Background: Treatment for refractory or relapsed primary CNS lymphoma (r/r PCNSL) is challenging. Salvage whole-brain radiation therapy (WBRT) is an option but has a short duration of disease control, so additional treatment modalities are warranted. Case: A 75-year-old female with r/r PCNSL who had multiple progressions after multiple lines of treatment underwent salvage WBRT. The patient received ibrutinib, a Bruton's tyrosine kinase inhibitor, as maintenance therapy for 18 months following WBRT with the intention of increasing survival duration after salvage WBRT. She survived 81 months from diagnosis, including 57 months after completion of WBRT. Conclusion: This case presentation describes the experience of using ibrutinib as maintenance therapy in treating r/r PCNSL after salvage WBRT.

In this editorial, we comment on the article by Wang et al. This manuscript explores the potential synergistic effects of combining zanubrutinib, a novel oral inhibitor of Bruton's tyrosine kinase, with high-dose methotrexate (HD-MTX) as a therapeutic intervention for primary central nervous system lymphoma (PCNSL). The study involves a retrospective analysis of 19 PCNSL patients, highlighting clinicopathological characteristics, treatment outcomes, and genomic biomarkers. The results indicate the combination's good tolerance and strong antitumor activity, with an 84.2% overall response rate. The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL, particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B. Furthermore, the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring. In essence, the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL. The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes. While the findings suggest promise, the study's limitations should be considered, and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.

The microenvironment of lymphomas is known to be highly variable and closely associated with treatment resistance and survival. We tried to develop a physiologic MR imaging-based spatial habitat analysis to identify regions associated with treatment resistance to facilitate the prediction of tumor response after initial chemotherapy in patients with primary central nervous system lymphoma.

Eighty-one patients with pathologically confirmed primary central nervous system lymphoma were enrolled. Pretreatment physiologic MR imaging was performed, and K-means clustering was used to separate voxels into 3 spatial habitats according to ADC and CBV values. Associations of spatial habitats and clinical and conventional imaging predictors with time to progression were analyzed using Cox proportional hazards modeling. The performance of statistically significant predictors for time to progression was assessed using the concordance probability index.

The 3 spatial habitats of hypervascular cellular tumor, hypovascular cellular tumor, and hypovascular hypocellular tumor were identified. A large hypovascular cellular habitat was most significantly associated with short time to progression (hazard ratio, 2.83; P = . 017). The presence of an atypical finding (hazard ratio, 4.41; P = . 016), high performance score (hazard ratio, 5.82; P = . 04), and high serum lactate dehydrogenase level (hazard ratio, 1.01; P = .013) was significantly associated with time to progression. A predictive model constructed using the habitat score and other imaging parameters showed a concordance probability index for prediction of time to progression of 0.70 (95% CI, 0.54-0.87).

A hypovascular cellular tumor habitat is associated with treatment resistance in primary central nervous system lymphoma, and its assessment may refine prechemotherapy imaging-based response prediction for patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma is a rare and aggressive extranodal non-Hodgkin lymphoma restricted to the brain, spinal cord, cerebrospinal fluid, and eyes. Optimization of treatment including high-dose methotrexate-based chemotherapy followed by consolidation therapy in the form of autologous stem cell transplant or whole-brain radiation leads to improved survival. However, several patients do not respond to upfront therapy and the relapse risk is high. Additionally, there is a risk of delayed neurotoxicity, particularly in older patients. Recent molecular insights underlying the pathophysiology of PCNSL have led to the development of clinical trials involving targeted therapies and immunotherapies for salvage.

Diffuse large B cells in the cerebrospinal fluid (CSF-DLBCs) have offered great promise for the diagnostics and therapeutics of central nervous system lymphoma (CNSL) leptomeningeal involvement. To explore the phenotypic states of CSF-DLBCs, we analyzed the transcriptomes of more than one thousand CSF-DLBCs from six patients with CNSL diffuse large B-cell lymphoma (DLBCL) using Smart-seq2 single-cell RNA sequencing. CSF-DLBCs were defined based on abundant expression of B-cell markers, the active cell proliferation and energy metabolism properties, and immunoglobulin light chain restriction. We identified inherent heterogeneity of CSF-DLBCs, which were mainly manifested in cell cycle state, cancer-testis antigen expression, and classification based on single-cell germinal center B-cell signature. In addition, the 16 upregulated genes in CSF-DLBCs compared to various normal B cells showed great possibility in the homing effect of the CNS-DLBCL for the leptomeninges. Our results will provide insight into the mechanism research and diagnostic direction of CNSL-DLBCL leptomeningeal involvement.

Primary lymphoid neoplasms of the central nervous system are rare tumors that span a wide range of histopathologic appearances and can overlap occasionally with non-neoplastic processes. Application of modern molecular techniques has not only begun to unravel their unique underlying biology but has also started to lay a valuable diagnostic and therapeutic framework for these frequently aggressive malignancies. This review summarizes the existing landscape of clinicopathologic and genomic features of lymphoid neoplasms that may arise primarily within the central nervous system.

Primary central nervous system lymphoma is a rare malignant tumor of the central nervous system. It is associated with poor prognosis and accounts for 0.7%-0.9% of all lymphomas and only 0.3%-1.5% of intracranial tumors. Typically, these lesions are in the cerebral white matter near the corpus callosum, the central gray matter, the basal ganglia-thalamus-hypothalamic region, the posterior fossa and the periventricular region. Only 2 cases with pure third ventricular lymphoma have been reported in the literature.

A 72-year-old female patient known to have type II diabetes mellitus treated with insulin, hypertension, chronic kidney disease, dyslipidemia, and obesity presented with a history of acute confusion and urinary incontinence. No headache was reported on admission, but previously she had intermittent mild headaches and generalized body aches. She had no history of visual symptoms. Her family said she was mildly confused and had memory difficulties that started acutely 2 days before presentation to the hospital. The patient had urgent computed tomography of the brain, which showed a hyperdense lesion in the region of the foramen of Monro. Pre-operative images diagnosed the case as colloid cyst, but post-operative histopathology proved the lesion to be primary CNS lymphoma.

Eleven months after surgery, the patient is fully consciousness and oriented, with no memory issues or neurologic deficit. She is back to her baseline activities. We are reporting this case for the rarity of the disease and the unusual location of it.

Primary Central Nervous System Lymphoma (PCNSL) and Metastatic (or Secondary) Central Nervous System Lymphoma (MCNSL) are rare central nervous system (CNS) malignancies that exhibit aggressive clinical behavior and have a poor prognosis. The majority of CNS lymphomas are histologically classified as diffuse large-B cell lymphoma (DLBCL). DLBCL harbors a high frequency of mutations in MYD88 and CD79b. The MYD88 p.L265P mutation occurs at high frequency in CNS lymphoma and is extremely rare in non-hematologic malignancies. Currently, brain biopsy is considered the gold standard for CNS lymphoma diagnosis. However, brain biopsy is invasive, carries a risk of complications, and can delay initiation of systemic therapy. Circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CSF) can be utilized to detect tumor-derived mutations. Testing of CSF-ctDNA is a minimally-invasive methodology that can be used to assess the genomic alterations present in CNS malignancies. We present a case of an 82-year-old man with a history of testicular lymphoma who presented with speech difficulty and a multifocal enhancing left inferior frontal mass. Analysis for both CSF-cytology and flow cytometry did not show evidence of neoplastic cells. A brain biopsy was performed and microscopic examination showed DLBCL. We isolated CSF-ctDNA and used droplet digital PCR (ddPCR) to detect the most common lymphoma-associated mutations in MYD88, L265P, and V217F. In conjunction, we evaluated the patient-matched CNS lymphoma tissue for MYD88 mutations. We detected the MYD88 p.L265P mutation in formalin fixed paraffin embedded (FFPE) tissue from the brain biopsy and the CSF-ctDNA. In contrast, both the tumor tissue and the CSF ctDNA were negative for the MYD88 p.V217F mutation. This study shows that testing CSF ctDNA for MYD88 mutations is a potentially minimally-invasive approach to diagnosing patients with suspected CNS lymphomas.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with poor long-term survival. This study assessed methotrexate (MTX) plus idarubicin (IDA) in treating patients of PCNSL comparing to MTX alone therapy. A total of 100 patients were retrospectively enrolled and subjected to MTX alone (n = 52) and MTX plus IDA (n = 48). The completed response (CR) rate in patients treated with MTX plus IDA was 62.50%, and overall response (OR) rate was 79.17%, which in MTX alone cohort were 42.31% and 63.46% respectively. Median progression-free survival (PFS) of patients treated with MTX plus IDA was significantly better than those treated with MTX alone (18.35 months vs.8.45months, P = 0.000). The MTX plus IDA regimen exhibited a significantly better control of PCNSL. Further studies would be needed to confirm these results.

Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic signatures. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs and PTLs exhibit frequent 9p24.1 copy-number alterations and infrequent translocations of 9p24.1 and associated increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations prompted us to test the efficacy of the anti-PD1 antibody, nivolumab, in 4 patients with relapsed/refractory PCNSL and 1 patient with CNS relapse of PTL. All 5 patients had clinical and radiographic responses to PD-1 blockade, and 3 patients remain progression-free at 13⁺ to 17⁺ months. Our data suggest that nivolumab is active in relapsed/refractory PCNSL and PTL and support further investigation of PD-1 blockade in these diseases.

The incidence of primary central nervous system lymphoma (PCNSL) has increased in the last two decades and the clinical research regarding the treatment for PCNSL patients has also increased. However, the optimal induction chemotherapy has not been fully established. In the present retrospective study, the aim was to analyze the outcome in PCNSL patients treated with the combination of rituximab, methotrexate (MTX), cytarabine (Ara-C) and dexamethasone (R-MAD). Eighteen patients from Beijing Tiantan Hospital (Beijing, China) between January 2010 and March 2014 were newly diagnosed with PCNSL [diffuse large B-cell lymphoma (DLBCL) type] and received R-MAD as first-line treatment. The dosage was as follows: 375 mg/m² rituximab was administered on day 0, 3.5 g/m² MTX was administered on day 1, 1 g/m² Ara-C was administered on day 2 and 10 mg dexamethasone was administered on days 1-3, every 3 weeks. After 6 cycles, the overall response rate was 94.5%. Ten (55.6%) patients achieved complete response (CR), 7 (38.9%) achieved partial response (PR) and 1 (5.6%) had progressive disease (PD). Patients were followed up from the start of the treatment, median 24.2 months (range 6-48). The overall survival (OS) rate was 94.5% and progression-free survival rate was 94.5%. The median OS was 22 months (95% confidence interval, 19.4-24.6). The high level of serum lactate dehydrogenase (LDH) concentration was associated with a poor outcome. Among 5 patients with an abnormally high LDH concentration, 1 achieved CR, 3 had PR and 1 had PD. None of the patients experienced any grade 4 toxicity. These results indicated that the R-MAD immunochemotherapy regimen is effective in PCNSL patients without serious toxicity. A prospective investigation with more patients should be administered in order to understand the more accurate effect of the regimen.

Primary central nervous system lymphoma (PCNSL) is a rare, highly malignant tumor type of the nervous system and is associated with poor prognosis. To investigate the efficacy of current treatment strategies for PCNSL, the present study retrospectively analyzed the clinical and pathological features, imaging results, clinical management, and prognoses of nine patients with PCNSL. Postoperative pathological examination confirmed a diagnosis of lymphoma in all the patients and the adopted treatment regimens were as follows: Stereotactic biopsy in combination with methylprednisolone (MP) and methotrexate (MTX) and/or radiotherapy; craniotomy in combination with dexamethasone or MP and/or radiotherapy; and neuroendoscopic surgery in combination with MP and MTX. The follow-up period was 5-27 months with an average duration of 10.1 months. After the initial three months of follow-up, the clinical symptoms of all the patients were significantly improved, with the tumor disappearing in seven patients and evidently reducing in size in two patients. However, six patients exhibited tumor recurrence, three of whom eventually succumbed to the disease during the follow-up period. Currently, comprehensive treatment strategies based on a combination of stereotactic biopsy, chemotherapy and radiotherapy are recommended for the treatment of PCNSL. However, the effectiveness of these treatments remains unsatisfactory. Thus, future studies are required to investigate methods for improving the efficacy of PCNSL treatment strategies.

We report a rare case of a primary central nervous system lymphoma (PCNSL) of the cerebellopontine angle (CPA) with infiltration into the pyramidal tract that initially presented as neurolymphomatosis (NL) of the acoustic nerve. A 60-year-old male suffered from right-side deafness and was referred to an otolaryngologist. Magnetic resonance imaging (MRI) showed fusiform enlargement of the right acoustic nerve with a hyperintense signal on a T₂-weighted image (T₂WI) and with gadolinium (Gd) enhancement, without an evidence of parenchymal CNS involvement. Although he was treated with steroids, his symptoms deteriorated. MRI was performed again and showed the mass lesion at the right CPA with enhancement. In addition to this, a lesion with slightly high intensity on a T₂WI with Gd enhancement was observed along the right pyramidal tract. Despite steroid pulse therapy, the lesion rapidly progressed. We performed a tumor biopsy, and the histological diagnosis was diffuse large B-cell lymphoma. Pelvic, abdominal, and chest computed tomography scans, gallium cintigraphy, and bone marrow biopsy failed to detect any other evidence of lymphomatous involvement of other organs. We attempted high-dose methotrexate therapy (3.5 g/m²). We found a discrepancy in the therapeutic effect between the CPA lesion and the infiltrated lesion along the pyramidal tract; the lesions were chemo-resistant and chemo-sensitive, respectively. After completion of the second courses of chemotherapy, we began radiotherapy (total dose: 36 Gy). Four months after radiotherapy, the CPA tumor completely disappeared. Thirty-three months after the biopsy, he is doing well with a normal daily life and no signs of recurrence.