Moderate, severe, and penetrating traumatic brain injury (TBI) is associated with an elevated risk of developing brain cancer, new research suggested. However, mild TBI appears to confer no increased risk.
In a large cohort of post-9/11 US veterans, those who suffered moderate/severe TBI had a nearly twofold increased risk for a subsequent brain cancer diagnosis, while those with penetrating TBI had a greater than threefold increased risk.
"While the absolute number of brain cancer diagnoses was small, these diagnoses are associated with profoundly poor outcomes. Further research of this rare but devastating condition is needed to better identify those at risk and develop screening protocols," investigators led by Ian Stewart, MD, with the Uniformed Services University of Health Sciences, Bethesda, Maryland, wrote.
The study was published online on February 15 in JAMA Network Open.
Common War Wound
TBI is one of the most common battlefield wounds among veterans of the Iraq and Afghanistan wars. But evidence to date on the potential association of TBI with the subsequent risk for brain cancer is conflicting, the authors noted.
To investigate further, they reviewed the records of nearly 2 million mostly male US veterans of the Iraq and Afghanistan wars. A total of 449,880 people experienced TBI, which was mild in 385,848 cases, moderate/severe in 46,859 cases, and penetrating in 17,173 cases.
During a median follow-up of 7.2 years, brain cancer occurred in 318 veterans without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (0.06% or less).
There was a stepwise increase in brain cancer incidence with worse TBI severity. Crude incidence rates per 100,000 person-years were 3.06 for no TBI, 2.85 for mild TBI, 4.88 for moderate/severe TBI, and 10.34 for penetrating TBI.
In the fully adjusted model, moderate/severe TBI showed a near-doubling of brain cancer risk vs no TBI (adjusted hazard ratio [aHR], 1.90; 95% CI, 1.16-3.12), while penetrating TBI was associated with a greater than tripling of risk (aHR, 3.33; 95% CI, 1.71-6.49). There was no significantly increased risk after mild TBI.
There are plausible biological mechanisms linking TBI to brain cancer, the authors noted, including alterations in metabolism, inflammation, astrocyte proliferation, and stem cell migration and differentiation.
They caution that with few female veterans and a predominantly young cohort, the findings may not extend to the general population.
Meaningful New Data
In an accompanying editorial, Elie Massaad, MD, MSc, and Ali Kiapour, PhD, MMSc, Massachusetts General Hospital, Boston, Massachusetts, noted that federal data show glioblastoma, the most aggressive malignant brain tumor, is the third leading cause of cancer-related death among active duty personnel.
"Post-9/11 veterans deployed to Iraq, Afghanistan, and elsewhere face a 26% higher glioblastoma rate vs the general public, with an average age of onset decades earlier than in broader populations," they wrote.
Overall, they note this new research provides "meaningful data clarifying associations between combat-related TBI severity and subsequent brain cancer risk among post-9/11 veterans."
"Elucidating potential connections between battlefield trauma and longer-term health outcomes is imperative to inform prevention and care approaches for those who have served," they added.
This study was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense through the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military Relevant Brain Injury Consortium. The authors and editorialists had declared no relevant conflicts of interest.