Cancer Versus Cardiac Mortality Risk with Adult Thymectomy

The role of the thymus in adult health is often overlooked. Our group recently demonstrated that following adult thymectomy, patients experience a significantly higher risk for cancer, autoimmunity, and mortality when compared with controls that underwent cardiothoracic surgery without thymectomy. Further, thymectomized adults produced fewer new T cells and shared a pro-inflammatory cytokine signature (Kooshesh et al., NEJM, 2023). In this study, we sought to understand the impact of thymus removal in adults on the two most common causes of adult mortality, cardiovascular disease and cancer.

All adult patients who underwent a thymectomy procedure at the Massachusetts General Hospital (MGH) over the past 30 years (N = 1532) were included for study. Controls included all 62422 patients who received care from the MGH Internal Medicine Associates. Thymectomy patients and controls were matched 5:1 (with replacement) at time of thymectomy on demographics (age within 5 years, sex, race), smoking status (never, former, current), usage of aspirin or statins, and comorbidities (hypertension, cancer, autoimmunity, hyperlipidemia, cardiovascular disease).

To determine the effect of thymectomy on life expectancy, all-cause mortality and cancer were assessed via Kaplan-Meier analysis after matching between the two groups. The 5-year risk of all-cause mortality in the thymectomy group was >double that of the control group (relative risk[95% CI]: 2.4[1.6-3.7]). Similarly, the 5-year risk of cancer was >double that of the control group (2.4[1.3-4.4]). Over multiple decades, all-cause mortality remained higher in the thymectomy group (hazard ratio[95% CI]: 1.9[1.5-2.3]), as did cancer (1.3[1.01-1.6]). Collectively, these results validate the findings of our prior study (Kooshesh et al., NEJM, 2023) of thymectomy risk compared to a novel, healthy control group, further supporting the importance of the adult thymus to human health.

Given that cardiovascular disease (CVD) is the leading cause of death worldwide, we also investigated whether major adverse cardiovascular events (MACE: myocardial infarction, heart failure, stroke) were responsible for the significantly increased risk of mortality after thymectomy. At 5 years and 20 years post matching, the thymectomy and control groups had similar rates of MACE (relative risk over 5 years [95% confidence interval]: 0.29[0.07-1.2]; hazard ratio over 20 years [95% confidence interval]: 0.75[0.56-1.02]).

To determine the cause of death, detailed medical record review was performed for all 80 thymectomy patients who died within 10 years of matching alongside 86 control patients. This analysis matched on post-operative rates of infections, malignancies, and autoimmune disease. Primary causes of death for thymectomy and control patients were found to be different: among thymectomy patients, cancer represented 81.4% of the causes of death compared with 31.4% in control patients (p < 0.001). Control patients largely died of cardiovascular disease or incidental causes (i.e., substance use, liver disease). The types of cancers that each group developed were different. Throughout their lives and leading up to death, thymectomy patients suffered thymomas, sarcomas, and a host of cancers from tissue types across the body, versus control patients that largely developed lung, skin, breast, colon, and prostate cancers, the most common types of cancers worldwide. Thymectomy patients who died suffered cancer recurrence more frequently after definitive treatment (65.4% vs. 38.8% of cancers, p = 0.001) and the types of cancers that recurred were also distinct between groups. Taken together, these findings demonstrate that cancer is the overwhelming driver of mortality in thymectomy patients, who experience more diverse and recurrent cancers than controls.

The adult thymus is important for human longevity. Retention of the thymus protects against the development of cancer and consequently reduces mortality. Despite the critical roles of the immune system in CVDs, patients who underwent thymectomy largely did not experience higher rates of MACE or non-MACE cardiovascular disease when compared with controls. These data provide clarity for physicians counseling patients on the risks and benefits of thymectomy: thymectomy performed during cardiothoracic surgery does not exacerbate MACE but instead significantly increases the risk of dying from cancer.