PMC6465023_01
The chronological changes in brain magnetic resonance imaging findings. Gadolinium-enhanced T1-weighted brain magnetic resonance imaging. (A, B) Gadolinium-enhanced "peppering" lesions in the brachium pontis, cerebellum, and spinal cord at the initial episode. (C, D) An unremarkable response after two 3-day courses of intravenous methylprednisolone. (E, F) Complete remission of the brain lesion after radiochemotherapy and high-dose chemotherapy followed by autologous stem cell transplantation (HCT-ASCT). (G, H) The "peppering" punctate enhancement relapse at the second episode. (I, J) A remarkable reduction after two courses of intravenous methylprednisolone followed by oral prednisolone. (K, L) Relapse in the pons, cerebellum, and right frontal lobe at 6 months after the initiation of steroid treatment.
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Brain and spine MRI revealed punctate hyperintense lesions predominantly in the cerebellar region that involved the brachium pontis, pons, and spinal cord, with enhancement after the administration of gadolinium (Fig. 1A and B). However, there was no clear clinical or radiological improvement (Fig. 1C and D), which supported the suspicion of another etiology, such as PCNSL. These treatments provided moderate clinical improvement and complete radiological remission based on the brain MRI findings (Fig. 1E and F), although bilateral lower-limb paresis persisted as a sequela due to the spinal cord lesions. Four years after the initial PCNSL treatment, brain MRI revealed recurrent "peppering" punctate enhancing lesions in the cerebellum (Fig. 1G and H) and an additional enhancing lesion in the right frontal white matter (Fig. 3A and B) with no uptake of FDG. There was a marked decrease in the size of the brain lesions after the steroid treatment (Fig. 1I and J), and a slight improvement of the bilateral lower-limb paresis, which were both considered compatible with the response of CLIPPERS to treatment. However, at 6 months after the start of steroid treatment, brain MRI revealed an exacerbation of the brain lesions (Fig. 1K and L), and we re-started 3-day intravenous methylprednisolone treatment (1,000 mg).
The first biopsy of the cerebellum revealed perivascular lymphocytic infiltration but was inconclusive for diagnosing PCNSL due to steroid modification. (A) Perivascular lymphocytic infiltration with a small number of atypical cells [Hematoxylin and Eosin (H&E) staining], (B) with a higher-power field of the small number of large atypical cells (arrows, H&E staining). Staining for (C) CD20, (D) CD3, (E) and Ki-67 (labeling index: 5%). Bars indicate 100 microm (A, E) or 25 microm (B-D). PCNSL: primary central nervous system lymphoma
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Biopsy of the enhanced cerebellar lesion was performed, and the specimen exhibited perivascular lymphocytic infiltration (Fig. 2A) with a small number of large atypical cells in a high-power field (Fig. 2B). Immunohistochemistry revealed that the perivascular lymphocytes consisted of CD20+ B-cells (Fig. 2C) and CD3+ T-cells (Fig. 2D), without monotonous lymphocytic proliferation, and the Ki-67 labeling index was approximately 5% (Fig. 2E).
The second biopsy of the frontal lobe revealed non-specific inflammation that clinically suggested CLIPPERS. (A) Gadolinium-enhanced T1-weighted brain magnetic resonance imaging before the biopsy revealed the right frontal enhanced lesion. (B) Gadolinium-enhanced T1-weighted MRI of the brain after the biopsy. (C) Perivascular lymphocytic infiltration (Hematoxylin and Eosin staining), (D) but no atypical cells in a high-power field from (C). Staining for (E) CD20 and (F) CD3. Bars indicate 100 microm (C) or 50 microm (D-F). CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
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At 6 months after the appearance of radiological abnormalities, we performed a second brain biopsy, which revealed perivascular lymphocytic infiltration with a lower cell density than the first biopsy specimen (Fig. 3C). There were no apparent atypical cells in a high-power field of the second specimen (Fig. 3D). T-cells (Fig. 3F) and that no CD20+ B-cells were present (Fig. 3E). The specimen was considered to have non-specific inflammatory changes with no evidence of malignancy, demyelination, granuloma, or vasculitis (Fig. 3C-E), and the histological evaluation revealed only reactive changes due to inflammation.
The third biopsy of the cerebellum confirmed PCNSL. (A) Perivascular lymphocytic infiltration (Hematoxylin and Eosin staining) and (B) large lymphoid cells with irregular nuclei, fine chromatin, and prominent nucleoli in a high-power field from (A). Staining for (C) CD20, (D) CD3, and (E) Ki-67 (labeling index: 70%). (F) In situ hybridization of Epstein-Barr virus-encoded RNA (EBER-ISH). Bars indicate 100 microm (A, E) or 25 microm (B-D, F). PCNSL: primary central nervous system lymphoma
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The specimen exhibited numerous lymphocytes aggregating to the Virchow-Robin spaces (Fig. 4A), with "perivascular cuffing", which is a characteristic feature of diffuse large B-cell lymphoma (DLBCL) in the central nervous system (CNS). A high-power field revealed diffuse proliferation of large lymphoid cells with irregular nuclei, fine chromatin, and prominent nucleoli (Fig. 4B). Immunohistochemistry revealed that the infiltrating cells were CD20+ B-cells (Fig. 4C) with almost no CD3+ T-cells (Fig. 4D) and that the Ki-67 labeling index was 70% (Fig. 4E). EBV involvement was confirmed using in situ hybridization of EBV-encoded RNA (EBER) (Fig. 4F).