Neuro-Oncology in the Elderly

Primary central nervous system (CNS) lymphoma is a rare disease, usually resistant to therapy. In the case presented, a 51-year-old woman with documented primary cerebellar CNS lymphoma, lymphoplasmacytoid type, underwent surgical resection and whole brain irradiation and then recurred within the CNS. Treatment with 17 courses of high-dose methotrexate resulted in complete disappearance of the tumor and clearing of all neurologic signs and symptoms. She is now free of disease 12 months after beginning chemotherapy. The potential usefulness of systemic anti-metabolites for treatment of CNS lymphoma, primary or disseminated, is discussed.

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

Polatuzumab vedotin in CNS lymphoma: proof-of-concept study for blood-brain barrier penetration.

Retrospective Review of Patients Treated with Intrathecal Rituximab for Primary and Secondary CNS Lymphoma and Leukemia

CD19-Targeting CAR-T Cell Therapy in CNS Lymphoma

Multiomic dissection of immune-privileged DLBCL reveals divergent immune subtypes in testicular and primary central nervous system lymphoma

Primary Central Nervous System Lymphoma Presenting as Growing Intracerebral Hemorrhage

Primary central nervous system lymphomas (PCNSLs) and high-grade gliomas (HGGs) arising in the cerebellum is extremely low, making the differential diagnosis difficult or even impossible. The purpose of this study was to define the MR features of cerebellar PCNSL in immunocompetent patients, and to determine whether a combination of conventional MR and DW imaging can assist in the differentiation of PCNSLs and HGGs. Twelve PCNSLs and 15 HGGs confirmed by pathological analysis were retrospectively identified. The apparent diffusion coefficient (ADC) and conventional MRI parameters were compared for differences between PCNSL and HGG groups using the independent sample t test or chi-square test. Both ADCmin and ADCtotal values were lower in the PCNSL group than those in the HGG group (ADCmin: 0.53 × 10−3 vs. 0.83 × 10−3 mm2/sec, P < 0.001; ADCtotal: 0.66 × 10−3 vs. 0.98 × 10−3 mm2/sec, P = 0.001). As for conventional MR features, there were significant difference in the tumor size, enhancement patterns, the presence of cystic changes, edema degree and streak-like edema (all P < 0.01); but there were no significant difference in lesion type, the presence of bleeding, and involvement of brain surface between two groups (P = 0.554, 0.657 and 0.157, respectively). The results revealed that several conventional MR features, including enhancement patterns, branch-like enhancement and streak-like edema may be useful for the differentiation of PCNSL and HGG in cerebellum and, when combined with ADC values, further improve the discriminating ability.

Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.

Keywords: Primary CNS lymphoma; Relapse; follow-up; magnetic resonance imaging; surveillance imaging

To evaluate the diagnostic value of a magnetic resonance imaging (MRI)-based imaging heterogeneity scoring system for differentiating high-grade glioma (HGG) from primary central nervous system lymphoma (PCNSL). This multicenter retrospective study analyzed clinical and preoperative MRI data from 314 pathologically confirmed cases (HGG = 167, PCNSL = 147), comprising 211 patients with single lesions (HGG = 130, PCNSL = 81) and 103 with multifocal lesions (HGG = 37, PCNSL = 66). Patients were randomly assigned to training (single-lesion: n = 147; multifocal: n = 72) and validation (single-lesion: n = 64; multifocal: n = 31) sets in a 7:3 ratio. Distinctive imaging features were used to construct separate logistic regression (LR) models for single-lesion and multifocal-lesion cases, with corresponding scoring systems developed. A baseline model incorporating conventional predictors was developed for comparison. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves (area under the curve [AUC], 95% confidence interval [CI]), Hosmer-Lemeshow tests (goodness-of-fit), calibration curves, and decision curve analysis (DCA). A sensitivity analysis was performed on excluded steroid-treated patients. For single-lesion cases, the training and validation AUCs were 0.940 (95%CI: 0.897-0.983) and 0.908 (0.836-0.981), respectively. Multifocal models achieved training and validation AUCs of 0.960 (0.921-0.999) and 0.927 (0.805-1.000). The heterogeneity scoring system demonstrated significant incremental value over the baseline model (ΔAUC: +0.160-0.290). Hosmer-Lemeshow tests indicated excellent model fit (single-lesion training: χ²= 2.489, P = 0.778; validation: χ² = 6.193, P= 0.185; multifocal training: χ² = 1.760, P = 0.881; validation: χ² = 9.241, P = 0.055). DCA demonstrated substantial net clinical benefit across threshold probabilities. The scoring systems established diagnostic thresholds as follows: ≥ 19 points for HGG (single-lesion) and > 19 points (multifocal), with lower scores indicating PCNSL. Center-stratified validation and repeated cross-validation confirmed strong generalizability across institutions (AUC: 0.934-0.941). The system maintained robust performance in the sensitivity analysis of steroid-treated patients. This MRI heterogeneity-based scoring system provides robust diagnostic accuracy for distinguishing HGG from PCNSL, serving as an objective clinical decision-support tool.

Vitreo-retinal lymphoma (VRL) is the most common intraocular lymphoma and is highly associated with central nervous system (CNS) lymphoma (CNSL), both posing a therapeutic challenge. We investigated patients' characteristics, efficacy and safety of intravitreal methotrexate (MTX) injections and their outcomes over 20years. The records of 129 patients diagnosed between 1997 and 2018 were retrospectively reviewed. Lymphoma involved both the CNS and vitreo-retina (49%), solely the CNS (37%) or solely the vitreo-retina (14%). In all, 45·5% of the patients with CNSL either presented with VRL or developed it after a mean (±SE) of 85·7(7·3)months. In all, 66·0% of the patients diagnosed with VRL either presented with CNSL or developed it after a mean (±SE) 42·6(7·6)months. The 81 patients with VRL (134 eyes) received a mean (±SD) of 19(7) injections; however, only 5(4) injections were needed to reach complete remission. Local recurrence occurred in two of the 81 patients. Overall, 80·2% of eyes had an initial moderate-severe visual loss, and >50% of them improved. Reversible keratopathy was the most prevalent side-effect. A total of 18·5% developed intraocular pressure (IOP) elevation due to angle neovascularisation after 16 injections, which could be reversed with prompt intravitreal injection of bevacizumab. Intravitreal MTX injections are a safe and effective treatment for VRL. Fewer injections (15) may offer similar results with fewer side-effects.

7549 Background: The cell of origin of primary central nervous system lymphoma (PCNSL) remains controversial. Data using immunohistochemistry (IHC) and Hans algorithm suggested that both germinal-center B-cell–like (GCB) and activated B-cell-like (ABC) subtypes can be seen in PCNSL. We explored the potential of DNA and RNA molecular profiling in characterizing the biology of PCNSL and compared this profile with ABC subtype of diffuse large B-cell lymphoma (DLBCL). Methods: RNA and DNA were extracted from 30 formalin-fixed paraffin-embedded (FFPE) tissue samples from PCNSL patients and 30 FFPE tissue samples from cases with lymph node DLBCL of ABC subtype. Subtyping of DLBCL cases was performed using IHC and gene expression profiling. We sequenced the DNA using a 275 gene panel (Qiagen) and the RNA using a 1382 gene panel (Illumina). Next Generation Sequencing on Illumina platform was used for detecting mutations and expression profiling. The levels of RNA expression were normalized to that of PAX5. Mutations detected by RNA sequencing were compared to those detected by DNA sequencing. Results: There was no significant difference between DLBCL-ABC and PCNSL in mutation rate of MYD88, CD79B, CARD11 or KMT2D: 33.3%, 10%, 10%, and 13.3%, respectively, in DLBCL-ABC vs 30%, 10%, 10%, and 10%, respectively, in PCNSL. However, NOTCH2 mutations were significantly different and detected in 16.7% of DLBCL-ABC as compared with 3% in PCNSL (P=.001). An algorithm that uses expression profiling of 46 different genes and distinguishes DLBCL-ABC from GCB showed that all PCNSL cases classified as ABC. The GCB classical marker LMO2 was expressed at very low level in both DLBCL-ABC and PCNSL, but was at relatively higher level in PCNSL (P=.002, Kruskal-Wallis ANOVA). There was significantly higher expression of the adhesion molecule CXCR4 (P=.008), activation molecules BTK (P=.0003) and PLCG2 (P=.002), and BCL6 (P=.002) in PCNSL as compared with DLBCL-ABC. There was no significant difference between the two groups in MYC, Ki67, BCL2, CD44, or CD274 (PD-L1) expression. Conclusions: DNA and RNA molecular profiling of PCNSL suggests similarity to DLBCL-ABC subtype. However, PCNSL is unique by expressing higher levels of the adhesion molecule CXCR4 and the activation molecules BTK and PLCG2. The lack of increased expression of MYC and Ki67 suggests that PCNSL is unlikely to be similar to Burkitt lymphoma.

A 41-year-old woman with a 14-month history of systemic lupus erythematosus (SLE) presented with headache, aphasia, and agraphia. A laboratory examination revealed mild proteinuria, hypocomplementemia, and elevated anti-double-stranded DNA antibody levels. A cerebrospinal fluid analysis demonstrated elevated protein and interleukin-6 levels. Magnetic resonance imaging (MRI) of the brain identified multiple lesions suggestive of brain edemas and small haemorrhages. She was diagnosed as having neuropsychiatric lupus and lupus nephritis and received remission induction therapy with high-dose corticosteroid and intravenous cyclophosphamide. She achieved a complete remission, and treatment with mycophenolate mofetil (MMF) was initiated 3 months thereafter for remission maintenance. At 13 months after the exacerbation of SLE, she complained of headache and nausea. A gadolinium-enhanced MRI of the brain revealed a low-signal-intensity tumour with marginal ring enhancement of 50 mm in the left frontal lobe. The tumour was excised, and the histological diagnosis was diffuse large B-cell lymphoma with positive Epstein-Barr virus (EBV). MMF was discontinued. Remission induction therapy with rituximab, high-dose methotrexate, procarbazine, and vincristine was administered, and she achieved remission. Previous reports suggest that use of MMF is associated with primary central nervous system (CNS) lymphoma (PCNSL) in patients with lupus nephritis or other autoimmune diseases or in post-transplant patients. Our observation that PCNSL occurred after CNS involvement of SLE suggests that EBV and CNS inflammation arising from SLE might have contributed to the development of PCNSL.

Large B-cell lymphoma (LBCL) with interferon regulatory factor 4 (IRF4)rearrangement (LBCL-IRF4r) is a rare type of lymphoma with an overall favorable prognosis, and has been included as a distinct entity in the 2022 revision of the World Health Organization Classification of Lymphoid Neoplasms. More common in pediatric/young adult populations and rare in older adults, it typically presents in the head and neck, specifically, the Waldeyer ring, and rarely in other sites. To our knowledge, it has not been reported as a primary central nervous system (CNS) lymphoma in the English language medical literature. Although IRF4 rearrangement can be seen in other hematolymphoid neoplasms, their histology and immunophenotype differ greatly. Familiarity with such unusual entities is important for pathologists in the work-up and diagnosis of hematolymphoid neoplasms of the CNS and is especially critical with this entity due to overall better prognosis and possible targeted treatments in the future. Here, we present a case of LBCL-IRF4r presenting as a primary CNS lymphoma in the brain.