According to our review of the literature, this study is the first to demonstrate the association between the severity of TBI and cancer development based on a national population-based database. In this study, we added new information to the field of oncology: in a comparison of patients with mild TBI and matched patients with moderate/severe TBI, no differences were observed in cancer incidence and the risk factors for mortality. Although moderate/severe TBI patients had a higher mortality rate and shorter interval from TBI to death, moderate/severe TBI patients aged 46–55 years old, were females, and had pre-existing renal disease show higher incidence risk of cancer than mild TBI patients. Mild TBI patients had a higher percentage of head and neck cancer.
Before matching, we found that patients with moderate/severe TBI were older and had a greater burden of all evaluated comorbidities (Table 1). We believe that the theoretical basis for an association between TBI and systemic cancer risk is tentative, and as such, we should consider the very real possibility that the reported associations are due to residual confounding related to older age and poorer health in the moderate/severe TBI group. Therefore, we consider that the HR for cancer in individuals with moderate/severe TBI could be attenuated after adjustment for these factors. This consideration was confirmed after matching, as the results show (Table 2).
In this study, during a mean follow-up period of 9.6 years for mild TBI patients and 8.9 years for moderate/severe TBI patients, the patients with moderate/severe TBI presented with a higher mortality (17.7% vs. 10.4%) and shorter time from TBI to death (mean 3.6 vs. 5.8 years). We also found that patients with mild TBI had a mortality rate of 10.4% within a mean time of 5.8 years. This information on the life expectancy of patients with mild or moderate/severe TBI can inform treatment decisions, assist in the utilization of limited medical resources, and provide plans for ongoing medical needs and lifelong planning.
Carcinogenesis is a multiple-step process that includes initiation, promotion, and progression [2]. Therefore, it takes a long time to develop malignancy; for example, clinical development period estimates range from 20–25 years for colon cancer [24]. However, the starting time point of malignant development is difficult to determine; therefore, we set the beginning of the observation period to 2000. Consistent with our previous study, the mean time from TBI to cancer diagnosis was 4.8 years among mild TBI patients and 5.0 years among moderate/severe TBI patients; these durations are shorter than that among the general population, which is approximately 5.9 years [19]. Because it is hard to understand that cancer can occur within such a short period of time after a traumatic brain injury, we believe that cancer may also be a risk factor for brain injury, given that the cause and effect relationship needs to be clarified. This issue needs to be clarified in the future.
In the current study, we found that moderate/severe TBI increased the cancer incidence risk by 1.1-fold with borderline significance (p = 0.0751) compared with mild TBI. This result implied that the severity of TBI may play a potential role in cancer incidence risk. Philip et al. indicated that inflammation, especially TNF-α production, is a tumor promoter in the context of cancer induction [25]. Ohana et al. demonstrated that the transcription factors of the p53, HIF-1a and c-Myc oncogenes play a role in inflammation and in the development of glioblastomas after TBI [14]. In our previous study, we demonstrated that TBI may activate local and systemic TNF-α production [26,27,28]; therefore, we speculate that if the inflammatory response continues and becomes chronic in moderate/severe TBI patients, it will persistently activate transcription factors and increase the probability of malignant transformation. We suggest that neuroinflammation may play a role in the development of systemic cancer, although we did not study neuroinflammation in the current report. However, the role of the neuroinflammatory cascade in the association between moderate/severe TBI and cancer warrants further investigation.
In the general population, females have a lower cancer risk than males [29, 30], and most cancer incidence increases with age [31, 32]. McCarthy et al.et al. indicated that among women, menopause and hormone replacement therapy were risk factors for cancer development [29]. In our current study, after matching and adjustment, we provided new information that female patients and patients aged 46 to 55 years had a higher cancer risk incidence in moderate/severe TBI patients (Table 2). These results implied that injury severity would affect the cancer incidence risk in these specific groups. This information reminds physicians to be careful of the long-term effects of moderate/severe TBI on cancer development. We consider these data to lay the foundation for future TBI and cancer research.
Previous studies have reported significantly higher new-onset cancer risk in end-stage renal disease patients than in the general population [32, 33]; the pathologies included renal cell carcinoma and urothelial cell carcinoma [33]. In the current study, we further found that TBI patients with renal disease had a higher new-diagnosis cancer risk than non-renal disease patients. However, the underlying mechanisms of increased cancer risk in patients with TBI stratified by renal disease are not well known, and the relationship warrants further investigation. Furthermore, in mild and moderate/severe TBI patients, whether the incidence of cancer is higher in patients with renal disease, not related to TBI but only related to the risk of cancer from renal disease, needs to be clarified in the future.
When analyzing patients with mild TBI and with moderate/severe TBI (Tables 3 and 4), head and neck cancer included mouth, esophageal, tongue, hypopharynx, nasopharynx, oropharynx, and thyroid gland cancers. There was no significant difference between the mild TBI and moderate/severe TBI patients (22.7% vs. 19.7%, p = 0.1960). This result implies that the severity of TBI does not affect cancer type. We compared the top 15 cancers with those in 2014 in Taiwan and found that hepatocellular and bile duct carcinomas were the most frequent cancers in patients with mild (19.4%) and moderate/severe (15.6%) TBI in our study; 11,358 new cases of hepatobiliary tumors were diagnosed in 2014, and hepatobiliary tumors accounted for 11.0% of the total cancer in Taiwan [34]. However, there was no significant difference between the mild TBI and moderate/severe TBI patients (19.4% vs. 15.6%, p = 0.08). This result also implies that the severity of TBI does not affect cancer type.
In the current study, we also found that patients had higher frequencies of head and neck cancer in both mild and moderate/severe TBI patients compared to the general population in Taiwan [30]. The detailed mechanisms are not well understood. We posit that patients with TBI had a greater chance of receiving brain computer tomography radiation exposure, which may have played a role in cancer development [35]. Berrington et al. estimated that the mean lifetime cancer risk is 0.04% to 0.09% per head CT [36]. Brenner and Hall demonstrated that as many as 1.5% to 2.0% of all cancers in the United States may be attributable to radiation from CT studies [37]. Sale et al. also showed that the incidence of radiation-induced head and neck cancer was 1% [38]. Because patients with TBI frequently receive large numbers of radiographic examinations during hospitalization [39], they are more likely to develop head and neck tumors. Other possible mechanisms are related to menopause and hormone replacement therapy as a risk for head and neck and esophageal cancer [39]. Because tobacco use and alcohol use are major risk factors for head and neck cancer [40, 41], it is necessary to compare smoking and alcohol consumption in the mild TBI group to the moderate/severe TBI group in the future.
On average, the death of TBI patients with cancer was 86.7% of cancer-specific causes. However, infection, diabetes mellitus, and cardiovascular disease accounted for 58.0% of all causes of death beyond malignancy in patients with mild TBI [Appendix A]. Cerebrovascular disease, infection, and accidents, including self-harm, accounted for 52.4% of all causes of death beyond malignancy in the patients with moderate/severe TBI [Appendix B]. Therefore, we consider identifying patients at high risk for mortality and developing preventive interventions to be necessary, especially in moderate/severe TBI patients with a risk of self-harm. Another topic for further research is to clarify the effects of TBI severity on each cancer cause of mortality.
In Taiwan, mortality from cancer remains the leading cause of death among all the population [17, 18]. Based on our results, we found 4.1% of each TBI patients with mild or moderate/severe developed cancer during the follow/up. Because of a subset of patients with more severe forms of TBI may lapse in their cancer treatment and patients symptomatic from mild TBI experience further gaps in evaluating for cancer symptoms and/or reaching systems of care for a new cancer diagnosis. Therefore, we recommend clinicians should be particularly aware that if a patient with a brain injury during follow-up has symptoms of suspected cancer such as loses weight, a lump on palpation and prolonged coughing, blood in the stool, etc., they should arrange tests to rule out the possibility of cancer.
The strengths of our study include the use of Taiwan’s NHIRD, which is a longitudinal nationwide database with a large sample size and a long follow-up period to address a topic about which relatively little is known. We combined the NHIRD with the Taiwan Cancer Registry and the Cause of Death Data, making it possible to estimate the cancer incidence risk among TBI patients.
Some limitations should be considered when interpreting these data. First, the NHIRD did not provide information on the severity of cancer, the use of drugs such as hormone replacement, the dosage of radiation exposure, lifestyle patterns, smoking, alcohol intake, or occupational hazards that may affect tumor progression and prognosis. Second, the radiographic injury location [42] and surgical interventions [43] were not considered during matching or controlled, which is a limitation when considering the severity of injury. Third, hepatobiliary cancers and breast cancers were rarely observed in this study, and a history of hepatobiliary and breast diseases should be considered as a comorbidity. Therefore, the existence of various confounding factors cannot be denied. Finally, both head trauma and cancer are frequent, and tangible proof of an association is required. These issues should be clarified in the future.
