Risk factors associated with myasthenia gravis in thymoma patients: The potential role of thymic germinal centers.

Lefeuvre CM1, Payet CA1, Fayet OM1, Maillard S1, Truffault F1, Bondet V2, Duffy D2, de Montpreville V3, Ghigna MR3, Fadel E3, Mansuet-Lupo A4, Alifano M4, Validire P5, Gossot D5, Behin A6, Eymard B6, Berrih-Aknin S1, Le Panse R7.

Author information

1: Sorbonne University, INSERM, Association Institute of Myology, Center of Research in Myology, UMRS 974, Paris, France.
2: Immunobiology of Dendritic Cells, INSERM U1223, Institut Pasteur, Paris, France.
3: Department of Pathology, Marie Lannelongue Hospital, Paris-Sud University, Le Plessis-Robinson, France.
4: Department of Pathology, Cochin University Hospital Group, AP-HP, Paris-Descartes University, Paris, France.
5: Department of Pathology, Institut Mutualiste Montsouris, Paris, France.
6: AP-HP, Referral Center for Neuromuscular Disorders, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.
7: Sorbonne University, INSERM, Association Institute of Myology, Center of Research in Myology, UMRS 974, Paris, France. Electronic address: rozen.lepanse@upmc.fr.

Abstract

Thymomas are associated with a very high risk of developing Myasthenia Gravis (MG). Our objectives were to identify histological and biological parameters to allow early diagnosis of thymoma patients susceptible to developing MG. We conducted a detailed retrospective analysis from a patient database, searching for differences between patients with thymoma-associated MG (MGT, n = 409) and thymoma without MG (TOMA, n = 111) in comparison with nonthymomatous MG patients (MG, n = 1246). We also performed multiplex and single molecule arrays to measure the serum levels of cytokines in these groups of patients and controls (n = 14-22). We identified a set of parameters associated with MG development in thymoma patients: 1) detection of anti-acetylcholine receptor (AChR) antibodies, 2) development of B1 or B2 thymoma subtypes, 3) presence of ectopic thymic germinal centers (GCs), 4) local invasiveness of thymoma, and 5) being a woman under 50 years old. Among these parameters, 58.8% of MGT patients displayed GCs with a positive correlation between the number of GCs and anti-AChR titers. By immunohistochemistry, we found thymic GCs in the adjacent tissues of thymomas encircled by high endothelial venules (HEVs) that could favor peripheral cell recruitment. We also clearly associated MG symptoms with higher IFN-γ, IL-1β and sCD40L serum levels, specifically in MGT patients compared to TOMA patients. Altogether, these analyses allowed the clear identification of histological, in particular the presence of GCs, and biological parameters that would facilitate the evaluation of the probability of the MG outcome postoperatively in thymoma patients.