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.

Radiomics for differentiation of gliomas from primary central nervous system lymphomas: a systematic review and meta-analysis.

Background and objective: Numerous radiomics-based models have been proposed to discriminate between central nervous system (CNS) gliomas and primary central nervous system lymphomas (PCNSLs). Given the heterogeneity of the existing models, we aimed to define their overall performance and identify the most critical variables to pilot future algorithms. Methods: A systematic review of the literature and a meta-analysis were conducted, encompassing 12 studies and a total of 1779 patients, focusing on radiomics to differentiate gliomas from PCNSLs. A comprehensive literature search was performed through PubMed, Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus databases. Overall sensitivity (SEN) and specificity (SPE) were estimated. Event rates were pooled using a random-effects meta-analysis, and the heterogeneity was assessed using the χ2 test. Results: The overall SEN and SPE for differentiation between CNS gliomas and PCNSLs were 88% (95% CI = 0.83 - 0.91) and 87% (95% CI = 0.83 - 0.91), respectively. The best-performing features were the ones extracted from the Gray Level Run Length Matrix (GLRLM; ACC 97%), followed by those obtained from the Neighboring Gray Tone Difference Matrix (NGTDM; ACC 93%), and shape-based features (ACC 91%). The 18F-FDG-PET/CT was the best-performing imaging modality (ACC 97%), followed by the MRI CE-T1W (ACC 87% - 95%). Most studies applied a cross-validation analysis (92%). Conclusion: The current SEN and SPE of radiomics to discriminate CNS gliomas from PCNSLs are high, making radiomics a helpful method to differentiate these tumor types. The best-performing features are the GLRLM, NGTDM, and shape-based features. The 18F-FDG-PET/CT imaging modality is the best-performing, while the MRI CE-T1W is the most used.

Retrospective Evaluation of Cases Undergoing Stereotaxic Brain Biopsy.

Objective: The aim of this study is to evaluate the demographic, radiological and histopathological findings, tumoral biomarkers, and survival rates of patients who underwent a stereotactic brain biopsy and those diagnosed with glioblastoma, metastasis, and lymphoma, and the changes in the diagnosis distribution over the years. Materials and Methods: The patients who underwent stereotactic biopsy in our clinic between 2012 and 2020 were evaluated retrospectively. Metastasis, glioblastoma, and lymphoma cases were evaluated as three main groups and the others were excluded. P53 gene expression, isocitrate dehydrogenase (IDH) mutation, and Ki-67 values in glioblastoma cases and Bcl-2, Bcl-6 proteins, and Ki-67 values in lymphomas and their relationship with survival were evaluated. Results: High p53 expression was observed in 27.5% cases diagnosed with glioblastoma. IDH mutation was negative in all glioblastoma cases. Presence of Bcl-2 and Bcl-6 proteins was not associated with survival in lymphomas. Survival rate was significantly higher in cases diagnosed with lymphoma (26.9%) compared to those diagnosed with glioblastoma. A statistically significant increase was determined in patients diagnosed with lymphoma considering the distribution of diseases and incidence and in the distribution of other diagnoses over the years ( p < 0.05). Conclusion: As per the distribution of the disease in recent times, it has been observed that there is an increase in lymphoma cases. Histopathology and biomarkers have great importance in the diagnosis and treatment of cerebral lesions. We think that our findings will be supported by studies in which larger patient population and detailed biomarkers will be studied.

Differentiating glioblastoma from primary central nervous system lymphoma of atypical manifestation using multiparametric magnetic resonance imaging: A comparative study.

Background: The aim of this study is to evaluate the diagnostic efficiency of magnetic resonance imaging (MRI) of single parameters, unimodality, and bimodality in distinguishing glioblastoma (GBM) from atypical primary central nervous system lymphoma (PCNSL) based on diffusion-weighted imaging (DWI), dynamic susceptibility contrast (DSC) enhancement, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H-MRS) findings. Methods: The cohort included 108 patients pathologically diagnosed with GBM and 54 patients pathologically diagnosed with PCNSL. Pretreatment morphological MRI, DWI, DSC, DTI and MRS were all performed on each patient. The quantitative parameters of multimodal MRI were measured and compared between the patients in the GBM and atypical PCNSL groups, and those parameters showing a significant difference (p < 0.05) between patients in the GBM and atypical PCNSL groups were used to develop one-parameters, unimodality, and bimodality models. We evaluated the efficiency of different models in distinguishing GBM from atypical PCNSL by performing receiver operating characteristic analysis (ROC). Results: Atypical PCNSL had lower minimum apparent diffusion coefficient (ADCmin), mean ADC (ADCmean), relative ADC (rADC), mean relative cerebral blood volume (rCBVmean), maximum rCBV (rCBVmax), fractional anisotropy (FA), axial diffusion coefficient (DA) and radial diffusion coefficient (DR) values and higher choline/creatine (Cho/Cr) and lipid/creatine (Lip/Cr) ratios than GBM (all p < 0.05). The rCBVmax, DTI and DSC + DTI data were optimal models of single-parameter, unimodality and bimodality for differentiation of GBM from atypical PCNSL, yielding areas under the curves (AUCs) of 0.905, 0.954, and 0.992, respectively. Conclusions: Models of single-parameter, unimodality and bimodality based on muti multiparameter functional MRI may help to discriminate GBM from atypical PCNSL.

Intracranial lymphoma in human immunodeficiency virus-infected patients: A diagnostic dilemma?

Primary central nervous system (CNS) lymphoma is an aggressive malignancy which constitutes one of the acquired immunodeficiency syndrome -defining illnesses. Early diagnosis and timely management can increase the chances of cure. Although many times the diagnosis is straightforward, we present a case of primary CNS lymphoma in a human immunodeficiency virus--positive individual which posed as a major diagnostic dilemma with initially normal imaging findings. A 42-year-old male presented with unremitting fever and a perianal ulcer for 3 months. A battery of diagnostic tests were negative, including a positron emission tomography-computed tomography scan and a magnetic resonance imaging brain. With unresolving symptoms and a high index of suspicion as he developed dizziness and loss of balance, the same were repeated which confirmed a space-occupying lesion in the cerebellum. Although treatment was instituted, the patient did not recover and died in the 4th month of treatment.

Primary dural lymphoma: Case report.

Primary Dural lymphoma (PDL) is a rare pathology that occurs in immunocompetent patients. In such cases, these lesions may mimic more common intracranial tumors. We present the case of a patient who presented an intra cranial hypertension syndrome; the brain MRI showed a tissular mass that we took for a meningioma; upon surgical intervention, an occult mass was discovered. Major excision and immunohistochemistry demonstrated PDL. Our case report highlights the rarity of these pathology and the importance of combined surgery and medical treatment, as the latter can be treated with chemoradiation with good clinical outcomes.

Less common intraparenchymal tumors.

The chapter outlines the management of a great variety of rare intraparenchymal tumors. For some like medulloblastomas or ependymomas, GKNS has little to offer. For others like neurocytomas, primary central nervous system lymphomas, and papillary pineal tumors the current findings look most hopeful. For choroid plexus papillomas there is currently not enough information to define the role of GKNS in their treatment. Pineal region tumors are a complex and varied group of neoplasms. Their complexity, variety and ethnic variability means that defining the role of GKNS will require continuing research before a consensus about management can be reached.

Primary central nervous system ALK-negative anaplastic large cell lymphoma: a case report and literature review.

Primary central nervous system anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an extremely rare type of primary central nervous system lymphoma (PCNSL). There are only nine cases reported in the literature to date, most of which have an overall survival time of no more than 8 months. Herein, we report such a rare case who has a good outcome with the longest survival time and perform a review of the literature. A 19-year-old male patient was admitted to the hospital complaining of dizziness. CT and MRI imaging showed a heterogeneous enhanced lesion in the left parieto-occipital lobe and the leptomeninges of the occipital lobe and the cerebellum. The lesion was resected and confirmed to be ALK-negative ALCL by pathological examination. Then, the patient received 10 cycles of chemotherapy with high-dose methotrexate (HD-MTX) and whole-brain radiotherapy. The patient recovered well and was regularly followed up. He was free of symptoms without recurrence on imaging examination 3 years later. ALCL is a rare type of PCNSL. HD-MTX combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify the biological characteristics of this rare type of PCNSL.

Primary central nervous system diffuse large B-cell lymphoma masqueraded as Bing-Neel syndrome: Steps in management and review of future directions.

Bing-Neel syndrome (BNS) remains a rare complication of Waldenstrom Macroglobulinemia. Given the paucity of this disease, treatment guidelines are based on small clinical trials with limited participants. Here, we present a case of primary CNS diffuse large B-cell lymphoma masqueraded as BNS that developed while on ibrutinib therapy.

Aggregative Perivascular Tumor Cell Growth Pattern of Primary Central Nervous System Lymphomas Is Associated with Hypoxia-Related Endoplasmic Reticulum Stress.

Primary central nervous system lymphomas (PCNSLs) often present a unique histopathological feature of aggregative perivascular tumor cells (APVT). Our previous studies showed that patients of PCNSL with APVTs exhibited poor long-term outcomes and increased expression of the endoplasmic reticulum stress (ERS) factor X-box-binding protein (XBP1). However, very little is known about molecular mechanism of the APVT formation in PCNSLs. The aim of this study is to determine if hypoxia-induced ERS is related to the APVT formation in PCNSLs. In this study, cell culture was used to observe the interplay between diffuse large B cell lymphoma (DLBCL) tumor cells and human brain microvascular endothelial cells (HBMECs) in different oxygen conditions. The expression of XBP1, CXCR and CD44 was manipulated by molecular cloning and siRNA technology. Mouse in vivo experiments and clinical studies were conducted to confirm our hypothesis. Our results showed that activated B-cell type-DLBCL cells easily migrated and invaded, and expressed high levels of XBP1 and stromal molecules CXCR4 and CD44 during hypoxia-induced ERS and dithiothreitol unfolded protein response (UPR). The gene upregulation (using overexpression vector) and downregulation (siRNA gene knock-out) in cultured cells and in mouse models further confirmed a close relation of the expression of XBP1, CXCR4, and CD44 with APVT formation, which is coincided with our clinical observation that increased expression of XBP1, CXCR4, and CD44 in the APVT cells in PCNSLs were associated with poor clinical outcomes. The results suggest that hypoxia-induced ERS and UPR might be associated with APVTs formation in PCNSL and its poor clinical outcomes. The results will help us better understand the progression of PCNSL with APVTs feature in daily pathological work and could be valuable for future target treatment of PCNSLs.

A Multiplex Assay for the Stratification of Patients with Primary Central Nervous System Lymphoma Using Targeted Mass Spectrometry.

Primary central nervous system lymphomas (PCNSL) account for approximately 2% to 3% of all primary brain tumors. Until now, neuropathological tumor tissue analysis, most frequently gained by stereotactic biopsy, is still the diagnostic gold standard. Here, we rigorously analyzed two independent patient cohorts comprising the clinical entities PCNSL (n = 47), secondary central nervous system lymphomas (SCNSL; n = 13), multiple sclerosis (MS, n = 23), glioma (n = 10), other tumors (n = 17) and tumor-free controls (n = 21) by proteomic approaches. In total, we identified more than 1220 proteins in the cerebrospinal fluid (CSF) and validated eight candidate biomarkers by a peptide-centric approach in an independent patient cohort (n = 63). Thus, we obtained excellent diagnostic accuracy for the stratification between PCNSL, MS and glioma patients as well as tumor-free controls for three peptides originating from the three proteins VSIG4, GPNMB4 and APOC2. The combination of all three biomarker candidates resulted in diagnostic accuracy with an area under the curve (AUC) of 0.901 (PCNSL vs. MS), AUC of 0.953 (PCNSL vs. glioma) and AUC 0.850 (PCNSL vs. tumor-free control). In summary, the determination of VSIG4, GPNMB4 and APOC2 in CSF as novel biomarkers for supporting the diagnosis of PCNSL is suggested.

Performance of diffusion and perfusion MRI in evaluating primary central nervous system lymphomas of different locations.

BACKGROUND: Diffusion and perfusion MRI can invasively define physical properties and angiogenic features of tumors, and guide the individual treatment. The purpose of this study was to investigate whether the diffusion and perfusion MRI parameters of primary central nervous system lymphomas (PCNSLs) are related to the tumor locations. METHODS: We retrospectively reviewed the diffusion, perfusion, and conventional MRI of 68 patients with PCNSLs at different locations (group 1: cortical gray matter, group 2: white matter, group 3: deep gray matter). Relative maximum cerebral blood volume (rCBVmax) from perfusion MRI, minimum apparent diffusion coefficients (ADCmin) from DWI of each group were calculated and compared by one-way ANOVA test. In addition, we compared the mean apparent diffusion coefficients (ADCmean) in three different regions of control group. RESULTS: The rCBVmax of PCNSLs yielded the lowest value in the white matter group, and the highest value in the cortical gray matter group (P < 0.001). However, the ADCmin of each subgroup was not statistically different. The ADCmean of each subgroup in control group was not statistically different. CONCLUSION: Our study confirms that rCBVmax of PCNSLs are related to the tumor location, and provide simple but effective information for guiding the clinical practice of PCNSLs.

HIV-Related Lymphoproliferative Diseases in the Era of Combination Antiretroviral Therapy.

HIV-positive patients have a 60- to 200-fold increased incidence of Non-Hodgkin Lymphomas (NHL) because of their impaired cellular immunity. Some NHL are considered Acquired Immunodeficiency Syndrome (AIDS) defining conditions. Diffuse large B-cell Lymphoma (DLBC) and Burkitt Lymphoma (BL) are the most commonly observed, whereas Primary Effusion Lymphoma (PEL), Central Nervous System Lymphomas (PCNSL), Plasmablastic Lymphoma (PBL) and classic Hodgkin Lymphoma (HL) are far less frequent. Multicentric Castleman disease (MCD) is an aggressive lymphoproliferative disorder highly prevalent in HIV-positive patients and strongly associated with HHV-8 virus infection. In the pre-Combination Antiretroviral Therapy (CART) era, patients with HIV-associated lymphoma had poor outcomes with median survival of 5 to 6 months. By improving the immunological status, CART extended the therapeutic options for HIV positive patients with lymphomas, allowing them to tolerate standard chemotherapies regimen with similar outcomes to those of the general population. The combination of CART and chemotherapy/ immuno-chemotherapy treatment has resulted in a remarkable prolongation of survival among HIVinfected patients with lymphomas. In this short communication, we briefly review the problems linked with the treatment of lymphoproliferative diseases in HIV patients. Combination Antiretroviral Therapy (CART) not only reduces HIV replication and restores the immunological status improving immune function of the HIV-related lymphomas patients but allows patients to deal with standard doses of chemotherapies. The association of CART and chemotherapy allowed to obtain better results in terms of overall survival and complete responses. In the setting of HIVassociated lymphomas, many issues remain open and their treatment is complicated by the patient's immunocompromised status and the need to treat HIV concurrently.

Primary central nervous system marginal zone B-cell lymphoma arising from the dural meninges: A case report and review of literature.

Primary central nervous system (CNS) marginal zone B-cell lymphoma (MZBCL) arising from the dural meninges is a rare but indolent disease. This malignancy can present in various ways, hence making it difficult to diagnose. Biopsy results dictate an appropriate treatment plan, which commonly consists of a combination of surgical resection, whole brain radiotherapy and systemic therapy.

Molecular Subtypes and Genomic Profile of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSL) are aggressive non-Hodgkin lymphomas affecting the central nervous system (CNS). Although immunophenotyping studies suggested an uniform activated B-cell (ABC) origin, more recently a spectrum of ABC and germinal center B-cell (GC) cases has been proposed, with the molecular subtypes of PCNSL still being a matter of debate. With the emergence of novel therapies demonstrating different efficacy between the ABC and GC patient groups, precise assignment of molecular subtype is becoming indispensable. To determine the molecular subtype of 77 PCNSL and 17 secondary CNS lymphoma patients, we used the NanoString Lymphoma Subtyping Test (LST), a gene expression-based assay representing a more accurate technique of subtyping compared with standard immunohistochemical (IHC) algorithms. Mutational landscapes of 14 target genes were determined using ultra-deep next-generation sequencing. Using the LST-assay, a significantly lower proportion (80% vs 95%) of PCNSL cases displayed ABC phenotype compared with the IHC-based characterization. The most frequently mutated genes included MYD88, PIM1, and KMT2D. In summary, we successfully applied the LST-assay for molecular classification of PCNSL, reporting higher proportion of cases with GC phenotype compared with IHC analyses, leading to a more precise patient stratification potentially applicable in the diagnostic algorithm of PCNSL.

R-IDARAM treatment in central nervous system lymphomas: A single-center experience and review of the literature.

INTRODUCTION: Central nervous system lymphomas (CNSLs) require effective treatment strategies due to aggressive nature of disease. Despite therapeutic approaches having improved in the last decades, there is no standard treatment for these patients. As a CNSL targeted-therapy IDARAM protocol was developed, the outcomes were reported with a few studies. We observed the R-IDARAM protocol in our CNSL cases, and we discuss the effectiveness, tolerability, and toxicity with a review of the literature in this article. SUBJECTS AND METHODS: We retrospectively analyzed response rates, progression-free survival, adverse events, and long-term side effects in patients who were treated by modified R-IDARAM as standard clinical care of CNSL in our hematology department. RESULTS: Response was achieved in five of nine patients. Three patients (two primary CNSL and one secondary CNSL) are still being followed up without disease progression with a median duration of follow-up of 79 months (88, 79, and 17 months, respectively). Manageable hematological side effects including thrombocytopenia and neutropenia were experienced by all patients. CONCLUSION: R-IDARAM protocol may be an option with high early response rates and manageable toxicity. Hematological side effects are the main problem, and long-term neurological toxicity is not common. Eligible patients must continue with autologous stem cell transplantation due to poor long-term survival outcomes.

Drug Delivery Technology to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience.

Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes questioned in the community. In this paper, we present our experience with CNS delivery strategies that have been developed in the laboratory and have made their way to the clinic in a continuum of translational research. Using the intra-arterial (IA) route as an avenue to deliver chemotherapeutics in the treatment of brain tumors, complemented by an osmotic breach of the blood-brain barrier (BBB) in specific situations, we have developed over the years a comprehensive research effort on this specialized topic. Looking at pre-clinical work supporting the rationale for this approach, and presenting results discussing the safety of the strategy, as well as results obtained in the treatment of malignant gliomas and primary CNS lymphomas, this paper intends to comprehensively summarize our work in this field.

Diffusion and perfusion MR patterns of central nervous system lymphomas.

BACKGROUND: Central nervous system lymphomas (CNSLs) are rare tumors which may show variable appearance in standard magnetic resonance imaging (MRI) depending on their origin (primary or secondary) or patients' immunological status. OBJECTIVES: The aim of the study was to analyze imaging patterns of different CNSLs, using diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). MATERIAL AND METHODS: Our material consisted of 16 CNSLs (14 primary, 2 secondary, 13 immunocompetent, 3 immunodeficient) which underwent magnetic resonance (MR) examinations including DWI and T2* dynamic susceptibility contrast (DSC) perfusion (without a preload in 13 cases, with a preload in 3 subjects). In DWI, apparent diffusion coefficient (ADC), and in PWI, parameters of relative cerebral blood volume (rCBV), relative peak height (rPH) and relative percentage of signal recovery (rPSR) were analyzed within the entire tumor (mean values) and in regions with minimal diffusion (ADCmin) and maximal perfusion values (rCBVmax, rPHmax, rPSRmax). RESULTS: All CNSLs showed low values of ADCmean (0.70 × 10-3), ADCmin (0.54 × 10-3), rCBVmean (0.80), rCBVmax (1.27), rPHmean (1.05), rPHmax (1.59), as well as high values of rPSRmean (1.99) and rPSRmax (2.41). There were no significant differences in rCBVmax, as well as in all ADC, rPH and rPSR values between primary and secondary CNSLs or between tumors in immunocompetent and immunodeficient patients. Dynamic susceptibility contrast PWI with a preload resulted in significantly higher rCBV, rPH and lower rPSR values. CONCLUSIONS: Despite various MR appearances, both primary and secondary CNSLs in immunocompetent and immunodeficient patients show very typical patterns of restricted diffusion and hypoperfusion with signal intensity curves returning above the baseline. Dynamic susceptibility contrast perfusion without a preload is recommended.

Intraventricular treatment of secondary central nervous system lymphoma - Case study and literature overview.

Secondary nervous system lymphoma (SCNSL) is a rare extranodal form of non-Hodgkin lymphoma (NHL). This applies to a particular form of lymphoma that does not originally derive from the central nervous system (CNS); it can be both an isolated form of relapse or a systemic part of disease progression. Due to poor prognosis and a lack of established algorithms of therapeutic procedures, it is a big challenge for physicians from many specializations. In our study, we present an interesting case of a patient with a relapsed form of SCNSL for whom a unique form of treatment was used - intraventricular administration of rituximab and methotrexate.