Research Letter
Cutaneous angiosarcoma (cAS) is an aggressive cancer of lymphatic/vascular endothelial origin that most frequently occurs on the head and neck and among non-Hispanic white individuals. Risk factors for angiosarcoma include radiotherapy, chronic immunosuppression, chronic lymphoedema, germline pathogenic variation in the POT1 gene, and exposure to exogenous toxins.1–3 Prior studies of cAS occurring on chronically sun-exposed skin of the head/neck have demonstrated an ultraviolet radiation (UVR) mutational signature4, but epidemiologic studies directly examining UVR levels and cAS incidence are lacking.
CAS incidence data were derived from 21 Surveillance, Epidemiology and End Results program cancer registries in the United States from 1992 to 2020. Satellite-based ambient UVR estimates were linked to county of residence (Supplementary Figure 1). To examine the association between ambient UVR and first primary cAS, we calculated incidence rate ratios and 95% confidence intervals using Poisson regression adjusting for sex, age, and race (Supplementary Methods).
There were 831 cases of first primary cAS diagnosed between 1992 and 2020 (Supplementary Table 1). CAS incidence was highest in older, male, and non-Hispanic white populations. Head/neck was the most frequent anatomic site grouping across all demographic groups considered. The IRR for ambient UVR (highest versus lowest quartile) and cAS was significantly increased in the total population for all anatomic sites on the skin and for cases occurring on the head/neck, areas often chronically sun-exposed (Table 1). Among non-Hispanic white individuals, the estimates were similar to those in the total population, but the trend was only statistically significant for head/neck cases. UVR was significantly associated with increased cAS incidence of the head and neck among individuals who were less than 65 years old, male, and non-Hispanic white (Figure 1).
Table 1.
Incidence rate ratio of ambient ultraviolet radiation and cutaneous angiosarcoma in the United States, SEER 1992–2020
| All sites | Head and neck | |||
|---|---|---|---|---|
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|
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| Total population | ||||
| UVR | N cases | IRR (95% CI) | N cases | IRR (95% CI) |
| Q1 | 244 | Reference | 193 | Reference |
| Q2 | 200 | 1.02 (0.85,1.23) | 161 | 1.04 (0.84,1.28) |
| Q3 | 177 | 1.03 (0.85,1.26) | 148 | 1.10 (0.88,1.36) |
| Q4 | 210 | 1.21 (1.00,1.46) | 177 | 1.29 (1.05,1.59) |
| p for trend | 0.06 | 0.02 | ||
| Non-Hispanic white | ||||
| UVR | N cases | IRR (95% CI) | N cases | IRR (95% CI) |
| Q1 | 220 | Reference | 175 | Reference |
| Q2 | 161 | 0.94 (0.76,1.15) | 126 | 0.92 (0.73,1.16) |
| Q3 | 135 | 1.09 (0.88,1.36) | 115 | 1.17 (0.93,1.48) |
| Q4 | 143 | 1.14 (0.92,1.40) | 124 | 1.23 (0.98,1.55) |
| p for trend | 0.15 | 0.03 | ||
Abbreviations: SEER, Surveillance, Epidemiology, and End Results Program; N, number; IRR, incidence rate ratio; CI, confidence interval.
Notes: Cutoffs for ambient UVR quartile: 17 to <26.4 (Reference), 26.4 to <40.0, 40.0 to <44.8 and 44.8 to 76.5 mW/m2. Adjusted for sex, age (<65, 65-79, 80+), race and ethnicity (non-Hispanic white, Hispanic white, Black, Asian/Pacific Islander). P-values for solar UVR were based on trend tests using ordinal UVR quartiles. From SEER12 and SEER22 registries.
Figure 1. Incidence rate ratio of ambient ultraviolet radiation and cutaneous angiosarcoma of the head and neck in the United States, SEER 1992–2020 by age, sex, and race and ethnicity.
Abbreviations: SEER, Surveillance, Epidemiology, and End Results Program; CI, confidence interval; UVR, ultraviolet radiation; IRR, incidence rate ratio.
Note: Adjusted for age, sex, age, and race and ethnicity. All interaction P-values>0.05. The incidence rate ratio per UVR quartile may be interpreted as the ratio of the cutaneous angiosarcoma rate for every increase in UVR quartile (e.g., going from quartile 1 to quartile 2 or quartile 2 to quartile 3).
Our findings are consistent with prior studies of UVR-related skin cancers that suggest that older, male, and non-Hispanic white populations have increased risk. Like cAS, established UVR-related skin cancers such as melanoma and keratinocyte carcinomas occur predominantly on the head and neck. A study sequencing several primary and secondary angiosarcomas found that among tumors lacking MYC amplification (which is associated with radiotherapy), 71% of remaining tumors had somatic TP53 variants with C to T alterations, a mutational signature associated with UVR damage.5
A major strength of this study is that the study population includes up to 48% of the U.S. population residing in locations with substantial heterogeneity in ambient UVR. Nondifferential misclassification of ambient UVR exposure may have resulted in bias towards the null because UVR was linked to location of residence only at diagnosis and individual exposure across the lifetime was not available. This may partly explain why the association was strongest in the youngest age group. In addition, we did not have information on other potential risk factors for cAS.
Our results suggest that solar UVR is associated with cAS and serve as a starting point for understanding the differences in the UVR relationship by age, sex, and race and ethnicity. Clinicians should be aware of the increased risk of cutaneous angiosarcoma in patients who reside in locations with high ambient UVR.
Funding source:
This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.
Footnotes
Conflicts of Interest: No potential conflicts or competing interests to disclose.
Supplemental Material: https://data.mendeley.com/datasets/md8vxcdrhh/1
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