-12.32) | 69 | 46 | 43.09*(31.55- | 821 | 599 | 66.01*(60.83-71.52) |
| 57.48) | |||||||||
| Yes | 851 | 238 | 5.00*(4.39-5.68) | 532 | 221 | 12.73*(11.11- | 1,051 | 495 | 54.45*(49.76-59.47) |
| 14.53) | |||||||||
| Chemotherapy | |||||||||
| No/unknown | 807 | 228 | 4.67#(4.08-5.31) | 323 | 160 | 10.66*(9.07-12.44) | 511 | 404 | 41.83*(37.85-46.12) |
| Yes | 177 | 62 | 14.58*(11.18- | 278 | 107 | 31.35#(25.69- | 1,361 | 690 | 81.11#(75.17-87.4) |
| 18.69) | 37.88) | ||||||||
| Radiotherapy | |||||||||
| No/unknown | 911 | 264 | 5.30*(4.68-5.98) | 475 | 217 | 13.57*(11.82-15.5) | 1,293 | 824 | 57.49*(53.63-61.55) |
| Yes | 73 | 26 | 7.92*(5.17-11.6) | 126 | 50 | 20.57#(15.27- | 579 | 270 | 70.48*(62.33-79.41) |
| 27.12) | |||||||||
Abbreviations: SMR, standardized mortality ratio; CI, confidence interval; NOS: Not otherwise specified “Statistical significance with P<0.05
250
225
Total
200
Localized
175
Regional
Frequency,n
Distant
150
125
100
75
50
25
0
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
| Total | 158 | 200 | 190 | 204 | 205 | 204 | 225 | 186 | 187 | 194 | 206 | 202 | 195 | 197 | 234 | 233 | 237 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Localized | 30 | 61 | 49 | 66 | 62 | 75 | 56 | 51 | 60 | 52 | 57 | 64 | 54 | 47 | 66 | 63 | 71 |
| Regional | 27 | 28 | 39 | 28 | 42 | 35 | 47 | 36 | 31 | 22 | 30 | 32 | 38 | 41 | 38 | 48 | 39 |
| Distant | 101 | 111 | 102 | 110 | 101 | 94 | 122 | 99 | 96 | 120 | 119 | 106 | 103 | 109 | 130 | 122 | 127 |
Fig. 1 The number of new cases diagnosed with malignant adrenal tumours from 2004 to 2020
and nontumour disease each year after diagnosis among patients with NB are shown in Supplementary Fig. 2.
The overall mortality rates of patients with localized, regional and distant disease after diagnosis were 3.40%, 11.98%, and 33.77%, respectively. Compared with the healthy population, patients with localized NB have a sig- nificant risk of death due to soft tissue neoplasms, including heart neoplasms, septicemia, accidents and adverse effects. In patients with regional disease, the risk of mortality due to SMNs of the brain and peripheral nervous system and of the female genital system, including ovarian cancers, is significantly elevated. In addition, in patients with distant disease, the risk of death due to SMNs including cancers of soft tissue, including the heart, bones and joints; leukaemia, including lymphocytic leukaemia, myeloid leukaemia, and monocytic leukaemia; and lymphoma, including non-Hodg- kin lymphoma, as well as nontumor diseases, including sep- ticemia and heart disease, was significantly greater than that in the general population (Table 3).
Causes of death for patients with PCC
The number of new patients diagnosed with malignant PCC remained stable from 2004 to 2020 (shown in Fig. 3). After a median follow-up of 121 months, 118 deaths were identi- fied among patients with PCC, 83 (70.34%) of which were caused by malignant tumours, including 67 (56.78%) deaths from primary malignant adrenal tumours. and 16 (13.56%) patients died from SMNs. In addition, 35 (29.66%) deaths
were due to nontumour diseases. The median overall sur- vival of patients with malignant PCC was 117 months (95% 103-154 months) (Fig. 4). In addition, 79 (66.86%) and 39 (33.14%) deaths occurred within 5 years and beyond 5 years after diagnosis, respectively. These results are shown in Supplementary Fig. 3.
The main causes of death for patients with malignant PCC are presented in Table 4. The main SMNs that led to death included malignancies of the lung and bronchus; the digestive system, including the liver, pancreas, bones and joints; and soft tissues, including the heart. The risk of death for patients with bone and joint tumours was significantly greater than that for the overall population. Common non- tumour causes of death for survivors with PCC were heart diseases, septicaemia, cerebrovascular disease and chronic obstructive pulmonary disease. The risk of mortality due to SMNs and nontumor causes within the year after diagnosis among patients with PCC are presented in Supplementary Fig. 3.
The overall mortality rates of patients with localized, regional and distant disease after diagnosis were 18.13%, 32.20%, and 73.68%, respectively. Compared with the gen- eral population, there was no significantly increased risk of death from SMNs or noncancer diseases among PCC patients, regardless of tumour stage (Table 4).
(A)
Localized disease
10
All causes of death
8
Adrenal Gland cancer
Mortality rate,%
SMTs
6
Non-tumor causes
4
2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(B)
Regional disease
18
16
All Causes of Death
Adrenal Gland cancer
14
Mortality rate,%
SMTs
12
Non-tumor causes
10
8
6
4
2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(C)
Distant disease
35
All Causes of Death
30
Adrenal Gland cancer
Mortality rate,%
25
SMTs
Non-tumor causes
20
15
10
5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
994
237
233
225
200-
200
204
204
206
202
197
190
194
195
100
87
158
150-
disease
Frequency
ACC
Neuroblastoma
Pheochromocytoma
105
Total
100-
85
04
88
70
02
79
79
OU
82
83
85
87
79
81
7
76
70
20
75
71
71
71
73
08
62
56
58
50
48
20
26
22
22
26
24
21
17
10
16
14
9
9
11
0-
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
Year
1.00
1
0.75
Overall survival
0.50
0.25
0.00
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
170
180
190
201
Time(months)
malignant adrenal tumors
ACC
Neuroblastoma Pheochromocytoma
| Causes of death | ACC | Localized | Regional | Distant | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Observed | No. Expected | SMR(95%CI) | No. | Observed No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | |
| All causes of death | 854 | 43.43 | 19.66#(18.37-21.03) | 186 | 26.41 | 7.04#(6.07-8.13) | 183 | 24.18 | 4.88*(4.04-5.84) | 485 | 7.32 | 66.27#(60.51-72.44) |
| All malignant cancers | 760 | 10.74 | 70.75#(65.81-75.97) | 150 | 6.36 | 23.57#(19.95-27.66) | 161 | 5.97 | 13.90*(11.07-17.23) | 449 | 1.99 | 225.94#(205.52-247.84) |
| Endocrine system | 657 | 0.05 | 12,804.79#(11844.26 13822.48) | 128 | 0.03 | 4,151.20#(3463.25- 4935.79) | 140 | 0.03 | 2,371.99"(1841.94 3007.06) | 389 | 0.01 | 41,434.38#(37418.67- 45763.63) |
| Adrenal gland | 656 | 0.02 | 40,191.37#(37174.21- 43388.19) | 128 | 0.01 | 13,340.06#(11129.29- 15861.37) | 140 | 0.01 | 7,859.47*(6090.98- 9981.25) | 388 | 0 | 121,538.60#(109744.63- 134254.67) |
| Digestive system | 13 | 2.75 | 4.73#(2.52-8.08) | 4 | 1.63 | 2.45(0.67-6.28) | 4 | 1.58 | 1.27(0.15-4.58) | 5 | 0.51 | 9.88#(3.21-23.07) |
| Stomach | 2 | 0.19 | 10.27#(1.24-37.08) | 1 | 0.11 | 8.76(0.22-48.81) | 1 | 0.12 | 0(0-31.44) | 0 | 0.04 | 0(0-98.72) |
| Colon excluding rectum | 2 | 0.74 | 2.71(0.33-9.81) | 1 | 0.44 | 2.26(0.06-12.6) | 0 | 0.41 | 0(0-8.96) | 1 | 0.13 | 7.56(0.19-42.11) |
| Liver | 4 | 0.33 | 12.26#(3.34-31.4) | 1 | 0.19 | 5.31(0.13-29.56) | 2 | 0.2 | 4.95(0.13-27.56) | 1 | 0.06 | 15.45(0.39-86.06) |
| Pancreas | 3 | 0.77 | 3.9(0.8-11.39) | 1 | 0.46 | 2.17(0.05-12.07) | 1 | 0.44 | 2.29(0.06-12.76) | 1 | 0.14 | 7.3(0.18 40.66) |
| Respiratory system | 14 | 2.93 | 4.78#(2.61-8.03) | 3 | 1.73 | 1.74(0.36-5.08) | 4 | 1.64 | 2.43(0.66-6.23) | 7 | 0.55 | 12.73#(5.12-26.22) |
| Lung and bronchus | 14 | 2.85 | 4.92#(2.69-8.25) | 3 | 1.68 | 1.79(0.37-5.22) | 4 | 1.59 | 2.51(0.68-6.43) | 7 | 0.53 | 13.10#(5.27-27) |
| Urinary system | 9 | 0.49 | 18.23#(8.34-34.6) | 1 | 0.29 | 3.51(0.09-19.53) | 2 | 0.29 | 0(0-12.85) | 6 | 0.09 | 64.25#(23.58-139.85) |
| Kidney and renal pelvis | 8 | 0.24 | 33.41#(14.42-65.83) | 1 | 0.14 | 7.14(0.18-39.76) | 2 | 0.14 | 0(0-27.21) | 5 | 0.04 | 111.63#(36.25-260.51) |
| Non-tumor cause | ||||||||||||
| Diseases of heart | 27 | 9.74 | 2.77#(1.83-4.03) | 12 | 5.93 | 2.02#(1.05-3.54) | 7 | 2.2 | 3.18#(1.28-6.54) | 8 | 1.61 | 4.96#(2.14-9.78) |
| Septicemia | 5 | 0.64 | 7.81#(2.54-18.23) | 1 | 0.39 | 2.58(0.07-14.35) | 3 | 0.14 | 21.12#(4.36-61.73) | 1 | 0.11 | 9.13(0.23-50.86) |
| Other infectious and parasitic diseases including HIV | 3 | 0.45 | 6.72#(1.39-19.65) | 0 | 0.27 | 0(0-13.85) | 1 | 0.1 | 10.23(0.26-56.99) | 2 | 0.17 | 11.76*(5.4-50.71) |
| Cerebrovascular diseases | 8 | 2.2 | 3.63#(1.57-7.16) | 4 | 1.39 | 2.89(0.79-7.39) | 1 | 0.48 | 2.08(0.05-11.59) | 3 | 0.33 | 8.96#(1.85-26.19) |
| Nephritis, nephrotic syndrome and nephrosis | 3 | 0.78 | 3.85(0.79-11.24) | 0 | 0.47 | 0(0-7.81) | 2 | 0.17 | 11.48#(1.39-41.48) | 1 | 0.13 | 7.49(0.19-41.74) |
Abbreviations: SMR: standardized mortality ratio; CI: confidence interval; ACC: adrenal cortical carcinoma
Statistical significance with P<0.05
Discussion
Previous studies have been performed to analyse the causes of death among patients with common cancers (e.g., pros- tate cancer [18], breast cancer [19], and kidney cancer). This SEER-based study is unique in that it was performed to anal- yse the causes of death and SMRs in patients with malig- nant adrenal tumours, rare and aggressive malignancies with poor prognoses, for the first time. Malignant adrenal tumours seem to be heterogeneous among different patho- logical types in terms of molecular characteristics, clinical manifestations, treatment strategies, and prognoses [20-23]. In our study, the most commonly diagnosed adrenal malig- nancies included ACC, malignant PCC, and NB. All these malignancies were rare and aggressive with unfavourable survival. Given the disparity of these adrenal malignan- cies, we separately analysed the risk of mortality due to all causes, secondary malignancies and noncancer diseases on the basis of pathological types compared with the risk of mortality in the general population. After all the available data were summarized, the median overall survival times for patients with ACC and malignant PCC were 21 months and 117 months, respectively, whereas the median overall survival for patients with NB was not reached during the follow-up period. In addition, we found that the 5-year over- all mortality rate of patients with malignant adrenal tumours was approximately 58.83% for ACC, 23.06% for NB, and 25.16% for PCC. From 2004~2020, the mortality rate among patients with malignant adrenal tumours who died from primary cancer, SMNs, or noncancer diseases substan- tially declined in the first 5 years after diagnosis. Similar to the observations for patients with other cancers, such as lung, pancreas and brain malignancies [24], patients with malignant adrenal tumour were most likely to die from orig- inal cancer during their follow-up period, accounting for 56.78%~87.69% of all deaths, whereas SMNs and noncan- cer diseases accounted for 28.83%~43.22% of all deaths.
Notably, compared with the general population, patients with malignant adrenal tumours were at increased risk of mortality due to secondary malignancies of the digestive system, including the stomach, liver, pancreas, retroperi- toneum; of the respiratory system, including the lung and bronchus; of the bones and joints; of soft tissue, including the heart; and of the urinary system, including the kidney and renal pelvis, among others (Table 5). Additionally, patients with different malignant adrenal tumours exhib- ited differences in terms of the mortality risk of secondary malignant tumours. In our study, death due to subsequent malignant tumours occurred in 12.18% of ACC patients, 7.21% of NB patients, and 13.56% of malignant PCC patients. Compared with patients with ACC or malignant PCC in any stage, those with NB had a significantly greater
risk of death from certain SMNs, including malignancies of the bones and joints; soft tissue, including the heart; malig- nancies of the female genital system, including the ovary, brain and peripheral nervous system; lymphoma, including non-Hodgkin lymphoma; and leukaemia, including lym- phocytic leukaemia; and myeloid and monocytic leukae- mia (Table 5). NB generally occurs in childhood, whereas ACC or malignant PCC typically affects adults. Moreover, NB patients have more time to develop SMNs and receive multimodal therapy (e.g., chemotherapy and radiotherapy) more frequently, resulting in increased risk of mortality due to SMNs. (see Supplementary Table 2). Additionally, in this study, the mean intervals from the diagnosis of ACC, malig- nant PCC, and NB to SMN diagnosis were 61.53 months, 44.68 months, and 71.69 months, respectively. As such, patients with malignant adrenal tumours, especially patients with NB, are likely to benefit from screening or early detec- tion of second malignancies during the first five years after diagnosis.
Secondary malignancies may be attributable to radio- therapy treatment after cancer diagnosis. According to previously published investigations from the Child Cancer Survivor Study, radiotherapy-related SMN risk has been identified among patients with many malignancies, includ- ing cancers of the breast, skin, sarcoma and thyroid gland [25]. Similarly, Ng et al. [26] described the risk of subse- quent breast cancer after radiotherapy for Hodgkin lym- phoma. For NB patients, particularly high-risk patients, radiotherapy is one of the standard treatments, and various adverse effects, including the development of subsequent malignant tumours, have been observed in long-term NB survivors who receive radiotherapy treatment [27]. Previ- ous studies reported similar findings. A retrospective cohort study of 954 NB patients reported a significantly increased risk of secondary renal carcinoma compared with that in the general population (SIR: 85.8) [28]. They noted that such results might be related to the use of abdominal radiotherapy or chemotherapy among cancer survivors [29]. Addition- ally, another study indicated that radiotherapy was linked to a dose-dependent increase in the risk of secondary thyroid cancer among 9170 cancer survivors, including NB patients [30]. In addition, a study was performed to analyse the late side effects of radiotherapy for localized NB and eventually revealed that patients who received radiotherapy were more likely to develop secondary cancers [27]. In another study conducted by Rubino et al. [31], a total of 544 NB patients with 5-year survival were included. Although no significant difference was identified in subsequent multivariate analy- sis, radiotherapy treatment was potentially correlated with an elevated risk of any SMNs. In our study, as information on radiotherapy treatment was missing for most patients, subset analysis on radiotherapy was not performed. More
| Causes of death | Neuroblastoma | Localized | Regional | Distant | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | |
| All causes of death | 333 | 4.68 | 71.05#(63.63-79.11) | 7 | 1.03 | 6.76#(2.72-13.93) | 20 | 0.76 | 26.32#(16.08-40.65) | 306 | 2.91 | 105.83#(94.31-118.38) |
| All malignant cancers | 316 | 0.28 | 1,148.94# | 4 | 0.14 | 29.16# (7.95-74.66) | 17 | 0.04 | 475.61# (277.06-761.49) | 288 | 0.1 | 2,928.53# |
| (1025.74-1282.86) | (2600.04-3287.03) | |||||||||||
| Endocrine system | 292 | 0.02 | 16,631.12# (14778.07-18652.26) | 3 | 0 | 755.65#(155.83- 2208.34) | 13 | 0 | 4,689.81#(2497.13- 8019.72) | 270 | 0.01 | 25,719.06#(22742.49- 28976.95) |
| Adrenal gland | 292 | 0.02 | 17,039.35# (15140.81-19110.1) | 3 | 0 | 828.74#(170.91- 2421.94) | 13 | 0 | 4,743.74#(2525.84 8111.94) | 270 | 0.01 | 25,807.71#(22820.88- 29076.83) |
| Bones and joints | 1 | 0.01 | 107.48#(2.72-598.85) | 0 | 0 | 0(0-1876.69) | 0 | 0 | 0(0-2202.96) | 1 | 0.01 | 185.67#(4.7-1034.47) |
| Soft tissue including heart | 2 | 0.01 | 160.07#(19.39-578.24) | 1 | 0 | 315.72#(7.99-1759.07) | 0 | 0 | 0(0-1782.34) | 1 | 0.01 | 143.30#(3.63-798.4) |
| Brain and other nervous system | 2 | 0.05 | 36.76#(4.45-132.78) | 0 | 0 | 0(0-1876.69) | 1 | 0.01 | 115.58#(2.93-643.96) | 1 | 0.03 | 31.91(0.81-177.79) |
| Leukemia | 2 | 0.05 | 44.43#(5.38-160.51) | 0 | 0.01 | 0(0-316.64) | 0 | 0.01 | 0(0-518.35) | 2 | 0.03 | 79.11#(9.58-285.79) |
| Lymphocytic leukemia | 1 | 0.02 | 53.88#(1.36-300.21) | 0 | 0 | 0(0-873.94) | 0 | 0 | 0(0-1208.02) | 1 | 0.01 | 92.07#(2.33-512.99) |
| Myeloid and monocytic leukemia | 1 | 0.02 | 55.26#(1.4-307.9) | 0 | 0.01 | 0(0-697.25) | 0 | 0 | 0(0-1346.8) | 1 | 0.01 | 102.98#(2.61-573.78) |
| Lymphoma | 1 | 0.01 | 122.01#(3.09-679.77) | 0 | 0 | 0(0-897.16) | 0 | 0 | 0(0-3666.66) | 1 | 0 | 342.52#(8.67-1908.43) |
| Non-hodgkin lymphoma | 1 | 0.01 | 133.47#(3.38-743.67) | 0 | 0 | 0(0-966.42) | 0 | 0 | 0(0-4163.73) | 1 | 0 | 376.01#(9.52-2095.01) |
| Female genital system | 1 | 0.01 | 80.94#(2.05-450.94) | 0 | 0.01 | 0(0-352.67) | 1 | 0 | 723.78#(18.32-4032.65) | 0 | 0 | 0(0-7399.42) |
| Ovary | 1 | 0.01 | 159.21#(4.03-887.07) | 0 | 0.01 | 0(0-697.51) | 1 | 0 | 1,454.96#(36.84-8106.5) | 0 | 0 | 0(0-12587.3) |
| Non-tumor cause | ||||||||||||
| Septicemia | 3 | 0.05 | 62.31#(12.85-182.1) | 1 | 0.01 | 66.98#(1.7-373.19) | 0 | 0.01 | 0(0-546.35) | 2 | 0.03 | 77.77#(9.42-280.93) |
| Accidents and adverse effects | 3 | 0.65 | 4.59(0.95-13.41) | 2 | 0.16 | 12.54#(1.52-45.32) | 0 | 0.11 | 0(0-34.91) | 1 | 0.37 | 2.71(0.07-15.12) |
| Diseases of heart | 2 | 0.16 | 12.49#(1.51-45.11) | 0 | 0.08 | 0(0-43.52) | 0 | 0.02 | 0(0-209.01) | 2 | 0.06 | 35.95#(4.35-129.88) |
| Pneumonia and influenza | 1 | 0.06 | 16.98(0.43-94.58) | 0 | 0.02 | 0(0-217.05) | 0 | 0.01 | 0(0-435.89) | 0 | 0.03 | 0(0-113.65) |
| Congenital anomalies | 1 | 0.76 | 1.31(0.03-7.31) | 1 | 0.17 | 5.81(0.15-32.34) | 0 | 0.12 | 0(0-31.7) | 0 | 0.46 | 0(0-8.02) |
Abbreviations: SMR: standardized mortality ratio; CI: confidence interval #Statistical significance with P<0.05
well-designed studies are warranted to determine the rela- tionship between radiation treatment and the occurrence of SMNs among patients with malignant adrenal tumours.
Some studies indicate that chemotherapy can increase the risk of the occurrence of and death due to SMNs in patients with several cancer types [32, 33]. However, there is no evidence that chemotherapy leads to the development of SMNs among adrenal cancer survivors. In our study, compared with survivors without chemotherapy treatment, those receiving chemotherapy presented an increased risk of mortality from cancers of the colon, excluding the rectum, lung and bronchus, bones and joints; soft tissues, including the heart, kidney and renal pelvis; the brain and peripheral nervous system; and of leukaemia but a decreased risk of death from cancers of the pancreas and retroperitoneum. Taken together, these results indicated that chemotherapy significantly increased the risk of death from SMNs (Sup- plementary Table 1). Notably, compared with the general population, three patients with adrenal malignancies who did not receive chemotherapy had an increased risk of mor- tality from SMNs, which suggested that other factors may also contribute to the increased risk of subsequent malig- nant tumours. Previous studies have suggested that the risk for the development of subsequent neoplasms might be modified by genetic predispositions among childhood cancer survivors [34]. As reviewed previously [35], stud- ies have revealed that genetic variants associated with DNA damage detection and repair might be underlying modifiers for management-correlated SMN risk. More recent studies involving NB survivors yielded similar results [36]. In some cancer predisposition syndromes, subsequent malignant tumours were frequently identified in patients with adrenal cancer as the primary tumour [37, 38]. Among ACC cases, 2-4% [39] are related to Li-Fraumeni syndrome (LFS), which is a typical hereditary syndrome composed of mul- tiple primary cancers, such as soft tissue sarcomas, brain tumours, ACC, and osteosarcoma. Additionally, approxi- mately 30% of pheochromocytoma cases are related to various inherited conditions, including Von Hippel-Lindau (VHL) disease, MEN2, and neurofibromatosis type 1 [7]. In addition, there is an increased risk of SMN morbidity in patients with familial neuroblastoma, which is related to multiple germline variations [37]. Notably, an ongoing study is attempting to further evaluate the relationships between treatment and genetic factors in NB patients with respect to the development of SMNs (ClinicalTrials.gov Identifier: NCT03057626).
In terms of nontumor diseases, the mean intervals from the diagnosis of ACC, malignant PCC, and NB to the occur- rence of noncancer death were 35.64 months, 50.27 months, and 31.80 months, respectively. Compared with the general population, among patients with malignant adrenal tumours,
those with malignant pheochromocytoma had increased risks of death due to septicemia; those with neuroblastoma had elevated risks of death due to heart disease and septice- mia; and those with ACC had increased risks of death due to heart disease, septicemia, cerebrovascular disease, and other infectious and parasitic diseases, including HIV (Table 5). In addition, nontumour causes accounted for only 11.01%, 5.11%, and 29.66% of all deaths in patients diagnosed with ACC, neuroblastoma, and malignant pheochromocytoma, respectively. Previous studies have indicated that noncan- cer diseases are important and even leading causes of death among patients with various malignancies, including pros- tate cancer, breast cancer, testicular cancer, and laryngeal cancer [18, 24, 40]. A study based on SEER data revealed that heart disease was the leading cause of non-cancer- related death among 28 individual cancers, especially those with prostate cancer, breast cancer, testicular cancer, endo- metrial cancer, laryngeal cancer and Hodgkin’s lymphoma, where it accounted for >40% of all deaths [24]. Addition- ally, a Korean group analysed noncancer causes of death among cancer survivors and reported that approximately 24% of deaths were from noncancer causes. The leading specific causes included cerebrovascular disease, diabetes mellitus, ischaemic heart disease, and suicide [40]. The increased risk of death due to noncancer diseases may be related to the cancer itself and related management (e.g., surgery, chemotherapy, or radiation). In this study, patients who received chemotherapy were more likely to die of heart disease, septicemia, and other infectious and parasitic diseases, including HIV, than were the overall population or those without chemotherapy treatment (Supplementary Table 1). These results concur with the findings of a prior SEER-based analysis that noted an increased risk of non- neoplastic diseases among testicular patients after chemo- therapy [41]. Danai et al. [42] reported that approximately 30% of all deaths in cancer patients were related to sepsis. Another study demonstrated that the mortality of patients with cancer-related sepsis was 2.5-fold greater than that of patients with noncancer-related sepsis [43].
This study first characterized the causes of death among individuals with ACC, NB, and malignant PCC according to their tumour stage and treatment. However, several draw- backs in this study should be recognized. First, we utilized the SEER Summary Stage 2000 to distinguish localized, regional and distant diseases, but these categories might not have the same definitions in subsequent periods. Hence, our results cannot fully represent the present staging profiles. Second, due to missing data regarding treatments, potential bias may affect the overall results. Moreover, death due to primary malignant adrenal tumours might be miscoded. One possible explanation is that tumour relapse was considered a new second cancer or metastasis to the adjuvant organ [16,
| Causes of death | Pheochromocytoma | Localized | Regional | Distant | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. | Observed | No. Expected | SMR(95%CI) | ||
| All causes of | 118 | 24.18 | 4.88#(4.04-5.84) | 29 | 15.25 | 1.90#(1.27-2.73) | 19 | 5.08 | 3.74#(2.25-5.84) | 70 | 3.85 | 18.17#(14.17-22.96) | ||
| death | ||||||||||||||
| All malig- | 83 | 5.97 | 13.90#(11.07- | 19 | 3.67 | 5.17#(3.11-8.07) | 14 | 1.36 | 10.27#(5.62-17.24) | 50 | 0.93 | 53.58#(39.77-70.64) | ||
| nant cancers | 17.23) | |||||||||||||
| Endocrine | 68 | 0.03 | 2,371.99#(1841.94 | 13 | 0.02 | 703.18#(374.42- | 12 | 0.01 | 2,014.89#(1041.13- | 43 | 0 | 10,177.65#(7365.62- | ||
| system | 3007.06) | 1202.46) | 3519.61) | 13709.23) | ||||||||||
| Adrenal | 67 | 0.01 | 7,859.47#(6090.98- | 12 | 0.01 | 2,245.94#(1160.51- | 12 | 0 | 6,391.78#(3302.73- | 43 | 0 | 32,966.22#(23857.81- | ||
| gland | 9981.25) | 3923.21) | 11165.16) | 44405.28) | ||||||||||
| Digestive | 2 | 1.58 | 1.27(0.15-4.58) | 1 | 0.97 | 1.03(0.03-5.75) | 0 | 0.37 | 0(0-10.06) | 1 | 0.24 | 4.12(0.1-22.96) | ||
| system | ||||||||||||||
| Stomach | 0 | 0.12 | 0(0-31.44) | 0 | 0.07 | 0(0-49.95) | 0 | 0.03 | 0(0-145.7) | 0 | 0.02 | 0(0-203.2) | ||
| Colon | 0 | 0.41 | 0(0-8.96) | 0 | 0.26 | 0(0-14.33) | 0 | 0.09 | 0(0-40.74) | 0 | 0.06 | 0(0-57.86) | ||
| excluding | ||||||||||||||
| rectum | ||||||||||||||
| Liver | 1 | 0.2 | 4.95(0.13-27.56) | 1 | 0.12 | 8.47(0.21-47.18) | 0 | 0.05 | 0(0-71) | 0 | 0.03 | 0(0-114.83) | ||
| Pancreas | 1 | 0.44 | 2.29(0.06-12.76) | 0 | 0.27 | 0(0-13.6) | 0 | 0.1 | 0(0-36.59) | 1 | 0.06 | 15.5(0.39-86.36) | ||
| Respiratory | 4 | 1.64 | 2.43(0.66-6.23) | 1 | 0.99 | 1.01(0.03-5.64) | 1 | 0.4 | 2.5(0.06-13.92) | 2 | 0.25 | 7.87(0.95-28.42) | ||
| system | ||||||||||||||
| Lung and | 4 | 1.59 | 2.51(0.68-6.43) | 1 | 0.96 | 1.04(0.03-5.8) | 1 | 0.39 | 2.59(0.07-14.41) | 2 | 0.25 | 8.14(0.99-29.39) | ||
| bronchus | ||||||||||||||
| Urinary | 0 | 0.29 | 0(0-12.85) | 0 | 0.17 | 0(0-21.92) | 0 | 0.07 | 0(0-53.95) | 0 | 0.05 | 0(0-73.03) | ||
| system | ||||||||||||||
| Kidney and | 0 | 0.14 | 0(0-27.21) | 0 | 0.08 | 0(0-45.99) | 0 | 0.03 | 0(0-110.17) | 0 | 0.02 | 0(0-168.61) | ||
| renal pelvis | ||||||||||||||
| Non-tumor | ||||||||||||||
| cause | ||||||||||||||
| Diseases of | 4 | 5.55 | 0.72(0.2-1.84) | 1 | 3.49 | 0.29(0.01-1.6) | 1 | 1.15 | 0.87(0.02-4.86) | 2 | 0.92 | 2.18(0.26-7.89) | ||
| heart | ||||||||||||||
| Septicemia | 3 | 0.36 | 8.31#(1.71-24.27) | 1 | 0.23 | 4.42(0.11-24.61) | 1 | 0.08 | 12.77(0.32-71.17) | 1 | 0.06 | 17.68(0.45-98.49) | ||
| Other infec- | 1 | 0.27 | 3.68(0.09-20.5) | 0 | 0.16 | 0(0-23.31) | 0 | 0.06 | 0(0-57.11) | 1 | 0.05 | 20.00(0.58-101.23) | ||
| tious and | ||||||||||||||
parasitic
diseases
including HIV
| Causes of death | Pheochromocytoma | Localized | Regional | Distant | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | |
| Cerebro- vascular | 2 | 1.27 | 1.58(0.19-5.69) | 0 | 0.84 | 0(0-4.38) | 0 | 0.24 | 0(0-15.55) | 2 | 0.19 | 10.52(0.12-38.26) |
| diseases | ||||||||||||
| Nephritis, nephrotic syndrome and nephrosis | 0 | 0.46 | 0(0-7.95) | 0 | 0.29 | 0(0-12.57) | 0 | 0.1 | 0(0-38.48) | 0 | 0.19 | 0(0-33.26) |
Abbreviations: SMR: standardized mortality ratio; CI: confidence interval
Statistical significance with P<0.05
17], which might result in a misestimation of the mortal- ity rate of SMNs. Moreover, owing to the rarity of malig- nant adrenal tumours, some patient subpopulations had a small number of patients, limiting the generalizability of the results to their corresponding subgroups. Additionally, owing to the sparsity of SEER data, we cannot provide sub- classification information on causes of death by the specific disease type, hindering further monitoring and intervention for specific diseases.
Conclusion
In addition to malignant adrenal tumours, the leading causes of death in patients with these tumours include SMNs, including lung and bronchial cancer; soft tissue cancer, including heart cancer and kidney and renal pelvis can- cer; and nonneoplastic diseases, including heart disease, septicemia, and cerebrovascular disease. Compared with that of the general population, the risk of secondary can- cer-related death is greater among patients with malignant adrenal tumours, particularly patients with NB or those who received additional chemotherapy. Heart disease, septicae- mia, and cerebrovascular disease are important causes of non-cancer-related death.
| Causes of death | Total | ACC | Pheochromocytoma | Neuroblastoma | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | ||
| All causes of | 1,651 | 89.69 | 18.41*(17.53-19.32) | 854 | 43.43 | 19.66*(18.37-21.03) | 118 | 24.18 | 4.88*(4.04-5.84) | 333 | 4.68 | 71.05#(63.63- | |
| death | 79.11) | ||||||||||||
| All malignant cancers | 1,436 | 20.91 | 68.68*(65.18-72.33) | 760 | 10.74 | 70.75*(65.81-75.97) | 83 | 5.97 | 13.90*(11.07- 17.23) | 316 | 0.28 | 1,148.94# (1025.74 | |
| 1282.86) | |||||||||||||
| Endocrine | 1,177 | 0.12 | 10,083.63"(9515.72- | 657 | 0.05 | 12,804.79*(11844.26- | 68 | 0.03 | 2,371.99*(1841.94- | 29 292 | 0.02 | 16,631.12# | |
| system | 10676.59) | 13822.48) | 3007.06) | (14778.07- | |||||||||
| 18652.26) | |||||||||||||
| Adrenal gland | 1,175 | 0.05 | 24,278.10*(22909.6- | 656 | 0.02 | 40,191.37 (37174.21- | 67 | 0.01 | 7,859.47 (6090.98- | 292 | 0.02 | 17,039.35# | |
| 25706.99) | 43388.19) | 9981.25) | (15140.81- | ||||||||||
| 19110.1) | |||||||||||||
| Digestive system | 26 | 5.35 | 4.86*(3.18-7.13) | 13 | 2.75 | 4.73*(2.52-8.08) | 2 | 1.58 | 1.27(0.15-4.58) | 0 | 0.03 | 0(0-111.01) | |
| Stomach | 3 | 0.38 | 7.82*(1.61-22.85) | 2 | 0.19 | 10.27*(1.24-37.08) | 0 | 0.12 | 0(0-31.44) | 0 | 0 | 0(0-1804.09) | |
| Colon excluding | 4 | 1.42 | 2.81(0.76-7.19) | 2 | 0.74 | 2.71(0.33-9.81) | 0 | 0.41 | 0(0-8.96) | 0 | 0.01 | 0(0-467.28) | |
| rectum | |||||||||||||
| Liver | 6 | 0.65 | 9.23*(3.39-20.1) | 4 | 0.33 | 12.26*(3.34-31.4) | 1 | 0.2 | 4.95(0.13-27.56) | 0 | 0.01 | 0(0-514.62) | |
| Pancreas | 5 | 1.49 | 3.36*(1.09-7.84) | 3 | 0.77 | 3.9(0.8-11.39) | 1 | 0.44 | 2.29(0.06-12.76) | 0 | 0.01 | 0(0-428.97) | |
| Retroperitoneum | 3 | 0.01 | 315.49*(65.06-922) | 0 | 0 | 0(0-753.19) | 0 | 0 | 0(0-1385.82) | 0 | 0 | 0(0-17970.56) | |
| Respiratory | 33 | 5.69 | 5.80*(3.99-8.15) | 14 | 2.93 | 4.78*(2.61-8.03) | 4 | 1.64 | 2.43(0.66-6.23) | 0 | 0.04 | 0(0-104.92) | |
| system | |||||||||||||
| Lung and | 33 | 5.53 | 5.97*(4.11-8.38) | 14 | 2.85 | 4.92*(2.69-8.25) | 4 | 1.59 | 2.51(0.68-6.43) | 0 | 0.03 | 0(0-108.32) | |
| bronchus | |||||||||||||
| Bones and joints | 6 | 0.05 | 111.92"(41.07- | 2 | 0.02 | 88.99*(10.78-321.46) | 1 | 0.01 | 81.56*(2.06- | 1 | 0.01 | 107.48#(2.72- | |
| 243.59) | 454.42) | 598.85) | |||||||||||
| Soft tissue | 32 | 0.16 | 193.97*(132.68 | 1 | 0.08 | 12.42(0.31-69.22) | 1 | 0.04 | 22.92(0.58-127.69) | 2 | 0.01 | 160.07#(19.39- | |
| including heart | 273.83) | 578.24) | |||||||||||
| Breast | 3 | 1.67 | 1.8(0.37-5.25) | 3 | 0.94 | 3.2(0.66-9.36) | 0 | 0.44 | 0(0-8.35) | 0 | 0.02 | 0(0-243.8) | |
| Urinary system | 20 | 0.99 | 20.12*(12.29-31.08) | 9 | 0.49 | 18.23*(8.34-34.6) | 0 | 0.29 | 0(0-12.85) | 0 | 0.01 | 0(0-439.48) | |
| Kidney and renal | 18 | 0.47 | 38.16*(22.62-60.32) | 8 | 0.24 | 33.41*(14.42-65.83) | 0 | 0.14 | 0(0-27.21) | 0 | 0.01 | 0(0-541.62) | |
| pelvis | |||||||||||||
| Brain and other | 5 | 0.59 | 8.45*(2.74-19.72) | 1 | 0.29 | 3.46(0.09-19.28) | 0 | 0.15 | 0(0-24.79) | 2 | 0.05 | 36.76#(4.45- | |
| nervous system | 132.78) | ||||||||||||
| Leukemia | 3 | 0.79 | 3.78(0.78-11.04) | 1 | 0.38 | 2.63(0.07-14.68) | 0 | 0.21 | 0(0-17.26) | 2 | 0.05 | 44.43#(5.38- | |
| 160.51) | |||||||||||||
| Lymphocytic | 1 | 0.24 | 4.22(0.11-23.53) | 0 | 0.09 | 0(0-42.78) | 0 | 0.05 | 0(0-70.35) | 1 | 0.02 | 53.88#(1.36- | |
| leukemia | 300.21) | ||||||||||||
| Myeloid and | 1 | 0.49 | 2.05(0.05-11.44) | 0 | 0.19 | 0(0-19.48) | 0 | 0.12 | 0(0- 31.38) | 1 | 0.02 | 55.26#(1.4 | |
| monocytic | 307.9) | ||||||||||||
| leukemia | |||||||||||||
| Lymphoma | 1 | 0.87 | 1.15(0.03-6.42) | 0 | 0.34 | 0(0-10.8) | 0 | 0.21 | 0(0- 17.77) | 1 | 0.01 | 122.01#(3.09 | |
| 679.77) | |||||||||||||
| Causes of death | Total | ACC | Pheochromocytoma | Neuroblastoma | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. Observed | No. Expected | SMR(95%CI) | No. | Observed | No. Expected | SMR(95%CI) | ||
| Non-hodgkin | 1 | 0.83 | 1.21(0.03-6.75) | 0 | 0.32 | 0(0-11.35) | 0 | 0.2 | 0(0- 18.66) | 1 | 0.01 | 122.01#(3.09 | ||
| lymphoma | 679.77) | |||||||||||||
| Female genital | 2 | 1.46 | 1.37(0.17-4.96) | 1 | 0.65 | 1.54(0.04-8.59) | 0 | 0.35 | 0(0- 10.56) | 1 | 0.01 | 80.94#(2.05- | ||
| system | 450.94) | |||||||||||||
| Ovary | 2 | 0.7 | 2.84(0.34-10.25) | 1 | 0.31 | 3.25(0.08-18.13) | 0 | 0.16 | 0(0- 22.8) | 1 | 0.01 | 159.21#(4.03- | ||
| 887.07) | ||||||||||||||
| Non-tumor cause | ||||||||||||||
| Diseases of heart | 46 | 19.47 | 2.36*(1.73-3.15) | 27 | 9.74 | 2.77"(1.83-4.03) | 4 | 5.55 | 0.72(0.2-1.84) | 2 | 0.16 | 12.49#(1.51- | ||
| 45.11) | ||||||||||||||
| Septicemia | 16 | 1.29 | 12.40*(7.09-20.14) | 5 | 0.64 | 7.81*(2.54-18.23) | 3 | 0.36 | 8.31*(1.71-24.27) | 3 | 0.05 | 62.31#(12.85- | ||
| 182.1) | ||||||||||||||
| Other infectious | 8 | 0.92 | 8.70*(3.75-17.14) | 3 | 0.45 | 6.72*(1.39-19.65) | 1 | 0.27 | 3.68(0.09-20.5) | 0 | 0.05 | 0(0-72.78) | ||
| and parasitic diseases includ- ing HIV | ||||||||||||||
| Diabetes mellitus | 4 | 2.72 | 1.47(0.4-3.76) | 2 | 1.38 | 1.44(0.17-5.22) | 1 | 0.82 | 1.22(0.03-6.8) | 0 | 0.02 | 0(0-198.1) | ||
| Cerebrovascular | 11 | 4.42 | 2.49*(1.24-4.45) | 8 | 2.2 | 3.63*(1.57-7.16) | 2 | 1.27 | 1.58(0.19-5.69) | 0 | 0.05 | 0(0-77.76) | ||
| diseases | ||||||||||||||
| Pneumonia and | 3 | 1.73 | 1.74(0.36-5.07) | 2 | 0.84 | 2.39(0.29-8.62) | 0 | 0.48 | 0(0-7.74) | 1 | 0.06 | 16.98(0.43- | ||
| influenza | 94.58) | |||||||||||||
| Chronic obstruc- | 6 | 5.17 | 1.16(0.43-2.52) | 2 | 2.63 | 0.76(0.09-2.74) | 2 | 1.42 | 1.41(0.17-5.08) | 0 | 0.05 | 0(0-72) | ||
| tive pulmonary | ||||||||||||||
| disease and | ||||||||||||||
| allied cond | ||||||||||||||
| Chronic liver | 2 | 1.3 | 1.54(0.19-5.55) | 2 | 0.72 | 2.78(0.34-10.05) | 0 | 0.37 | 0(0-9.99) | 0 | 0.01 | 0(0-376.8) | ||
| disease and cirrhosis | ||||||||||||||
| Nephritis, | 5 | 1.58 | 3.16*(1.03-7.38) | 3 | 0.78 | 3.85(0.79-11.24) | 0 | 0.46 | 0(0-7.95) | 0 | 0.02 | 0(0-161.02) | ||
| nephrotic | ||||||||||||||
| syndrome and nephrosis | ||||||||||||||
| Accidents and | 6 | 4.27 | 1.41(0.52-3.06) | 1 | 1.93 | 0.52(0.01-2.89) | 1 | 1.02 | 0.98(0.02-5.47) | 3 | 0.65 | 4.59(0.95- | ||
| adverse effects | 13.41) | |||||||||||||
| Suicide and self- inflicted injury | 4 | 1.07 | 3.74*(1.02-9.57) | 2 | 0.54 | 3.72(0.45-13.44) | 1 | 0.27 | 3.76(0.1-20.96) | 0 | 0.1 | 0(0-36.9) | ||
Abbreviations: SMR: standardized mortality ratio; CI: confidence interval #Statistical significance with P<0.05
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s40618-0 25-02555-y.
Acknowledgements This study was supervised by Dr Pan Song of the Department of Urology, Institute of Urology, West China Hospital of Sichuan University.
Funding This study is supported by 2022YFS0135, 2023YFS0173 and SCR2023-210.
Data availability The data of this study are available in the SEER.The original data has been uploaded as the Supplementary materials.
Declarations
Conflict of interest The authors declare that there is no conflict of in- terest regarding the publication of this paper.
Ethical approval All data were obtained from the public database; no ethical approval was required.
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