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We explored the utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) sequencing as a noninvasive diagnostic tool for detecting central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma (DLBCL). Secondary CNS involvement in DLBCL, although rare (~5% of cases), presents diagnostic and prognostic challenges during systemic disease progression or relapse. Effective treatment is impeded by the blood-brain barrier. This was a prospective cohort study (Samsung Lymphoma Cohort Study III) involving 17 patients with confirmed CNS involvement. High-throughput sequencing was conducted using targeted gene panels designed to detect low-frequency variants and copy number alterations pertinent to lymphomas in ctDNA extracted from archived CSF samples. Despite challenges such as low DNA concentrations affecting library construction, the overall variant detection rate was 76%. Detected variants included those in genes commonly implicated in CNS lymphoma, such as MYD88. The study highlights the potential of CSF ctDNA sequencing to identify CNS involvement in DLBCL, providing a promising alternative to more invasive diagnostic methods such as brain biopsy, which are not always feasible. Further validation is necessary to establish the clinical utility of this method, which could significantly enhance the management and outcomes of DLBCL patients with suspected CNS involvement.

Cerebrospinal fluid (CSF) cytology of primary central nervous system lymphoma arising in the immune deficiency/dysregulation setting (IDD-PCNSL) has not been described. This study presented a case of IDD-PCNSL-DLBCL, a GCB phenotype who was successfully diagnosed by CSF cytology in conjunction with ICC, ISH, FCM and clinical information., (© 2024 John Wiley & Sons Ltd.)

Objective: The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours., Methods: A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included., Results: Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated., Conclusion: Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms., (© 2023 John Wiley & Sons Ltd.)

Background: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy., Case Presentations: The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3., Conclusions: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment., (© 2024. The Author(s).)

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The diagnosis of primary central nervous system (CNS) lymphoma, which is predominantly of the diffuse large B-cell lymphoma type (CNS DLBCL), is challenging. MicroRNAs (miRs) are gene expression-regulating non-coding RNAs that are potential biomarkers. We aimed to distinguish miR expression patterns differentiating CNS DLBCL and non-malignant CNS diseases with tumor presentation (n-ML). Next generation sequencing-based miR profiling of cerebrospinal fluids (CSFs) and brain tumors was performed. Sample source-specific (CSF vs. brain tumor) miR patterns were revealed. Even so, a set of 17 miRs differentiating CNS DLBCL from n-ML, no matter if assessed in CSF or in a tumor, was identified. Along with the results of pathway analyses, this suggests their pathogenic role in CNS DLBCL. A combination of just four of those miRs (miR-16-5p, miR-21-5p, miR-92a-3p, and miR-423-5p), assessed in CSFs, discriminated CNS DLBCL from n-ML samples with 100% specificity and 67.0% sensitivity. Analyses of paired CSF-tumor samples from patients with CNS DLBCL showed significantly lower CSF levels of miR-26a, and higher CSF levels of miR-15a-5p, miR-15b-5p, miR-19a-3p, miR-106b-3p, miR-221-3p, and miR-423-5p. Noteworthy, the same miRs belonged to the abovementioned set differentiating CNS DLBCL from non-malignant CNS diseases. Our results not only add to the basic knowledge, but also hold significant translational potential.

Background: Primary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown., Methods: A 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing., Results: In the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with TP53 mutation and BCL6 - LPP fusion, disease progressed although different chemotherapy regimens were given., Conclusion: The gene mutation of TP53 and BCL6 may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Ma, Liu, Zhu, Lu, Deng, Ma, Pan, Wang and Yao.)

Objective: To investigate the characteristics of central nervous system (CNS) involvement in children with non-Hodgkin's lymphoma (NHL) and the value of flow cytometry (FC) in the diagnosis of CNS disease in pediatric NHL., Methods: The data of 56 newly diagnosed pediatric NHL patients with CNS involvement (CNS+/mass, CNS+/palsy, CNS+/CSF) were analyzed. The proportions and formats of CNS disease in different pathological types were compared. In addition, FC and conventional cytology (CC) of cerebrospinal fluid (CSF) were carried out in 383 newly diagnosed NHL cases., Results: A total of 383 children with NHL were enrolled. Among these patients, 56 (14.6%) were diagnosed with positive CNS involvement (CNS+), 33 had bulky disease (tumor diameter >10 cm), 32 had bone marrow invasion, 32 had lactate dehydrogenase levels >1000 U/L, and 25 had invasion of more than 4 organs at the time of diagnosis. There were 14 patients with T lymphoblastic lymphoma (T-LBL), 9 with B lymphoblastic lymphoma (B-LBL), 26 with Burkitt's lymphoma (BL), and 2 with Epstein-Barr virus-positive diffuse large B cell lymphoma (EBV + DLBCL). Among the 56 CNS+ patients, 35 were CSF-positive (CSF+); there were 2 patients who were CSF+ via CC detection and 35 who were CSF+ via FC detection. The difference between CC and FC was statistically significant ( P < 0.01). In the T-LBL group, 14 patients were CNS+/CSF, and in the B-LBL group, 8 were CNS+/mass. In the BL group, 22 patients were CNS+/mass and 15 were CNS+/CSF. In the anaplastic large-cell lymphoma group, 5 patients were CNS+/mass. Nine of the 56 CNS+ patients had events. The 2-year overall survival rate was 87% ± 0.046%, and the 2-year event-free survival rate was 76.2% ± 0.07%., Conclusion: CNS+ diagnoses were more common in pediatric NHL patients with bulky disease and/or bone marrow involvement and/or involvement of more than 4 organs at the time of diagnosis, and they were also common in the EBV + DLBCL and BL groups. FC of CSF showed important clinical significance in the diagnosis of CNS disease in pediatric NHL patients, and it can be used to significantly improve the CNS+ detection rate.

A 67-year-old male was transferred to our hospital with diplopia, decreased deep tendon reflex and ataxia. He had been suspected Fisher syndrome because of previous upper respiratory tract infection. A cerebrospinal fluid examination showed marked hypoglycorrhachia, pleocytosis and elevated protein, and cytological examination suggested malignant lymphoma. Abdominal computed tomography revealed a left adrenal mass. A biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. He was treated with a combination of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin and prednisolone) and intrathecal administration of methotrexate, cytarabine and prednisolone. Neurological symptoms were gradually improved. Malignancy should be considered in addition to bacterial, fungal or tuberculous meningitis in a case with marked hypoglycorrhachia.

A 72-year-old woman developed excessive somnolence as one of the symptoms of diffuse large B-cell lymphoma in the central nervous system (CNS). Although somnolence might be caused by reduced orexin secretion associated with hypothalamic lesions, neither brain MRI nor 18F-fluorodeoxyglucose positron emission tomography identified hypothalamic lesions. However, the decreased cerebrospinal fluid (CSF) orexin levels recovered to near normal values with improvement of somnolence after chemotherapy. The alteration of CSF orexin levels suggested the involvement of potential hypothalamic lesions. Therefore, measurements of CSF orexin levels may be useful for understanding the pathological background of somnolence in CNS lymphoma without hypothalamic lesions., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Primary central nervous system lymphoma (PCNSL) is the most prevalent brain, spinal cord, eyes, and leptomeningeal lymphoma. It is often misdiagnosed due to an unspecific presentation or unavailable biopsy and results in a poor prognosis. Although the craniocerebral imaging examination of PCNSL has some characteristics, it is limited, and atypical cases are especially difficult to identify with intracranial tumours and other diseases. The biopsy, as the gold standard for PCNSL diagnosis, is not eligible for all patients suspected of having PCNSL., Case Presentation: This report documents a woman who presented with a three-month history of numbness and weakness in the right leg. She was treated with drugs at a local hospital for one month. She developed demyelination lesions and her symptoms were aggravated. The patient was admitted to the Department of Nerve Infection and Immunology at Tiantan Hospital. Head magnetic resonance imaging (MRI) enhanced scanning indicated significant inflammatory demyelinating disease, and lymphoma was not excluded. CSF revealed a high protein level and CSF cytology detected abnormal cells, PCNSL was eventually presumed according to positive CSF cytology and cytological detection of the cerebrospinal fluid flow., Conclusions: PCNSL is a highly invasive tumour. With the development of technologies such as cerebrospinal fluid cytology and flow cytology, CSF analysis has become one of the definite diagnosis methods, and the tumour cell finding in CSF is the only reliable basis for diagnosis. Flow cytometric analysis and gene rearrangement testing also provide objective evidence.

Background: Background: Central Nervous System (CNS) relapse in Diffuse Large B-cell Lymphoma occurs mostly 6-8 months after disease onset. This has led to propose that CNS infiltration is an early event in the evolution of the disease. We intend to evaluate the role of magnetic resonance imaging (MR) at diagnosis to detect early SNC compromise., Methods: Prospective longitudinal cohort’s study in DGCB patients treated at Hospital de Clínicas between 2013 and 2015. Skull MRI was performed in all patients at diagnosis and lumbar puncture was done according to predefined risk factors., Results: 35 patients were analyzed. Median age: 68 years (24-85 years). Stage III-IV: 62%, 57% good prognosis according to RIPI score and 43% poor prognosis. MRI was performed in all patients, with no pathological findings in any of them. Twenty-one patients fullfilled criteria for cerebrospinal fluid study. Twenty-two patients were studied and received intrathecal methotrexate prophylaxis. Meningeal relapse was observed in a single patient who had negative studies at diagnosis and had received complete prophylaxis at the end of the 6 R-CHOP series., Conclusions: Only one of the 35 patients relapsed in the CNS. This patient had a noral MRI and CSF study at diagnosis and had received prophylaxis with intrathecal chemotherapy. This results lead us to believe that the value of MRI to detect early infiltration in asymptomatic patients at diagnosis is low.

Primary lymphomas of the central nervous system (PCNSL) are highly aggressive tumors affecting exclusively the CNS, meninges, and eyes. PCNSL must be separated from secondary spread of systemic lymphoma to the CNS (SCNSL), which may occur at diagnosis or relapse of systemic lymphomas. At present, there are no valid methods to distinguish PCNSL from SCNSL based on tumor biopsy because of similar histological presentation. However, SCNSL and PCNSL are different in terms of prognosis and adequate therapy protocols. MicroRNA expression profiles of CSF samples collected from SCNSL and PCNSL patients were compared using microRNA arrays. MiR-30c revealed the largest differential expression and was selected for validation by RT-PCR on 61 CSF samples from patients with PCNSL and 14 samples from SCNSL. MiR-30c was significantly increased in patients with SCNSL compared to PCNSL (p < 0.001). MiR-30c levels in CSF enabled the differentiation of patients with PCNSL from SCNSL with an area under the curve (AUC) of 0.86, with a sensitivity of 90.9% and a specificity of 85.5%. Our data suggest that miR-30c detected in the CSF can serve as biomarker for distinction between PCNSL and SCNSL. The validation in a larger cohort is needed. With respect to its function, miR-30c may facilitate lymphoma cells to engraft into CNS by interaction with CELSR3 gene that controls the function of ependymal cilia and, thus, affects the circulation of CSF.

A biomarker for early diagnosis of central nervous system (CNS) lymphoma would permit early treatment for attenuation of disease progression and neurological deterioration. High interleukin-10 (IL-10) or an IL-10/IL-6 ratio >1.0 are informative parameters for discriminating intraocular lymphomas from uveitis. Recent reports have also shown that CSF IL-10 is a potential diagnostic biomarker for CNS lymphoma. The purpose of this study was to evaluate the diagnostic value of IL-10 in cerebrospinal fluid (CSF) in patients with CNS lymphoma compared with other CNS diseases, including CNS tumors and inflammatory diseases. CSF IL-10, IL-6, beta-2 microglobulin, soluble IL-2 receptor and FDG-PET SUVmax were measured in 19 patients with CNS lymphoma (15 primary and 4 secondary diffuse large B-cell lymphomas) and 26 non-lymphoma patients with various brain tumors and inflammatory diseases. The diagnostic accuracy of the respective examinations for differentiation of CNS lymphomas from non-lymphomas was evaluated by receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) was calculated. CSF IL-10 was detected at significant levels (median, 28 pg/ml; range <2-4,100 pg/ml) in all except one patient with CNS lymphoma, but not detected in any non-lymphoma patients. CSF IL-10 had the highest diagnostic accuracy with AUC = 0.974. At an IL-10 cutoff of 3 pg/ml, the sensitivity and specificity were 94.7 and 100 %, respectively. These results indicate that CSF IL-10 is a superior biomarker for initial screening for patients with CNS lymphoma.

Flow cytometry (FCM) is more sensitive than conventional cytology for detection of occult leptomeningeal lymphoma; however, some FCM-negative patients show central nervous system (CNS) recurrence. Here, we evaluated the cerebrospinal fluid (CSF) levels of 13 B-cell-associated markers and their contribution to the diagnosis of CNS lymphoma in 91 diffuse large B-cell lymphomas (DLBCL) and 22 Burkitt lymphomas (BLs). From all markers tested, CD19 was the most informative. Thus, higher soluble CD19 (sCD19) levels were associated with a greater frequency of neurological symptoms in DLBCL and BL and with parenchymal CNS lymphoma in DLBCL; sCD19 emerged as a powerful predictor of event-free and overall survival in DLBCL and BL, particularly when combined with FCM detection of CNS disease. These results support the utility of combined FCM detection of lymphoma cells and assessment of sCD19 levels in CSF, for more accurate identification of CNS disease in DLBCL and BL patients.

The purpose of this study was to develop a sensitive method for the detection of malignant B lymphocytes in cerebrospinal fluid (CSF) from patients with diffuse large B-cell lymphoma (DLBCL) who were considered as risk of central nervous system (CNS) involvement. Nine CSF samples were collected and then centrifuged. The cell precipitate was lysed directly. The supernatant was used to detect immunoglobulin heavy chain (IgH) gene rearrangement (characteristic changes of malignant B lymphocytes ) by BIOMED-2 PCR. The sensitivity of this method was compared with that of cytology defection and flow cytometry. In addition, through a series of quantity/concentration of tumor cells, the sensitivity differences caused by two sample handling methods (direct cell lysis vs traditional DNA extraction) were analyzed, and the sensitivity of direct cell lysis combined with BIOMED-2 PCR was evaluated. The results showed that the positive clonality of IgH gene rearrangement were detected by BIOMED-2 PCR in 5 cases, but the positive were detected by cytology defection/flow cytometry only in 2 cases, which indicated that the BIOMED-2 PCR assay gives a better yield. In addition, when combined with BIOMED-2 PCR, direct cell lysis produced sensitivity much higher than DNA extraction. The former can enable clonality detection from a minimum of 0.1%/20 tumor cells. It is concluded the method of direct cell lysis combined with BIOMED-2 PCR is sensitive and suitable for paucicellular CSF detection. It may aid the diagnosis of CNS involvement in patients with DLBCL.

Background: Secondary central nervous system lymphoma (SCNSL) without extra-central nervous system (CNS) involvement is characterized by isolated secondary CNS relapse in malignant lymphoma patients. SCNSL is a rare disease, and no standard treatment has yet been established., Patients and Methods: To elucidate the clinical characteristics and outcomes of SCNSL, we retrospectively analyzed 12 patients (median age 67 years) in Miyazaki prefecture for the last 5 years., Results: The initial histological diagnoses of the patients were diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma, and adult T-cell lymphoma in 9, 2, and 1 patient, respectively. We focused on analysis of the 9 SCNSL cases originating from DLBCL. The locations of CNS relapse were the cerebral hemisphere, basal ganglia, and cerebellum in 7, 1, and 1 patient, respectively. Three patients were treated with high-dose methotrexate (HD-MTX) therapy; 4 with whole-brain radiation therapy (WBRTX); and 1 with both HD-MTX and WBRTX. The remaining patients were treated with rituximab. Partial remission was achieved in 6 out of 9 patients (67%); the other 3 patients (33%) did not respond to therapy. Median survival of the 9 patients with CNS relapse was 253 days; 6 of the 9 patients survived for more than 6 months. As of March 2011, 2 HD-MTX group patients but none of the WBRTX group patients were alive., Conclusions: In this retrospective study, 6 of 9 patients with SCNSL originating from DLBCL survived for more than 6 months. Both HD-MTX and WBRTX had clinical benefits in the treatment of SCNSL.

Background: Central nervous system (CNS) relapse is an uncommon but dramatic complication of diffuse large B-cell lymphoma (DLBCL). Several studies have demonstrated the superiority of cerebrospinal fluid (CSF) flow cytometry (FCM), as compared with conventional cytology (CC), in detecting occult leptomeningeal disease. The clinical relevance of a positive FCM still has to be clarified., Patients and Methods: We analyzed CSF from 114 DLBCL patients at diagnosis (n = 95) or at relapse (n = 19) by FCM and CC. Most patients received meningeal prophylaxis. FCM results did not influence treatment strategies., Results: Fourteen samples were FCM+, versus one CC+ (also FCM+). Within all patients without neurological symptoms (n = 101), four (4%) relapsed in the CNS, with a median time to relapse of 5.2 months. Only one-fourth (25%) was FCM+ before relapse. More than one extranodal disease site and elevated lactate dehydrogenase levels were associated with an increased risk of CNS relapse., Conclusions: FCM gives far more positive results than CC. However, a positive FCM result did not translate into a significant increase in CNS relapse rate in this histologically uniform population receiving CNS prophylaxis.

An 83-year-old woman was admitted to our hospital with abdominal pain. Examination revealed mediastinal lymphoadenopathy, hepatosplenomegaly, and infiltration of abnormal cells into the bone marrow with hemophagocytosis, and CD5-positive diffuse large B cell lymphoma was diagnosed. Chemotherapy was administered and progressive weakness of the limbs, resembling a Guillain-Barré-like syndrome, subsequently appeared. Cerebrospinal fluid examination indicated lymphoma cell infiltration. Although immune globulin and steroid therapies were not effective, intrathecal injection of methotrexate, predonisolone, and cytarabine improved these symptoms. Subsequent to chemotherapy, cell surface antigen changes were observed in the cerebrospinal fluid relative to those in bone marrow.

Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma and commonly presents as an oral mass in HIV patients. Extraoral PBL has been reported, including one case of primary central nervous system PBL (PCNSPBL). The cytological features of PBL have been described, including cerebrospinal fluid (CSF) cytology findings for secondary CNS involvement by PBL. The etiology of PCNSPBL is still unknown. We report here the CSF cytology of a PCNSPBL, which shows a hypercellular specimen composed of markedly atypical, singly dispersed plasmacytoid cells with frequent abnormal mitoses and binucleation. The neoplastic cells are positive for CD138. Flow cytometry of the CSF specimen demonstrates a monoclonal neoplastic cell population, which is CD138 positive, kappa light chain positive, lambda light chain negative, and CD19 negative. Molecular analysis and immunohistochemical stains on a tissue biopsy confirmed the diagnosis and reveal concurrent infections with Epstein-Barr virus and human polyomavirus JC virus. Clinical and radiological correlations are reported, and the literature is reviewed. To the best of our knowledge, this is the first case report for CSF cytology of a PCNSPBL, demonstrating the utility of the cytological examination in the triage and diagnosis of this disease. Because of its dismal prognosis, it is critical for cytopathologists to be aware of the entity and recognize the neoplastic cells in CSF specimen. This report also emphasizes the importance of clinical and radiological correlation in the diagnosis of this lethal disease., (Copyright © 2010 Wiley-Liss, Inc.)

The diagnosis of primary central nervous system lymphoma (PCNSL) depends on histopathology of brain biopsies, because disease markers in the cerebrospinal fluid (CSF) with sufficient diagnostic accuracy are not available yet. MicroRNAs (miRNAs) are regulatory RNA molecules that are deregulated in many disease types, including cancer. Recently, miRNAs have shown promise as markers for cancer diagnosis. In this study, we demonstrate that miRNAs are present in the CSF of patients with PCNSL. With a candidate approach and miRNA quantification by reverse transcription polymerase chain reaction, miRNAs with significant levels in the CSF of patients with PCNSL were identified. MiR-21, miR-19, and miR-92a levels in CSF collected from patients with PCNSL and from controls with inflammatory CNS disorders and other neurologic disorders indicated a significant diagnostic value of this method. Receiver-operating characteristic analyses showed area under the curves of 0.94, 0.98, and 0.97, respectively, for miR-21, miR-19, and miR-92a CSF levels in discriminating PCNSL from controls. More importantly, combined miRNA analyses resulted in an increased diagnostic accuracy with 95.7% sensitivity and 96.7% specificity. We also demonstrated a remarkable stability of miRNAs in the CSF. In conclusion, CSF miRNAs are potentially useful tools as novel noninvasive biomarker for the diagnosis of PCNSL.

Reliable detection of leptomeningeal disease has the potential of facilitating the diagnosis of central nervous system (CNS) lymphoma and is important for therapeutic considerations. Currently, the standard diagnostic procedure for the detection of lymphoma in the cerebrospinal fluid is cytopathology. To improve the limited specificity and sensitivity of cytopathology, flow cytometry has been suggested as an alternative. Here, we evaluated multi-parameter flow cytometry in combination with conventional cytopathology in cerebrospinal fluid (CSF) samples from 30 patients with primary CNS lymphoma and seven patients with secondary CNS lymphoma. Overall, in 11 of 37 (29.7%) patients with CNS lymphoma, lymphoma cells were detected in CSF by flow cytometry, while cytopathology was less sensitive displaying unequivocally malignant CSF cells in only seven of all 37 (18.9%) patients. Six (16.2%) patients showed cytopathological results suspicious of lymphoma; however, in only one of these patients, the diagnosis of CSF lymphoma cells could be confirmed by flow cytometry. In primary CNS lymphomas (PCNSL), seven of 30 (23.3%) patients were positive for CSF lymphoma cells in flow cytometry, in contrast to four (13.3%) patients with PCNSL with definitely positive cytopathology. In summary, our results suggest that multi-parameter flow cytometry increases the sensitivity and specificity of leptomeningeal disease detection in CNS lymphomas. Both methods should be applied concurrently for complementary diagnostic assessment in patients with CNS lymphoma., (© 2010 John Wiley & Sons A/S.)

Diagnosis of central nervous system (CNS) lymphoma depends on histopathology of brain biopsies, because no reliable disease marker in the cerebrospinal fluid (CSF) has been identified yet. B-cell lymphomas such as CNS lymphomas are clonally restricted and express either kappa or lambda immunoglobulin light chains. The aim of this study was to find out a potential diagnostic value of free immunoglobulin light chains released into the CSF of CNS lymphoma patients. Kappa (kappa) and lambda (lambda) free immunoglobulin light chains (FLC) were measured in CSF and serum samples collected from 21 patients with primary and secondary CNS lymphomas and 14 control patients with different neurologic disorders. FLC concentrations and ratios were compared between patient groups and were further analyzed in correlation with clinical, cytopathological, and radiological findings. FLC concentrations for all patients were lower in CSF when compared to serum. In patients with CNS lymphoma, the FLC ratios in CSF were higher (range 392-0.3) compared to control patients (range 3.0-0.3). Irrespective of cytopathological proven lymphomatous meningitis, in 11/21 lymphoma CSF samples the FLC ratios were markedly above 3.0 indicating a clonally restricted B-cell population. Increased FLC ratios in CSF were found in those patients showing subependymal lymphoma contact as detected in magnetic resonance imaging. In summary, this is the first report demonstrating that a significant proportion of patients with CNS lymphomas display a markedly increased FLC ratio in the CSF.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus. We describe a rare case of PML in a 48-year-old female patient with diffuse large B-cell lymphoma who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. While she was undergoing five cycles of R-CHOP, she noticed gradually progressive neurological symptoms, such as slurred speech and gait disturbance, and she eventually developed high-grade fever. She also developed Pneumocystis jiroveci pneumonia. The neurological symptoms deteriorated thereafter, and she developed spastic quadriparesis and bulbar palsy. Magnetic resonance imaging showed hyperintensity within the right cerebellar hemisphere on T2-weighted images. Polymerase chain reaction-based tests of the cerebrospinal fluid revealed the presence of the JC virus. Despite intravenous and intrathecal cytarabine treatment, the patient died of PML 5 months after it was diagnosed. Retrospective analysis of her laboratory data showed that her CD4(+) T-cell count before R-CHOP therapy had decreased to 68 microL(-1). Thus, when administering rituximab-containing chemotherapy, even to patients with no prior history of opportunistic infections, attention should be paid to the potential occurrence of PML, particularly in patients with low CD4(+) T-cell counts.

Purpose: Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions., Methods: We used a liquid chromatography/mass spectrometry-based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases., Results: Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (> 75% sensitivity; > 98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome., Conclusion: Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.

HIV-associated Primary brain lymphomas (PBLs) are usually diffuse, large B-cell lymphomas (DLBCLs). In contrast to those occurring in immunocompetent patients, nearly all HIV-associated PBLs are associated with Epstein-Barr virus (EBV). Since viral latency proteins are target antigens for anti-viral cytotoxic T lymphocytes, the double immunodeficiency (HIV infection, central nervous system microenvironment) favors the expression of viral latency proteins (LMP-1, EBNA2). These proteins play a major role in immortalization and transformation of infected B lymphocytes through cell cycle activation and apoptosis inhibition.

Introduction: Two forms of growth are reported in the neuroradiology of cerebral lymphomas: mass, single or multiple lesions, with homogeneous contrast enhancement, and diffuse infiltration. Flow cytometry enables us to diagnose non-Hodgkin's lymphoma, when clonality of B cells is detected. It is usually employed with peripheral blood or bone marrow samples but can be used with cerebrospinal fluid (CSF)., Case Report: We report the case of a 68-year-old female, who was admitted to hospital because of rapidly progressive onset of confusion and right-side hemiparesis that developed in a matter of days. Magnetic resonance imaging (MRI) of the head showed a diffuse infiltrative lesion, without contrast enhancement, which covered the left basal nuclei, the left frontal white matter, the genu of the corpus callosum and the right frontal white matter. The CSF showed slight pleocytosis (20 cells/mL) and a notable degree of hypoglycorrhachia (10 mg/dL). The cytological examination only revealed lymphocytes, with no data indicating atypicality. The flow cytometry assay detected large mononuclear B cells, with the CD19 + CD20 + CD10-lambda phenotype, which is characteristic of diffuse non-Hodgkin's lymphoma of large B cells. The clinical course ran quickly towards a fatal outcome; it progressed to left-side hemiplegia and coma, and the patient died two weeks after admission to hospital., Conclusions: In cases of cerebral lymphoma, especially when the neuroradiological pattern displays diffuse infiltration and there are anomalies involving CSF, the flow cytometry in CSF can be diagnostic, thus avoiding the need for other invasive brain procedures to deal with lesions that are usually located deep inside the brain at badly defined sites.

We measured rituximab concentrations in the cerebrospinal fluid (CSF) in 2 patients with diffuse large B-cell lymphoma in whom central nervous system (CNS) invasion had developed. They received rituximab intravenously following irradiation therapy (patient no.1) or along with chemotherapy (patient no.2). The rituximab concentrations in the CSF were considered to be very low (0.2-0.6 microg/ml), and could not be increased significantly by serial intravenous administrations of rituximab. The lymphoma relapsed in patient no.1, and the combined therapy was not effective in patient no.2. An alternative approach such as intrathecal administration of rituximab could be anticipated as a new therapeutic strategy for CNS lymphoma.

Detection of Epstein-Barr virus (EBV) DNA in the cerebrospinal fluid (CSF) is associated with acquired immunodeficiency syndrome (AIDS)-related brain lymphoma. Real-time polymerase chain reaction (PCR) was performed to quantify EBV DNA in CSF and plasma from 42 patients with AIDS-related non-Hodgkin's lymphoma (NHL). Twenty patients had primary central nervous system lymphoma (PCNSL) and 22 systemic NHL, including 12 with central nervous system involvement (CNS-NHL). As controls, 16 HIV-infected patients with other CNS disorders were examined. EBV DNA was detected in the CSF from 16/20 (80%) patients with PCNSL, 7/22 (32%) with systemic NHL, 8/12 (67%) with CNS-NHL, and 2/16 (13%) of the controls. The viral EBV DNA levels were significantly higher in the CSF from patients with PCNSL or CNS-NHL compared to patients with systemic NHL or controls. EBV DNA was detected in plasma from 5/16 (31%) patients with PCNSL, 9/16 (56%) with systemic NHL, 4/9 (44%) with CNS-NHL, and 4/15 (27%) controls. No difference in plasma viral load was found between patient groups. From the patients with CNS-NHL, plasma samples drawn prior to CNS involvement contained significantly higher EBV DNA levels than those from systemic NHL patients without subsequent CNS involvement. EBV DNA levels in the CSF, but not in plasma, from patients treated with antiherpes drugs were significantly lower than in untreated patients. High CSF EBV DNA levels were found in HIV-associated brain lymphomas and the viral load can be clinically useful. High plasma EBV DNA levels might predict CNS involvement in systemic NHL.

Background: Intravascular lymphomatosis (IVL) is an uncommon systemic disease characterized by occlusion of small vessels by malignant lymphomatous cells. Central nervous system involvement usually presents as subacute encephalopathy, dementia, seizures, or multifocal cerebrovascular events., Objective: To increase awareness about IVL, an uncommon cause of neurological disease., Design: This is a retrospective case series of 8 pathologically proved cases of IVL with neurological disease. Patients were part of a pathological series collected between April 1962 and October 1998 at Indiana University School of Medicine and the Armed Forces Institute of Pathology, Washington, DC., Setting: Neurological and neuropathological examinations were performed at tertiary referral hospitals., Patients: Eleven patients were diagnosed pathologically as having IVL, but 3 were not included in this evaluation because of a lack of appropriate clinical information. Of the final sample (n = 8), there were 4 men and 4 women (mean +/- SD age, 62.9 +/- 9.9 years)., Results: All 8 patients had focal neurological deficits, 7 had encephalopathy or dementia, 5 had epileptic seizures, and 2 had myelopathy. Death occurred at a mean of 7.7 months (range, 1-24 months) after the onset of symptoms. All patients had elevated cerebrospinal fluid protein levels, 4 had pleocytosis, and 2 had an elevated IgG level in their cerebrospinal fluid. Of the 4 patients who underwent a brain biopsy, 1 was diagnosed as having IVL before death., Conclusions: Intravascular lymphomatosis is an uncommon disease with a myriad of potential neurological manifestations. Diagnosis requires a high index of suspicion and a pathological examination. If diagnosed early, aggressive chemotherapy is potentially curative, although the overall prognosis remains dismal.

Purpose: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance., Patients and Methods: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage)., Results: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease., Conclusion: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.

Introduction: The authors report a case of neurologic manifestations revealing Richter's syndrome in chronic lymphocytic leukemia., Exegesis: Cranial nerve palsies were the initial manifestation of the disease. Computed tomography and magnetic resonance imaging were normal. Cerebrospinal fluid analysis with alkaline phosphatase-antialkaline phosphatase revealed the existence of a large-cell lymphoma., Conclusions: Clinical aspects of this unusual localization of Richter's syndrome are reviewed.

The aim of this study is to determine the diagnostic value of cerebrospinal fluid (CSF) soluble CD27 (sCD27) as a tumor marker for primary central nervous system lymphoma (PCNSL). We examined sCD27 levels in CSF obtained from various types of brain tumor patients. Forty-two patients were studied (including 12 PCNSL patients) who had not received any therapy for their tumors. In all PCNSL cases, CSF sCD27 levels were more than 15 U/ml (median 84.5 U/ml, range 17-484 U/ml) and in other brain tumor cases, CSF sCD27 levels were all less than 15 U/ml. Our data suggest that CSF sCD27 levels are useful to distinguish PCNSL from other brain tumors.

We measured the level of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) of patients with various kinds of tumors, including malignant tumors, using radioimmunoassay. The CSF had been obtained by lumbar puncture through an Ommaya reservoir or a shunt device placed in the lateral ventricle. The level of MBP was high (> 4 ng/ml) in the patients with meningeal dissemination of malignant tumors, but in those who showed a good response to chemotherapy and/or radiation, it decreased or returned to the normal level, with improvement on the computed tomography and magnetic resonance imaging, cytological, general CSF, and neurological findings. Of seven malignant gliomas without CSF dissemination, six showed an elevated level of MBP before selective intra-arterial chemotherapy with a combination of etoposide and cisplatin administered via a microcatheter placed at A1, M1, P1-P2, and the basilar top. All CSF specimens obtained during the period of the intra-arterial chemotherapy showed an abnormally high (> 4 ng/ml) level of MBP that exceeded the prechemotherapy level. The MBP level decreased or returned to normal in the patients with a good response to chemotherapy after intra-arterial chemotherapy. In some patients with multiple metastatic brain tumors, the MBP level was elevated before treatment and returned to normal after treatment (surgical removal, chemotherapy, and/or irradiation) in all except one. Thus, there was a clear correlation between the timing of treatment and changes in imaging studies and MBP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

A 42-year-old man who was human immunodeficiency virus (HIV)-positive complained of floaters in his right eye, which had existed for 1 week, followed by loss of central vision. Results of ophthalmoscopic examination disclosed confluent yellowish-white retinochoroidal infiltrates with perivascular sheathing, which were more prominent superiorly in the right eye. Approximately 10 small, white, intraretinal and choroidal lesions were observed in the nasal periphery of the left eye. Results of cytologic examination of the vitreous of the right eye showed neoplastic cells characteristic of large cell type malignant lymphoma. Shortly thereafter, cytologic examination of the cerebrospinal fluid also showed large cell malignant lymphoma. Magnetic resonance imaging (MRI) showed a mass involving the left cerebellar hemisphere. After bilateral whole-eye radiation therapy, there was complete resolution of the lymphomatous retinochoroidal infiltrates in both eyes. The ophthalmologic and neurologic manifestations of acquired immune deficiency syndrome (AIDS) are discussed. The authors believe this is the first report of ocular malignant lymphoma occurring in a patient with AIDS.

This is a report of an unusual case in which cytologic monitoring played a key role in the six-and-one-half-year survival of a 21-year-old woman with disseminated histiocytic lymphoma involving the central nervous system. At this writing the patient showed no further evidence of malignant disease. After primary diagnosis, remissions and exacerbations of the tumor were accurately detected by periodic cytologic examinations of 78 spinal fluid specimens. Therapeutic measures included total brain irradiation, implantation of an Ommaya reservoir and combination chemotherapy. This case study demonstrates that cytologic examination of cerebrospinal fluid is an important method of monitoring the responses of tumors to therapeutic measures.

Neoplastic cells were found in the cerebrospinal fluid (CSF) cytograms in 57% of patients with lymphocytic leukemia and reticulum cell sarcoma. Tumor cells may be observed in CSF specimens showing normal cell count and total proteins. Quantitative and/or qualitative changes in CSF proteins in absence of corresponding abnormalities in serum may indicate a malignant lymphorproliferative process involving the central nervous system even in absence of neoplastic cells.

The case of a 65 year-old female with an immunoblastic sarcoma of T cell type (reticulosarcoma) is reported. Post mortem tumor cell infiltrations with the typically histomorphological criteria of an immunoblastic sarcoma were found in the uterus, bone marrow and leptomeninges. With the aid of immunological markers the T cell type of this malignant lymphoma was diagnosed intra vitam on the basis of CSF cells. Until now, only one case of an immunoblastic sarcoma of the T cell type has been described in the literature.