Intracerebral lymphoproliferative disorder in an MS patient treated with fingolimod

Case report

In January 2017, a 38-year-old man diagnosed with RRMS 3 years before presented with progressive dysarthria, vertigo, vomiting, and deficits in balance 6 months after starting fingolimod therapy. Fingolimod was initiated because of persistent disease activity after treatment with dimethyl fumarate (2014–2015) and interferon-beta 1a (2015–2016). The patient had no significant medical history other than MS. Neurologic examination showed profound dysarthria and mild left-sided ataxia; with a normal gait. Fingolimod-induced peripheral blood lymphopenia (0.24 × 10⁹/L) was noted. MRI scan of the brain revealed new multifocal contrast-enhancing lesions (figure, A) suggestive of CNS lymphoma. Fingolimod was discontinued immediately. There were no signs of systemic or ocular lymphoma involvement based on history, physical examination, and whole-body PET-CT. Six days after the MRI scan, a stereotactic biopsy of a left cerebellar lesion was performed and dexamethasone 8 mg daily was administered. Three weeks later, MRI scan of the brain revealed a decrease in the size of lesions observed in the previous scan; however, a new contrast-enhancing lesion was observed in the left frontal lobe. Shrinkage of the cerebellar lesion enabled lumbar puncture, which was contraindicated before because of compression on the fourth ventricle. Cerebrospinal fluid showed elevated protein levels (1.02 g/L) and leukocyte count (10 × 10⁶/L) without morphological or immunophenotypical abnormalities. Dexamethasone was tapered and stopped. A second follow-up MRI showed progression of left cerebellar and frontal lesions. A second stereotactic brain biopsy was performed because the first biopsy was considered inconclusive at that time. Both biopsy samples showed a lymphoproliferative process in the normal-appearing brain parenchyma, predominantly T cells with a small subpopulation of small B cells (figure, B; figure e-1, links.lww.com/NXI/A58). Immunohistochemical and molecular analysis supported oligoclonal proliferation of both B and T cells. However, the aberrant T-cell phenotype (CD4⁺/PD1⁺) and genotype were most consistent with a reflection of dominant T-cell dysregulation, possibly with premalignant features and likely an association with a minor dysregulated B-cell proliferation (small cell, EBV negative). A diagnosis of overt malignant lymphoma was not appropriate based on these features. Considering the clinical context, a working diagnosis of T-cell primary CNS lymphoma (PCNSL) was made, despite the absence of confirmed T-cell monoclonality. Treatment with 2 induction chemotherapy cycles of MBVP (methotrexate, carmustine, teniposide, and prednisone) resulted in a significant shrinkage of the tumor-like lesions on repeated brain MRI. A subsequent single course of high-dose cytarabine resulted in further remission of the multifocal intracranial process. Consolidation treatment consisted of a conditioning regimen containing carmustine and thiotepa, followed by autologous hematopoietic stem cell transplantation. During treatment and 6 months of follow-up, MS remained clinically and radiologically stable and the tumor-like lesions shrunk.

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Figure Brain MRI findings before and during appearance of lymphoproliferative disorder and pathology findings of cerebellar lesion

(A) 3D dimensional FLAIR in the axial plane at the time just before fingolimod initiation (July 2016) and after the patient became symptomatic (February 2017). Multifocal new lesions bilateral in the posterior fossa, thalamus, caudate nucleus, and frontal cortical gray matter occurred (arrows). In particular, the lesions in the left cerebellar hemisphere showed mass effect and vasogenic edema. Homogeneous contrast-enhancement patterns on the contrast-enhanced T1-weighed images (T1 Gd) and the intermediate low apparent diffusion coefficient (ADC) values of the diffusion weighted (DWI) images suggesting a higher cellularity raised the suspicion of a multifocal lymphoid proliferation. (B) Brain biopsy showing features of a moderately dense small cell lymphoid infiltrate without cellular atypia and without necrosis. Immunohistochemical staining underpinned a T-cell phenotype (CD3, CD4, CD5, and CD2) with a remarkable large proportion of PD1 positive T cells. There were only few small B cells (CD20, CD79a, and PAX5) and large, transformed cells were lacking. CD3- and CD20-positive cells are shown in figure e-1 (links.lww.com/NXI/A58). Sporadic EBER-positive small cells were present. Molecular T-cell receptor gene rearrangement analysis showed a pattern consistent with several synchronous dominant clones that differed between the 2 biopsies. This pattern further supported an oligoclonal process. Immunoglobulin gene rearrangement also showed a pattern consistent with an oligoclonal B-cell proliferation. The T-cell phenotype and genotype were most consistent with a reflection of a dominant T-cell dysregulation, possibly with premalignant features and likely in association with a dysregulated B-cell proliferation, which was also of the nontransformed type and EBV negative. Immunohistochemical staining for CCR6 in the lymphoid infiltrate brain tissue was performed according to standard methods (see data supplement, links.lww.com/NXI/A59). After washing, nuclear counterstaining was performed using DAPI. ADC = apparent diffusion coefficient; DAPI = 4′,6-diamidino-2-phenylindole; DWI = diffusion weighted images; EBER = in situ hybridization for Epstein-Barr virus; FLAIR = fluid-attenuated inversion recovery; T1 Gd = contrast-enhanced T1-weighted. Scale bars 50 μm.