Histologische Veränderungen von primären ZNS-Lymphomen nach Steroidtherapie im Vergleich zu chronisch-entzündlichen ZNS-Erkrankungen
Histological changes of primary CNS lymphomas after steroid therapy compared to chronic inflammatory CNS diseases
by Aylin Sophie Handan Engel née Haskiris
Date of Examination:2022-05-04
Date of issue:2022-04-22
Advisor:Prof. Dr. Christine Stadelmann-Nessler
Referee:Prof. Dr. Christine Stadelmann-Nessler
Referee:Prof. Dr. Björn Chapuy
Referee:Prof. Dr. Ralf Dressel
Persistent Address:
http://dx.doi.org/10.53846/goediss-9202
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Abstract
English
Primary central nervous system lymphomas (PCNSL) can resemble multiple sclerosis (MS) lesions not only clinically and radiologically, but also histologically if they have been pre-treated by glucocorticoids. They then appear as an inflammatory-demyelinating lesion. Lymphoma cells can be completely absent. Since the therapeutic approaches of both entities differ fundamentally and timely therapy is crucial, the histologically correct diagnosis is of great importance. Stereotactic biopsy and histological evaluation are the gold standard for PCNSL diagnosis. In the present work, to our knowledge, the largest cohort of histologically confirmed steroid-mediated lymphoma (SML) cases without detection of malignant lymphoma cells, but with clear features of inflammatory demyelination, was examined and analyzed for the first time in direct comparison to early-active multiple sclerosis cases. In addition to clinical data, traditional histological and immunohistochemical techniques were used to provide information about the myelin sheat in the brain as well as cell types and cell densities. The clearest distinguishing feature is the increase in T cell count in steroid-mediated lymphoma cases, so primary CNS lymphoma should always be considered for differential diagnosis in the case of older patient age and abundant presence of T cells. Both the T helper cells and the cytotoxic T cells were massively elevated and far above typical demyelinating diseases. Furthermore, a significantly increased proliferation rate in steroid-mediated lymphomas was noticed, even if it was far below the values of typical PCNSL without previous steroid administration. Furthermore, a focal demyelination without a sharp lesion boundary with mostly preserved axons and diffuse macrophage infiltration are characteristics of a steroid-mediated lymphoma. In contrast, MS lesions usually have a clear demyelination boundary, along which macrophages accumulate. In the margins of typical primary CNS lymphomas, neither increased T cell density nor myelin loss could be detected, so it can be assumed that these are not typical characteristics of lymphoma. With the help of the criteria described here, both entities can be better distinguished based on the higher T cell density in patients with steroid-treated lymphoma and the more pronounced demyelination with macrophages at the edge of MS lesions. From a clinical point of view, a significantly higher age of onset of the disease spoke in favor of the presence of primary CNS lymphoma. Nevertheless, one should not lose sight of the late forms of multiple sclerosis. However, these often have a primary-progressive course of the disease and are characterized by motor dysfunction and spinal lesions. In contrast, sight disorders and lesions in the cerebral hemispheres predominate in PCNSL. In the case of rapid clinical deterioration or radiologically increasing lesions that remain contrast enhanced, PCNSL should always be considered and excluded by differential diagnosis. Up to now, the exact molecular mechanisms of lesion formation in steroid-mediated lymphoma are unknown. Currently, glucocorticoids are assumed to be apoptosis triggers that cause cytotoxic T cell activation and macrophage infiltration. The macrophages phagocyte lymphoma cells and myelin, which could explain a low B cell density and diffuse demyelination in the SML cases. However, a high T cell density and the predominance of T helper cells indicate an inflammatory rather than apoptotic mechanism. In order to clarify the exact signaling pathways, further molecular studies will be necessary in the future.
Keywords: PCNSL; diffuse large B cell lymphoma; multiple sclerosis; inflammation; demyelination; corticosteroids
Schlagwörter: PZNSL; Diffus großzelliges B-Zell-Lymphom; Multiple Sklerose; Entzündung; Demyelinisierung; Glucocorticoide