Diagnosis Of Primary Central Nervous System Lymphoma Research Articles

Primary CNS Lymphoma of Diffuse B cells in a Patient with Neurofibromatosis Type 1: A Case Report.

Objective: To describe the case of a patient diagnosed with Neurofibromatosis Type 1 (NF1), who developed her first neoplastic lesion as Primary Central Nervous System Lymphoma (PCNSL). To our knowledge, this is the third case of PCNSL in the context of NF1. Background: PCNSL represents 1% of non-Hodgkin extranodal Lymphomas, and 3% of CNS tumors. Diffuse Large B-Cell Lymphoma accounts for 30-40% of the cases, commonly found in the encephalus, spinal cord, leptomeninges, or the eye. Predominant malignant tumors in NF1 are gliomas and Malignant Peripheral Nerve Sheath Tumor (MPNST). Methods: A 53-year-old Mexican female, with a history of NF1, arrived at the emergency department with left-side subacute progressive numbness and weakness. Left hemiplegia. MRI showed a ring-enhancing lesion in the right central lobe and a lesion in the subcutaneous tissue. Additionally, the patient underwent a full body 18-FDG PET scan, which reported activity only in the CNS. Results: Lesion-centered craniectomy and surgical evacuation were performed. Histopathological examination revealed lymphoid lineage cells, CD20, PAX-5, and Ki-67 were positive for neoplastic cells, confirming the diagnosis of PCNSL. At the 6-months follow-up visit, strength improved significantly, and the follow-up MRI did not show residual mass. Conclusions: It is necessary to study the prevalence of LPSNC in these patients, as well as the relative risk, and to develop guidelines for its best approach. We believe that the real incidence of the disease is underestimated, since the genetic and pathophysiological mechanisms that promote its origin still need to be clarified.

Primary CNS Lymphoma of Diffuse B cells in a Patient with Neurofibromatosis Type 1: A Case Report.

Objective: To describe the case of a patient diagnosed with Neurofibromatosis Type 1 (NF1), who developed her first neoplastic lesion as Primary Central Nervous System Lymphoma (PCNSL). To our knowledge, this is the third case of PCNSL in the context of NF1.
 Background: PCNSL represents 1% of non-Hodgkin extranodal Lymphomas, and 3% of CNS tumors. Diffuse Large B-Cell Lymphoma accounts for 30-40% of the cases, commonly found in the encephalus, spinal cord, leptomeninges, or the eye. Predominant malignant tumors in NF1 are gliomas and Malignant Peripheral Nerve Sheath Tumor (MPNST).
 Methods: A 53-year-old Mexican female, with a history of NF1, arrived at the emergency department with left-side subacute progressive numbness and weakness. Left hemiplegia. MRI showed a ring-enhancing lesion in the right central lobe and a lesion in the subcutaneous tissue. Additionally, the patient underwent a full body 18-FDG PET scan, which reported activity only in the CNS. 
 Results: Lesion-centered craniectomy and surgical evacuation were performed. Histopathological examination revealed lymphoid lineage cells, CD20, PAX-5, and Ki-67 were positive for neoplastic cells, confirming the diagnosis of PCNSL. At the 6-months follow-up visit, strength improved significantly, and the follow-up MRI did not show residual mass. 
 Conclusions: It is necessary to study the prevalence of LPSNC in these patients, as well as the relative risk, and to develop guidelines for its best approach. We believe that the real incidence of the disease is underestimated, since the genetic and pathophysiological mechanisms that promote its origin still need to be clarified.

Usefulness of dual isotope 123I-IMP and 201Tl SPECT for the diagnosis of primary central nervous system lymphoma and glioblastoma.

Preoperative differential diagnosis between primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM) is important because these tumors require different surgical strategies. This study investigated the usefulness of dual isotope, iodine-123-labeled N-isopropyl-p-iodo-amphetamine (123I-IMP) and thallium-201 chloride single-photon emission computed tomography (201Tl SPECT) for the differential diagnosis. Twenty-five PCNSL patients and 27 GBM patients who underwent dual isotope imaging, 123I-IMP and 201Tl SPECT, are included. Tumor-to-normal (T/N) ratio was calculated from the ratio of maximum tracer counts in the lesion to the mean counts in the contralateral cerebral cortex. The mean and minimum apparent diffusion coefficient values (ADCmean and ADCmin, respectively) on magnetic resonance imaging were also analyzed. Delayed phase 123I-IMP SPECT was the most useful imaging examination for the differentiation between PCNSL and GBM compared with early phase 123I-IMP SPECT, early and delayed phase 201Tl SPECT, ADCmean, and ADCmin. However, the median T/N ratios of PCNSL and GBM were 1.32 and 0.83, respectively, in the delayed phase 123I-IMP SPECT. On the other hand, the median T/N ratios of PCNSL and GBM were 3.10 and 2.34, respectively, in the delayed phase 201Tl SPECT, with excellent tumor detection. Delayed phase 123I-IMP SPECT could differentiate between PCNSL and GBM with high accuracy, but T/N ratio was low and tumor detection was poor. 201Tl SPECT was useful for estimation of the malignancy and localization of the tumors with high T/N ratio. Dual isotope 123I-IMP and 201Tl SPECT was useful for the preoperative diagnosis of PCNSL and GBM.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Systemic inflammatory biomarkers in primary central nervous system lymphoma versus high-grade glioma: exploratory, comparativeand correlative analysis.

Aim:To assess systemic inflammatory biomarkers in non invasive differential diagnosis of primary central nervous system lymphoma (PCNSL) from high-grade glioma (HGG).Materials & methods:Patients with similar morphology (PCNSL or HGG) on conventional neuro-imaging were included. Systemic inflammatory indices were calculated from pretreatment complete blood counts and liver function tests and compared against histopathology as reference standard.Results:Mean values of absolute lymphocyte count and prognostic nutritional index were significantly different between PCNSL (n = 42) versus HGG (n = 16). Area under receiver operating characteristics curve for absolute lymphocyte count and prognostic nutritional index in the diagnosis of PCNSL was 0.70 and 0.72 respectively suggesting fair and acceptable diagnostic accuracy.Conclusion:Systemic inflammatory biomarkers complement established clinico-radiological features and aid in the differential diagnosis of PCNSL from HGG.

Optical Coherence Tomography Benefits the Diagnosis and Follow-Up of Primary Central Nervous System Lymphoma with Intraocular Involvement.

PurposeTo describe the characteristic manifestations of vitreoretinal lymphoma (VRL) with optical coherence tomography (OCT) and monitor their outcomes after treatmEnt.Patients and MethodsPatients with primary central nervous system lymphoma (PCNSL) and intraocular involvement were assigned to the VRL group. OCT manifestations were analyzed and changes in abnormalities were recorded after intravitreal methotrexate injections. OCT manifestations of PCNSL patients without intraocular involvement were analyzed as well (non-VRL group).ResultsThere were 48 eyes with high-quality OCT records in the VRL group, of which 19 had abnormal manifestations. The most frequent abnormality was outer retina (OR) fuzzy borders (14 of 19, 73.7%). Other abnormalities included: focal subretinal deposits (8 of 19, 42.1%), hyperreflective subretinal dots (2 of 19, 10.5%), pigment epithelium detachment (PED) (5 of 19, 26.3%), preretinal deposits (5 of 19, 26.3%), epiretinal membrane (3 of 19, 15.8%), cystoid macular edema (3 of 19, 15.8%), subretinal fluid (3 of 19, 15.8%), outer retina atrophy (2 of 19, 10.5%), unilateral optic papilledema (2 of 19, 10.5%), retinal thickening (1 of 19, 5.3%), and subretinal fibrosis (1 of 19, 5.3%). Nine eyes with retinal abnormalities were receiving regular intravitreal methotrexate. The retinal structure of seven eyes (only outer retina involved) returned to almost normal on OCT images. The remaining two eyes (with severe retinal vasculitis) showed little improvement after treatment.ConclusionOCT is helpful for the diagnosis of PCNSL with intraocular involvement and long-term follow-up of the disease.Summary StatementThe characteristic manifestations of vitreoretinal lymphoma (VRL) with optical coherence tomography (OCT) were described and their outcomes after treatment were monitored. These findings suggested that OCT is helpful for the diagnosis of PCNSL with intraocular involvement and long-term follow-up of the disease.

Clinical outcomes following intravitreal methotrexate for primary vitreoretinal lymphoma

PurposeTo describe the visual acuity and anatomic outcomes of intravitreal methotrexate (MTX) for the treatment of primary vitreoretinal lymphoma (PVRL).MethodsSingle-center retrospective case series of patients with a diagnosis of PVRL treated with intravitreal MTX. Patient records were reviewed for demographic information, ocular exam findings, and treatment regimens including number of MTX injections. Clinical outcomes recorded included visual acuity (VA), time to partial (PR) or complete response (CR), disease-free survival, time to relapse, and any CNS progression.ResultsTen eyes of 7 patients (4 male, 6 female) were reviewed. The mean age ± standard deviation (SD) was 70 ± 12 years. Five patients had prior or concomitant diagnosis of primary CNS lymphoma with a history of systemic chemotherapy including MTX. Three eyes (30%) exhibited isolated vitreous involvement, four (40%) had subretinal lesions, and three (30%) presented with both vitreous and subretinal disease. Mean initial logMAR VA was 0.38 ± 0.52 (Snellen visual equivalent 20/50), while mean final logMAR VA ± SD was 0.34 ± 0.27 (Snellen visual equivalent 20/40) with a mean follow-up time of 26 months (Range, 3–49 months). Patients received an average of 6 intravitreal MTX injections (Range 1–10) over the course of treatment. Two patients received concomitant systemic chemotherapy. Mean time to either PR or CR was 57 days, and 6 eyes (60%) exhibited regression with no relapse after local treatment. For the 4 eyes that eventually relapsed, the mean time ± SD to first relapse was 193 days ± 155 days, and one eye experienced a second relapse. Two of 3 patients with subretinal disease showed complete regression with extended follow-up of 1 and 4 years following treatment with less than 3 doses of intravitreal MTX. One patient with PVRL developed CNS lymphoma during the study period. VA remained stable overall between the initial treatment visit, 3, 6, and 12-months (P > 0.05 for paired comparisons of VA over time).ConclusionsIntravitreal methotrexate was well-tolerated and led to local disease response in the majority of patients at approximately 2 months after initiation of treatment of intraocular lymphoma. Further studies on the efficacy of intravitreal treatment alone versus combined systemic and intravitreal treatment are warranted.

Evaluating optical coherence tomography (OCT) findings as potential biomarkers in central nervous system (CNS) lymphoma with or without ocular involvement

BackgroundTo evaluate spectral domain optical coherence tomography (SD-OCT) findings as biomarkers in primary central nervous system lymphoma (PCNSL) with or without ocular involvement.MethodsThis study was a cross-sectional study and patients with a confirmed diagnosis of PCNSL with or without ocular involvement were included. Patient cohort finder tool was used to identify patients with lymphoma using ICD-10 codes (C82–C88), from January 2004 to October 2017. A total of 14,820 patients were identified. Procedure code (92134) for optical coherence tomography (OCT) was then applied to identify patients who had underdone OCT imaging at ophthalmology clinic. Clinic charts of 460 patients with lymphoma and available OCT were reviewed to identify patients with confirmed diagnosis of PCNSL and divided into two groups (Group 1: with and Group 2: without ocular involvement). OCT scans of patients in both study groups were analyzed for the presence of (1) Hyperreflective deposits in choroid, retinal pigment epithelium (RPE), outer and inner retina; (2) RPE thickening; (3) Vitreous debris; (4) Intraretinal fluid; (5) Ellipsoid zone disruption by masked graders. Chi-square was used to analyze the difference between the groups.ResultsTwenty-two eyes (11 patients) with PCNSL were included this study (Group 1: 6 eyes and Group 2: 16 eyes). Mean age of subjects was 65 years. Five patients (45.45%) were female. There was no statistically significant difference between the groups for the presence of hyperreflective deposits in choroid, RPE, outer and inner retina, and presence of RPE thickening, intraretinal fluid, and ellipsoid zone disruption. Vitreous debris was found more commonly in group 1 subjects (83%) than group 2 (31.25%) (p = 0.029). All subjects in both groups showed hyperreflective deposits in the RPE demonstrating RPE infiltration. However, RPE thickening was noted only in 3 patients (Group1: 1 and Group2: 2).ConclusionsOCT finding of hyperreflective deposits present in eyes with lymphoma secondary to PCNSL are also observed in eyes with PCNSL without ocular disease. However, the vitreous deposits are more commonly found in eyes with ocular disease. These hyperreflective deposits can serve as biomarkers for early detection of ocular involvement by PCNSL.

Impact of Anticonvulsant - Methotrexate Interactions on High Dose Methotrexate Clearance and Outcomes in Patients with Primary CNS Lymphoma

Background: Patients with primary CNS Lymphoma (PCNSL) often present with neurologic complications such as focal defects, neuropsychiatric symptoms, increased intracranial pressure, aphasia, seizures, and ocular symptoms which require initiation of prophylactic or therapeutic anticonvulsants. Most anticonvulsants are notorious for their pharmacodynamic and pharmacokinetic drug interactions. The cornerstone of PCNSL therapy is the utilization of high-dose methotrexate (HD-MTX). The pharmacokinetics of HD-MTX are uniquely sensitive to both disease biology and drug interactions. Due to the importance of both HD-MTX and anticonvulsants in PCNSL patients, these medications are frequently given in concert with one another despite theoretical and proven drug interactions published in the literature. This is a retrospective analysis of patients treated with a modified R-MPV regimen (rituximab, methotrexate, procarbazine, vincristine alternating with intrathecal methotrexate) and the effects of various anticonvulsants on HD-MTX clearance.Methods: Patients ≥18 years of age with a biopsy proven diagnosis of PCNSL at Roswell Park Comprehensive Cancer Center who received R-MPV between January 2002 and December 2019 were included in this retrospective analysis. The electronic health record of each patient was reviewed for specific patient demographics, laboratory results, confounding drug interactions, toxicity, and treatment outcomes. Descriptive statistics were computed for all categorical variables. The time to MTX clearance in hours and the potential impact of concomitant use of various anticonvulsants were assessed using the Wilcoxon Rank Sum test in the case of ordinal responses and the Pearson chi-square test or Fisher's Exact test for categorical variables where appropriate.Results: A total of 67 patients met the inclusion criteria of which 53 patients (79.1%) received anticonvulsants (189 cycles of R-MPV) and 14 did not (69 cycles of R-MPV). Patients who had seizures or frontal brain PCNSL were more likely to receive anticonvulsants (p <0.001). When considering all possible medication interactions with HD-MTX, use of any interacting medication within 48 hours prior to HD-MTX was a predictor of delayed clearance (p = 0.0398). The most common confounding interaction seen in this population were with proton pump inhibitors. Levetiracetam was the most common anticonvulsant used at any point in time during treatment (83.1%). Compared to no anticonvulsant, levetiracetam did not significantly prolong HD-MTX clearance (52.6h v. 72.7h, p = 0.1586). Other anticonvulsants utilized included phenytoin (24.5%), gabapentin (3.8%), valproate (3.8%), carbamazepine (1.9%), lacosamide (1.9%), lamotrigine (1.9%), and phenobarbital (1.9%). Of the patients who received an anticonvulsant, 11 received more than one over the treatment period. Time to clearance of HD-MTX for patients not on an anticonvulsant was 53.8 hours compared to a clearance time of 68.2 hours for those who received an anticonvulsant (p = 0.0571). Patients who received anticonvulsants had a significantly higher complete response rate (79.2% vs 35.7%, p = 0.009), longer progression free survival (25.4 mo vs 3 mo, p = 0.014) and overall survival (56.6 mo vs 4.6 mo, p = 0.002) compared to those who did not (Table 1). There was no difference in grade 3/4 toxicities between anticonvulsants and no anticonvulsants except for thrombocytopenia (p = 0.047) and respiratory side effects (p = 0.035).Conclusion: Anticonvulsants are an essential component to PCNSL therapy in patients on HD-MTX. They are well tolerated, do not alter HD-MTX clearance in a clinically significant manner and may help improve patient outcomes. [Display omitted] DisclosuresTorka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

An audit on the diagnosis of primary CNS lymphoma

AimsPrimary central nervous system lymphoma (PCNSL) is a rare form of non–Hodgkin lymphoma with exclusive manifestations in the central nervous system, leptomeninges and eyes. It forms around 5% of all primary brain tumours. It is an aggressive tumour which has a poor prognosis if left untreated. It is imperative that diagnosis is made timely so treatment can be started promptly. Therefore, we performed an audit looking into the speed of diagnostic process of PCNSL in our tertiary Neuro–oncology Unit.MethodSingle-centre retrospective review of PCNSL cases referred to a tertiary Neuro–Oncology Unit over a six month period from June to November 2020.ResultsA total of 1309 cases were discussed in the Neuro–oncology MDT meeting over the study period. Fourteen cases (6 male, 8 female; median age [range] 66 [59–83] years) were identified as highly likely PCNSL. Neuroimaging suggested PCNSL as the likely diagnosis in twelve patients. Twelve patients were started on steroids after CT or MRI brain scans. Nine patients had a surgical target and proceeded to have diagnostic brain biopsy. Two patients had different working diagnoses and three patients were deemed unsuitable for brain surgery. One patient required repeat brain biopsy. A tissue diagnosis was made in twelve patients. One patient deteriorated rapidly and one patient had a brain lesion that was deemed too high risk for surgery. The median time between neuroimaging and biopsy was 25 days. The median time taken from first investigation to the pathological confirmation of PCNSL was 36 days (range 6–86 days).ConclusionThe chief reason for delay in diagnosis of PCNSL was that patients were started on steroids before diagnostic investigations were completed. Steroids caused the brain lesions to become smaller or disappear. Accordingly, time was needed to allow withdrawal of steroids before diagnostic investigations could be repeated. Diagnostic delays may have been exacerbated by logistical issues associated with COVID–19. We propose that there needs to be greater awareness of how early introduction of steroids can markedly delay the diagnosis of PCNSL.

Primary Central Nervous System Lymphoma: How Do Neurologists Deal with its Management?

What are desirable roles of general neurologists in the diagnosis and treatment of primary central nervous system lymphoma (PCNSL)? These issues were discussed 7 years back in the special feature articles of this journal. In the last 7 years genome analyses using liquid biopsy specimens have progressed and are becoming popular in the management of PCNSL, thereby enabling neurosurgeons to avoid invasive brain biopsy. The role of general neurologists in this country is not to be directly engaged in the PCNSL management, but to make an early diagnosis of PCNSL and to refer patients with PCNSL to specialists for a combination of chemotherapy and irradiation therapy.

MicroRNAs as Diagnostic Biomarkers in Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.

BackgroundDiagnosing primary central nervous system lymphoma (PCNSL) remains a challenge. MicroRNAs (miRNAs) are promising noninvasive markers for the identification of PCNSL. The present study aims to assess the diagnostic value of miRNAs for PCNSL patients as biomarkers.MethodsWe systematically searched PubMed, Embase, and the Cochrane library from inception to January 31, 2021. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), together with the summary receiver operator characteristic (SROC) curve, and the area under the SROC curve (AUC) value were used to estimate the overall diagnostic performance. We used Q statistic and I2 to test heterogeneity and used subgroup analyses to investigate the source of heterogeneity. The statistical analyses were independently performed by two investigators using Stata 14.0 and Revman 5.3.ResultsIn total, 11 studies from 6 records were included in the current meta-analysis with 281 PCNSL patients and 367 controls. Our statistical analysis demonstrated that the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.91 (95% CI 0.84–0.95), 0.88 (95% CI 0.84–0.91), 7.48 (95% CI 5.71–9.78), 0.11 (95% CI 0.06–0.19), 70 (95% CI 35–142), and 0.90 (95% CI 0.87–0.92), respectively. The studies had substantial heterogeneity (I2 = 54%, 95% CI 0–100). Two subgroup analyses were conducted based on the type of specimen and miRNAs profiled.ConclusionsThis meta-analysis indicated that miRNAs were suitable as noninvasive diagnostic biomarkers for PCNSL with high accuracy. In addition, both cerebrospinal fluid-based and blood-based miRNAs assays for PCNSL detection were considered reliable for clinical application. MicroRNA-21 assays also seemed to be more accurate in the diagnosis of PCNSL. Good quality studies with large samples should be conducted to verify our results.

Primary central nervous system lymphoma in neurosurgery

Primary central nervous system lymphoma (PCNSL) most commonly (&gt;95%) constitutes a specific kind of diffuse large B-cell lymphoma, which shows expression of CD20, CD19 and CD79a antigens on its surface and belongs to non-germinal center B-cell-like type (non-GCB). This results from both its limited localization as well as immunophenotypic and molecular features. It frequently has an aggressive clinical course and its prognosis remains highly uncertain. PCNSL’s development in areas normally free from lymphoid tissue has not been adequately explained thus far. PCNSL is usually a solitary lesion (60–70%), with the majority (c.60%) occurring in supratentorial areas, and less frequently in telencephalic nuclei and periventricular areas, corpus callosum, infratentorial structures, spinal cord or orbital cavities. Lymphoid cells can occasionally create diffuse infiltration with no mass effect — a PCNSL variant known as lymphomatosis cerebri. Reported clinical symptoms depend on the localization of the tumor in central nervous system. The most common include: cognitive impairment, behavioral changes, focal neurological deficit and symptoms of increased intracranial pressure. A final diagnosis of PCNSL requires histopathological evaluation of tissue samples obtained usually during a stereotactic biopsy. Identifying lymphoid cells in cerebrospinal fluid may also be sufficient. Chemotherapy combined with radiotherapy is the standard treatment of PCNSL. For many years, surgical treatment has been controversial. This provides constant encouragement to explore effective treatment methods, with neurosurgical involvement waiting to be further defined.

Clinical Outcome and Characteristics of Patients with Primary Central Nervous System Lymphomas (PCNSL) in a Brazilian Population

Background: PCNSL is an Extranodal Non-Hodgkin Lymphoma (NHL), corresponding to 2.2% of all Central Nervous System (CNS) tumors and 1% of total NHL. It may develop in the brain, leptomeninges, spinal cord, or eyes, and is associated with a poor prognosis (median Overall Survival- OS: 30 months, when treated with High Dose Methotrexate based Therapy- HDMBT). There is scarce medical literature and further information is urgently needed to better categorize/evaluate this enthity.Purpose: To evaluate the clinical outcome and the risk of death in patients with DLBCL PCNSL in a mixed ethnicity population (Brazil), to describe the characteristics of these patients.Methods: Retrospective observational study. Patients diagnosed with DLBCL PCNSL, HIV negative and not immunosuppressed were identified in the biggest academic Brazilian Cancer Institute- ICESP- from 1995 to 2016 (n=35). All histopathology slides and blocks were reviewed by a trained pathologist. OS and Progression Free Survival-PFS- were estimated using Kaplan-Meier analysis. Univariate Cox regression analysis was used to assess the association between clinical characteristics and the survival endpoints.Results: Thirty-five patients with diagnosis of DLBCL PCNSL were identified between January 1995 and December 2016 at ICESP. Data was available for all 35 patients. Mean age at diagnosis: 66.7 years (SD: 15.88). Immunohistochemistry: CD20+: 94% (missing: 6%), high Ki67: 80% (missing: 20%), CD10+: 11.4% (missing: 57%), BCL6+: 17% (missing: 62%), MUM1+: 25% (missing: 65%). Cerebral Spinal Fluid (CSF) cytology was negative in 90.6%. Most patients had Performance Status PS 2-4 at diagnosis (66.7%), were male (54.3%), had involvement of Deep Brain Structures (79.4%). IELSG score: 0-1: 17%, 2-3: 45%, 4-5: 28%. Most patients received at least 1 line of treatment (94.3%), and most received HDMBT(80%). Twenty-six patients (74%) died (date of analysis: 01/06/2017). OS in 1, 5 and 10 years were 76.9 % (95% CI 56.1-87.7), 38.1% (95% CI 21-54.5) and 11.4 (95% CI 2.3-28.6), respectively. PFS in 1 and 5 years were 68.2% (95% CI 50-81) and 25.1% (95% CI 11.5-41.4), respectively. At Univariate Cox Regression, PS 2-4 compared to PS 0-1 at diagnosis was associated with increased risk of death (HR: 3.58, 95% CI: 1.29-9.91, p=0.014) and an increased risk of disease progression (HR: 2.61, 95% CI: 1.02-6.70, p=0.046).Conclusions: This is the largest Brazilian cohort with PCNSL reported so far. PCNSL is an aggressive tumor with worse prognosis compared to systemic DLBCL. Despite the small series of patients to perform a risk factor analysis, poor Performance Status seems to be associated with decreased OS and PFS rates- as suggested by the MSKK Prognostic Model. Further biomarker analysis and clinical correlation are needed, and are under investigation for these patients, in order to identify better prognostic and predictive biomarkers. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence, risk factors and management of venous thromboembolism in patients with primary CNS lymphoma.

Venous thromboembolism (VTE) is a known complication of malignancy. While brain tumors in general predispose to VTE, the incidence in primary central nervous system lymphoma (PCNSL) is poorly characterized. We sought to characterize incidence, risk factors, management, and outcome of VTE in PCNSL METHOD: Retrospective study of 78 PCNSL patients from 2/1/2002 to 4/1/2020 at the University of Virginia RESULTS: 31% (24/78) of patients developed VTE. 12.8% (10/78) had deep venous thrombosis (DVT) alone, 11.5% (9/78) isolated pulmonary embolism (PE) and 6.4% (5/78) both. The median time from PCNSL diagnosis to VTE was 3months. In a univariate competing risks analysis, previous VTE (p < 0.001), impaired ambulation (p = 0.035), baseline hemoglobin < 10g/dL (p = 0.025) and history of diabetes mellitus (type 1 or 2) (p = 0.007) were associated with increased VTE risk. 34.8% were anticoagulated acutely with heparin (8/23) or 65.2% LMWH (15/23), and 25.0% (6/24) received warfarin, 41.7% (10/24) LMWH, and 33.3% (8/24) DOACs long-term. One adverse event was attributable to anticoagulation (arm hematoma with hemoglobin decrease). Five patients received IVC filters with concomitant oral anticoagulation; one experienced IVC thrombosis after anticoagulation discontinuation. Six of the 24 patients experienced recurrent VTE, four while anticoagulated. Patients with PCNSL are at high risk of VTE, most of which accrues in the first few months. History of VTE, diabetes mellitus (type 1 or 2), impaired ambulatory status, or hemoglobin < 10g/dL may predispose patients to this complication. While optimal management is uncertain, anticoagulation prevented recurrent VTE in most patients without intracranial bleeding.

Narrative review: biomarkers, a hope towards early diagnosis in primary CNS lymphoma

: Primary central nervous system lymphoma (PCNSL) arises in the central nervous system and remains confined into the brain, an organ with singular biological and immunological characteristics, where the structured lymphoid tissue is not normally present. Early diagnosis represents one of the main tasks for clinicians approaching PCNSL patients, because it would allow both a reduction of the risk of cerebral damage due to the presence of lymphomatous tissue and a limited time of use of steroid therapy, that raises a higher risk of immunosuppression. To date, diagnostic stereotactic biopsy is required in the most of the cases with suspicious PCNSL, however the use of less invasive and alternative diagnostic procedures would limit the surgery related-risks and morbidities, that are described in 8% of the cases. The PCNSL molecular profile and biological characteristics are poorly known, and the researchers’ efforts have been focused on studying these aspects only in the last years. In particular, the progressive knowledge on the genomic and molecular profile of lymphomatous cells and their microenvironment have helped to better characterize the pathophysiology of PCNSL. However, their diagnostic predictive and prognostic roles still remain unclear and have not yet been applied into the clinical practice. In this review we have reported the important advances on the knowledge of the main biomarkers detectable on biological fluids [blood, cerebrospinal fluid (CSF) and vitreous humor] that include genomic fragments, cytokines and their receptors, surface molecules. These biomarkers demonstrated a potential role in the early diagnosis of PCNSL, particularly when they are detected in combination, and some of them showed to have a prognostic value and a role in monitoring disease response.

Differentiation between glioblastoma and primary CNS lymphoma: application of DCE-MRI parameters based on arterial input function obtained from DSC-MRI.

This study aimed to evaluate whether arterial input functions (AIFs) obtained from dynamic susceptibility contrast (DSC)-MRI (AIFDSC) improve the reliability and diagnostic accuracy of dynamic contrast-enhanced (DCE)-derived pharmacokinetic (PK) parameters for differentiating glioblastoma from primary CNS lymphoma (PCNSL) compared with AIFs derived from DCE-MRI (AIFDCE). This retrospective study included 172 patients with glioblastoma (n = 147) and PCNSL (n = 25). All patients had undergone preoperative DSC- and DCE-MRI. The volume transfer constant (Ktrans), volume of the vascular plasma space (vp), and volume of the extravascular extracellular space (ve) were acquired using AIFDSC and AIFDCE. The relative cerebral blood volume (rCBV) was obtained from DSC-MRI. Intraclass correlation coefficients (ICC) and ROC curves were used to assess the reliability and diagnostic accuracy of individual parameters. The mean Ktrans, vp, and ve values revealed better ICCs with AIFDSC than with AIFDCE (Ktrans, 0.911 vs 0.355; vp, 0.766 vs 0.503; ve, 0.758 vs 0.657, respectively). For differentiating all glioblastomas from PCNSL, the mean rCBV (AUC = 0.856) was more accurate than the AIFDSC-driven mean Ktrans, which had the largest AUC (0.711) among the DCE-derived parameters (p = 0.02). However, for glioblastomas with low rCBV (≤ 75th percentile of PCNSL; n = 30), the AIFDSC-driven mean Ktrans and vp were more accurate than rCBV (AUC: Ktrans, 0.807 vs rCBV, 0.515, p = 0.004; vp, 0.715 vs rCBV, p = 0.045). DCE-derived PK parameters using the AIFDSC showed improved reliability and diagnostic accuracy for differentiating glioblastoma with low rCBV from PCNSL. • An accurate differential diagnosis of glioblastoma and PCNSL is crucial because of different therapeutic strategies. • In contrast to the rCBV from DSC-MRI, another perfusion imaging technique, the DCE parameters for the differential diagnosis have been limited because of the low reliability of AIFs from DCE-MRI. • When we analyzed DCE-MRI data using AIFs from DSC-MRI (AIFDSC), AIFDSC-driven DCE parameters showed improved reliability and better diagnostic accuracy than rCBV for differentiating glioblastoma with low rCBV from PCNSL.

Pituitary Lymphoma Presenting as Diabetes Insipidus

Introduction: Primary CNS lymphomas are rare accounting for 1-3% of CNS neoplasms. They lack specific clinical or radiological features and are diagnosed histologically. We describe a case of Primary CNS lymphoma involving pituitary gland presenting with confusion and diabetes insipidus. Case: 74-year-old presented with anorexia, weight loss, visual hallucinations and acute confusion. Initial evaluation revealed hypernatremia (148 mmol/L), an old cerebral infarct and new extensive thrombus in aorta and lower limb deep vein thrombosis. During hospital stay, he sustained a fall and a CT head showed a new high attenuation change around the temporal horn and left temporal lobe. MRI head was done to characterize the lesion but because of confusion and irritability, this was inconclusive. Patient continued to have hypernatremia with serum sodium ranging from 148 - 154 mmol/L (135-145 mmol/L) that failed to improve after rehydration. He continued to have negative fluid balance and urine output >2.5 litres a day with dilute urine and urine osmolarity of 134 mosm/L. Due to confusion, we were unable to conduct a water deprivation test. Anterior pituitary profile was consistent with secondary hypothyroidism (TSH was 0.09 (0.02-6.00), Free T4 8.2 (8.0-18.0) and (Free T3 was 2.8 (3.0- 4.8)), and secondary hypogonadism (Testosterone 0.9 nmol/L (6.1-27.1), FSH 1.0 IU/L and LH was <0.2 IU/L). Hypothalamic- adrenal axis was intact as cortisol showed adequate increment after corticotropin stimulation (Cortisol at 0 min 386 nmol/L, 30 minutes 584 nmol/L and 60 minutes 640 nmol/L). Further CT Head with contrast was carried out in view of new findings of hypopituitarism that showed smooth hyperattenuating pituitary gland that was consistent with diabetes insipidus and intense contrast enhancement seen in the periventricular regions and the caudate and dentate nuclei bilaterally. Based on clinical and radiological picture, diagnosis of CNS lymphoma and diabetes insipidus was made and commenced on desmopressin nasal spray. We were unable to perform brain biopsy or quantify the response to desmopressin due to rapid deterioration of patient who died 9 weeks after his initial presentation. An autopsy was carried out and histopathology of pituitary yielded normal anterior pituitary but posterior pituitary was completely infiltrated by Non-Hodgkin’s Lymphoma of Diffuse large B cell type that was also infiltrating parts of the cerebellum, temporal cortex and the basal ganglia hence proving diagnosis of Primary CNS lymphoma. Conclusion: Sudden onset of DI with pathological appearance of posterior pituitary and equivocal/non diagnostic CNS imaging should raise the suspicion of CNS lymphoma. Although diagnosis is histopathological, early detection with high index of suspicion and treatment and lead to better outcomes.

A rapid genotyping panel for detection of primary central nervous system lymphoma

AbstractDiagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.