AACE
Endocrine Practice™
AACE. Endocrine Practice™
Original Article
Bowlenw Article
Original Article Incidence and Geographical Distribution of Adrenocortical Carcinoma: Retrospective Analysis of a State Cancer Registry
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Vania Balderrama-Brondani, MD, PhD 1, Allison M. Griffin, BSBA 2, Taylor J. Owen, BSGIS 2, Kelly W. Merriman, PhD 3, Brenda B. Chahla, MD 1, Jeena Varghese, MD 1, Camilo Jimenez, MD 1, Steven G. Waguespack, MD 1, Paul H. Graham, MD 4, Nancy D. Perrier, MD 4, Sarah B. Fisher, MD 4, Jose A. Karam, MD 5, 6, Amishi Y. Shah, MD 7, Matthew Campbell, MD, MS 7, Manal M. Hassan, MD, PhD 8, Mouhammed Amir Habra, MD 1, *
1 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
2 Department of Financial Planning & Analysis, The University of Texas MD Anderson Cancer Center, Houston, Texas
3 Department of Tumor Registry, The University of Texas MD Anderson Cancer Center, Houston, Texas
4 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
5 Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas
6 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
7 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
8 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
ARTICLE INFO
Article history: Received 30 July 2023 Received in revised form 11 October 2023 Accepted 13 October 2023 Available online 18 October 2023
Key words: adrenocortical carcinoma cancer incidence rare disease Texas heatmap
ABSTRACT
Objective: Adrenocortical carcinoma (ACC) is a rare malignancy without established association with environmental risk factors. ACC incidence is stable based on large surgical databases while referral centers data reported increasing number of cases seen. We studied ACC incidence and distribution at a county level to find potential ACC “hot spots” that could be linked to environmental exposures. Methods: A retrospective analysis of Texas Cancer Registry that included ACC patients diagnosed between 2000 and 2018. County-level heatmaps were created and compared with breast, prostate, and lung cancer.
Results: We identified 448 ACC cases during the study period. Cases were registered in 110 of the 254 counties (43.3%) in Texas, representing 92.74% of the total population. The median incidence was 23 new cases/y (range 14-33). The mean population-adjusted ACC incidence rate was 0.104 per 100 000 per year (standard deviation 0.005; 95% CI, 0.092-0.116). Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each and median standardized incidence ratio (SIR) of 0.1 (range, 0.0-0.9). One hundred three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county. The highest standardized incidence ratios were found in counties with a median population of fewer than 14 000 residents and with only one reported case. Conclusion: Our analysis is the first report to create ACC heatmap and could not detect any geographic clustering of ACC in Texas. The incidence of ACC remained stable and consistent with data from other large databases.
@ 2023 AACE. Published by Elsevier Inc. All rights reserved.
Abbreviations: ACC, Adrenocortical Carcinoma; AJCC, American Joint Committee on Cancer; IBM, International Business Machines Corporation; SEER, Surveillance, Epidemiology, and End Results; SIR, Standardized Incidence Ratio; SPSS, Statistical Package for the Social Sciences; TCR, Texas Cancer Registry; US, United States.
* Address correspondence to Dr Mouhammed Amir Habra, Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail address: mahabra@mdanderson.org (M.A. Habra).
Introduction
Adrenocortical carcinoma (ACC) is a rare and challenging ma- lignancy with a heterogeneous presentation and variable prog- nosis.1 The Surveillance, Epidemiology, and End Results (SEER) database provided an overall age-adjusted annual incidence of
https://doi.org/10.1016/j.eprac.2023.10.004
0.102 per 100 000 persons per year in the United States (US) in 2018, on the basis of cases from 1973 to 2014.2 This incidence had slightly increased compared to that in the last publication in 2006.3 Unlike other malignancies, ACC seems to be less influenced by behavioral and environmental factors; for example, only a few studies have shown an association between ACC incidence and tobacco use, especially in men.4-6
Recently, a large cohort of ACC cases seen at a referral center between 1998 and 2021 (621 cases) showed increasing numbers of cases registered annually which is likely due to referral bias.7
There are no data to explore ACC incidence at a populational/ county/zip code level to resolve the discrepancy between data from surgical databases vs data emerging from large volume centers. Furthermore, the possibility of geographic ACC clusters has not been reported. We attempted to evaluate the incidence and geographical distribution of ACC cases in Texas from 2000 to 2018 at a county level. Our study results will guide the future exploration of environmental risk factors that may be related to ACC.
Methods
This is a retrospective review of ACC cases registered in the Texas Cancer Registry (TCR) of the Texas Department of State Health Services.8 Only grouped data from the TCR limited-use dataset were used for the analysis after a previous registration and approval required by state law and rule (Health and Safety Code, §82.009; Texas Administrative Code, Title 25, Part 1, Chapter 91, Subchapter A).8 This cohort study did not require individual informed consent since this is a de-identified state-level report, and no protected health information was used.
Study Design and Population
In this cohort study, our inclusion criterion was cases of ACC registered between January 1, 2000, and December 31, 2018, in the Texas Cancer Registry (TCR) of the Texas Department of State Health Services.8 The time period was used to ensure the accuracy of the entries and available data. Data were collected retrospec- tively from the TCR database, with ACC cases defined according to the International Classification of Diseases for Oncology (Third Edition) using the site codes 740-749 and the histology code 8370. Demographic and clinical characteristics were collected from the TCR database: age, sex as a biological variable (male or female), race and ethnicity, disease stage (American Joint Committee on Cancer [AJCC], seventh edition), last follow-up date, patient status (alive or dead), and residency information specific to the patient (county level). We had access to aggregate data from the TCR database. We did not exclude any case in the analysis. As ACC is a rare disease and this is a retrospective study focused on a geographic area, we did not perform sample size estimation.
ACC heatmaps were made using patients’ county information and year of diagnosis to evaluate the geographic distribution of ACC in Texas and identify possible ACC clusters. The cancer clusters are considered a higher-than-expected number of cancer cases occur- ring within a group of people in a geographic area over a specified period.9 The ACC county-level heatmaps were created with Tableau software (version 2020.3).
We also assessed new cases of breast, lung and bronchus, and prostate cancer in Texas (identified from the TCR database, 2000- 2018)8 and aimed to compare those trends in incidence to ACC incidence. Breast and prostate cancer were selected because they are sex-linked malignancies, while lung and bronchus cancer were selected due to its association with smoking. We also analyzed the
Highlights
· Adrenocortical carcinoma (ACC) is a rare malignancy without clear environmental or other obvious risk factors in the vast majority of patients.
· The incidence of ACC in Texas over the past 2 decades has remained stable consistent with data derived from other publicly available databases.
· The lack of obvious geographic clusters of ACC in our study argues against the presence of environmental risk factors.
Clinical Relevance
Our study is the first report to link the adrenocortical carcinoma (ACC) incidence in the past 2 decades to area of residence. ACC incidence remained stable with slight female preponderance in line with published literature. There was no ACC clustering or obvious association between ACC and potential environmental exposures.
geographic distribution of those cancers in Texas to compare to the ACC geographic analysis.
Since Texas is an important energy-producing state, we also compared the ACC geographic distribution to the distribution of Texas’ energy plants, as provided by the U.S. Energy Information Administration,10 to verify any association of incidence of cases with oil and gas activity. Also, the distribution of petroleum re- fineries and coal mines plant was compared to ACC distribution.
Our data were from 110 of the 254 counties (43.3%) in Texas, representing 92.74% (26 619 932) of the total population of Texas in 2018 (28 702 243 in 2018, according to the Texas Demographic Center).11 Fifty-four counties (49.1%) in our cohort are classified as rural or nonmetropolitan by the US Office of Budget and Management.12
Statistical Methods and Software
Surveillance, Epidemiology, and End Results (SEER) Stat soft- ware (version 8.4.0) was used to pool the data and calculate incidence rates. We used IBM SPSS (version 24) statistical soft- ware to calculate the Kaplan-Meier overall survival curve and Pearson’s correlations. P values less than .05 were considered statistically significant. All the cases were analyzed, and all the data points were considered in the statistical analysis. The mean incidence rates were calculated as the mean number of newly diagnosed cases by year divided by the mean number of persons in the cohort in the specified period per 100 000 population. The ACC and other cancer standardized incidence ratios (SIRs) were calculated considering the Texas incidence rate (expressed per 100 000 population and age-adjusted to the 2000 US standard population). The age-adjusted incidence rate was defined as the number of new cases of ACC in a specified age group divided by the strata of the population during that period. The age-adjusted and mean incidence rates were calculated using the population registered in Texas according to the US Census Bureau in 2000 and 2010 and the population estimates for each county according to the Texas Population Estimates Program in the other years of the study (2001-2009 and 2011-2018).11 Rates were expressed per 100 000 population.
The lack of data due to retrospective data collection were recognized as a potential factor impacting the final analysis by underestimating the rates and incidence.
| Variables | N (%) |
|---|---|
| Sex | |
| Female | 270 (60.3) |
| Male | 178 (39.7) |
| Age (y) | |
| <5 | 15 (3.3) |
| 5-19 | 18 (4.0) |
| 20-64 | 293 (65.4) |
| ≥65 | 122 (27.3) |
| Race | |
| American Indian/Alaska Native | 2 (0.4) |
| Asian or Pacific Islander | 10 (2.2) |
| Black | 42 (9.4) |
| White | 393 (87.8) |
| Unknown | 1 (0.2) |
| Ethnicity | |
| Hispanic | 100 (22.3) |
| Non-Hispanic | 348 (77.7) |
| Stage | |
| I | 12 (7.7) |
| II | 43 (27.8) |
| III | 25 (16.1) |
| IV | 75 (48.4) |
| NA | 293 (65.4) |
| Status | |
| Alive | 129 (28.8) |
| Dead | 319 (71.2) |
| Overall survival | |
| Median | 2 y (range 0-19) |
Data Availability
The data that support the findings of this study are available in the Texas Cancer Registry, at [www.dshs.texas.gov/tcr]. No new databases were created.
Results
This study included 448 cases of ACC registered in Texas from January 1, 2000, to December 31, 2018, with a median incidence of 23 new ACC cases per year (range, 14-33 cases per year). De-
identified patient demographics are shown in Table. Thirty-three (7.4%) patients were aged 19 years or younger (15 were under 5 years), 293 (65.4%) were between 20 and 64 years, and 122 (27.23%) patients were 65 years or older (Fig. 1). Most of the patients were female (270 cases [60.3%]), with a female: male ratio of 1.5:1. Twelve (2.6%) patients were American Indian/Alaska Native or Asian/Pacific Islander, 42 (9.4%) were Black, and most patients were White (393 [87.8%]). Although 40.2% of the population of Texas is Hispanic, according to the 2010 Census, only 22.3% (100) of patients were of Hispanic ethnicity.
The proportions of patients with stage I, II, III, and IV disease at diagnosis were 7.7%, 27.8%, 16.1%, and 48.4%, respectively, of 155 cases. These patients were classified using the AJCC seventh staging system since its release in 2011. One hundred twenty-nine (28.8%) patients were alive until December 31, 2020, which was the last entry in the database. The median overall survival duration was 2 years (range, 0-19 years; std error, 0.354; 95% CI, 1.307-2.693) (Table).
The mean ACC incidence rate overall was 0.095 cases per 100 000 per year in Texas (std = 0.005; 95% CI, 0.084-0.106). The mean population-adjusted ACC incidence rate for the counties registered in the TCR database was 0.104 per 100 000 per year (std = 0.005; 95% CI, 0.092-0.116) (Fig. 2). The sex-adjusted ACC incidence rates were 0.125 and 0.083 per 100 000 per year for fe- males and males, respectively. The age-adjusted ACC incidence rates were 0.047 for <5 year old, 0.019 for 5 to 19 years, 0.062 for 20 to 44 years, 0.195 for 45 to 64 years, and 0.251 for 65 years or older. There was no obvious difference in stage or survival between male and female patients (median overall survival 2 years both in men and women).
Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each in the time period (median, 34 cases per county; range, 11-66 cases) and a median SIR of 0.1 (range, 0.0-0.9). One hundred and three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county (median, 1 case; range, 1-9 cases). Of those counties, 79 (76.7%) had SIRs higher than 1 (range, 1.1-30.8). The higher SIRs (corresponding to >10 [range, 11.2-30.8]) were found in counties with a median population of fewer than 14000, with only one reported case in the studied period.
We did not observe the presence of any obvious ACC clusters in the geographic analysis of Texas cases through the years (2000-
40
35
30
Number of cases
25
20
Male
15
Female
10
5
0
<1 year
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
>84 years
Adrenocortical carcinoma incidence in Texas (2000-2018)
0.200
ACC Cases per 100,000 population
0.150
0.100
0.050
0.000
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
Texas ACC incidence
Population-adjusted ACC incidence
Mean population- adjusted ACC incidence
2018). Rural counties had a median of 1 ACC case (range, 1-3 cases) registered between 2000 and 2018, while urban counties had a median of 3 (range, 1-66 cases), with a significant difference be- tween groups (P < . 01). Comparing the geographic distribution of ACC cases with the energy plant of Texas, we did not find a pattern between the occurrence of ACC cases and the presence of energy- producing facilities.
We compared ACC geographic distribution to breast, prostate, and lung and bronchus cancer distribution and noticed that each tumor type had similar geographic distributions. Counties with a high frequency of breast, prostate, and lung and bronchus cancer also had more cases of ACC, with a positive correlation (Pearson correlation 0.982, 0.981, and 0.982, respectively [P < . 01 for all tests]) (Fig. 3).
Discussion
In this study, the mean population-adjusted ACC incidence rate of ACC in Texas was 0.104 per 100 000 per year, consistent with the US annual incidence derived from other databases.2 This further supports the notion that the reported increased number of cases seen at major centers is likely due to referral bias.13,14 We found a higher incidence rate in <5-year-old patients than in 5- to 19-year- old patients. McAteer et al15 showed an incidence of 0.021 per 100 000 person-years in patients under 20 years of age. This inci- dence is similar to that in our 5- to 19-year-old patients but lower than that in our 5-year-old patients (0.047 per 100 000).15 We identified a bimodal peak of ACC incidence, with a slight elevation in cases in early childhood and patients older than 45 years, different from previous published by Sharma et al.2
The female: male ratio of overall ACC cases was slightly higher than the previously published national cohort ratio.2,3 Neverthe- less, we did not observe an obvious association between sex and survival. The prevalence of ACC in White people in our study was similar to that in the national cohort.2,3 Almost half of our cohort (48.4%) presented with stage IV disease, which was higher than previously published; this could be due to late access to the health system since Texas has the highest percentage (18%) of residents without health insurance in the US.2,3,16 We found a median overall
survival duration of 24 months, which is slightly higher than the 17 months in the national cohort.2 We could not calculate overall survival rate according to the disease stage since we did not have access to the case details. Our ACC heatmap did not reveal any obvious ACC clusters.
Onyije et al17 showed a correlation between the risk of cancer and living or working in or near petroleum facilities. Texas is an important energy-producing state, accounting for 43% of the na- tion’s crude oil production and 25% of its marketed natural gas production.10 Texas has the highest number of crude oil refineries and the most refining capacity of any state, representing at least 31 active petroleum refineries in 2021.10 However, we did not find a pattern between the geographic distribution of ACC cases and the presence of energy-producing facilities.
The Air Toxics Assessment of the US Environmental Protection Agency published a map of the distribution of hazardous air pol- lutants in Texas.18 It revealed a high risk of cancer in areas with increased rates of hazardous air pollutants, such as east Texas.18 Cicalese et al19 suggested that increased exposure to hazardous air pollutants could be related to a higher rate of liver cancer in certain Texan counties. Hughes et al2º described a heterogeneous distri- bution of lung cancer cases in Texas; some counties had almost a 4- fold higher rates than others, mainly in the eastern portion of the state. The same group also reported a positive correlation between air pollution, represented by particulate matter less than 2.5 um, and lung cancer incidence.2º We identified high frequencies of ACC and lung and bronchus cancer cases in east Texas in the heatmaps. However, the relationship between high rates of hazardous air pollutants and ACC is unknown.
Texas has the highest hepatocellular carcinoma incidence rate in the United States.21 El-Serag et al21 attributed this high incidence to the Hispanic population in the state. However, we did not find a relationship between ACC and Hispanic ethnicity, as only 22.3% of patients were Hispanic; we also did not find clusters on the Texas border, as El-Serag et al21 identified in his study.
Cancer is the second leading cause of death in the US and was the leading cause of death in 40 counties in Texas, from 2009 to 2019.22-24 One hundred and seventy-two of Texas’ 254 counties are classified as rural; as in the rest of the US, most Texans (89%) live in
A
Adrenocortical carcinoma
B
Adrenocortical carcinoma
C
Adrenocortical carcinoma
ew México
IN Mexico
tw Mexico
0
Total cases (2000)
4
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4
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Total cases (2008)
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Total cases (2018)
3
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Nugyo León
HŰBus Leon
D
Adrenocortical carcinoma
E
Adrenocortical F carcinoma
Adrenocortical carcinoma
ew Mexico
ww Mexico
IW Mexico
Texas
0.0
SIRs (2000)
14.7
2
0.0
SIRs (2008)
7.4
0.0
SIRs (2018)
5.2
Nuevo Lườn
G
Breast cancer
H
Lung and bronchus cancer
I
Prostate cancer
C
ew Mexico
A
ew Mexico
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0.0
SIRs (2018)
282.1 de
0.0
SIRs (2018)
138.7 de
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171.3
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SIRs (2018)
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1
Nuevo León
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urban counties.12 Rural counties can have differing specific popu- lation characteristics, risk factors, and healthcare access than urban counties, which impacts cancer incidence and the mortality rates.12 We found statistically significant more ACC cases in urban counties than in rural counties, directly correlated to the higher population in the former.
We also found that standardized incidence ratios may not be useful for analyzing a rare disease such as ACC. We reported higher SIRs in counties with only one ACC case in the 19-year period and a median population of fewer than 14000. Breast, lung and bronchus, and prostate cancer accounted for a higher total number of cancer cases, and the SIR is a valuable tool for analyzing the frequency of these cases; ACC is a rare disease, and higher SIRs may occur by chance.
ACC has a heterogeneous presentation and highly variable prognosis; while it is challenging to treat, overall survival duration has improved over the last few years.7 The ACC tumorigenesis background has not been completely elucidated as well as the participation of environmental and behavioral risk factors in it. In this study, we showed that the incidence of ACC in Texas remained relatively stable and consistent with the US annual incidence. We did not observe any obvious ACC cluster, and SIR may not be useful for analyzing this rare disease. Further studies should be per- formed to determine whether there are any modifiable risk factors related to ACC, and a follow-up of this cohort is needed to clarify whether these rates will persist or any ACC clusters will develop in Texas.
V. Balderrama-Brondani, A.M. Griffin, T.J. Owen et al.
Disclosure
The authors have no multiplicity of interest to disclose.
Acknowledgment
Cancer data have been provided by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services, 1100 West 49th Street, Austin, TX 78756 (www.dshs.texas.gov/tcr).
Editorial assistance was provided by Ann M Sutton, MD Ander- son Editing Services, Research Medical Library. We would also like to thank the Dan Hund Family Fund and the Stomp Out Cancer Fundraiser for the philanthropic support of our adrenal cancer research program.
Data Availability
The data that support the findings of this study are available in Texas Cancer Registry, at [www.dshs.texas.gov/tcr], and are avail- able from the corresponding author upon reasonable request.
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