Potential role of tirabrutinib as part of an optimal treatment strategy for lymphomatosis cerebri: illustrative case

Abstract

BACKGROUND

Lymphomatosis cerebri (LC) is a rare variant of primary CNS lymphoma characterized by diffuse fluid-attenuated inversion recovery (FLAIR) hyperintensity on MRI.

OBSERVATIONS

A 71-year-old woman presented with a 1-month history of nausea. On admission, she showed no focal neurological deficits except dizziness. MRI revealed diffuse FLAIR hyperintensity from the cerebellar vermis to the midbrain involving the right temporal and parietal lobes, accompanied by partial diffusion-weighted imaging (DWI) hyperintensity and no gadolinium enhancement. ¹⁸F-fluorodeoxyglucose positron emission tomography demonstrated no abnormal uptake, and CSF analysis demonstrated elevated β2-microglobulin (MG) levels and an MYD88 mutation on cell-free DNA that leaked into the CSF. A targeted biopsy of the DWI-hyperintense region confirmed CD20-positive diffuse large B-cell lymphoma. She underwent therapy with rituximab, methotrexate, procarbazine, and vincristine followed by high-dose cytarabine, achieving temporary remission; however, relapse occurred 1 month after consolidation therapy. Tirabrutinib was initiated, resulting in complete radiological resolution for 5 months.

LESSONS Diffuse white matter abnormalities without enhancement should raise suspicion of LC and prompt targeted biopsy, particularly from DWI-hyperintense regions. CSF β2-MG and MYD88 mutation analysis provide valuable diagnostic clues for distinguishing LC from malignant glioma. This case also suggests a potential therapeutic role for tirabrutinib in early-relapsing LC.

https://thejns.org/doi/10.3171/CASE26337

Lymphomatosis cerebri (LC) represents a rare distinct subtype of primary CNS lymphoma (PCNSL) characterized on MRI by diffuse fluid-attenuated inversion recovery (FLAIR) hyperintensity without definitive contrast enhancement or, at most, minimal enhancement lacking discrete mass formation.¹ This often results in substantial delays in diagnosis and the initiation of appropriate therapeutic interventions.^2,3 Herein, we report a rare case of LC presenting as a completely nonenhancing, diffuse lesion on MRI, in which determining the optimal therapeutic strategy proved challenging. We also highlight the usefulness of preoperative CSF analysis, particularly β2-microglobulin (MG) levels and MYD88 mutation testing, as valuable indicators for distinguishing LC from glioma. In addition, we describe the potential applicability of tirabrutinib in the management of this rare entity.

Illustrative Case

A 71-year-old woman with no relevant medical history was admitted to our hospital with nausea and gradually worsening dizziness over 1 month. On admission, she was alert with no focal deficits except dizziness. MRI showed FLAIR hyperintensity from the cerebellar vermis to the midbrain and in the right temporal and parietal lobes, with partial diffusion-weighted imaging (DWI) hyperintensity and no gadolinium enhancement (Figs. 1 and 2). ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated no abnormal uptake in either the intracranial lesions or elsewhere in the body (Fig. 2), and the CSF β2-MG level was elevated at 5.1 mg/L, accompanied by the detection of an MYD88 gene mutation on cell-free DNA that leaked into the CSF using the ultrarapid GeneSoC real-time polymerase chain reaction (PCR) system (Kyorin Pharmaceutical Co., Ltd.). No other laboratory findings were abnormal. Despite the markedly atypical presentation, the integration of the patient’s clinical history with laboratory and radiological evaluations initially pointed toward malignant lymphoma as the most likely diagnostic consideration. To refine the histopathological diagnosis and guide an optimal treatment strategy, we performed a surgically navigated biopsy of the right parietal lesion, specifically targeting the area corresponding to the region of high signal intensity on DWI (Fig. 3A). Intraoperatively, the specimen appeared slightly yellowish and exhibited no red fluorescence on photodynamic diagnosis using 5-aminolevulinic acid. Rapid intraoperative genetic testing by tumor tissue detected an MYD88 mutation, consistent with the CSF-based molecular analysis above (Fig. 3B). Intraoperative rapid histopathological frozen-section evaluation revealed atypical lymphoid cells predominantly distributed in a perivascular pattern. Immunohistochemical analysis showed that the tumor cells were positive for CD20 and negative for CD3 (Fig. 3C– F). Based on these pathological and molecular findings, the lesion was diagnosed as malignant lymphoma, and surgery was performed following acquisition of the biopsy samples. Postoperative histopathological examination with hematoxylin and eosin staining revealed focal lymphocytic infiltration composed of atypical large lymphocytes with irregular nuclei (Fig. 4A and B). Immunohistochemical analysis demonstrated CD20 positivity (Fig. 4C), leading to a histological diagnosis of diffuse large B-cell lymphoma (MIB-1 index 50%). In addition, a nongerminal center B-cell-like phenotype was identified based on CD10 negativity and BCL6 and MUM1 positivity, according to the decision tree proposed by Hans et al. (Supplementary Fig. 1).⁴ Treatment based on the PCNSL protocol was initiated on postoperative day 2. The patient received four cycles of R-MPV (rituximab, methotrexate [MTX], procarbazine, and vincristine) as induction therapy, resulting in complete radiological resolution of the target lesions on MRI, with the exception of residual FLAIR hyperintensity at the biopsy site. Subsequently, two cycles of high-dose cytarabine were administered as consolidation therapy. At 6 months after treatment initiation, MRI demonstrated no evidence of recurrence (Fig. 4D– G), and the patient’s symptoms had fully resolved, allowing for discharge from the hospital. However, 1 month after completion of consolidation therapy (7 months after treatment initiation), the patient developed recurrent dizziness and nausea. MRI demonstrated the reappearance of a FLAIR-hyperintense lesion at the original tumor site, consistent with relapse (Fig. 5A– D). Consequently, tirabrutinib therapy was initiated. The lesion decreased in size within 1 month and achieved complete radiological resolution by 2 months. At 5 months after initiation of tirabrutinib, MRI showed no evidence of recurrence (Fig. 5E– H).

FIG. 1.

A–D: Preoperative axial MR images obtained on initial admission showing multiple lesions from the cerebellar vermis to the midbrain and in the right temporal and parietal lobes. The lesions show FLAIR hyperintensity.

FIG. 2.

A–H: FLAIR-hyperintense lesions demonstrating partial hyperintensity on diffusion-weighted images (A–D) and no gadolinium enhancement on T1-weighted images (E–H). I–M: FDG-PET scans showing no abnormal uptake in either the intracranial lesions or elsewhere in the body. N: Molecular analysis of the CSF using the GeneSoC ultrarapid PCR system revealed the presence of an MYD88 mutation (green line: MYD88 wildtype, blue line: MYD88 mutation). The dotted circle indicates the amplification derived from the mutation plotted as the y-axis signal intensity, and the x‑axis represents PCR cycle number. a.u. = arbitrary unit of fluorescence detected with GeneSoC.

FIG. 3.

A: Surgically navigated biopsy of the right parietal lesion, specifically targeting the area corresponding to the region of high signal intensity on DWI. Photomicrographs revealed intraoperative rapid pathological analysis including immunostaining. B: Intraoperative rapid genetic analysis using GeneSoC shows the presence of an MYD88 mutation (green line: MYD88 wildtype, blue line: MYD88 mutation). The dotted circle indicates the amplification derived from the mutation. C and D: Hematoxylin and eosin staining. E and F:Immunohistochemically, cells are negative for CD3 (E) but positive for CD20 (F). Original magnification ×200, scale bar 200 μm (C, E, and F); ×400, scale bar 100 μm (D).

FIG. 4.

A and B: Histological examination of a paraffin-embedded specimen from surgical biopsy showed lymphocytic tumor infiltration composed of atypical large lymphocytes with irregular nuclei. C:Immunohistochemical analysis demonstrating CD20 positivity, leading to a histological diagnosis of diffuse large B-cell lymphoma. D–G: Axial MR images obtained after consolidation therapy showing no evidence of obvious tumor. Original magnification ×200, scale bar 200 μm (A and C); ×400, scale bar 100 μm (B).

FIG. 5.

A–D: Axial MR images obtained 1 month after completion of consolidation therapy (7 months after treatment initiation), demonstrating the reappearance of a FLAIR-hyperintense lesion at the original tumor site. E–H: Axial MR images obtained 5 months after initiation of tirabrutinib showing no evidence of recurrence.

Discussion

PCNSL, which accounts for approximately 6.2% of malignant brain tumors, typically presents as a homogeneously enhancing intraparenchymal mass on MRI.^2,5 By contrast, LC is an extremely rare subtype of PCNSL characterized by diffuse, tract-based infiltration without a distinct mass lesion. LC usually shows limited perivascular clustering and preservation of the blood-brain barrier, resulting in absent or only subtle contrast enhancement, which often makes its diagnosis particularly challenging.¹ Li et al.⁶ defined LC as T2-hyperintense lesions involving at least three anatomical regions of the brain on early-stage MRI without mass-forming enhancement. In their cohort, 64.4% of cases demonstrated no initial enhancement, whereas 35.6% exhibited enhancement without mass formation; notably, 15.6% developed mass-forming enhancement during follow-up.⁶ In the present case, MRI revealed diffuse FLAIR hyperintensity without the homogeneous, well-defined contrast-enhancing mass, making it difficult to determine the appropriate treatment strategy based on imaging findings alone.

In our previous report, we demonstrated that CSF β2-MG levels and FDG-PET findings are useful markers for distinguishing lymphoma from other intracranial pathologies, including glioblastoma.⁷ Building on our previous findings, in the present case, we applied these two diagnostic modalities with the expectation that they would aid in differentiating lymphoma from other intracranial pathologies.⁷ Although FDG-PET showed no focal hypermetabolic uptake and therefore contributed little to diagnostic clarification, the marked elevation of CSF β2-MG proved highly informative and favored malignant lymphoma over malignant glioma, consistent with our clinical experience. In addition, detection of an MYD88 mutation in the CSF further increased our diagnostic confidence in this case and supported the decision to proceed with early histopathological confirmation. A critical consideration in this case was the selection of the biopsy target. Previous studies have indicated that, in LC without a clearly contrast-enhancing lesion, biopsies performed on FLAIR-hyperintense white matter may fail to yield a definitive diagnosis, necessitating meticulous selection of the sampling region.⁸ Accordingly, in our present case, rather than stereotactically targeting FLAIR-hyperintense white matter, we adopted a microscopic direct approach to the right parietal lesion displaying high signal intensity on DWI, which had emerged during the clinical course. On the basis of these findings and in light of the diagnostic challenges posed by LC, we proceeded with rapid diagnostic evaluations, which ultimately enabled an expedited and definitive diagnosis at an early stage.

Observations

Regarding therapeutic management following the diagnosis of LC, cohort data have shown that although 92.3% of patients receive some form of therapy, outcomes are generally poor: the median overall survival was 2 months in patients treated with corticosteroids alone or left untreated, 4.9 months with chemotherapy, 9 months with radiotherapy alone, and 20 months with combined chemoradiotherapy.⁹ By contrast, among patients who were able to receive MTX, a previous study reported a longer median overall survival of 13.8 months, identifying MTX as an independent favorable prognostic factor.³ In the present case, we administered R-MPV therapy, which resulted in radiological and clinical improvement for up to 6 months after treatment. However, despite consolidation therapy with high-dose cytarabine, the disease eventually recurred, suggesting that additional or alternative consolidation strategies may be required to achieve durable disease control. Of particular note, the subsequent administration of tirabrutinib resulted in a sustained remission lasting at least 5 months. To the best of our knowledge, no prior reports have described the use of tirabrutinib specifically in LC, suggesting that Bruton tyrosine kinase inhibition may represent a promising therapeutic option for this rare and diagnostically challenging phenotype. Given that MYD88 mutations, frequently detected in PCNSL,¹⁰ activate downstream Bruton tyrosine kinase signaling, the favorable response observed in this case is biologically plausible, although evidence in LC remains limited. While preliminary, this outcome supports the potential value of tirabrutinib as a salvage or adjunctive therapy in LC. Further accumulation of cases and prospective evaluation will be essential to clarify its efficacy, safety, and optimal integration into the treatment paradigm for LC.

Lessons

The present report describes an extremely rare case of LC. Given the rarity and diagnostic complexity of this entity, a multidisciplinary approach is essential. Diffuse white matter abnormalities on MRI should prompt consideration of LC and support the need for targeted brain biopsy, particularly from regions demonstrating high signal intensity on DWI. Moreover, preoperative analysis of CSF biomarkers, including β2-MG and MYD88 mutations, can provide valuable diagnostic clues and help differentiate LC from glioma. During follow‑up, careful monitoring of clinical symptoms combined with short‑interval MRI surveillance, with particular attention to FLAIR findings, was considered most informative in this case. The early relapse seen in the present case highlights the limitations of current therapeutic strategies. Notably, the subsequent administration of tirabrutinib resulted in a sustained remission lasting at least 5 months. This observation suggests that Bruton tyrosine kinase inhibition may be a promising therapeutic option for this rare and diagnostically challenging phenotype.

Acknowledgments

We express our gratitude to Takuya Kondo and Eiji Katayama of the Department of Pathology and to Taichi Furumochi and Yasuhiro Shiraishi of the Department of Neurology at Ehime University Hospital, Japan, for their assistance with the pathological and radiological imaging.

We used DeepL for translation of the Japanese draft to English and Copilot for verification of logic in the text.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Inoue, Ono. Acquisition of data: Inoue, Ono, Miyazaki, Nakamura, Ohno, Taniwaki, Yano, Watanabe. Analysis and interpretation of data: Inoue, Ono, Nakamura, Taniwaki, Yano. Drafting the article: Inoue, Ono. Critically revising the article: Inoue, Ono. Approved the final version of the manuscript on behalf of all authors: Inoue. Statistical analysis: Inoue. Administrative/technical/material support: Watanabe. Study supervision: Kunieda.

Supplemental Information

Online-Only Content

  Supplementary Fig. 1. https://thejns.org/doi/suppl/10.3171/CASE26337.

Correspondence

Akihiro Inoue: Ehime University School of Medicine, Shitsukawa, Toon, Ehime, Japan. iakihiro3@gmail.com.