Don’t Underestimate the Health Consequences of Thymus Removal in Adults

If you have ever looked at a pediatric chest radiograph, you may recall seeing a large thymic shadow overlying the mediastinum. That shadow disappears with age as the thymus atrophies and involutes. Children born with an absent or hypoplastic thymus, such as those with DiGeorge syndrome, are at increased risk for infections due to the role of the thymus in the development of T lymphocytes. The function of the thymus in adults is less certain. In a recent retrospective study published in NEJM, researchers tried to fill this knowledge gap by comparing health outcomes in 1146 adults who had undergone thymectomy and matched controls who had undergone similar cardiothoracic surgery without thymectomy.

Five years after surgery, mortality was significantly higher in the thymectomy group than in the control group (8.1% vs. 2.8%; relative risk [RR], 2.9; 95% confidence interval [CI], 1.7–4.8; P<0.001 ), and remained significantly higher 20 years after surgery (hazard ratio 1.5; 95% CI, 1.3–1.7; P=0.001). Risk of cancer at 5 years was also higher among patients who had undergone thymectomy (7.4% vs. 3.7%; RR, 2.0; 95% CI, 1.3–3.2), even after excluding patients with preoperative cancer, thymoma, myasthenia gravis, infection, and autoimmune disease. Post-thymectomy patients had more cancers per patient and more diverse cancers, regardless of preoperative cancer history.

Patients who had undergone thymectomy did not have higher risk of autoimmune disease than controls at 5 years, but the risk was higher after excluding patients with preoperative infection, cancer, or autoimmune disease (12.3% vs. 7.9%; RR, 1.5; 95% CI, 1.02–2.2). This difference dissipated during the 20-year follow-up period, suggesting that the increased risk was transient.

The authors also assessed T-cell production and blood plasma cytokine levels in a subset of thymectomy patients and controls. Patients who had undergone thymectomy produced fewer T cells and had a consistent proinflammatory profile that was not observed in the control group. The authors posited that thymectomy was associated with a shared cytokine signature of immune dysregulation.

Even though the thymus begins to atrophy in the first year of life and is sometimes overlooked, this study suggests that the function of the thymus remains important into adulthood. The findings of increased mortality and cancer risks among patients who had undergone thymectomy do not imply causation and may be affected by unadjusted residual confounding. Nonetheless, the authors conclude that thymectomy disrupts immune homeostasis and may lead to adverse health outcomes. They recommend prioritizing preservation of the thymus whenever possible. Even if you are not the one making intraoperative decisions, keep in mind that patients who have undergone thymectomy might be at increased risk for cancer or immune conditions.

Read the following NEJM Journal Watch summary for more details of this study.

David J. Amrol, MD, reviewing Kooshesh KA et al. N Engl J Med 2023 Aug 3 Taylor N. N Engl J Med 2023 Aug 3

Infants born without a thymus have severe combined immunodeficiency, and children who undergo thymectomy have long-lasting lymphopenia. However, in adults, the thymus involutes and sometimes is removed during thyroid or cardiac surgery with little concern for adverse immunologic effects.

In a retrospective analysis from Massachusetts General Hospital, 1146 patients who underwent thymectomy were matched to control patients who underwent cardiothoracic procedures with thymus sparing. In the thymectomy group, 511 had cancerous thymomas, and 370 had “suspected thymic masses;” additionally, 265 underwent thymectomy during cardiac surgery, thyroid/parathyroid surgery, or for indeterminate reasons. At 5 years, thymectomy patients were significantly more likely than controls to have died (8.1% vs. 2.8%) or to have developed cancer (7.4% vs. 3.7%); types of cancer varied, and they were more aggressive and recurrent in thymectomy patients. Even when all prior malignancies were excluded, mortality and postoperative cancer were significantly more common in thymectomy patients at 20 years. New T cell production decreased, and levels of inflammatory cytokines increased in thymectomy patients.

Comment: Even as a practicing immunologist, I rarely think about the importance of the thymus in adults. Despite the problems of possible confounding, the author of an accompanying editorial calls this a landmark study. Perhaps the adult thymus should be given more respect and preserved whenever possible.

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Julie Barzilay, MD, MPhil, is a 2023–2024 NEJM Editorial Fellow. She is currently a pediatrician in the Division of General Pediatrics at Boston Children's Hospital. She completed her pediatrics residency in the Boston Combined Residency Program at Boston Children's Hospital and Boston Medical Center.