Routinely Removed Organ Linked to Increased Mortality, Cancer Risk

Thymectomy carried a substantially increased risk of all-cause mortality and cancer for adults, a "landmark" study showed.

Adults who had undergone thymectomy had at least double the risk of all-cause mortality and cancer at 5 years post-surgery compared with matched patients who had undergone cardiothoracic surgery without thymectomy:

• All-cause mortality: 8.1% vs 2.8% (relative risk [RR] 2.9, 95% CI 1.7-4.8)
• Cancer: 7.4% vs 3.7% (RR 2.0, 95% CI 1.3-3.2)

Autoimmune disease did not differ substantially between groups overall, reported David T. Scadden, MD, of the Center for Regenerative Medicine at Massachusetts General Hospital in Boston, and colleagues in the New England Journal of Medicine.

But after excluding patients with potentially confounding conditions (preoperative infection, cancer, or pre-existing autoimmune disease), autoimmune disease was a relative 50% more common after thymectomy (12.3% vs 7.9%; RR 1.5, 95% CI 1.02-2.2).

Even when comparing unmatched thymectomy patients to the general population, all-cause mortality was higher in the thymectomy group (9.0% vs 5.2%), as was mortality due to cancer (2.3% vs 1.5%).

Incidental thymectomy is common during cardiothoracic surgery due to the pyramid-shaped organ's location in the chest in front of the heart where surgeons need to access the surgical field.

While the thymus plays a critical role in normal immune system development, it was thought to be safe to remove in adulthood, "particularly since the thymus naturally involutes with age," the researchers noted.

Their conclusion from the study was that the thymus continues to be functionally important for human health in adulthood.

In an accompanying editorial, Naomi Taylor, MD, PhD, of the National Cancer Institute Pediatric Oncology Branch in Bethesda, Maryland, called the research a "landmark" study with "important repercussions for the care of patients undergoing cardiothoracic surgery and strongly argues against total thymectomy if it can be avoided."

Prior studies had shown that the adult thymus continues to produce T lymphocytes, under both pathologic and physiologic conditions, and this study supports an important role of that function, she noted.

"[I]t is remarkable that the possibility that thymectomy would lead to detrimental effects in adults without underlying pathologic conditions was only studied in depth 25 years later," she added.

The study used the Mass General Brigham Research Patient Data Registry to identify all 1,420 adults who had thymectomy at Massachusetts General Hospital from January 1993 to March 2020. Patients who died within 90 days after the procedure or who had nonlaparoscopic cardiac surgery within 5 years after the procedure were excluded.

Patients were matched by sex, race, preoperative conditions (infections, cancers, or autoimmune disease), and age (within 5 years) to all 6,021 adults who had nonlaparoscopic cardiac surgery and no history of thymectomy at the same center from January 2000 through December 2019. Along with the exclusions for mortality or repeat cardiac surgery, the control group couldn't have preoperative heart failure.

The general population comparison with CDC data included an adjustment of 17% to account for the difference between overall U.S. mortality and that in Massachusetts, as well as proportional weighting to the distribution of ages at thymectomy and years in which surgery was performed.

The study also included some blood testing to start unraveling the mechanism. A subset of 22 thymectomy group patients and 19 control group patients with a mean follow-up of 14.2 postoperative years had T-cell production and plasma cytokine levels measured.

Among the significantly altered levels of 15 different cytokines in the thymectomy versus control groups, interleukin-23, interleukin-33, thrombopoietin, and thymic stromal lymphopoietin were more than 10 times as high as control levels, Taylor pointed out.

Thymectomy patients had reduced production of newly formed T cells compared with controls.

Higher T-cell receptor oligoclonality was found after thymectomy in the subset of patients with postoperative cancer, which would tend to support "a mechanism of attenuation of T-cell differentiation after thymus removal," Taylor noted.

"However, the diminished richness of the [T-cell receptor] repertoire may be related to the significantly higher levels of inflammatory cytokines that were detected in patients who had undergone thymectomy, regardless of whether cancer developed after surgery," she added.

"Thus, the immune environment in patients who have undergone thymectomy is biased toward a cytokine milieu that is known to result in immune dysregulation and inflammation," she wrote. "Although the mechanisms contributing to this microenvironment are not clear, it is tempting to speculate that the thymus may regulate T-cell function through the physiological recirculation of mature T cells into this organ."

"[O]ne could hypothesize that the recirculation of activated T cells to the thymus may induce self-tolerance or negative selection, providing a level of regulation that would be removed by thymectomy," she said.

The researchers cautioned that the retrospective and observational study design precluded determination of causality of the findings.

"However, they provide evidence of an association between thymectomy and adverse outcomes in patients," Scadden and colleagues concluded. "These results strongly suggest that when possible, preservation of the thymus should be a clinical priority."

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