Pathology for severe inflammatory PML with PD1/PD-L1 expression of favorable prognosis: What's a prognostic factor for PML-IRIS?

Abstract

A 72-year-old woman with dermatomyositis (DM) developed neurological manifestation, and magnetic resonance imaging (MRI) revealed multiple T2/fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions predominantly in the deep white matter of the cerebral hemisphere. Punctate or linear contrast enhancement was observed surrounding the T1-hypointense area. Multiple T2/FLAIR-hyperintense lesions were aligned along with the corona radiata. Malignant lymphoma was first suspected, and a brain biopsy was performed. Pathological investigation suggested the provisional diagnosis of "suspicious of malignant lymphoma." Owing to emergent clinical conditions, high-dose methotrexate (MTX) therapy was conducted, and then T2/FLAIR-hyperintense lesions were dramatically reduced. However, the diagnosis of malignant lymphoma was concerning since multiplex PCR demonstrated clonal restriction of the Ig H gene for B cells and TCR beta genes for T cells. Histopathology revealed the infiltration of both CD4⁺ and CD8⁺ T cells, and the CD4⁺ /CD8⁺ ratio was 4.0. Moreover, prominent plasma cells were observed, in addition to CD20⁺ B cells. Atypical cells with enlarged nuclei were present, and they were not hematopoietic but found as glial cells. JC virus (JCV) infection was verified with both immunohistochemistry and in situ hybridization; the final diagnosis was progressive multifocal leukoencephalopathy (PML). The patient was treated with mefloquine and discharged. This case is informative in understanding the host anti-viral response. Variable inflammatory cells were observed, including CD4⁺ and CD8⁺ T cells, plasma cells, and a small amount of perivascular CD20⁺ B cells. PD-1 and PD-L1 expression was observed in lymphoid cells and macrophages, respectively. PML with inflammatory reactions was thought fatal, and autopsy cases of PML with immune reconstitution inflammatory syndrome (IRIS) demonstrated excessive infiltration of only CD8⁺ T cells. However, this case revealed infiltration of variable inflammatory cells, and a favorable prognosis would be expected under PD-1/PD-L1 immune-checkpoint regulation.

Keywords: JC virus; PD-1/PD-L1; immune reconstitution inflammatory syndrome (IRIS); methotrexate (MTX); progressive multifocal leukoencephalopathy (PML).