Summary The Second Conference on Biological and Clinical Aspects of Thymic Epithelial Tumors in Leiden, The Netherlands, 1998, set the stage for an interdisciplinary meeting of immunologists, pathologists and membersof various clinical disciplines to exchange their recent findings in the field of thymus-related biology, pathology, and medicine. The contributions covered such diverse subjects as the role of transcription factors and cytokines in the development of the thymic microenvironment, thymic T, B and NK cell development, the pathogenesis of myasthenia gravis and other thymomaassociated autoimmunities, the pathology of thymic epithelial tumors and germ cell neoplasms, and new approaches to their diagnosis and treatment. This editorial will briefly sum up the data presented at the Conference and will comment on related novel findings that have been reported since then. Because it was also at the Leiden Conference, that the proposal of the WHO committee for the classification of thymic tumors was discussed for the first time, a description of the upcoming WHO Classification of Tumors of the Thymus is given with emphasis on the diagnostic criteria of thymic epithelial tumors, that should now be termed as type A, AB, B1-3 and type C thymomas, to make pathological and clinical studies comparable in the future.

From basic immunobiology to the upcoming WHO-classification of tumors of the thymus. The Second Conference on Biological and Clinical Aspects of Thymic Epithelial Tumors and related recent developments.

Recent advances in tissue culture technology and molecular biology have extended our understanding of the functional morphology of the thymus. The importance of a crosstalk between lymphoid cells and stroma has been appreciated as a prerequisite for the normal development of both. The network of direct cellular interactions and soluble factors comprising part of the microenvironment is far from being elucidated but the highly ordered thymic architecture clearly plays a pivotal role in normal thymic function. Insight into the genetic control of stroma development is only emerging while knowledge on the genetic control of the various steps in T cell development is already advanced and rapidly expanding. The present paper gives an overview on the cellular components and matrix molecules of the human thymic microenvironment and their development during ontogeny. The intrathymic cytokine network is shortly reviewed. Special emphasis is put on molecules mediating lymphoepithelial interactions that are necessary for the expansion and early selection of immature thymocytes from precursor cells and for the generation of an MHC restricted and self tolerant T cell repertoire by positive and negative selection. Considering these physiological mechanisms we summarize the molecular pathology of the microenvironment and lymphocyte/stroma interactions in thymic epithelial tumors (thymomas). Finally, a pathogenetic model for paraneoplastic myasthenia gravis is given. We suggest abnormal auto-antigen-specific positive selection of naive T cells as the essential molecular mechanism by which thymomas contribute to the autoimmunization against the acetylcholine receptor and other muscle proteins.

https://www.jstage.jst.go.jp/article/aohc1988/60/1/60_1_9/_pdf

Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma.

Thymomas occurring in myasthenia gravis (MG) are usually of the cortical subtype and are usually treated by thymectomy. However, the factors that influence MG outcome in thymoma MG patients are not known. In a long-term study, MG severity and treatment was observed in 24 thymoma and 24 non-thymoma MG patients for up to 30 years, and the occurrence of muscle autoantibodies was assayed. The rate of complete stable remission was low and did not differ between the two groups. There was no significant difference in MG severity between thymoma and non-thymoma MG patients at any time during the study. Titin and ryanodine receptor (RyR) antibody occurrence was significantly higher in thymoma MG patients. Four thymoma (all titin and RyR antibody positive) and two non-thymoma (both titin and one RyR antibody positive) MG patients died from MG-related respiratory insufficiency. Seventy percent of thymoma and 75% of non-thymoma MG patients were treated with immunosuppressive drugs. The number of patients who received plasmapheresis did not differ in those who were treated because of acute MG deterioration, irrespective of planned surgery.This study shows equal MG severity and outcome in thymoma and non-thymoma MG, but the presence of RyR antibodies in thymoma MG and titin/RyR in non-thymoma MG indicates a less favorable prognosis.

Disease severity and outcome in thymoma myasthenia gravis: a long-term observation study

https://www.exphem.org/article/S0301-472X(99)00010-7/pdf

Adhesion molecules involved in the interactions between early T cells and mesenchymal bone marrow stromal cells.

Progress in the pathogenesis, diagnosis, and treatment of thymomatous myasthenia gravis (MG) has been made in the past several decades. These advances have occurred along diverse lines of immunology, molecular genetics, and tumor cytopathology. The most widely used classification for thymoma closely correlates with tumor biology, prognosis, and the likelihood of association with MG. There is a sensitive immunoassay for the detection of striational autoantibodies, which are closely related to the presence of thymoma, although their precise origin is still debated. Chest computed tomography (CT) can delineate a thymoma with extraordinary accuracy and sensitivity. The goal of treatment is complete removal of the tumor and remission or sustained improvement of MG. This is usually achievable with trans-sternal maximal thymectomy and chronic immunosuppressant medication. In this article, we consider aspects of the historical background, pathogenesis, diagnosis, and treatment of thymomatous MG.

There was no mention of thymic abnormalities in the classic descriptions of myasthenia patients by Wilks, [1] Erb, [2] Goldflam, [3] and Jolly, [4] or among the autopsies reported by Campbell and Bramwell at the turn of the century [5] until 1901 when Laquer and Weigert [6,7] described a patient with myasthenia and a thymic tumor. Later, Bell, [8] Blalock, [9,10] and others found that the thymus gland in myasthenia was enlarged or the site of a tumor in the majority of patients at surgery or autopsy. Thymectomy, with the intention to resect the gland totally became standard treatment. [11-15]

The estimated overall frequeny of thymoma in MG varies from 15 to 30%. [16-22] It is more common with increasing age, with an estimated frequency of 3% for age 20 years or younger, 12% for ages 21 to 45, and 35% for age 46 years and older. [23] Although detection of thymoma most often follows the clinical diagnosis of MG, …

Myasthenia gravis with thymoma

Two findings in thymic epithelial tumors are correlated with the occurrence of myasthenia gravis(MG): (1) the expression of an acetylcholine receptor (AChR)-like-epitope in the neoplastic epithelium, and (2) the preservation of thymus-like features in the neoplasms, indicated by the presence of immature thymocytes. On this background it has been proposed that paraneoplastic MG may start with an intratumorous abnormal T cell selection due to aberrantly expressed AChR-epitopes (self-peptides). As appropriate thymocyte-stroma-interactions are prerequisites for thymocyte development in the thymus (and probably in MG-associated thymic tumors, too), we analyzed the expression of CD28/B7(BB1), CD2/:LFA3, LFA-1/ICAM-1 and VLA-4/VCAM-1 in human thymus and thymomas by immunohistochemistry. In normal thymuses and thymitis the stromal molecules were expressed at higher levels in the medulla than in the cortex. This was particularly true for B7(BB1) that was undetectable by immunoperoxidase techniques in the cortex. In contrast, cortical-type thymic epithelial tumors (cortical thymoma and well differentiated thymic carcinoma), known to exhibit the highest association with myasthenia, expressed the stromal molecules at almost medullary levels. The findings may be a clue to a functional difference between neoplastic and normal cortical epithelial cells: while we find the former to have the capacity to present soluble antigen to antigen-specific CD4+ T cells in vitro, normal cortical epithelium failed to do so. This altered microenvironment in thymomas might contribute to the autoimmunization by stimulating mature recirculating AChR-specific T cells.

Distribution of molecules mediating thymocyte-stroma-interactions in human thymus, thymitis and thymic epithelial tumors.

Autoantibodies against striated muscle proteins (particularly against titin), neuronal structures and the acetylcholine receptor are a hallmark of paraneoplastic Myasthenia gravis (MG). The stimulus for this autoimmunity remains enigmatic, because complete titin or nicotinic acetylcholine receptors are not found in these tumors. This study reports, that a monoclonal antibody (mAb 155) directed against the “Very Immunogenic Cytoplasmic Region” (VICE-α) of the acetylcholine receptor (α373 – 380) crossreacts with a 153 kD molecule only in cortical type thymomas. We could show by immunostaining and west-ernblotting that this molecule might be the medium molecular weight neurofilament NF-M. Since NF-M and titin share a common epitope, we observed that a crossreactive anti-titin antibody showed a similar staining pattern in cortical type thymomas as antibodies against NF-M and mAb 155. We suggest that one molecule, NF-M, which does contain titin and AChR epitopes and which is expressed in an inappropriate cortical environment in thymoma, might autosensitize maturing T-cells and initiate autoimmunity in patients with paraneoplastic MG against the three main autoantigen targets: AChR, titin and neuronal structures.

Titin Epitope in Thymoma

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Distribution of molecules mediating thymocyte-stroma-interactions in human thymus, thymitis and thymic epithelial tumors.

Titin Epitope in Thymoma