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The Who, When, and Why of Primary Adrenal Malignancies: Insights Into the Epidemiology of a Rare Clinical Entity
Thenappan Chandrasekar, MD ID 1,2; Hanan Goldberg, MD (D 1; Zachary Klaassen, MD ID 1; Christopher J. D. Wallis, MD1; Dixon T. S. Woon, MD1; Jaime O. Herrera-Caceres, MD1; Girish S. Kulkarni, MD1; and Neil E. Fleshner, MD1
BACKGROUND: Primary malignancies of the adrenal glands are rare. Epidemiologic assessment of primary adrenal malignancies is lacking and has been limited to case reports and series. Population-level data can provide a better understanding of the incidence, distribution, and prognostic factors associated with these rare malignancies. METHODS: The Surveillance, Epidemiology, and End Results database (1973-2013) was queried for all patients who were diagnosed with primary adrenal malignancies, categorized in 5 histologic groups: adrenocortical carcinoma (ACC), pheochromocytoma and paraganglioma (PH), neuroblastoma (NE), non-Hodgkin lymphoma (NHL), and sarcoma (SA). Age-adjusted incidence, distribution trends, and cancer-specific survival (CSS) for each group were analyzed. RESULTS: In total, 4695 patients with primary adrenal malignancies were identified, including 2057 with ACC, 512 with PH, 1863 with NE, 202 with NHL, and 61 with SA. The age-adjusted incidence of all 5 histologic subtypes was rising. Age at presentation differed substantially by histologic group: NE was the most prevalent during the first decade of life, whereas ACC predominated after age 30 years, and NHL outnumbered PH after age 70 years. Patient-specific factors were not associated with advanced disease at the time of presentation. The 5-year CSS rate for each histologic subtype was 38% for ACC, 69% for PH, 64% for NE, 38% for NHL, and 42% for SA. Survival outcomes for patients with ACC, NHL, PH and SA remained unchanged over the 40-year study period. Multimodal therapy was associated with higher CSS in patients with NE. CONCLUSIONS: This first population- level analysis of all primary adrenal malignancies provides important initial data regarding presentation and clinical outcomes. Notably, except for patients with NE, the survival of patients with these rare cancers has not improved over the past 40 years. Cancer 2018;0:1-10. @ 2018 American Cancer Society.
KEYWORDS: adrenal cancer, neuroblastoma, outcomes, pheochromocytoma, survival.
INTRODUCTION
Adrenal incidentalomas (AIs), which are asymptomatic masses measuring >1 cm, are increasingly identified on cross-sectional imaging, with recent reports indicating rates as high as 4% to 5%.2 However, malignant tumors of the adrenal gland are most commonly metastases from extra-adrenal primary tumors. In patients with known cancer, from 50% to 75% of adrenal masses may represent metastatic disease.1,2
The conundrum for patients and physicians lies in the setting of primary adrenal malignancies. Because from 5% to 10% of incidentalomas are true malignancies,3,4 functional and radiographic assessment can help further stratify patients according to risk. Because primary adrenal malignancies are rare, what little is known is derived from cases se- ries and case reports. Although each of the malignancies has been explored in isolation,5-13 to our knowledge, there have been no prior studies examining the epidemiology of all primary adrenal malignancies together.
The 5 primary adrenal malignancies examined are adrenocortical carcinoma (ACC), pheochromocytomas and paraganglioma (PH), neuroblastoma (NE), non-Hodgkin lymphoma (NHL), and sarcoma (SA). By using a large, estab- lished, national database-the Surveillance, Epidemiology, and End Results (SEER) database-a better understanding of the epidemiology of these 5 histologies, both in isolation and in relation to 1 another, can be established. This novel information is critical for the primary care physician, the oncologist, and the patient to understand the presentation and prognosis of these rare entities.
MATERIALS AND METHODS
Study Population
The SEER database reports cancer-specific outcomes from geographic areas representing 28% of the US population.14 We first identified patients who had a primary adrenal malignancy diagnosed between 1973 and 2013; subsequently,
Corresponding author: Thenappan Chandrasekar, MD, Department of Urology, Thomas Jefferson University, 1025 Walnut Street, Suite 1100, Philadelphia PA 19107; thenappan.chandrasekar@gmail.com
1Department of Surgical Oncology, Division of Urology, University Health Network, University of Toronto, Toronto, Ontario, Canada; 2 Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Additional supporting information may be found in the online version of this article.
DOI: 10.1002/cncr.31916, Received: July 9, 2018; Revised: September 24, 2018; Accepted: October 19, 2018, Published online Month 00, 2018 in Wiley Online Library (wileyonlinelibrary.com)
we limited the analysis to patients who had 11 spe- cific histology codes (representing 84% of the total co- hort) (Supporting Table 1) grouped into 5 previously established histologic entities (ACC, PH, NE, NHL, and SA).15 Excluded histologies (“not otherwise speci- fied” or representing <1% of the cohort) are detailed in Supporting Table 2.
Description of Covariates
The demographic variables of interest included age at diagnosis, sex, race, insurance status, marital status, and region based on SEER registry. On the basis of previous literature,16,17 a county-level socioeconomic status measure was created. The clinical variables included disease laterality; treatment with surgery, chemotherapy, or radiation; SEER historic stage and Ann Arbor lymphoma stage; cancer-specific survival (CSS) and overall survival (OS). SEER historic stage was defined as distant, regional, or localized based on established definitions.18
Statistical Analysis
Descriptive statistics for demographic and socioeconomic variable comparisons were performed using the Student t test (continuous variables) and the chi-square test (categorical variables). Temporal trends in incidence- stratified by histology, age at diagnosis, and era of di- agnosis-were assessed. The study period was divided into four 10-year eras for temporal analysis. Age-adjusted incidence rates were calculated per million individuals and were age-adjusted to the 2000 US standard popu- lation. Kaplan-Meier survival curves were generated to evaluate CSS and OS. Multivariable logistic regression analyses were performed to generate odds ratios for the identification of factors associated with advanced dis- ease at diagnosis. Fine and Gray competing-risks pro- portional regression modeling, censoring for noncancer mortality, was performed to generate hazards ratios (HRs) to identify predictors of cancer-specific mortality (CSM); SA was excluded because of a limited number of events. Given the sample size and the appropriate num- ber of events, our variable selection was exploratory in nature, including all variables in the regression models. All statistical tests were 2-tailed, and P values < . 05 were considered statistically significant. Statistical tests were performed using the R statistical package (R Foundation for Statistical Computing, Vienna, Austria) and SAS (version 9.4; SAS Institute, Cary, NC).
RESULTS
Patient Demographics
Of an initial 5586 patients who were diagnosed with a primary adrenal malignancy between 1973 and 2013, 4695 had 1 of the 11 predominant histologic subtypes. Of these, 43.8% (n = 2057) had ACC, 39.7% (n = 1863) had NE, 10.9% (n = 512) had PH, 4.3% (n = 202) had NHL, and 1.3% (n = 61) had SA. Table 1 delin- eates the key demographic features of each of the co- horts. The median follow-up for the entire cohort was 28 months (interquartile range, 8-87 months). The man age of patients with NE was 2.9 years, consistent with the natural history of the disease. Patients with ACC and PH tended be younger (mean age 53.1 and 51.5 years, respectively) than those with NHL and SA (mean age, 70.2 and 64.9 years, respectively). NHL was more com- mon in men (64.4%) and patients often presented with bilateral disease (33.2%); there was no difference in inci- dence based on sex or laterality for all the other groups. Surgery was the primary mode of treatment for ACC, PH, and SA (71%-77%), although multimodality ther- apy was not uncommon. Patients with NHL primarily received chemotherapy (70.3%), whereas approximately 70% of patients with NE received both chemotherapy and surgery. Patients who had NE predominantly pre- sented with distant disease (67.1%), whereas those who had ACC, PH, and SA more often presented with local- ized or regional disease.
Incidence of Primary Adrenal Malignancies
The incidence of each histologic subtype varied with patient age. Figure 1 illustrates the incidence of each histologic category stratified by age of diagnosis. Figure 1A depicts the absolute incidence rates over 40 years, and Figure 1B depicts the proportional inci- dence. Although NE predominates the absolute and proportional incidence in the first decade of life, ACC becomes predominant by the third decade of life. In the interim, second decade (ages 10-19 years), there is a tran- sition between these 2 dominant histologic subtypes. PH retains its status as the predominant secondary histology after ACC until age 70 years, at which point NHL inci- dence exceeds PH incidence.
Figure 2 illustrates the age-adjusted incidence rates of all primary adrenal malignancies and all histo- logic subtypes by era of diagnosis. The total incidence and the incidence of all subtypes increased steadily with each era, with a proportionally greater incidence of ACC and NE.
| Characteristic | No. of Patients (%) | ||||
|---|---|---|---|---|---|
| Adrenocortical Carcinoma | Pheochromocytoma and Paraganglioma | Neuroblastoma | Non-Hodgkin Lymphoma | Sarcoma | |
| Total no. | 2057 | 512 | 1863 | 202 | 61 |
| Age: Mean ± SD, y | 53.08 ± 18.74 | 51.55 ± 17.46 | 2.90 ± 6.46 | 70.23 ± 12.45 | 64.93 ± 13.02 |
| Male | 886 (43.1) | 252 (49.2) | 1034 (55.5) | 130 (64.4) | 33 (54.1) |
| Laterality | |||||
| Bilateral | 27 (1.3) | 7 (1.4) | 33 (1.8) | 67 (33.2) | 3 (4.9) |
| Right | 1061 (51.6) | 223 (43.6) | 960 (51.5) | 77 (38.1) | 29 (47.5) |
| Left | 870 (42.3) | 230 (44.9) | 795 (42.7) | 53 (26.2) | 29 (47.5) |
| Region | |||||
| Southeast | 246 (12.0) | 61 (11.9) | 276 (14.8) | 26 (12.9) | 8 (13.1) |
| Midwest | 410 (19.9) | 97 (18.9) | 345 (18.5) | 42 (20.8) | 11 (18.0) |
| West | 1097 (53.3) | 261 (51.0) | 982 (52.7) | 104 (51.5) | 31 (50.8) |
| Northeast | 304 (14.8) | 93 (18.2) | 260 (14.0) | 30 (14.9) | 11 (18.0) |
| Race | |||||
| Hispanic | 207 (10.1) | 56 (10.9) | 327 (17.6) | 14 (6.9) | 5 (8.2) |
| American Indian/Alaskan | 10 (0.5) | 2 (0.4) | 9 (0.5) | 1 (0.5) | 2 (3.3) |
| Asian/Pacific Islander | 122 (5.9) | 41 (8.0) | 153 (8.2) | 23 (11.4) | 2 (3.3) |
| Black | 146 (7.1) | 80 (15.6) | 240 (12.9) | 4 (2.0) | 11 (18.0) |
| Other | 6 (0.3) | 3 (0.6) | 10 (0.5) | 0 (0.0) | 0 (0.0) |
| White | 1566 (76.1) | 330 (64.5) | 1124 (60.3) | 160 (79.2) | 41 (67.2) |
| Insurance | |||||
| Medicaid | 95 (14.0) | 21 (11.7) | 236 (37.6) | 15 (14.2) | 3 (11.5) |
| Uninsured | 35 (5.2) | 15 (8.4) | 8 (1.3) | 1 (0.9) | 1 (3.8) |
| Insured | 548 (80.8) | 143 (79.9) | 384 (61.1) | 90 (84.9) | 22 (84.6) |
| Marital status | |||||
| Single | 440 (22.0) | 123 (25.6) | 1848 (99.4) | 24 (12.6) | 10 (17.2) |
| Divorced/separated | 179 (9.0) | 39 (8.1) | 1 (0.1) | 15 (7.9) | 8 (13.8) |
| Widowed | 190 (9.5) | 39 (8.1) | 3 (0.2) | 21 (11.0) | 9 (15.5) |
| Married | 1188 (59.5) | 280 (58.2) | 8 (0.4) | 131 (68.6) | 31 (53.4) |
| Socioeconomic status | |||||
| First quartile, highest | 464 (22.6) | 111 (21.7) | 432 (23.2) | 45 (22.3) | 15 (24.6) |
| Second quartile | 292 (14.2) | 65 (12.7) | 308 (16.5) | 28 (13.9) | 3 (4.9) |
| Third quartile | 635 (30.9) | 163 (31.8) | 518 (27.8) | 74 (36.6) | 15 (24.6) |
| Fourth quartile, | 666 (32.4) | 173 (33.8) | 605 (32.5) | 55 (27.2) | 28 (45.9) |
| lowest | |||||
| Surgery | 1462 (71.1) | 381 (74.4) | 1328 (71.3) | 36 (17.8) | 47 (77) |
| Chemotherapy | 617 (30.0) | 45 (8.8) | 1354 (72.7) | 142 (70.3) | 13 (21.3) |
| Radiation | 168 (8.2) | 26 (5.1) | 453 (24.3) | 5 (2.5) | 9 (14.8) |
| SEER historic stage | |||||
| Distant | 751 (36.5) | 130 (25.4) | 1250 (67.1) | NA | 14 (23.0) |
| Regional | 976 (47.4) | 257 (50.2) | 354 (19.0) | NA | 38 (62.3) |
| Localized | 237 (11.5) | 69 (13.5) | 227 (12.2) | NA | 6 (9.8) |
| Lymphoma stage | |||||
| 1 | NA | NA | NA | 80 (39.6) | NA |
| 2 | NA | NA | NA | 41 (20.3) | NA |
| 3 | NA | NA | NA | 10 (5.0) | NA |
| 4 | NA | NA | NA | 57 (28.2) | NA |
Abbreviations: NA, not applicable; SD, standard deviation; SEER, Surveillance, Epidemiology, and End Results program.
Supporting Figure 1 stratifies the incidence of each histologic subtype by both era of diagnosis and stage of disease, specifically, SEER historic stage (ACC, PH, SA, NE) and Ann Arbor lymphoma stage (NHL). For ACC and PH, localized and regional disease represented most of the increased incidence over time, whereas there was less distant disease at the time of diagnosis in later eras. For NHL, NE, and SA, the relative proportion of distant disease (NE and SA) or stage 3 and 4 disease (NHL) did not change significantly over time.
Survival Outcomes
Figure 3 presents the 1-year, 5-year, and 10-year CSS and OS rates for each histologic subtype, stratified by era of diagnosis. Except for NE, which experiences steady im- provement in both CSS and OS, the CSS and OS rates for the other 4 histologic subtypes remains relatively un- changed over the treatment eras.
In a subset analysis of the most recently diagnosed patients (2004-2013), Figure 4 illustrates 10-year CSS outcomes stratified by histology (Fig. 4A) and
A
2000
1800
1600
Sarcoma
1400
Pheochromocytoma + Paraganglionoma
1200
Neuroblastoma
1000
Non-Hodgkins Lymphoma
800
Adrenocortical Carcinoma
600
400
200
0
Age 0-9
Age 10-19
Age 20-29
Age 30-39
Age 40-49
Age 50-59
Age 60-69
Age 70-79
Age 80+
B
100%
90%
Sarcoma
80%
Pheochromocytoma + Paraganglionoma
70%
Neuroblastoma
60%
50%
Non-Hodgkins Lymphoma
40%
Adrenocortical Carcinoma
30%
20%
10%
0%
Age 0-9
Age 10-19
Age 20-29
Age 30-39
Age 40-49
Age 50-59
Age 60-69
Age 70-79
Age 80+
then subsequently by histology and stage at diagnosis (Fig. 4B-F). Patients with PH and NE have the best survival outcomes in with most recent treatment, whereas those with ACC, NHL, and SA have signif- icant room for improvement. Although the survival of patients with ACC is driven by regional and dis- tant disease (Fig. 4B), in patients with NE, survival is driven primarily by distant disease alone (Fig. 4D), whereas patients with regional and localized disease have high 10-year CSS rates.
Predictors of Advanced Disease and CSM by Histology
Predictors of advanced disease at the time of diagnosis, defined as regional/distant SEER historic stage or Ann Arbor lymphoma stages 3 and 4, also were assessed (Supporting Table 3). For all histologic subtypes, age, region, race, insurance status, marital status, and socio- economic status were not associated with more advanced disease. For NHL, women were much less likely to pre- sent with advanced disease (odds ratio, 0.20; P = . 02),
8.0
7.40
7.0
Age-adjusted Incidence (per Million person-years)
Adrenocortical Carcinoma
6.0
-Pheochromocytoma +
5.0
5.03
Paraganglionoma
-Neuroblastoma
4.0
3.0
-Non-Hodgkins Lymphoma
2.57
2.0
Sarcoma
1.82
1.0
All Histologies
0.0
1974-1983
1984-1993
1994-2003
2004-2013
Era of Diagnosis
| Era | All Histologies | ACC | PH | NE | NHL | SA |
|---|---|---|---|---|---|---|
| 1974-1983 | 1.82 | 0.90 | 0.20 | 0.69 | 0.01 | 0.02 |
| 1984-1993 | 2.57 | 1.18 | 0.24 | 1.07 | 0.07 | 0.02 |
| 1994-2003 | 5.03 | 2.22 | 0.50 | 2.06 | 0.18 | 0.07 |
| 2004-2013 | 7.40 | 2.92 | 0.79 | 3.17 | 0.42 | 0.10 |
Figure 2. The age-adjusted incidence of primary adrenal malignancy is illustrated according to the era of diagnosis stratified by histology.
but there was no difference based on sex for any of the other histologic subtypes.
Finally, we evaluated the predictors of CSM for each histology, except SA (because of insufficient events) (Supporting Table 4), accounting for available demo- graphic characteristics, staging, and treatment regimen. Older age was associated with higher CSM in all patients. Patient-specific factors were not associated with higher CSM in patients with ACC and PH, but higher CSM was noted in patients with NE who received treatment in the Midwest (vs the Northeast; HR, 1.76; P < . 01) and in patients with NHL who were Hispanic (vs white; HR, 2.77; P = . 02) and on Medicaid (vs insured; HR, 2.62; P = . 02). Clinical stage was the strongest predictor of CSM. Patients with distant ACC, PH, and NE had much higher CSM than patients with localized disease; con- versely, regional disease was only associated with higher CSM in patients with ACC and NE. For ACC and NHL, the receipt of monotherapy and multimodal therapy were associated with lower CSM than not receiving any inter- vention; however, there was no significant difference be- tween monotherapy and multimodal therapy. In patients with NE, however, multimodal therapy was associated with a lower CSM, whereas monotherapy was not.
DISCUSSION
Primary adrenal malignancies remain rare entities that are encountered infrequently by oncologists and primary care physicians. However, before the current study, there was a dearth of literature on this disease. By using an established national cancer registry, the SEER database, the limitations of small cases series and institutional stud- ies can be overcome to provide a broader understanding of this disease process.
The incidence of primary adrenal malignancies, although still low, continues to grow steadily. And, as cross-sectional imaging has increasingly identified adre- nal incidentalomas, the incidence of these often asymp- tomatic primary malignancies also has steadily increased. The age-adjusted incidence of all primary malignancies and subtypes increased steadily with each era, with a proportionally greater incidence of ACC and NE, as il- lustrated in Figure 2. The incidence of ACC, PH, and NE over this 40-year timeframe is consistent with prior population-based analyses,13,19-24 but few have ever assessed the temporal change in age-adjusted incidence rates. Although the rising incidence is not surprising in itself, it highlights the importance of better understand- ing by primary care physicians of the disease process,
A
1-year CSS stratified by Histology and Era of Diagnosis
B 1-year OS stratified by Histology and Era of Diagnosis
100.00%
100.00%
90.00%
91%
90.00%
91%
80.00%
84%
80%
80.00%
81%
80%
70.00%
Adrenocortical Carcinoma
70.00%
Adrenocortical Carcinoma
60.00%
64%
61%
Pheochromocytoma & paraganglioma
60.00%
60%
Pheochromocytoma &
50.00%
Neuroblastoma
50.00%
56%
paraganglioma
Neuroblastoma
40.00%
Non-Hodgkin’s Lymphoma
40.00%
Non-Hodgkin’s Lymphoma
30.00%
Sarcoma
30.00%
Sarcoma
20.00%
20.00%
10.00%
10.00%
0.00%
0.00%
1974-1983
1984-1993
1994-2003
2004-2013
1974-1983
1984-1993
1994-2003
2004-2013
C 5-year CSS stratified by Histology and Era of Diagnosis
D 5-year OS stratified by Histology and Era of Diagnosis
100.00%
100.00%
90.00%
90.00%
80.00%
80.00%
70.00%
73%
Adrenocortical Carcinoma
69%
70.00%
71%
Adrenocortical Carcinoma
60.00%
Pheochromocytoma & paraganglioma
60.00%
64%
Pheochromocytoma & paraganglioma
50.00%
Neuroblastoma
50.00%
Neuroblastoma
40.00%
41%
35%
Non-Hodgkin’s Lymphoma
40.00%
Non-Hodgkin’s Lymphoma
30.00%
Sarcoma
30.00%
30%
Sarcoma
20.00%
20.00%
10.00%
10.00%
0.00%
0.00%
1974-1983
1984-1993
1994-2003
2004-2013
1974-1983
1984-1993
1994-2003
2004-2013
E 10-year CSS stratified by Histology and Era of Diagnosis
F 10-year OS stratified by Histology and Era of Diagnosis
100.00%
100.00%
90.00%
90.00%
80.00%
80.00%
70.00%
Adrenocortical Carcinoma
67%
70.00%
Adrenocortical Carcinoma
60.00%
59%
Pheochromocytoma &
60.00%
63%
Pheochromocytoma & paraganglioma
paraganglioma
50.00%
Neuroblastoma
50.00%
48%
Neuroblastoma
40.00%
Non-Hodgkin’s Lymphoma
40.00%
Non-Hodgkin’s Lymphoma
30.00%
28%
Sarcoma
30.00%
Sarcoma
20.00%
20.00%
21%
10.00%
10.00%
0.00%
0.00%
1974-1983
1984-1993
1994-2003
2004-2013
1974-1983
1984-1993
1994-2003
2004-2013
because they are more likely to identify and triage these newly identified tumors. In that context, although these primary adrenal malignancies represent a small propor- tion of incidentalomas, appropriate early evaluation is critical to early intervention.4,25,26 Diagnosis encompasses an evaluation of the functional status of the adrenal mass with appropriate blood and urine testing, as well as very specific radiographic testing. 25,27
Figure 1A,B further helps guide physicians in the diagnostic pathway, if a primary adrenal malignancy is suspected, by risk stratifying patients based on age at the time of diagnosis. NE predominates absolute and propor- tional incidence in the first decade of life, but ACC be- comes predominant by the third decade of life. Between ages 10 and 19 years, there is a transition from NE to ACC. The absolute incidence of ACC in our study does
A 10-year Cancer Specific Survival Stratified by Histology (2004-2013)
B Cancer-specific Survival 2004-2013, Stratified by SEER Historic Stage Adrenocortical Carcinoma
1.0-
Histology
Adrenocortical
Carcinoma
SEER
Pheochromocytoma &
1.0-
Historic Stage
Paraganglioma
Neuroblastoma
0.8-
Non-Hodgkin’s
Distant
Cumulative Survival
Lymphoma Sarcoma
Localized Regional
0.8-
Cumulative Survival
0.6
0.6-
0.4
0.4-
0.2-
0.2-
0.0
0.0
0
20
40
60
80
100
120
0
20
40
60
80
100
120
Survival months
Survival months
C Cancer-specific Survival 2004-2013, Stratified by SEER Historic Stage Pheochromocytoma & Paraganglioma
D Cancer-specific Survival 2004-2013, Stratified by SEER Historic Stage Neuroblastoma
1.0
SEER Historic Stage
1.0
SEER Historic Stage
Distant
Localized
Distant
0.8-
Regional
Localized
0.8-
Regional
Cumulative Survival
Cumulative Survival
0.6
0.6-
0.4-
0.4-
0.2
0.2-
0.0
0.0
0
20
40
60
80
100
120
0
20
40
60
80
100
120
Survival months
Survival months
E Cancer-Specific Survival 2004-2013 Stratified by Lymphoma Ann Arbor Stage Non-Hodgkins Lymphoma
F Cancer-specific Survival 2004-2013, Stratified by SEER Historic Stage Sarcoma
Lymphoma Stage
1.0
SEER Historic Stage
1.0
Distant
Stage 1
Localized
Stage 2
Missing
Stage 3
0.8-
0.8-
Stage 4
Cumulative Survival
Cumulative Survival
0.6-
0.6-
0.4-
0.4-
0.2-
0.2-
0.0
0.0-
0
20
40
60
80
100
120
0
20
40
60
80
Survival months
Survival months
contrast with traditional reports of a bimodal distribu- tion of ACC in the first and fourth decades of life, 28 although it is consistent with comparable international registries.29 In later life, PH is the second most common histologic subtype until age 70 years, at which point, NHL incidence exceeds PH incidence.
To gain a better understanding of the rising inci- dence of primary adrenal malignancies, Supporting Figure 1 stratified the incidence of each histologic sub- type by both era of diagnosis and stage of disease. For ACC and PH, increasing incidence of localized and regional disease drove the overall rising incidence over time, whereas the proportion of distant disease at the time of diagnosis in later eras diminished.11,29 For NHL, NE, and SA, the relative proportion of distant disease (NE and SA) or stage 3 and 4 disease (NHL) did not change significantly over time.15
From a counseling perspective, Figure 3 provides 1-year, 5-year. and 10-year CSS and OS rates stratified by era of diagnosis and highlights important trends in survival outcomes. It is important to note that, for the most part, there has been a significant lack of improve- ment in survival over the past 40 years. The greatest improvements have come in the treatment of NE, with 1-year and 10-year CSS rates now exceeding 90% and 65%, respectively. These are comparable to other in- ternational reports on NE outcomes.12 Unfortunately, there has been little improvement in the poor CSS out- comes for ACC, NHL, and SA. ACC, in particular, despite representing a large subset of primary adre- nal malignancies, has not experienced any significant change in survival outcomes3,7,11,29; the 1-year, 5-year, and 10-year CSS rates have remained relatively stable at 64%, 35%, and 28%, respectively. Patients with PH have had better survival outcomes over the entire study period, although there has been some incremental im- provement in CSS and OS. Figure 4, which specifically focuses on patients who were diagnosed between 2004 and 2013, highlights trends in the modern era. Patients with PH and NE have the best survival outcomes over a 10-year period, whereas those with ACC, NHL, and SA have significant room for improvement. Survival in ACC is driven by regional and distant disease (Fig. 4B), which highlights the importance of early diagno- sis in this disease process. For NE, however, survival is primarily driven by distant disease alone (Fig. 4D), whereas patients with regional and localized disease have high 10-year CSS rates.
In assessing this large series for predictors of ad- vanced disease at the time of diagnosis (Supporting
Table 3), we note that, for all histologic subtypes, age, region, race, insurance status, marital status, and socio- economic status were not associated with more advanced disease. These findings, although reassuring that there are no patient-level variables that predispose to more ad- vanced disease, highlight the importance of maintaining a high suspicion of malignancy in all patients who pres- ent with adrenal incidentalomas.
However, on competing-risks analysis assessing for cancer-specific mortality (Supporting Table 4), whereas certain patient-factors were associated with worse CSM, clinical stage, as expected, was the strongest predictor of CSM. Patients with distant ACC, PH, and NE had much higher CSM than those with localized disease; con- versely, regional disease was associated with higher CSM only in patients with ACC and NE. With regard to treat- ment, for patients with ACC and NHL, monotherapy and multimodal therapy were associated with lower CSM than not receiving any intervention; however, there was no significant difference between monotherapy or mul- timodal therapy. In patients with NE, conversely, multi- modal therapy was associated with a lower CSM, while monotherapy was not. Because there has been a drastic improvement in survival outcomes for patients with NE over the 40-year study period because of the introduction of multimodal therapy, improved multimodal therapy is desperately needed in the setting of ACC and PH, and surgical excision remains the mainstay of therapy for patients who have these 2 histologic subtypes.7,11,28,30
Like any large population-level analysis, the cur- rent study is limited in its lack of granularity regard- ing the disease itself and patient factors. Because of the rarity of the disease, the level of detail reported to the SEER registry is significantly less than that for other malignancies. The lack of detail regarding TNM staging, metastatic spread, tumor size, and diagnos- tic evaluation (imaging, functional testing) precludes any ability to further risk stratify patients within each histologic subtype. It is well established that specific imaging modality findings and functional tests are critical to the diagnosis and management of adrenal malignancies.4,31 In addition, no details regarding the treatment provided were available, specifically missing were data on chemotherapy regimens, radiotherapy tar- get and dose, and nature of the surgery. Chemotherapy, in particular, is a relatively new variable introduced into the SEER database; and, although prior compari- sons with SEER-Medicare data sets have demonstrated 65% to 80% sensitivity, but very high specificity,32 it should be noted that the receipt of chemotherapy
may be under-represented. Finally, as practice patterns changed over the timeframe of this study, we were unable to capture effectively any strong conclusions regarding treatment modalities. Despite the limita- tions of the current study, it does provide an import- ant epidemiologic assessment of the primary adrenal malignancy landscape and highlights areas of potential improvement.
CONCLUSION
Because of the rarity of primary adrenal malignancies, the current study, which is the first to our knowledge evaluating primary adrenal malignancies using popu- lation-level data, highlights important epidemiologic trends and outcomes that will be essential for patient counseling and an impetus for changing practice pat- terns. Notably, the survival of patients with these rare cancers has not improved over the past 40 years. Because of drastically worse outcomes for patients who present with advanced disease, it is critical that physicians main- tain a high suspicion of malignancy in all those who pre- sent with adrenal incidentalomas.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
AUTHOR CONTRIBUTIONS
Thenappan Chandrasekar: Conceptualization, data curation, formal analysis, writing-original draft, and writing-review and editing. Hanan Goldberg: Formal analysis and writing-review and editing. Zachary Klaassen: Formal analysis and writing-review and editing. Christopher J. D. Wallis: Formal analysis and writing-review and editing. Dixon T. S. Woon: Formal analysis and writing-review and editing. Jaime O. Herrera-Caceres: Formal analysis and writing-review and edit- ing. Girish S. Kulkarni: Resources and supervision. Neil E. Fleshner: Resources and supervision.
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