Better Surgery Outcomes Tied to More, Larger Thymus B-cell Clusters

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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More or larger clusters of developing B-cells, called germinal centers, in the thymus may predict better outcomes after thymus removal surgery in people with myasthenia gravis (MG), according to a recent study that utilized modern tools of digital pathology to support its findings.

“Digital pathology can thus help in providing a predictive tool to the clinician … to guide the post-thymectomy treatment decisions,” the researchers wrote. Pathology refers to the study of an illness based on the examination of tissue samples.

The study, “Ectopic germinal centers in the thymus accurately predict prognosis of myasthenia gravis after thymectomy,” was published in Modern Pathology.

Ectopic germinal centers may form during autoimmune diseases in organs that are involved in the attack on the immune system. They are called ectopic because they normally do not form there.

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They are found in the thymus of most patients with early-onset MG and in less than 25% of patients with late-onset MG. In early-onset MG, the first symptoms typically appear before age 50, while in late-onset MG, they start after 50. The thymus is a gland-like organ behind the breastbone and above the heart that is part of the immune system.

Antibodies against acetylcholine receptors (AChR), which block AChR on muscle cells, cause muscle weakness in people with MG. These antibodies are made in the thymus and their levels are linked to an increase in the number of cells in the thymus, as well as the number of ectopic germinal centers.

Although thymus removal surgery, or thymectomy, is often considered for people with MG,  its real effects are unclear, even for those without thymus involvement.

“Most patients do not reach remission after operative treatment, and the use of immunosuppressants is often advised for years, which can lead to severe side effects,” the researchers wrote. “Better biomarkers to identify patients with a high likelihood of remission are thus needed to guide treatment decisions.”

A deeper examination of thymus tissues might be of help.

Hematoxylin and eosin staining, also known as H&E staining, is a common laboratory procedure that uses two dyes — hematoxylin and eosin — that aid pathologists’ ability to identify different types of cells and structures in a tissue sample. This is usually done manually.

The researchers examined portions of the thymus from MG patients using modern tools of digital pathology. Then they compared their pathological findings with clinical data to predict the chance of remission after thymectomy.

The study included 83 people with MG, 69 with early-onset and 14 with late-onset disease (67 women and 16 men), whose records were available at Helsinki University Hospital, Finland.

The study included 37 children (21 girls and 16 boys) who had undergone corrective open-heart surgery between the ages of four days and 6 years who served as controls.

Slides with H&E-stained tissues were digitized using a scanner and analyzed using QuPath, an open-access software tool for digital pathology.

The researchers observed that QuPath’s automated workflow yielded similar results to manual annotation.

Compared to patients with late-onset MG, those with early-onset MG had a larger thymus. Its structures — medulla, cortex, and stroma — were also larger, but the amount of fatty tissue was lower than that seen in patients with late-onset MG. The control children had a smaller thymus than MG patients.

Researchers observed at least one ectopic germinal center in 73% of patients with early-onset MG and in 57% with late-onset MG. The older the patients were at the time of thymectomy, the fewer ectopic germinal centers. Patients with early-onset MG had 4.8-times more ectopic germinal centers than those with late-onset MG, and they were 11 times larger.

The presence of antibodies against AChR was linked to the number of ectopic germinal centers in patients with early-onset MG, but not in those with late-onset MG. According to the researchers, this finding supports previous ideas that antibodies against AChR are made in ectopic germinal centers in the thymus.

The researchers then compared their pathological findings with clinical data collected at two years after thymectomy and at the last follow-up visit in patients with early-onset MG. They found that patients with a higher number of ectopic germinal centers had better outcomes after thymectomy, meaning they required either no treatment or minimal use of medication.

Both the number and the area of ectopic germinal centers were found to predict the outcomes of thymectomy in patients with early-onset MG.

“A high number of ectopic germinal centers in MG thymus at the time of thymectomy correlates with a better post-thymectomy outcome,” the researchers wrote, adding that a “lack of thymic ectopic germinal centers could be used as a predictive marker for disease progression in [early-onset MG].”

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