{"paper_id":"3950d985-a910-43a0-840d-b591c1c23e97","body_text":"Primary CNS Lymphoma: age as a prognostic biomarker | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Primary CNS Lymphoma: age as a prognostic biomarker Sona Ohanyan, Chen Buxbaum, Polina Stein, Shimrit Ringelstein-Harlev, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4146111/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Lymphomatous involvement of the CNS incidence has been increasing in recent years. However, the rarity of these diseases results in a scarcity of available data regarding their clinical presentation natural history and prognosis. We aimed to investigate neurological characteristics of uncommon lymphomatous involvements confined to the central nervous system (CNS) and identify key variables that could serve as predictive biomarkers for treatment outcomes. Methods We searched for patients presenting with neurological symptoms and diagnosed with CNS-restricted lymphomatous involvement between 2005 and 2023. Results We identified 44 cases (41 with primary central nervous system lymphoma diagnosis, 93%; 3 intravascular lymphoma 7%). Overall median time from the onset of symptoms onset to diagnosis was 47 days: range (6-573 days) and was not statistically different comparing patients > 60 years old, p = 0.22. The median follow-up time was 1144 days (27-3501 days). Cognitive deterioration was the most common presenting symptom in 19/44 (43%). Brain MRI revealed lobar lesions as the most frequent location of pathology (24/44, 55%). Death was reported in 30 patients (68%) by the end of the study period with a median survival of 666 days; (median range 17-3291 days) and was significantly more common in the group experiencing relapses p = 0.04(CI: 0.99,0.03). Patients with relapses had a 4 times higher chance of death p = 0.04 (95% CI: 0.03–0.99) HR = 4.1 (CI 1.01–16.09). Time to diagnosis was associated with higher mortality, p = 0.04 (95% CI: 0.02–0.97) and survival p = 0.02 (95% CI: 0.005–0.54) as well with Eastern Cooperative Oncology Group at the last follow-up p = 0.006 (95% CI: 0.0012–0.62). Conclusions Patients had significant delays in diagnosis, affecting patient outcomes. Cognitive deterioration and lobar lesions were prominent clinical and radiological features. Mortality was notably higher in older patients, relapses, and a longer time to diagnosis. primary central nervous system lymphoma early diagnosis mortality age Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Primary central nervous system lymphoma (PCNSL) a rare and aggressive variant of Non-Hodgkin Lymphoma (NHL) affecting the brain, is a diagnostic challenge, particularly when clinical presentation is so diverse . 1 Diffuse large B cell lymphoma (DLBCL) is the most common histology in PCNSL which occurs in 90% of cases, with the rest being T cell lymphoma, Burkitt’s lymphoma and low-grade lymphomas. 2 In recent years PCNSL has shown a notable increase in incidence, reaching 0.5 per 100,000 people in immunocompetent patients. 3 Over the last three decades there has been significant progress in treatments and prognosis due to insightful retrospective series, single-arm phase II trials, and a set of randomized trials that have collectively contributed to the establishment of treatment guidelines. 4 Another even more rare entity is lymphoma confined to the blood vessels within the CNS, intravascular lymphoma (IVL). The incidence of IVL is extremely rare, estimated at 0.001 per 1,000,000 per year. 5 It can affect any organ in the body but most commonly involves the CNS, seen in 48% of all IVL cases. 6 The clinical presentations are heterogeneous, ranging from cognitive alterations, headaches, focal neurological deficits, and seizures. 7 Additionally, constitutional symptoms such as fever, malaise, weight loss, night sweats, and fatigue 8 may further cloud the clinical picture. 4, 9, 10 Historically, the prognosis for PCNSL has been dismal, typified by an untreated survival span of 1.5 months with a 5-year survival rate of 30%. 10, 11 The landscape has evolved with the advent of combined modality therapies, incorporating high-dose methotrexate-based chemotherapy and whole-brain radiation therapy. Nonetheless, survival remains influenced by multifaceted determinants most important of which is age at time of diagnosis, performance status, disease extent, and molecular tumor characteristics. 8 Notably, age over 60, an Eastern Cooperative Oncology Group (ECOG) performance status exceeding 2, and leptomeningeal involvement independently correlate with shorter survival. 12 Other aggressive NHL can intricately weave its path within the CNS, e.g. intravascular lymphoma which may present as acute clinically, pathologically with cerebral blood vessel involvement. 13 Prompt diagnosis proves pivotal, as the time to diagnosis and initiation of treatment significantly influence prognosis. 1 Delay in diagnosis is frequently attributed to the puzzling and nonspecific clinical features of PCNSL, such as headaches and cognitive decline. In view of the rarity of lymphoma restricted to CNS, this study aims to describe the real-life prognostic effects of variables affecting prognosis, specifically patient age at the time of diagnosis. We confined our cohort to individuals whose sole primary manifestation was neurological in nature and comprehensively investigated the spectrum of clinical characteristics for this distinctive cohort. Methods Cohort selection The Rambam Medical Center (RMC) institutional review board ethical committee approved this study. We retrospectively identified all patients with confirmed pathological diagnoses comprised of primary lymphomas process of the CNS in our oncology department, which also had available clinical information at our center from 01/01/2005 to 6/3/2023. Clinical information was obtained through an electronic record retrieval system, recording all newly diagnosed PCNSL cases. We created a database hosted on a secure website and includes demographic information, data on comorbidities, clinical characteristics, radiologic presentation, diagnostic workup, treatment, response to treatment, side effects, and relapse. To guarantee the quality of the database, all the information implemented was double-checked by a research technician and a neuro-oncologist after a review of the patient’s medical chart. Patients enrolled in the present study had to fulfill the following criteria: ( 1 ) Lymphoma diagnosis by pathologic or cytologic (CSF or vitreous biopsy) confirmed diagnosis; ( 2 ) negative full-body CT scan or FDG-PET scan; ( 3 ) age older than 18 years; ( 4 ) immunocompetence and negative HIV status. Patients with primary vitreoretinal lymphoma were excluded from the present study. Endpoints and statistical considerations The tumor response was assessed according to International PCNSL Collaborative Group criteria. 2 ECOG scale was used to assess physical outcomes. The ECOG 14 uses a 5-point score to assess performance status (PS) using an ordinal 5-point scoring system that measures oncological disability. ECOG scale was calculated at two-time points: before onset and at the last follow-up. Oncological and neurological outcomes, as reported in the last medical records, were also mentioned in this study and included cancer status and neurological symptoms status as assessed by the attending physicians. Mortality and causes of mortality were reported as noted in medical records. Statistical analysis Group differences with ages (above and below age 60 years) were established using Wilcoxon statistics between the means of continuous variables. Survival was analyzed, using Kaplan–Meier and Cox regression analysis following further grouping of our patients into those who died or survived. P < 0.05 was regarded as statistically significant. Full Data Access Statements Authors take full responsibility for the data, the analyses and interpretation, and the conduct of the research; they have full access to all the data; and that they have the right to publish all data. Anonymized data not published within this article will be made available by request from any qualified investigator. Results Clinical and demographic factors: We identified 44 cases with primary lymphoproliferative process and neurological presentation, 41 of whom had a histopathological diagnosis of PCNSL and 3 of IVL, between January 1st, 2005, and June 3rd, 2023. Of these cases, 22 were male. The median age at the time of diagnosis was 64 (range 29–81) with 28 patients diagnosed older than 60 years. The overall median time from the onset of symptoms onset to diagnosis was 47 days: range (6-573 days) and was not statistically different comparing patients > 60 years old group, p = 0.22. All patients had histopathological diagnosis via brain biopsy (42 cases) or vitreous body biopsy (2 cases with vitral and CNS) in conjugation with cerebrospinal fluid (CSF) analysis. The median follow-up time was 1144 days: (range 27-3501 days). Clinical presentation exhibited a varied array of neurological manifestations, as shown in Table 1 . Specifically, cognitive complaints were reported in 43% (19/44), ataxia in 30% (13/44) and dizziness in 25% (11/44) cases. Additionally, a range of neurologic symptoms were noted, including speech disturbances, muscle weakness, visual field defects or unspecified visual disturbances, headaches, epileptic seizures, and nausea and vomiting in one case. CSF, histopathological laboratory, and radiology evaluations CSF studies were conducted in 30 patients. The median time to LP from symptoms onset was 48 days (range 5 to 563 days). In most cases, CSF protein elevation was observed (24/30), with a median CSF protein level of 62 mg/dL (range 22–458 mg/dL). Lymphocytic pleocytosis was observed in nearly half of the patients (14/30), with a median of 3 cells/mm3 (0-120 cells/mm3). CSF cytological evaluation was abnormal in only 10% (3/30 patients), 7 patients had 2nd CSF testing, but it did not improve sensitivity. Deep vein thrombosis (DVT) occurred in 6 patients, 2 had consequential pulmonary embolism. Out of patients with DVT, 5 (83%) died during the study. Cytology was abnormal in 2 cases of DLBCL and 1 case with non-differentiated lymphoma. PET CT or total body CT were performed in all patients, with no evidence of extracranial involvement. All patients underwent brain magnetic resonance imaging (MRI), except for three cases in which the brain biopsy was done based on CT scans due to contraindications for MRI. Most patients exhibited lobar lesions on MRI (n = 24), while other locations included the cerebellum (n = 6), hypophysis (n = 2), ocular bulb (n = 2), hypothalamus (n = 1), intraventricular (n = 1), basal ganglia (n = 8), leptomeninges (n = 1), and periventricular regions (n = 8). Notably, seven patients had brainstem lymphoma, and three patients exhibited intravascular lymphoma. All IVL patients had a stroke-like appearance on MRI scans. PCNSL patients had primary infiltrating appearance (11/44), 8 had ring-enhancing appearance, and 5 had hemorrhagic involvement. Histopathological examination revealed that 42 patients had pathologic findings consistent with diffuse large B-cell lymphoma (DLBCL), with others being Burkitt-like lymphoma (n = 1) or non-differentiated(n = 1). Serum lactate dehydrogenase (LDH) elevation at the time of diagnosis was observed in 14 out of 34 patients (41%). Comparison between IVL and PCNSL Comparison between IVL and PCNSL groups showed no differences in age at diagnosis p = 0.2 (CI: 0.28 to 0.85), or sex p = 0.5(CI: 0.006 to 0.54). Time to histological diagnosis was relatively longer in the IVL group with a median time of 192 days (range: 172–285) versus a median time of 38.5 days (range 6-573) p = 0.01 (CI: 0.03 to 0.98). DVT was not statistically more common in the PCNSL group with 1 case in the IVL group and 5 cases in the PCNSL group p = 0.3 (CI:0.3 to 0.95). Cognitive symptoms were present in all 3 IVL groups, p = 0.03 (CI: 0.02–0.08). CSF protein levels were not different between groups p = 0.3 (CI: 0.1 to 0.8). Relapses were present only in the PCNSL group (26 cases) p = 0.03 (CI: 0.01 to 0.09). Death was more common in the PCNSL group with 30 patients versus none in the IVL group p = 0.008(CI:0.006 to 0.13). The median follow-up time was 958.5 days in the PCNSL group versus 1794 days in the IVL group. Chemotherapy radio and Immunotherapy Induction treatment with HD-MTX was given to 42 patients (95%), mostly as combination chemotherapy. The median number of HD-MTX cycles was 6 (range 1–10). Rituximab was given to 30 patients (68%), mostly after the year 2011, and the median number of rituximab treatments was 4(range: 2–10). Intra-CSF therapy was administered to 34 patients (77%) with a median number of 4 treatments (range 1–10). Ommaya device served for this purpose in 2 patients (4.5%). Intraocular MTX therapy was given to 4 patients (9%). Procarbazine was given at induction as a combination chemotherapy with HD-MTX in 40 patients (90%). Treatment was stopped prematurely in 10 patients (22%). The leading factors included treatment-induced renal, hepatic and lung toxicities (n = 1), poor performance status (n = 2), hematological complications (n = 4), infections (n = 3), death (n = 2) and patient wish (n = 1). Consolidation treatment was given to 38 patients (95%). The reported reasons to avoid consolidation were relapse (n = 1) or unknown (n = 5). Cytarabine was given to 36 patients (81%) with a median number of 4 courses (range courses) and vincristine was given to 39 patients as induction treatment (88%) with a median number of 5 courses (range: 1–10 courses). Maintenance treatment was given to 4 patients (9%), 1 received temozolomide, and 3 received other therapy. Treatment response and outcome data were available in all cases and showed clear deterioration for the whole group. Two patients (4.5%) received stem cell transplantation after relapse, and both responded with complete response. Eight patients (18%) received whole brain radiation therapy (WBRT) at induction, the radiation dose median was 41.4 (Gy) with a range of 23–60 (Gy). Salvage radiation was given in 12 patients (27%). Clinical outcomes The median overall follow-up period was 3.1 years (range: 27-3501 days). The median survival was 3.7 years (range: 599–2378 days, Fig. 3 ). Of all patients, 59% (26/44) relapsed (n = 26 in the PCNS versus n = 0 in the IVL groups). Patients aged > 60 years did not show a higher chance of death (p = 0.19, OR = 2.3 CI: 0.63 to 8.61) however differences in time to death (p = 0.25); serum LDH (p = 0.47); CSF protein levels p = 0.06; time to LP p = 0.24; functional state pre- and post-treatment (p = 0.06 and p = 0.09 respectively) were not associated with higher mortality. Death was reported in 30 patients (68%) by the end of the study period with a median of 666 days (1.8 years, median range 17-3291 days) and was significantly more common in the group experiencing relapses p = 0.04 (CI: 0.99 to 0.03). The cause of death among these 30 patients included refractory lymphoma (n = 13), treatment-related complications (n = 1), ischemic stroke (n = 2), sepsis (n = 7), lymphoma relapse (n = 2), unknown (n = 4), and hospice care (n = 2). (27-3501 days) measured from symptom onset to last follow-up or death. Twenty cases (46%) had > 3 years of follow-up with repeated neurological evaluation. The median number of relapses per patient was 1 (range: 0 to 2 times) during the follow-up period. The median time to relapse was 19.1 months (range: 22 to 3210 days). Six patients experienced relapses < 1 year from disease onset. Time from symptoms onset to diagnosis appeared shorter in the group who had no relapses with a median of 31 days (range 6-285 days) versus a median of 52 days (range: 6-573 days) however this was not statistically significant p = 0.24. At baseline, all 44 patients had abnormal neurological examinations. Neurological functional outcomes (assessed at first neurological visit post-treatment, by ECOG performance status) showed 11 patients returned to normal physical function (ECOG = 0), 17 patients had abnormal neurologic examination but were completely ambulatory (ECOG 1) 16 still required ambulatory aids (ECOG 2,3,4) (cane; 6, wheelchair; 4, bedridden; 6). Prognostic factors Age and time to diagnosis did not correlate with mortality, p = 0.05 (CI: 0.02 to 0.18) but did with time elapsed from symptoms to diagnosis p = 0.04 (95% CI: 0.02–0.97). Looking at various cutoff ages versus mortality between elderly patients with a group > 60, a group with age > 70 and lastly, a group with age > 80 years, none of the cutoff ages reached statistical significance nor sex, p = 0.51 (OR = 0.65 CI:0.18 to 2.35) for 60 years, p = 0.89 (CI: 0.58-1) and ages > 80 p = 0.95 (CI: 0.69-1). Patients who had relapses did show higher mortality, p = 0.04 (95% CI: 0.03–0.99) with a hazard ratio of 4.1 (CI 1.01–16.09). The threshold age at diagnosis maximally predicting mortality was 64 years (ROC = 0.73 p = 0.03). Time from symptoms to lumbar puncture did not significantly correlate with death p = 0.23. Patients treated with anti-CD20 did not show differences in overall survival p = 0.37(CI:0.18 to 0.81). DVT showed no correlation with mortality p = 0.36 (OR = 2.6 CI: 0.27 to 24.64). Time to diagnosis significantly correlated with survival p = 0.02 (95% CI: 0.005–0.54) as well as ECOG performance status at last follow-up p = 0.006 (95% CI: 0.0012–0.62). Patients with relapses commonly present with cognitive symptoms p = 0.04 (CI:0.04 to 0.98) at the initial diagnosis. Time to relapse did not correlate with death p = 0.32 (CI: 0.16 to 0.83). To look for variables more common in the relapse group we examined the relapse groups versus non relapse group to find no significant differences in age > 60 p = 0.72, serum LDH p = 0.19, CSF protein p = 0.12, time to diagnosis p = 0.35 or diagnosis age p = 0.29. DVT was not more common in the relapse group p = 0.64. Discussion In this study, we focused on the influence of age at diagnosis on the prognosis of PCNSL, and age at diagnosis was simply divided into 3 groups to comprehensively analyze the different ages. The median age at the time of diagnosis was 64 years with most patients being older than 60 years (63%) with a trend observed demonstrating higher prevalence in the elderly population (Fig. 1 A) also reported in other studies. 15 16 17 As in many cancers, age is known as the most widely accepted prognostic marker as well as performance status in PCNSL. 18 however in recent large data studies in a few cancers and advanced biological treatments older patients show better response to treatments and survive longer. 3, 4 Age cutoffs are controversial with 50 years used as a prognostic score developed by researchers at Memorial Sloan-Kettering Cancer Center 19 (MSKCC) and 60 years cutoff used in the International Extranodal Lymphoma Study Group (IELSG) score. 12 A recent publication using an alternative age cutoff of 80 stated to enhance the prognostic power compared to other mentioned scales. 20 In our cohort of patients older than 60 years, close to 75% died during the study period, however, none of the age groups statistically reached clinically meaningful significance per association with mortality. We did show that delay in diagnosis or relapsed patients had a higher chance of death. The time from symptom appearance to clinical diagnosis was two months in our study and was shown to be a valid prognostic biomarker before. 12 Our observation suggests shortening the pretreatment evaluation timeframe, and not preventing treatment in older patients might improve survival. Delay in diagnosis might stem from nonspecific clinical with a wide array of neurological manifestations shown in Table 1 , most commonly progressive cognitive symptoms, and ataxia. Commonly reported neurological symptoms at presentation such as severe headache, nausea, and vomiting 9, 11 were not as common in our cohort and only occurred in one-third of our patients. Comparison between IVL and PCNSL groups showed the time to histological diagnosis was longer in the IVL group with a median time of 192 days (range: 172–285) versus a median of 38.5 days (range 6-573) p = 0.01. CSF protein levels were not different between. We estimate the prolonged time to diagnosis in IVL was related to the rarity of IVL and to the stroke-like episodes preventing future investigations after the initial stage. Recent publications suggest that random skin biopsy in patients without lymphadenopathy, splenomegaly or bone marrow abnormalities can improve diagnosis time. 21 Incidence of PCNSL appears to be increasing with 0.5:1,000,000 cases per year 22, 23 as we have also shown in our cohort, with almost twice as many new cases in 2023 compared to previous years. Incidence in rising mostly in older individuals in parallel to evolving treatments in the past 3 decades. Real-world and population-based studies are still lacking to allow a better understanding of how to predict outcomes and stratify patients clinically and for experimental trials. The wide range of survival for PCNSL patients in our cohort (months to years) emphasizes the need for valid prognostic markers and improved clinical suspicion. In our study, the cutoff age of 60 as previously published did not reach statistical significance however a threshold of 63 as the age at diagnosis maximally predicted mortality. We show that patients with relapses had higher mortality and were 4 times at risk for death (HR = 4.1), supporting the need to improve the efficacy and durability of responses to 1st line therapy. We have also looked at various prognostic markers for survival as well as risk for relapses. We show that those who presented with cognitive complaints commonly demonstrated involvement of deep brain structures and lower survival rates (p = 0.03), with higher relapse risk (p = 0.04), and. This may be the result of the double involvement of deep brain structures (ie, periventricular regions, basal ganglia, brainstem, and/or cerebellum) as well as the meningeal spread of the brain which are a strategic site for tumor dissemination and were already shown to be significant markers for prognosis. 12 We investigated the diagnostic utility for CSF testing as a factor that contributes to delay in diagnosis. CSF studies are routine tests in the evaluation of chronic or subacute neurological presentation such as in cognitive complaints. 24 In our cohort the most common CSF abnormality was elevated protein in 80% of cases, with a median CSF protein level of 62 mg/dL. Lymphocytic pleocytosis was present in half of the patients, however, the median number of cells was low (cells/mm). Cytological analysis sensitivity was very low. Other studies showed any CSF abnormality in 80% of PCNSL cases 25 with CSF flow cell type analysis reported to have variable sensitivity of 2–16%. 26 In a review of 3 large studies including more than 150 PCNSL patients with leptomeningeal involvement CSF cytological pathology was noted in only 16% of the patients. 27–29 In our cohort for 93% of patients, the CSF did not help in the diagnostic workup, not even when repeated in 16% of patients. The very low frequency of detection by cytological testing in this study is not self-evident, as seems to be low given the common periventricular location and high rate of leptomeningeal involvement. One likely explanation for this apparent contradiction may be the fragility of the tumor cells in CSF in the changing environment after lumbar puncture, and by prior use of corticosteroids. 30 The ratio of false-negative results may be reduced by increased volume of the CSF specimen to be analyzed (to 10.5 ml) and by immediate processing of the sample. The overall prognosis was poor with median survival of 3.7 years similar to what has been reported in the literature. 5 In our cohort, after relapse median survival was 2 years which is higher than reported. In our cohort, 26 out of 44 patients (59%) experienced relapses in the PCNSL group, while none in the IVL group. Death was reported in 68% by the end of the study. We investigated various factors cited to be relevant for survival 12 with neither increased CSF protein level, blood LDH none of which correlated with survival. Shorted time to diagnosis did correlate with reduced survival. Rituximab has been reported to improve outcomes 31 however we did not observe this effect in our study like other phase III study by Bromberg et al. 32 Currently High-dose methotrexate (HD-MTX) based chemotherapy is considered the cornerstone of PCNSL treatment. In our study Induction treatment with HD-MTX was given to 42 patients (95%), mostly as combination chemotherapy. We found several significant prognostic factors including age, time to diagnosis and relapsed patients which were 4 times more likely to die. Our work has several limitations, mainly due to the inherent biases of a retrospective study. There was some missing data and loss of follow-up, but not exceeding 10% for most items. Although important, notably in elderly patients, data on toxicity, especially quality of life questionnaires, are lacking. A longer follow-up will be necessary to describe the population of long-term survivors and late relapses. In summary, PCNSL poses a diagnostic challenge due to its subacute presentation and non-localizing signs, often resulting in diagnostic delay which impacts survival as it prolongs the pretreatment phase. Diagnosis is challenging and the most sensitive diagnostic clues are abnormal brain MRI and brain biopsy supporting diagnosis. CSF had a low sensitivity in the detection of abnormal cells and usually does not lead to diagnosis. Survival seems not directly affected by age at symptom onset; however, by time to treatment initiation with the overall prognosis is poor. Given the rarity of PCNSL long-term follow-up studies are crucial. Understanding the long-term outcomes will guide the development of optimal surveillance strategies and supportive care interventions. Although recent advances have improved our understanding of PCNSL, the need for additional collaborative research is critical. Declarations Conflict of interest statement and funding The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included. There was no funding source. Author Contribution S.O. and S.S. wrote the main manuscript text and prepared figures. S.O. prepared tables. P.S. prepared Figure 3. S.O and S.S. C.B. aided in data collection and manuscript preparation. All authors reviewed the manuscript. References Schaff LR, Grommes C (2022) Primary central nervous system lymphoma. Blood 140:971–979 Fox CP, Phillips EH, Smith J (2019) Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. Br J Haematol 184:348–363 Lv C, Wang J, Zhou M, Xu JY, Chen B, Wan Y (2022) Primary central nervous system lymphoma in the United States, 1975–2017. 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Neuro Oncol 12:409–417 Ferreri AJ, Cwynarski K, Pulczynski E (2016) Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 3:e217–227 Bromberg JEC, Issa S, Bakunina K (2019) Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 20:216–228 Tables Table 1: Clinical signs at admission in 44 patients with lymphoma Symptom No. of Patients (%) Cognitive complaints 19(43) Ataxia 13(30) Weakness 12(27) Headache 11(25) Dizziness 11(25) Speech disturbances 6(14) Unspecified visual disturbances 4(9) Visual field defects 3(7) Seizures 2(5) Nausea and vomiting 1(2) Table 2: Summary of variables and demographic information Variable No. (%) Age <60 yrs >60 yrs 16 (36) 28 (64) Sex male female 22 (50) 22 (50) Duration of symptoms pre-diagnosis <6 wks >6 wks 17 (39) 27 (73) Lesion multiple single 19 (44) 25 (56) Surgery complete resection stereotactic biopsy partial resection 4 (9) 37(84) 1(2) Postsurgical treatment untreated radiation therapy chemo combined treatment 0 0 35 (80) 9 (20) Radiation therapy yes no 8 (18) 36 (82) Chemo regimens MPV MP R-MT R-MPV HIDAC MTX ARA-C MPV/HDMTX 39 (89) 1(2) 1(2) 3 (7) 36 (81) 2 (5) 1(2) 1(2) Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4146111\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":283629424,\"identity\":\"66dc290f-5df1-4348-988d-16e0cd9c9102\",\"order_by\":0,\"name\":\"Sona Ohanyan\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYDACCQglx8DA3EaaFmMGBkaQFgPitSQ2EK2FX7r52WOemjvpG44fbHvwcc8feQb2ww/wapGcc8zcmOfYs9wNZxLbDWc8MzBs4EnDb5XBjQQzaR62w7kbDiS2SfMcMGBskCDgOoMb6d+kef4dTjc4/7BN+s8BA/sGCfYPBLTkmEnzth1OMLgBtIXhgEFigwQPflskZ+SUSc7tO2w488bDdsOeA8bJbTw5BXi18Eukb5N48+2wPN/55GMPfhyQs+1nP74BrxYQYOJB5rERVA8EjD+IUTUKRsEoGAUjFwAAR1xJhg+NoY4AAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"University of Alberta Hospital\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Sona\",\"middleName\":\"\",\"lastName\":\"Ohanyan\",\"suffix\":\"\"},{\"id\":283629426,\"identity\":\"5cbbf0e3-47b5-4a09-baf5-90f664a012b0\",\"order_by\":1,\"name\":\"Chen Buxbaum\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Rambam Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chen\",\"middleName\":\"\",\"lastName\":\"Buxbaum\",\"suffix\":\"\"},{\"id\":283629429,\"identity\":\"731aa37c-0c2d-4096-bfdc-542783182ae4\",\"order_by\":2,\"name\":\"Polina Stein\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Technion – Israel Institute of Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Polina\",\"middleName\":\"\",\"lastName\":\"Stein\",\"suffix\":\"\"},{\"id\":283629433,\"identity\":\"fa63ac71-d1b2-47ce-bad7-7bae4737ac66\",\"order_by\":3,\"name\":\"Shimrit Ringelstein-Harlev\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Rambam Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shimrit\",\"middleName\":\"\",\"lastName\":\"Ringelstein-Harlev\",\"suffix\":\"\"},{\"id\":283629438,\"identity\":\"333c8c28-7dfe-4a46-98c3-22ba8c7364c3\",\"order_by\":4,\"name\":\"Shahar Shelly\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Rambam Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shahar\",\"middleName\":\"\",\"lastName\":\"Shelly\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-03-21 23:59:26\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-4146111/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4146111/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":53580389,\"identity\":\"3522ac4f-a109-497f-8a98-54469cc72a1d\",\"added_by\":\"auto\",\"created_at\":\"2024-03-27 17:27:53\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":56380,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eAge distribution at the time of diagnosis in our cohort of patients with PCNSL. The mean age of diagnosis is 64 years. There was a statistical difference between males and females (p=0.3).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4146111/v1/30b9be5f96ec1701b4af7134.png\"},{\"id\":53580391,\"identity\":\"0b70edd3-96fe-4985-ac3a-4bb176954915\",\"added_by\":\"auto\",\"created_at\":\"2024-03-27 17:27:53\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":604628,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eA series of imaging findings of patients with PCNSL and various neurological symptoms, demonstrating initial presentation, treatment response, as well as follow-up imaging providing insights into the diagnostic process and radiographic treatment outcomes. Figure 1A: T2-Flair MRI with gadolinium of a 79-year-old patient presenting with ataxia and episodes of delirium, showing bi-thalamic hyperintensity. Figure 1B: T2-Flair MRI with gadolinium of the same patient after treatment, demonstrating evidence of near-complete resolution. Figure 2C: T2-Flair MRI with gadolinium of a 64-year-old patient presenting with 6 months of ataxia and dizziness. Figure 3D: A CT scan of a 64-year-old patient with left hemi-syndrome, initially presenting as a hemorrhage. Figure 3E: T1+gadolinium MRI scan of the same patient exhibiting the same hemorrhage with contrast enhancement, as well as small periventricular gadolinium enhancement that was not visible on the earlier CT scan. Figure 3F: Diffusion-weighted imaging (DWI) of the hemorrhagic lesion, confirming the diagnosis of hemorrhagic stroke. Figure 3G: ADC (Apparent Diffusion Coefficient) MRI series of the same patient, providing additional information about the hemorrhagic stroke.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4146111/v1/3956eec1a0af8af9bd6d4d45.png\"},{\"id\":53580393,\"identity\":\"5b67c9b8-3943-4762-8953-afee20337f7e\",\"added_by\":\"auto\",\"created_at\":\"2024-03-27 17:27:53\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1262043,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFigure 3A\\u003cstrong\\u003e:\\u003c/strong\\u003e Histological appearance of brain tissue showing diffuse infiltration by large, atypical cells. The tissue is stained with hematoxylin and eosin at a magnification of 100x. Figure 3B: Immunoperoxidase staining at a magnification of 100x reveals a Ki67 proliferation index of approximately 85% in the large cells compared to the surrounding brain tissue. This indicates a high level of cellular proliferation. Figure 3C: At higher magnification (400x), large cells with prominent nuclear atypia are evident, along with numerous mitotic figures (indicated by arrows). The tissue is stained with hematoxylin and eosin.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4146111/v1/dc81808e535d86128f3e28ec.png\"},{\"id\":53580390,\"identity\":\"7750929f-4111-4c79-bde2-fe22c7bb16a5\",\"added_by\":\"auto\",\"created_at\":\"2024-03-27 17:27:53\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":46473,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan-Meier survival analysis illustrating the overall survival of patients diagnosed with PCNSL. The median survival time from symptom onset is 1376 days.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4146111/v1/c5501d0fe4bfdc317e32725d.png\"},{\"id\":53581590,\"identity\":\"75695312-a5fc-46c6-b690-eacad99201d6\",\"added_by\":\"auto\",\"created_at\":\"2024-03-27 17:35:53\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":88300,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan-Meier survival analysis depicting the overall survival in patients with primary central nervous system lymphoma (PCNSL) across different variables. (A) Comparison of overall survival between patients older or younger than 60 years. (B) Assessment of overall survival in patients with and without relapse. (C) Evaluation of overall survival in patients with concurrent deep vein thrombosis (DVT). (D) Within the relapsed patient group, the impact of age at diagnosis on survival is examined. The dotted lines represent the median survival for each group\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4146111/v1/df9584612dbb4be2addcdcfc.png\"},{\"id\":54154871,\"identity\":\"8782bb1b-a21f-43b5-bf68-ad16c85179e7\",\"added_by\":\"auto\",\"created_at\":\"2024-04-05 11:47:48\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2097152,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4146111/v1/b892f9c3-6710-4fa7-ae98-9e1830137237.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Primary CNS Lymphoma: age as a prognostic biomarker\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003ePrimary central nervous system lymphoma (PCNSL) a rare and aggressive variant of Non-Hodgkin Lymphoma (NHL) affecting the brain, is a diagnostic challenge, particularly when clinical presentation is so diverse .\\u003csup\\u003e1\\u003c/sup\\u003e Diffuse large B cell lymphoma (DLBCL) is the most common histology in PCNSL which occurs in 90% of cases, with the rest being T cell lymphoma, Burkitt\\u0026rsquo;s lymphoma and low-grade lymphomas.\\u003csup\\u003e2\\u003c/sup\\u003e In recent years PCNSL has shown a notable increase in incidence, reaching 0.5 per 100,000 people in immunocompetent patients.\\u003csup\\u003e3\\u003c/sup\\u003e Over the last three decades there has been significant progress in treatments and prognosis due to insightful retrospective series, single-arm phase II trials, and a set of randomized trials that have collectively contributed to the establishment of treatment guidelines.\\u003csup\\u003e4\\u003c/sup\\u003e Another even more rare entity is lymphoma confined to the blood vessels within the CNS, intravascular lymphoma (IVL). The incidence of IVL is extremely rare, estimated at 0.001 per 1,000,000 per year.\\u003csup\\u003e5\\u003c/sup\\u003e It can affect any organ in the body but most commonly involves the CNS, seen in 48% of all IVL cases. \\u003csup\\u003e6\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eThe clinical presentations are heterogeneous, ranging from cognitive alterations, headaches, focal neurological deficits, and seizures.\\u003csup\\u003e7\\u003c/sup\\u003e Additionally, constitutional symptoms such as fever, malaise, weight loss, night sweats, and fatigue\\u003csup\\u003e8\\u003c/sup\\u003e may further cloud the clinical picture.\\u003csup\\u003e4, 9, 10\\u003c/sup\\u003e Historically, the prognosis for PCNSL has been dismal, typified by an untreated survival span of 1.5 months with a 5-year survival rate of 30%.\\u003csup\\u003e10, 11\\u003c/sup\\u003e The landscape has evolved with the advent of combined modality therapies, incorporating high-dose methotrexate-based chemotherapy and whole-brain radiation therapy. Nonetheless, survival remains influenced by multifaceted determinants most important of which is age at time of diagnosis, performance status, disease extent, and molecular tumor characteristics.\\u003csup\\u003e8\\u003c/sup\\u003e Notably, age over 60, an Eastern Cooperative Oncology Group (ECOG) performance status exceeding 2, and leptomeningeal involvement independently correlate with shorter survival.\\u003csup\\u003e12\\u003c/sup\\u003e Other aggressive NHL can intricately weave its path within the CNS, e.g. intravascular lymphoma which may present as acute clinically, pathologically with cerebral blood vessel involvement.\\u003csup\\u003e13\\u003c/sup\\u003e Prompt diagnosis proves pivotal, as the time to diagnosis and initiation of treatment significantly influence prognosis.\\u003csup\\u003e1\\u003c/sup\\u003e Delay in diagnosis is frequently attributed to the puzzling and nonspecific clinical features of PCNSL, such as headaches and cognitive decline.\\u003c/p\\u003e \\u003cp\\u003eIn view of the rarity of lymphoma restricted to CNS, this study aims to describe the real-life prognostic effects of variables affecting prognosis, specifically patient age at the time of diagnosis. We confined our cohort to individuals whose sole primary manifestation was neurological in nature and comprehensively investigated the spectrum of clinical characteristics for this distinctive cohort.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCohort selection\\u003c/h2\\u003e \\u003cp\\u003e The Rambam Medical Center (RMC) institutional review board ethical committee approved this study.\\u003c/p\\u003e \\u003cp\\u003eWe retrospectively identified all patients with confirmed pathological diagnoses comprised of primary lymphomas process of the CNS in our oncology department, which also had available clinical information at our center from 01/01/2005 to 6/3/2023. Clinical information was obtained through an electronic record retrieval system, recording all newly diagnosed PCNSL cases. We created a database hosted on a secure website and includes demographic information, data on comorbidities, clinical characteristics, radiologic presentation, diagnostic workup, treatment, response to treatment, side effects, and relapse. To guarantee the quality of the database, all the information implemented was double-checked by a research technician and a neuro-oncologist after a review of the patient\\u0026rsquo;s medical chart.\\u003c/p\\u003e \\u003cp\\u003ePatients enrolled in the present study had to fulfill the following criteria: (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e) Lymphoma diagnosis by pathologic or cytologic (CSF or vitreous biopsy) confirmed diagnosis; (\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e) negative full-body CT scan or FDG-PET scan; (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e) age older than 18 years; (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e) immunocompetence and negative HIV status. Patients with primary vitreoretinal lymphoma were excluded from the present study.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEndpoints and statistical considerations\\u003c/h2\\u003e \\u003cp\\u003eThe tumor response was assessed according to International PCNSL Collaborative Group criteria.\\u003csup\\u003e2\\u003c/sup\\u003e ECOG scale was used to assess physical outcomes. The ECOG\\u003csup\\u003e14\\u003c/sup\\u003e uses a 5-point score to assess performance status (PS) using an ordinal 5-point scoring system that measures oncological disability. ECOG scale was calculated at two-time points: before onset and at the last follow-up. Oncological and neurological outcomes, as reported in the last medical records, were also mentioned in this study and included cancer status and neurological symptoms status as assessed by the attending physicians. Mortality and causes of mortality were reported as noted in medical records.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eGroup differences with ages (above and below age 60 years) were established using Wilcoxon statistics between the means of continuous variables. Survival was analyzed, using Kaplan\\u0026ndash;Meier and Cox regression analysis following further grouping of our patients into those who died or survived. P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was regarded as statistically significant.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eFull Data Access Statements\\u003c/h3\\u003e\\n\\u003cp\\u003eAuthors take full responsibility for the data, the analyses and interpretation, and the conduct of the research; they have full access to all the data; and that they have the right to publish all data. Anonymized data not published within this article will be made available by request from any qualified investigator.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eClinical and demographic factors:\\u003c/h2\\u003e \\u003cp\\u003eWe identified 44 cases with primary lymphoproliferative process and neurological presentation, 41 of whom had a histopathological diagnosis of PCNSL and 3 of IVL, between January 1st, 2005, and June 3rd, 2023. Of these cases, 22 were male. The median age at the time of diagnosis was 64 (range 29\\u0026ndash;81) with 28 patients diagnosed older than 60 years. The overall median time from the onset of symptoms onset to diagnosis was 47 days: range (6-573 days) and was not statistically different comparing patients\\u0026thinsp;\\u0026gt;\\u0026thinsp;60 years old group, p\\u0026thinsp;=\\u0026thinsp;0.22. All patients had histopathological diagnosis via brain biopsy (42 cases) or vitreous body biopsy (2 cases with vitral and CNS) in conjugation with cerebrospinal fluid (CSF) analysis. The median follow-up time was 1144 days: (range 27-3501 days). Clinical presentation exhibited a varied array of neurological manifestations, as shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. Specifically, cognitive complaints were reported in 43% (19/44), ataxia in 30% (13/44) and dizziness in 25% (11/44) cases. Additionally, a range of neurologic symptoms were noted, including speech disturbances, muscle weakness, visual field defects or unspecified visual disturbances, headaches, epileptic seizures, and nausea and vomiting in one case.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCSF, histopathological laboratory, and radiology evaluations\\u003c/h2\\u003e \\u003cp\\u003eCSF studies were conducted in 30 patients. The median time to LP from symptoms onset was 48 days (range 5 to 563 days). In most cases, CSF protein elevation was observed (24/30), with a median CSF protein level of 62 mg/dL (range 22\\u0026ndash;458 mg/dL). Lymphocytic pleocytosis was observed in nearly half of the patients (14/30), with a median of 3 cells/mm3 (0-120 cells/mm3). CSF cytological evaluation was abnormal in only 10% (3/30 patients), 7 patients had 2nd CSF testing, but it did not improve sensitivity. Deep vein thrombosis (DVT) occurred in 6 patients, 2 had consequential pulmonary embolism. Out of patients with DVT, 5 (83%) died during the study. Cytology was abnormal in 2 cases of DLBCL and 1 case with non-differentiated lymphoma.\\u003c/p\\u003e \\u003cp\\u003ePET CT or total body CT were performed in all patients, with no evidence of extracranial involvement. All patients underwent brain magnetic resonance imaging (MRI), except for three cases in which the brain biopsy was done based on CT scans due to contraindications for MRI. Most patients exhibited lobar lesions on MRI (n\\u0026thinsp;=\\u0026thinsp;24), while other locations included the cerebellum (n\\u0026thinsp;=\\u0026thinsp;6), hypophysis (n\\u0026thinsp;=\\u0026thinsp;2), ocular bulb (n\\u0026thinsp;=\\u0026thinsp;2), hypothalamus (n\\u0026thinsp;=\\u0026thinsp;1), intraventricular (n\\u0026thinsp;=\\u0026thinsp;1), basal ganglia (n\\u0026thinsp;=\\u0026thinsp;8), leptomeninges (n\\u0026thinsp;=\\u0026thinsp;1), and periventricular regions (n\\u0026thinsp;=\\u0026thinsp;8). Notably, seven patients had brainstem lymphoma, and three patients exhibited intravascular lymphoma. All IVL patients had a stroke-like appearance on MRI scans. PCNSL patients had primary infiltrating appearance (11/44), 8 had ring-enhancing appearance, and 5 had hemorrhagic involvement. Histopathological examination revealed that 42 patients had pathologic findings consistent with diffuse large B-cell lymphoma (DLBCL), with others being Burkitt-like lymphoma (n\\u0026thinsp;=\\u0026thinsp;1) or non-differentiated(n\\u0026thinsp;=\\u0026thinsp;1). Serum lactate dehydrogenase (LDH) elevation at the time of diagnosis was observed in 14 out of 34 patients (41%).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eComparison between IVL and PCNSL\\u003c/h2\\u003e \\u003cp\\u003eComparison between IVL and PCNSL groups showed no differences in age at diagnosis p\\u0026thinsp;=\\u0026thinsp;0.2 (CI: 0.28 to 0.85), or sex p\\u0026thinsp;=\\u0026thinsp;0.5(CI: 0.006 to 0.54). Time to histological diagnosis was relatively longer in the IVL group with a median time of 192 days (range: 172\\u0026ndash;285) versus a median time of 38.5 days (range 6-573) p\\u0026thinsp;=\\u0026thinsp;0.01 (CI: 0.03 to 0.98). DVT was not statistically more common in the PCNSL group with 1 case in the IVL group and 5 cases in the PCNSL group p\\u0026thinsp;=\\u0026thinsp;0.3 (CI:0.3 to 0.95). Cognitive symptoms were present in all 3 IVL groups, p\\u0026thinsp;=\\u0026thinsp;0.03 (CI: 0.02\\u0026ndash;0.08). CSF protein levels were not different between groups p\\u0026thinsp;=\\u0026thinsp;0.3 (CI: 0.1 to 0.8). Relapses were present only in the PCNSL group (26 cases) p\\u0026thinsp;=\\u0026thinsp;0.03 (CI: 0.01 to 0.09). Death was more common in the PCNSL group with 30 patients versus none in the IVL group p\\u0026thinsp;=\\u0026thinsp;0.008(CI:0.006 to 0.13). The median follow-up time was 958.5 days in the PCNSL group versus 1794 days in the IVL group.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eChemotherapy radio and Immunotherapy\\u003c/h2\\u003e \\u003cp\\u003eInduction treatment with HD-MTX was given to 42 patients (95%), mostly as combination chemotherapy. The median number of HD-MTX cycles was 6 (range 1\\u0026ndash;10). Rituximab was given to 30 patients (68%), mostly after the year 2011, and the median number of rituximab treatments was 4(range: 2\\u0026ndash;10). Intra-CSF therapy was administered to 34 patients (77%) with a median number of 4 treatments (range 1\\u0026ndash;10). Ommaya device served for this purpose in 2 patients (4.5%). Intraocular MTX therapy was given to 4 patients (9%). Procarbazine was given at induction as a combination chemotherapy with HD-MTX in 40 patients (90%).\\u003c/p\\u003e \\u003cp\\u003eTreatment was stopped prematurely in 10 patients (22%). The leading factors included treatment-induced renal, hepatic and lung toxicities (n\\u0026thinsp;=\\u0026thinsp;1), poor performance status (n\\u0026thinsp;=\\u0026thinsp;2), hematological complications (n\\u0026thinsp;=\\u0026thinsp;4), infections (n\\u0026thinsp;=\\u0026thinsp;3), death (n\\u0026thinsp;=\\u0026thinsp;2) and patient wish (n\\u0026thinsp;=\\u0026thinsp;1). Consolidation treatment was given to 38 patients (95%). The reported reasons to avoid consolidation were relapse (n\\u0026thinsp;=\\u0026thinsp;1) or unknown (n\\u0026thinsp;=\\u0026thinsp;5). Cytarabine was given to 36 patients (81%) with a median number of 4 courses (range courses) and vincristine was given to 39 patients as induction treatment (88%) with a median number of 5 courses (range: 1\\u0026ndash;10 courses). Maintenance treatment was given to 4 patients (9%), 1 received temozolomide, and 3 received other therapy. Treatment response and outcome data were available in all cases and showed clear deterioration for the whole group. Two patients (4.5%) received stem cell transplantation after relapse, and both responded with complete response. Eight patients (18%) received whole brain radiation therapy (WBRT) at induction, the radiation dose median was 41.4 (Gy) with a range of 23\\u0026ndash;60 (Gy). Salvage radiation was given in 12 patients (27%).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eClinical outcomes\\u003c/h2\\u003e \\u003cp\\u003eThe median overall follow-up period was 3.1 years (range: 27-3501 days). The median survival was 3.7 years (range: 599\\u0026ndash;2378 days, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). Of all patients, 59% (26/44) relapsed (n\\u0026thinsp;=\\u0026thinsp;26 in the PCNS versus n\\u0026thinsp;=\\u0026thinsp;0 in the IVL groups). Patients aged\\u0026thinsp;\\u0026gt;\\u0026thinsp;60 years did not show a higher chance of death (p\\u0026thinsp;=\\u0026thinsp;0.19, OR\\u0026thinsp;=\\u0026thinsp;2.3 CI: 0.63 to 8.61) however differences in time to death (p\\u0026thinsp;=\\u0026thinsp;0.25); serum LDH (p\\u0026thinsp;=\\u0026thinsp;0.47); CSF protein levels p\\u0026thinsp;=\\u0026thinsp;0.06; time to LP p\\u0026thinsp;=\\u0026thinsp;0.24; functional state pre- and post-treatment (p\\u0026thinsp;=\\u0026thinsp;0.06 and p\\u0026thinsp;=\\u0026thinsp;0.09 respectively) were not associated with higher mortality.\\u003c/p\\u003e \\u003cp\\u003eDeath was reported in 30 patients (68%) by the end of the study period with a median of 666 days (1.8 years, median range 17-3291 days) and was significantly more common in the group experiencing relapses p\\u0026thinsp;=\\u0026thinsp;0.04 (CI: 0.99 to 0.03). The cause of death among these 30 patients included refractory lymphoma (n\\u0026thinsp;=\\u0026thinsp;13), treatment-related complications (n\\u0026thinsp;=\\u0026thinsp;1), ischemic stroke (n\\u0026thinsp;=\\u0026thinsp;2), sepsis (n\\u0026thinsp;=\\u0026thinsp;7), lymphoma relapse (n\\u0026thinsp;=\\u0026thinsp;2), unknown (n\\u0026thinsp;=\\u0026thinsp;4), and hospice care (n\\u0026thinsp;=\\u0026thinsp;2). (27-3501 days) measured from symptom onset to last follow-up or death. Twenty cases (46%) had\\u0026thinsp;\\u0026gt;\\u0026thinsp;3 years of follow-up with repeated neurological evaluation.\\u003c/p\\u003e \\u003cp\\u003eThe median number of relapses per patient was 1 (range: 0 to 2 times) during the follow-up period. The median time to relapse was 19.1 months (range: 22 to 3210 days). Six patients experienced relapses\\u0026thinsp;\\u0026lt;\\u0026thinsp;1 year from disease onset. Time from symptoms onset to diagnosis appeared shorter in the group who had no relapses with a median of 31 days (range 6-285 days) versus a median of 52 days (range: 6-573 days) however this was not statistically significant p\\u0026thinsp;=\\u0026thinsp;0.24. At baseline, all 44 patients had abnormal neurological examinations. Neurological functional outcomes (assessed at first neurological visit post-treatment, by ECOG performance status) showed 11 patients returned to normal physical function (ECOG\\u0026thinsp;=\\u0026thinsp;0), 17 patients had abnormal neurologic examination but were completely ambulatory (ECOG 1) 16 still required ambulatory aids (ECOG 2,3,4) (cane; 6, wheelchair; 4, bedridden; 6).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePrognostic factors\\u003c/h2\\u003e \\u003cp\\u003eAge and time to diagnosis did not correlate with mortality, p\\u0026thinsp;=\\u0026thinsp;0.05 (CI: 0.02 to 0.18) but did with time elapsed from symptoms to diagnosis p\\u0026thinsp;=\\u0026thinsp;0.04 (95% CI: 0.02\\u0026ndash;0.97). Looking at various cutoff ages versus mortality between elderly patients with a group\\u0026thinsp;\\u0026gt;\\u0026thinsp;60, a group with age\\u0026thinsp;\\u0026gt;\\u0026thinsp;70 and lastly, a group with age\\u0026thinsp;\\u0026gt;\\u0026thinsp;80 years, none of the cutoff ages reached statistical significance nor sex, p\\u0026thinsp;=\\u0026thinsp;0.51 (OR\\u0026thinsp;=\\u0026thinsp;0.65 CI:0.18 to 2.35) for 60 years, p\\u0026thinsp;=\\u0026thinsp;0.89 (CI: 0.58-1) and ages\\u0026thinsp;\\u0026gt;\\u0026thinsp;80 p\\u0026thinsp;=\\u0026thinsp;0.95 (CI: 0.69-1). Patients who had relapses did show higher mortality, p\\u0026thinsp;=\\u0026thinsp;0.04 (95% CI: 0.03\\u0026ndash;0.99) with a hazard ratio of 4.1 (CI 1.01\\u0026ndash;16.09). The threshold age at diagnosis maximally predicting mortality was 64 years (ROC\\u0026thinsp;=\\u0026thinsp;0.73 p\\u0026thinsp;=\\u0026thinsp;0.03). Time from symptoms to lumbar puncture did not significantly correlate with death p\\u0026thinsp;=\\u0026thinsp;0.23. Patients treated with anti-CD20 did not show differences in overall survival p\\u0026thinsp;=\\u0026thinsp;0.37(CI:0.18 to 0.81). DVT showed no correlation with mortality p\\u0026thinsp;=\\u0026thinsp;0.36 (OR\\u0026thinsp;=\\u0026thinsp;2.6 CI: 0.27 to 24.64). Time to diagnosis significantly correlated with survival p\\u0026thinsp;=\\u0026thinsp;0.02 (95% CI: 0.005\\u0026ndash;0.54) as well as ECOG performance status at last follow-up p\\u0026thinsp;=\\u0026thinsp;0.006 (95% CI: 0.0012\\u0026ndash;0.62).\\u003c/p\\u003e \\u003cp\\u003ePatients with relapses commonly present with cognitive symptoms p\\u0026thinsp;=\\u0026thinsp;0.04 (CI:0.04 to 0.98) at the initial diagnosis. Time to relapse did not correlate with death p\\u0026thinsp;=\\u0026thinsp;0.32 (CI: 0.16 to 0.83). To look for variables more common in the relapse group we examined the relapse groups versus non relapse group to find no significant differences in age\\u0026thinsp;\\u0026gt;\\u0026thinsp;60 p\\u0026thinsp;=\\u0026thinsp;0.72, serum LDH p\\u0026thinsp;=\\u0026thinsp;0.19, CSF protein p\\u0026thinsp;=\\u0026thinsp;0.12, time to diagnosis p\\u0026thinsp;=\\u0026thinsp;0.35 or diagnosis age p\\u0026thinsp;=\\u0026thinsp;0.29. DVT was not more common in the relapse group p\\u0026thinsp;=\\u0026thinsp;0.64.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this study, we focused on the influence of age at diagnosis on the prognosis of PCNSL, and age at diagnosis was simply divided into 3 groups to comprehensively analyze the different ages. The median age at the time of diagnosis was 64 years with most patients being older than 60 years (63%) with a trend observed demonstrating higher prevalence in the elderly population (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eA) also reported in other studies.\\u003csup\\u003e15 16 17\\u003c/sup\\u003e As in many cancers, age is known as the most widely accepted prognostic marker as well as performance status in PCNSL.\\u003csup\\u003e18\\u003c/sup\\u003e however in recent large data studies in a few cancers and advanced biological treatments older patients show better response to treatments and survive longer.\\u003csup\\u003e3, 4\\u003c/sup\\u003e Age cutoffs are controversial with 50 years used as a prognostic score developed by researchers at Memorial Sloan-Kettering Cancer Center\\u003csup\\u003e19\\u003c/sup\\u003e (MSKCC) and 60 years cutoff used in the International Extranodal Lymphoma Study Group (IELSG) score.\\u003csup\\u003e12\\u003c/sup\\u003e A recent publication using an alternative age cutoff of 80 stated to enhance the prognostic power compared to other mentioned scales.\\u003csup\\u003e20\\u003c/sup\\u003e In our cohort of patients older than 60 years, close to 75% died during the study period, however, none of the age groups statistically reached clinically meaningful significance per association with mortality. We did show that delay in diagnosis or relapsed patients had a higher chance of death. The time from symptom appearance to clinical diagnosis was two months in our study and was shown to be a valid prognostic biomarker before.\\u003csup\\u003e12\\u003c/sup\\u003e Our observation suggests shortening the pretreatment evaluation timeframe, and not preventing treatment in older patients might improve survival.\\u003c/p\\u003e \\u003cp\\u003eDelay in diagnosis might stem from nonspecific clinical with a wide array of neurological manifestations shown in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e, most commonly progressive cognitive symptoms, and ataxia.\\u003c/p\\u003e \\u003cp\\u003eCommonly reported neurological symptoms at presentation such as severe headache, nausea, and vomiting \\u003csup\\u003e9, 11\\u003c/sup\\u003e were not as common in our cohort and only occurred in one-third of our patients. Comparison between IVL and PCNSL groups showed the time to histological diagnosis was longer in the IVL group with a median time of 192 days (range: 172\\u0026ndash;285) versus a median of 38.5 days (range 6-573) p\\u0026thinsp;=\\u0026thinsp;0.01. CSF protein levels were not different between. We estimate the prolonged time to diagnosis in IVL was related to the rarity of IVL and to the stroke-like episodes preventing future investigations after the initial stage. Recent publications suggest that random skin biopsy in patients without lymphadenopathy, splenomegaly or bone marrow abnormalities can improve diagnosis time.\\u003csup\\u003e21\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eIncidence of PCNSL appears to be increasing with 0.5:1,000,000 cases per year \\u003csup\\u003e22, 23\\u003c/sup\\u003e as we have also shown in our cohort, with almost twice as many new cases in 2023 compared to previous years. Incidence in rising mostly in older individuals in parallel to evolving treatments in the past 3 decades. Real-world and population-based studies are still lacking to allow a better understanding of how to predict outcomes and stratify patients clinically and for experimental trials. The wide range of survival for PCNSL patients in our cohort (months to years) emphasizes the need for valid prognostic markers and improved clinical suspicion.\\u003c/p\\u003e \\u003cp\\u003eIn our study, the cutoff age of 60 as previously published did not reach statistical significance however a threshold of 63 as the age at diagnosis maximally predicted mortality. We show that patients with relapses had higher mortality and were 4 times at risk for death (HR\\u0026thinsp;=\\u0026thinsp;4.1), supporting the need to improve the efficacy and durability of responses to 1st line therapy. We have also looked at various prognostic markers for survival as well as risk for relapses. We show that those who presented with cognitive complaints commonly demonstrated involvement of deep brain structures and lower survival rates (p\\u0026thinsp;=\\u0026thinsp;0.03), with higher relapse risk (p\\u0026thinsp;=\\u0026thinsp;0.04), and. This may be the result of the double involvement of deep brain structures (ie, periventricular regions, basal ganglia, brainstem, and/or cerebellum) as well as the meningeal spread of the brain which are a strategic site for tumor dissemination and were already shown to be significant markers for prognosis.\\u003csup\\u003e12\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eWe investigated the diagnostic utility for CSF testing as a factor that contributes to delay in diagnosis. CSF studies are routine tests in the evaluation of chronic or subacute neurological presentation such as in cognitive complaints.\\u003csup\\u003e24\\u003c/sup\\u003e In our cohort the most common CSF abnormality was elevated protein in 80% of cases, with a median CSF protein level of 62 mg/dL. Lymphocytic pleocytosis was present in half of the patients, however, the median number of cells was low (cells/mm). Cytological analysis sensitivity was very low. Other studies showed any CSF abnormality in 80% of PCNSL cases \\u003csup\\u003e25\\u003c/sup\\u003e with CSF flow cell type analysis reported to have variable sensitivity of 2\\u0026ndash;16%. \\u003csup\\u003e26\\u003c/sup\\u003e In a review of 3 large studies including more than 150 PCNSL patients with leptomeningeal involvement CSF cytological pathology was noted in only 16% of the patients. \\u003csup\\u003e27\\u0026ndash;29\\u003c/sup\\u003e In our cohort for 93% of patients, the CSF did not help in the diagnostic workup, not even when repeated in 16% of patients. The very low frequency of detection by cytological testing in this study is not self-evident, as seems to be low given the common periventricular location and high rate of leptomeningeal involvement. One likely explanation for this apparent contradiction may be the fragility of the tumor cells in CSF in the changing environment after lumbar puncture, and by prior use of corticosteroids. \\u003csup\\u003e30\\u003c/sup\\u003e The ratio of false-negative results may be reduced by increased volume of the CSF specimen to be analyzed (to 10.5 ml) and by immediate processing of the sample.\\u003c/p\\u003e \\u003cp\\u003eThe overall prognosis was poor with median survival of 3.7 years similar to what has been reported in the literature.\\u003csup\\u003e5\\u003c/sup\\u003e In our cohort, after relapse median survival was 2 years which is higher than reported. In our cohort, 26 out of 44 patients (59%) experienced relapses in the PCNSL group, while none in the IVL group. Death was reported in 68% by the end of the study. We investigated various factors cited to be relevant for survival\\u003csup\\u003e12\\u003c/sup\\u003e with neither increased CSF protein level, blood LDH none of which correlated with survival. Shorted time to diagnosis did correlate with reduced survival. Rituximab has been reported to improve outcomes\\u003csup\\u003e31\\u003c/sup\\u003e however we did not observe this effect in our study like other phase III study by Bromberg et al.\\u003csup\\u003e32\\u003c/sup\\u003e Currently High-dose methotrexate (HD-MTX) based chemotherapy is considered the cornerstone of PCNSL treatment. In our study Induction treatment with HD-MTX was given to 42 patients (95%), mostly as combination chemotherapy. We found several significant prognostic factors including age, time to diagnosis and relapsed patients which were 4 times more likely to die.\\u003c/p\\u003e \\u003cp\\u003eOur work has several limitations, mainly due to the inherent biases of a retrospective study. There was some missing data and loss of follow-up, but not exceeding 10% for most items. Although important, notably in elderly patients, data on toxicity, especially quality of life questionnaires, are lacking. A longer follow-up will be necessary to describe the population of long-term survivors and late relapses.\\u003c/p\\u003e \\u003cp\\u003eIn summary, PCNSL poses a diagnostic challenge due to its subacute presentation and non-localizing signs, often resulting in diagnostic delay which impacts survival as it prolongs the pretreatment phase. Diagnosis is challenging and the most sensitive diagnostic clues are abnormal brain MRI and brain biopsy supporting diagnosis. CSF had a low sensitivity in the detection of abnormal cells and usually does not lead to diagnosis. Survival seems not directly affected by age at symptom onset; however, by time to treatment initiation with the overall prognosis is poor. Given the rarity of PCNSL long-term follow-up studies are crucial. Understanding the long-term outcomes will guide the development of optimal surveillance strategies and supportive care interventions. Although recent advances have improved our understanding of PCNSL, the need for additional collaborative research is critical.\\u003c/p\\u003e \"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eConflict of interest statement and funding \\u003c/h2\\u003e\\n\\u003cp\\u003eThe authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included. \\u0026nbsp;There was no funding source.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eS.O. and S.S. wrote the main manuscript text and prepared figures. S.O. prepared tables. P.S. prepared Figure 3. S.O and S.S. C.B. aided in data collection and manuscript preparation. All authors reviewed the manuscript.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eSchaff LR, Grommes C (2022) Primary central nervous system lymphoma. Blood 140:971\\u0026ndash;979\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFox CP, Phillips EH, Smith J (2019) Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. Br J Haematol 184:348\\u0026ndash;363\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLv C, Wang J, Zhou M, Xu JY, Chen B, Wan Y (2022) Primary central nervous system lymphoma in the United States, 1975\\u0026ndash;2017. Ther Adv Hematol 13:20406207211066166\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHoang-Xuan K, Bessell E, Bromberg J (2015) Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. 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Ann Oncol 23:2374\\u0026ndash;2380\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFischer L, Martus P, Weller M (2008) Meningeal dissemination in primary CNS lymphoma: prospective evaluation of 282 patients. Neurology 71:1102\\u0026ndash;1108\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBlay JY, Conroy T, Chevreau C (1998) High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 16:864\\u0026ndash;871\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKiewe P, Fischer L, Martus P, Thiel E, Korfel A (2010) Meningeal dissemination in primary CNS lymphoma: diagnosis, treatment, and survival in a large monocenter cohort. Neuro Oncol 12:409\\u0026ndash;417\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFerreri AJ, Cwynarski K, Pulczynski E (2016) Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 3:e217\\u0026ndash;227\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBromberg JEC, Issa S, Bakunina K (2019) Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 20:216\\u0026ndash;228\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eTable 1:\\u0026nbsp;\\u003c/strong\\u003eClinical signs at admission in 44 patients with lymphoma\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"462\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSymptom\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eNo. of Patients (%)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eCognitive complaints\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e19(43)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eAtaxia\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e13(30)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eWeakness\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e12(27)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eHeadache\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e11(25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eDizziness\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e11(25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eSpeech disturbances\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e6(14)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eUnspecified visual disturbances\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e4(9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eVisual field defects\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e3(7)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eSeizures\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e2(5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"51.94805194805195%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eNausea and vomiting\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"48.05194805194805%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e1(2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u003cbr\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 2:\\u0026nbsp;\\u003c/strong\\u003eSummary of variables and demographic information\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"438\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eVariable\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eNo. (%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eAge\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026lt;60 yrs\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026gt;60 yrs\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e16 (36)\\u003c/p\\u003e\\n \\u003cp\\u003e28 (64)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eSex\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; male\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; female\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e22 (50)\\u003c/p\\u003e\\n \\u003cp\\u003e22 (50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eDuration of symptoms pre-diagnosis\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;\\u0026lt;6 wks\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026gt;6 wks\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e17 (39)\\u003c/p\\u003e\\n \\u003cp\\u003e27 (73)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eLesion\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;multiple\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;single\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e19 (44)\\u003c/p\\u003e\\n \\u003cp\\u003e25 (56)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eSurgery\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; complete resection\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; stereotactic biopsy\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp; partial resection\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e4 (9)\\u003c/p\\u003e\\n \\u003cp\\u003e37(84)\\u003c/p\\u003e\\n \\u003cp\\u003e1(2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003ePostsurgical treatment\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;untreated\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;radiation therapy\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;chemo\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;combined treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003cp\\u003e35 (80)\\u003c/p\\u003e\\n \\u003cp\\u003e9 (20)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eRadiation therapy\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;yes\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp; \\u0026nbsp;no\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e8 (18)\\u003c/p\\u003e\\n \\u003cp\\u003e36 (82)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd width=\\\"53.42465753424658%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003eChemo regimens\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;MPV\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;MP\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;R-MT\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;R-MPV\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;HIDAC\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;MTX\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;ARA-C\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp; \\u0026nbsp; \\u0026nbsp;MPV/HDMTX\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd width=\\\"46.57534246575342%\\\" valign=\\\"top\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e39 (89)\\u003c/p\\u003e\\n \\u003cp\\u003e1(2)\\u003c/p\\u003e\\n \\u003cp\\u003e1(2)\\u003c/p\\u003e\\n \\u003cp\\u003e3 (7)\\u003c/p\\u003e\\n \\u003cp\\u003e36 (81)\\u003c/p\\u003e\\n \\u003cp\\u003e2 (5)\\u003c/p\\u003e\\n \\u003cp\\u003e1(2)\\u003c/p\\u003e\\n \\u003cp\\u003e1(2)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"primary central nervous system lymphoma, early diagnosis, mortality, age\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4146111/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4146111/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eLymphomatous involvement of the CNS incidence has been increasing in recent years. However, the rarity of these diseases results in a scarcity of available data regarding their clinical presentation natural history and prognosis. We aimed to investigate neurological characteristics of uncommon lymphomatous involvements confined to the central nervous system (CNS) and identify key variables that could serve as predictive biomarkers for treatment outcomes.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eWe searched for patients presenting with neurological symptoms and diagnosed with CNS-restricted lymphomatous involvement between 2005 and 2023.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eWe identified 44 cases (41 with primary central nervous system lymphoma diagnosis, 93%; 3 intravascular lymphoma 7%). Overall median time from the onset of symptoms onset to diagnosis was 47 days: range (6-573 days) and was not statistically different comparing patients\\u0026thinsp;\\u0026gt;\\u0026thinsp;60 years old, p\\u0026thinsp;=\\u0026thinsp;0.22. The median follow-up time was 1144 days (27-3501 days). Cognitive deterioration was the most common presenting symptom in 19/44 (43%). Brain MRI revealed lobar lesions as the most frequent location of pathology (24/44, 55%). Death was reported in 30 patients (68%) by the end of the study period with a median survival of 666 days; (median range 17-3291 days) and was significantly more common in the group experiencing relapses p\\u0026thinsp;=\\u0026thinsp;0.04(CI: 0.99,0.03). Patients with relapses had a 4 times higher chance of death p\\u0026thinsp;=\\u0026thinsp;0.04 (95% CI: 0.03\\u0026ndash;0.99) HR\\u0026thinsp;=\\u0026thinsp;4.1 (CI 1.01\\u0026ndash;16.09). Time to diagnosis was associated with higher mortality, p\\u0026thinsp;=\\u0026thinsp;0.04 (95% CI: 0.02\\u0026ndash;0.97) and survival p\\u0026thinsp;=\\u0026thinsp;0.02 (95% CI: 0.005\\u0026ndash;0.54) as well with Eastern Cooperative Oncology Group at the last follow-up p\\u0026thinsp;=\\u0026thinsp;0.006 (95% CI: 0.0012\\u0026ndash;0.62).\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003ePatients had significant delays in diagnosis, affecting patient outcomes. Cognitive deterioration and lobar lesions were prominent clinical and radiological features. Mortality was notably higher in older patients, relapses, and a longer time to diagnosis.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Primary CNS Lymphoma: age as a prognostic biomarker\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-03-27 17:27:48\",\"doi\":\"10.21203/rs.3.rs-4146111/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"6c19c3a1-e222-4068-818b-26c9d82c7d25\",\"owner\":[],\"postedDate\":\"March 27th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-04-05T11:39:41+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-03-27 17:27:48\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4146111\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4146111\",\"identity\":\"rs-4146111\",\"version\":[\"v1\"]},\"buildId\":\"J0_U0BvcaRcwD8yVFaRlm\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}