Central Nervous System Lymphoma Research Articles

A Challenging Case of Primary Central Nervous System Lymphoma: Diagnostic Dilemmas and Therapeutic Insights

Introduction: Primary Central Nervous System Lymphoma (PCNSL) is a rare malignancy primarily located in the brain, spinal cord, leptomeninges, and eyes. The origin of PCNSL is uncertain, but it is thought to arise from lymphocytes within the central nervous system. Diagnosis and treatment can be complex, especially in immunocompetent patients. Case Report: A 65-year-old immunocompetent woman presented with symptoms including weight loss, severe weakness, and left hemiplegia. Initial brain MRI revealed an irregular mass with vasogenic edema in the right parietal lobe. Stereotactic biopsy confirmed large cell lymphoma (T-cell variant). The patient initially responded well to high-dose steroid treatment. Subsequent chemotherapy and radiotherapy were planned, but due to a positive PCR test, treatment was delayed. Discussion: PCNSL presents with non-specific symptoms, making early diagnosis challenging. Diagnostic tools such as MRI, PET-CT, and immunohistochemistry play crucial roles. Steroid use before biopsy should be cautious, as it may affect tissue necrosis and diagnosis accuracy. Prompt diagnostic and therapeutic measures are essential for improved outcomes. Conclusion: PCNSL is a rare and aggressive malignancy with a poor prognosis if left untreated. Early diagnosis and appropriate treatment, including chemotherapy and radiotherapy, are crucial for patient survival. Larger studies are needed to further understand and manage this challenging condition.

Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application.

Effective diagnosis, prognostication, and management of CNS malignancies traditionally involves invasive brain biopsies that pose significant risk to the patient. Sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid, and noninvasive alternative that offers a snapshot of the intracranial milieu while overcoming the challenge of sampling error that plagues conventional brain biopsy. Although numerous biomarkers have been identified, translational challenges remain, and standardization of protocols is necessary. Here, we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; between January 2000 and September 29, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis, and primary and secondary CNS lymphomas. We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, cell of origin, and site of CSF acquisition (eg, lumbar and ventricular). We also performed a meta-analysis of proteomic data sets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.

Impact of SUSAN Denoising and ComBat Harmonization on Machine Learning Model Performance for Malignant Brain Neoplasms.

Feature variability in radiomics studies due to technical and magnet strength parameters is well known and may be addressed through various pre-processing methods. However, very few studies have evaluated downstream impact of variable pre-processing on model classification performance in a multi-class setting. We sought to evaluate the impact of SUSAN denoising and ComBat harmonization on model classification performance. A total of 493 cases (410 internal and 83 external dataset) of glioblastoma (GB), intracranial metastatic disease (IMD) and primary CNS lymphoma (PCNSL) underwent semi-automated 3D-segmentation post baseline image processing (BIP) consisting of resampling, realignment, co-registration, skull stripping and image normalization. Post BIP, two sets were generated, one with and another without SUSAN denoising (SD). Radiomics features were extracted from both datasets and batch corrected to produce four datasets: (a) BIP, (b) BIP with SD, (c) BIP with ComBat and (d) BIP with both SD and ComBat harmonization. Performance was then summarized for models using a combination of six feature selection techniques and six machine learning models across four mask-sequence combinations with features derived from one-three (multi-parametric) MRI sequences. Most top performing models on the external test set used BIP+SD derived features. Overall, use of SD and ComBat harmonization led to a slight but generally consistent improvement in model performance on the external test set. The use of image pre-processing steps such as SD and ComBat harmonization may be more useful in a multiinstitutional setting and improve model generalizability. Models derived from only T1-CE images showed comparable performance to models derived from multiparametric MRI.

Liquid biopsy for improving diagnosis and monitoring of CNS lymphomas: a RANO review.

The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors. The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and CSF-liquid biopsy in central nervous system lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL). Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, steroids responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments and prediction of outcome. Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes and type of technique to perform the molecular analysis. The various assays should be evaluated through well organized central testing within clinical trials.

Recent advances in liquid biopsy of central nervous system lymphomas: case presentations and review of the literature.

Surgical biopsy is the gold standard for diagnosing central nervous system (CNS) lymphomas. However, reliable liquid biopsy methods for diagnosing CNS lymphomas have quickly developed and have been implicated in clinical decision-making. In the current report, we introduce two patients for whom liquid biopsy was essential for diagnosing CNS lymphomas and discuss the rapidly growing applications of this technology.

CAR T Cells in Primary and Secondary CNS Lymphoma (S27.003)

CAR T Cells in Primary and Secondary CNS Lymphoma (S27.003)

Primary T Cell CNS Lymphoma Mimicking Inflammatory/Demyelinating Disease (P1-6.016)

Primary T Cell CNS Lymphoma Mimicking Inflammatory/Demyelinating Disease (P1-6.016)

Discrepancy in CSF Flow Cytometry Results from Lumbar Puncture and Ventricular Sampling Leading to Delay in Diagnosis Recurrent CNS Lymphoma: A Case Report (P4-5.025)

Discrepancy in CSF Flow Cytometry Results from Lumbar Puncture and Ventricular Sampling Leading to Delay in Diagnosis Recurrent CNS Lymphoma: A Case Report (P4-5.025)

Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma.

A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.

An update on susceptibility-weighted imaging in brain gliomas.

Susceptibility-weighted imaging (SWI) has become a standard component of most brain MRI protocols. While traditionally used for detecting and characterising brain hemorrhages typically associated with stroke or trauma, SWI has also shown promising results in glioma assessment. Numerous studies have highlighted SWI's role in differentiating gliomas from other brain lesions, such as primary central nervous system lymphomas or metastases. Additionally, SWI aids radiologists in non-invasively grading gliomas and predicting their phenotypic profiles. Various researchers have suggested incorporating SWI as an adjunct sequence for predicting treatment response and for post-treatment monitoring. A significant focus of these studies is on the detection of intratumoural susceptibility signals (ITSSs) in gliomas, which are indicative of microhemorrhages and vessels within the tumour. The quantity, distribution, and characteristics of these ITSSs can provide radiologists with more precise information for evaluating and characterising gliomas. Furthermore, the potential benefits and added value of performing SWI after the administration of gadolinium-based contrast agents (GBCAs) have been explored. This review offers a comprehensive, educational, and practical overview of the potential applications and future directions of SWI in the context of glioma assessment. CLINICAL RELEVANCE STATEMENT: SWI has proven effective in evaluating gliomas, especially through assessing intratumoural susceptibility signal changes, and is becoming a promising, easily integrated tool in MRI protocols for both pre- and post-treatment assessments. KEY POINTS: • Susceptibility-weighted imaging is the most sensitive sequence for detecting blood and calcium inside brain lesions. • This sequence, acquired with and without gadolinium, helps with glioma diagnosis, characterisation, and grading through the detection of intratumoural susceptibility signals. • There are ongoing challenges that must be faced to clarify the role of susceptibility-weighted imaging for glioma assessment.

Treatment of primary central nervous system lymphoma (PCNSL) – single center experience.

Treatment of primary central nervous system lymphoma (PCNSL) – single center experience.

Detection of circulating tumor DNA in plasma of patients with primary CNS lymphoma by digital droplet PCR

BackgroundPrimary central nervous system lymphoma (PCNSL) are rare mature B-cell lymphoproliferative diseases characterized by a high incidence of MYD88 L265P and CD79B Y196 hotspot mutations. Diagnosis of PCNSL can be challenging. The aim of the study was to analyze the detection rate of the MYD88 L265P and CD79B Y196 mutation in cell free DNA (cfDNA) in plasma of patients with PCNSL.MethodsWe analyzed by digital droplet PCR (ddPCR) to determine presence of the MYD88 L265P and CD79B Y196 hotspot mutations in cfDNA isolated from plasma of 24 PCNSL patients with active disease. Corresponding tumor samples were available for 14 cases. Based on the false positive rate observed in 8 healthy control samples, a stringent cut-off for the MYD88 L265P and CD79B Y196 mutation were set at 0.3% and 0.5%, respectively.ResultsMYD88 L265P and CD79B Y196 mutations were detected in 9/14 (64%) and 2/13 (15%) tumor biopsies, respectively. In cfDNA samples, the MYD88 L265P mutation was detected in 3/24 (12.5%), while the CD79B Y196 mutation was not detected in any of the 23 tested cfDNA samples. Overall, MYD88 L265P and/or CD79B Y196 were detected in cfDNA in 3/24 cases (12.5%). The detection rate of the combined analysis did not improve the single detection rate for either MYD88 L265P or CD79B Y196.ConclusionThe low detection rate of MYD88 L265P and CD79B Y196 mutations in cfDNA in the plasma of PCNSL patients argues against its use in routine diagnostics. However, detection of MYD88 L265P by ddPCR in cfDNA in the plasma could be considered in challenging cases.

Machine learning-based pathomics signature of histology slides as a novel prognostic indicator in primary central nervous system lymphoma.

To develop and validate a pathomics signature for predicting the outcomes of Primary Central Nervous System Lymphoma (PCNSL). In this study, 132 whole-slide images (WSIs) of 114 patients with PCNSL were enrolled. Quantitative features of hematoxylin and eosin (H&E) stained slides were extracted using CellProfiler. A pathomics signature was established and validated. Cox regression analysis, receiver operating characteristic (ROC) curves, Calibration, decision curve analysis (DCA), and net reclassification improvement (NRI) were performed to assess the significance and performance. In total, 802 features were extracted using a fully automated pipeline. Six machine-learning classifiers demonstrated high accuracy in distinguishing malignant neoplasms. The pathomics signature remained a significant factor of overall survival (OS) and progression-free survival (PFS) in the training cohort (OS: HR 7.423, p < 0.001; PFS: HR 2.143, p = 0.022) and independent validation cohort (OS: HR 4.204, p = 0.017; PFS: HR 3.243, p = 0.005). A significantly lower response rate to initial treatment was found in high Path-score group (19/35, 54.29%) as compared to patients in the low Path-score group (16/70, 22.86%; p < 0.001). The DCA and NRI analyses confirmed that the nomogram showed incremental performance compared with existing models. The ROC curve demonstrated a relatively sensitive and specific profile for the nomogram (1-, 2-, and 3-year AUC = 0.862, 0.932, and 0.927, respectively). As a novel, non-invasive, and convenient approach, the newly developed pathomics signature is a powerful predictor of OS and PFS in PCNSL and might be a potential predictive indicator for therapeutic response.

Complete response to front-line therapies is associated with long-term survival in HIV-related lymphomas in Taiwan

BackgroundThe prognosis for people living with HIV (PLWH) who develop lymphomas has been greatly improved by combination antiretroviral therapy (cART) and anti-CD20 monoclonal antibodies. However, real-world clinical data on this patient group in Asia are limited. MethodsTreatment outcomes were retrospectively examined for 104 PLWH with lymphomas between 2000 and 2019. The cohort comprised five PLWH with Hodgkin lymphoma (HL) and 99 with non-Hodgkin lymphomas, including 61 with diffuse large B-cell lymphoma (DLBCL), 19 with Burkitt lymphoma (BL), nine with primary central nervous system lymphoma (PCNSL) and ten with other subtypes. ResultsThe 5-year overall survival (OS) rates were as follows: HL (100%), PCNSL (76.2%), other subtypes (60.0%), BL (57.4%), and DLBCL (55.6%). Individuals who achieved complete response (CR) to front-line therapies had a significantly better 5-year OS rate than those without (96.2% vs. 17.8%, p < 0.001). PLWH who received cART for ≤6 months had significantly lower CD4+ T-cell counts at lymphoma diagnosis than those who received cART for longer periods (p = 0.048). Additionally, the 5-year OS rate was better for PLWH who received cART for ≤6 months before lymphomas diagnosis than those who received cART for longer periods (64.5% vs. 51.9%, p = 0.114). ConclusionsPLWH with DLBCL or BL had OS rates compatible to patients without HIV infection. Better outcomes for patients achieving CR to front-line therapy and those with shorter cART duration before lymphoma diagnosis suggest an underlying biological distinction in the lymphomas and the involvement of immunity, which warrants further studies.

Elderly long-term survivors in the Nordic phase II study with first-line maintenance temozolomide for primary central nervous system lymphoma: a 10-year follow-up.

Not available.

Posterior Uveitis in Ocular-Involving Chronic Lymphocytic Leukemia and the Utility of Negative MYD88 L265P Testing in the Diagnosis

Purpose: To investigate if a negative test result for MYD88 L265P mutation, associated with vitreoretinal lymphoma (VRL) and primary CNS lymphoma (PCNSL), in liquid biopsies from intraocular fluids can be a useful adjuvant test to diagnose chronic lymphocytic leukemia in clinically challenging cases. Design: Observational case series. Participants: Patients with a past medical history or examinations findings suspicious for intraocular lymphoma. Methods: We evaluated both vitreous and aqueous humor-derived (AHD) MYD88 L265P mutation from patients that had suspect intraocular lymphoma that warranted a liquid biopsy procedure. Gold-standard cytopathology, flow cytometry, and gene rearrangement studies were also performed. Main Outcomes: Detection of AHD MYD88 L265P mutation in liquid biopsies. Results: All four patients had negative AHD MYD88 L265P mutation testing. Gold-standard testing (cytology) either showed paucicellular specimens (1/4) or specimens with high background inflammation (3/4). One case showed a rare B-cell clonal population (CD5+, Kappa-restricted by flow cytometry), but this was not sufficient to make any definitive diagnosis. All patients were subsequently initiated on systemic therapy and had improvement in their disease burden. Conclusions: Negative AHD MYD88 L265P mutation testing can serve as an adjuvant molecular test to diagnose difficult cases of intraocular CLL.

Abstract 1022: Integration of cerebrospinal fluid methylome and proteome can obviate the need for biopsy in central nervous system lymphoma

Abstract Background: The diagnosis of intra-axial brain tumors requires histopathological examination of tissue obtained by neurosurgery in current clinical practice, which comes with inherent risks. Some patients, particularly those with primary CNS lymphoma (PCNSL), only undergo surgery to obtain a diagnosis and do not derive any therapeutic benefit from surgical resection or debulking. Less-invasive techniques for diagnosis, such as liquid biopsy, therefore provides an opportunity to mitigate surgical risk in these patients. Methods: Patients with histopathology confirmed glioblastoma (GBM, IDH wild type), brain metastases (BM), and PCNSL with accompanying cerebrospinal fluid (CSF) samples were included in our study. Cell-free DNA methylation profiling and shotgun proteomics were obtained for all patients and used to train classifiers to distinguish each tumour entity from others. Specifically, binomial elastic net regression models were built by combining both data modalities using established early and late integration paradigms and performance was compared to classifiers built from individual data types alone. Each model was repeated 100 fold and performance assessed on an untouched testing subset. Results: Our cohort includes 20 patients with GBM, 17 with BM, and 14 with PCNSL, each with matching CSF cell-free DNA methylation and shotgun proteomic profiling. We show that these data can be integrated to fully discriminate PCNSL from its major diagnostic counterparts with a perfect median AUC of 1.00 (95% CI 1-1) and 100% specificity. Integrated "lymphoma vs other" models significantly outperform models trained on methylation or protein data alone, though the same dramatic improvement was not demonstrated in GBM or BM, suggesting synergistic biological information is specific to lymphoma. Conclusions: There is a critical need to diagnose patients with intra-axial tumours, particularly PCNSL, without relying on invasive and costly surgery. We present the most specific and accurate CNS lymphoma classifier to date by integrating the methylome and proteome of CSF. This has the potential for immediate clinical utility, eliminating the need for biopsy in an important subset of these patients. Citation Format: Alex P. Landry, Jeffrey A. Zuccato, Vikas Patil, Mathew Voisin, Justin Z. Wang, Yosef Ellenbogen, Chloe Gui, Andrew Ajisebutu, Farshad Nassiri, Gelareh Zadeh. Integration of cerebrospinal fluid methylome and proteome can obviate the need for biopsy in central nervous system lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1022.

Retracted: Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma.

[This retracts the article DOI: 10.1155/2021/3291762.].

Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma

AbstractAlthough CD20×CD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in central nervous system (CNS) lymphoma is unknown. Here, we report the CD20×CD3 bispecific, glofitamab, penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces clinical responses in secondary CNS lymphoma patients.

Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma

Central nervous system lymphoma (CNSL) is a type of hematological tumor. Treatment of CNSL is difficult due to the existence of the blood–brain barrier (BBB). Here, we used exosomes (Exos), a type of extracellular vesicle, and iRGD to construct a new drug carrier system and use it to load doxorubicin (DOX). The results of in vitro and in vivo experiments showed that the iRGD-Exo-DOX system can efficiently and securely transport DOX through the BBB and target tumor cells. The results suggest that iRGD-Exo-DOX may cross the BBB through brain microvascular endothelial cell-mediated endocytosis. Together, our study indicates an impactful treatment of central nervous system tumors.