Diagnosis Of Central Nervous System Lymphoma Research Articles

Rapid tumor DNA analysis of cerebrospinal fluid accelerates treatment of central nervous system lymphoma

AbstractDelays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown cause. Participants underwent genotyping of CSF-derived DNA using a quantitative polymerase chain reaction–based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF, and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma, and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7 of 33 cases (21.2%) of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median, 3 vs 12 days; P = .027). This assay was then implemented in a Clinical Laboratory Improvement Amendments environment, with 2-day median turnaround for diagnosis of CNS lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.

Factors related to central nervous system involvement of primary vitreoretinal lymphoma.

This single center retrospective study aimed to investigate the factors associated with central nervous system (CNS) involvement of primary vitreoretinal lymphoma (PVRL). Clinical features of patients with PVRL (Group 1), those diagnosed with vitreoretinal lymphoma (VRL) after primary CNS lymphoma diagnosis (Group 2), and those concurrently diagnosed with CNS lymphoma and VRL (Group 3), were compared. The main outcomes included sex, age, types of treatment, survival, visual acuity, diagnostic methods, VRL recurrence, ocular manifestations, and interleukin levels in the aqueous humor. Groups 1, 2, and 3 included 66 eyes in 38 patients, 29 eyes in 18 patients, and 14 eyes in 8 patients, respectively. Group 3 had shorter overall survival (OS) than Groups 1 and 2 (P = 0.042 and P = 0.009, respectively). The three groups did not differ in progression-free survival (P = 0.060). The 5-year survival rates of Groups 1, 2, and 3 were 56.5%, 44.0%, and 25.0%, respectively (P = 0.001). Patients with CNS involvement in Group 1 exhibited VRL recurrence (P < 0.001), high interleukin-10 (P = 0.024), and sub-retinal pigment epithelium (RPE) infiltration (P = 0.009). Patients experiencing VRL recurrence in Group 1 tended to show CNS involvement (P < 0.001). Patients concurrently diagnosed with CNS lymphoma and VRL had a shorter OS and a lower 5-year survival rate. In patients with PVRL, the recurrence of VRL, high interleukin-10, and sub-RPE infiltration were associated with CNS involvement.

Ocular motor and vestibular dysfunction in central nervous system lymphoma.

Diagnosis of lymphoma involving the central nervous system (CNS) is challenging. This study aimed to explore the abnormal vestibular and ocular motor findings in CNS lymphoma. A retrospective search of the medical records identified 30 patients with CNS lymphoma presenting ocular motor and vestibular abnormalities from four neurology clinics of university hospitals in South Korea (22 men, age range 14-81 years, mean 60.6 ± 15.2). The demographic and clinical features and the results of laboratory, radiological and pathological evaluation were analyzed. Patients presented with diplopia (13/30, 43%), vestibular symptoms (15/30, 50%) or both (2/30, 7%). In 15 patients with diplopia, abnormal ocular motor findings included ocular motor nerve palsy (n = 10, 67%), internuclear ophthalmoplegia (n = 2, 13%), external ophthalmoplegia (n = 2, 13%) and exophoria (n = 1, 7%). The vestibular abnormalities were isolated in 14 (82%) of 17 patients with vestibular symptoms and included combined unilateral peripheral and central vestibulopathy in three from lesions involving the vestibular nuclei. CNS lymphoma involved the brainstem (53%), cerebellum (33%), leptomeninges (30%), deep gray nuclei (23%) or cranial nerves (17%). Two patients showed the "double-panda" sign by involving the midbrain. This study expands the clinical and radiological spectra of CNS lymphoma. Neuro-ophthalmological and neuro-otological evaluation may guide the early diagnosis of CNS lymphoma.

The Neurosurgical Challenge of Primary Central Nervous System Lymphoma Diagnosis: A Multimodal Intraoperative Imaging Approach to Overcome Frameless Neuronavigated Biopsy Sampling Errors

Background: Intracranial lymphoma remains a challenging differential diagnosis in daily neurosurgical practice. We analyzed our early experience with a surgical series of frameless neuronavigated biopsies in Primary CNS Lymphomas (PCNSLs), highlighting the importance of using an intraoperative combined imaging protocol (5-ALA fluorescence, i-CT and 11C-MET-PET) to overcome potential targeting errors secondary to tumor volume reduction after corticosteroid therapy. Materials and methods: All patients treated for PCNLSs at our center in a 24-month period (1/1/2019 to 31/12/2020) were analyzed. Our cohort included 6 patients (4 males), with a median age of 67 years (59–82). A total of 45 samples were evaluated for correlation between intraoperative fluorescence and pathological findings. 39 samples biopsy were evaluated. Results: 54% samples showed a clear diagnosis of PCNSL. 64% of samples had a lava like fluorescence. i-CT scan showed tumor volume changes, in comparison to preoperative MRI, in all cases and helped in planning correct trajectories on updated imaging; after biopsy i-CT confirmed sampling accuracy and excluded procedural complications in all cases. Conclusions: We believe that the use of a multimodal intraoperative imaging approach overcomes the demonstrated PCNSL morphological changes caused by corticosteroid therapy and gives a reliable tissue diagnosis by frameless biopsy.

Cerebrospinal fluid flow cytometry: utility in central nervous system lymphoma diagnosis

Flow cytometry of the cerebrospinal fluid (CSF) is used in isolation or as an adjunct to cytology to increase the sensitivity of detecting primary central nervous system (CNS) lymphoma. We aim to evaluate the sensitivity of CSF flow cytometry as a diagnostic tool for primary CNS lymphoma in patients presenting with undifferentiated neurologic symptoms. We retrospectively reviewed all CSF samples received by the Calgary Laboratory Services Flow Cytometry Laboratory from 2012- 2015. Clinical data, laboratory investigations, radiologic imaging studies, and pathological data were analyzed. Clinical review extended to 2 years post CSF flow cytometric testing. The number of samples of CSF flow cytometry that were positive for a hematological malignancy was 43/763 (5.6%). The overall sensitivity of the test was 69.4%. A positive result was more likely to occur in patients with a prior history of a hematological malignancy or abnormal enhancement on MRI (p&lt;0.0001). CSF flow cytometry was negative in all patients who did not have a previous hematological malignancy or abnormal enhancement on MRI (n = 247). CSF flow cytometry has a limited role in screening for primary CNS lymphoma, unless a strictly endorsed testing algorithm is applied. It is, however, an invaluable tool in evaluating CNS involvement in patients with a previous diagnosis of hematolymphoid malignancy or abnormal enhancement on MRI.LEARNING OBJECTIVESThis presentation will enable the learner to:Discuss the costs and benefits of using CSF flow cytometry to diagnose CNS lymphoma 1.Identify appropriate clinical indications for using CSF flow cytometry as a first-line test2.Apply a testing algorithm to increase the diagnostic yield of CSF flow cytometry

Provision of rapid and specific ex vivo diagnosis of central nervous system lymphoma from rodent xenograft biopsies by a fluorescent aptamer.

Differentiating central nervous system (CNS) lymphoma from other intracranial malignancies remains a clinical challenge in surgical neuro-oncology. Advances in clinical fluorescence imaging contrast agents and devices may mitigate this challenge. Aptamers are a class of nanomolecules engineered to bind cellular targets with antibody-like specificity in a fraction of the staining time. Here, the authors determine if immediate ex vivo fluorescence imaging with a lymphoma-specific aptamer can rapidly and specifically diagnose xenografted orthotopic human CNS lymphoma at the time of biopsy. The authors synthesized a fluorescent CNS lymphoma-specific aptamer by conjugating a lymphoma-specific aptamer with Alexa Fluor 488 (TD05-488). They modified human U251 glioma cells and Ramos lymphoma cells with a lentivirus for constitutive expression of red fluorescent protein and implanted them intracranially into athymic nude mice. Three to 4 weeks postimplantation, acute slices (biopsies, n = 28) from the xenografts were collected, placed in aptamer solution, and imaged with a Zeiss fluorescence microscope. Three aptamer staining concentrations (0.3, 1.0, and 3.0 μM) and three staining times (5, 10, and 20 minutes) followed by a 1-minute wash were tested. A file of randomly selected images was distributed to neurosurgeons and neuropathologists, and their ability to distinguish CNS lymphoma from negative controls was assessed. The three staining times and concentrations of TD05-488 were tested to determine the diagnostic accuracy of CNS lymphoma within a frozen section time frame. An 11-minute staining protocol with 1.0-μM TD05-488 was most efficient, labeling 77% of positive control lymphoma cells and less than 1% of negative control glioma cells (p < 0.001). This protocol permitted clinicians to positively identify all positive control lymphoma images without misdiagnosing negative control images from astrocytoma and normal brain. Ex vivo fluorescence imaging is an emerging technique for generating rapid histopathological diagnoses. Ex vivo imaging with a novel aptamer-based fluorescent nanomolecule could provide an intraoperative tumor-specific diagnosis of CNS lymphoma within 11 minutes of biopsy. Neurosurgeons and neuropathologists interpreted images generated with this molecular probe with high sensitivity and specificity. Clinical application of TD05-488 may permit specific intraoperative diagnosis of CNS lymphoma in a fraction of the time required for antibody staining.

Apparent diffusion coefficient as a valuable quantitative parameter for predicting clinical outcomes in patients with newly diagnosed primary CNS lymphoma

BackgroundThis study attempted to identify novel prognostic factors in patients with newly diagnosed primary central nervous system lymphoma (PCNSL) using magnetic resonance imaging (MRI).MethodsWe retrospectively evaluated 67 patients diagnosed with central nervous system (CNS) tumors. The enrollment criteria were as follows: i) pathologic diagnosis of CNS lymphoma, ii) no evidence of systemic involvement, iii) no evidence of human immunodeficiency virus-1 infection or other immunodeficiencies, and iv) MRI scans available at diagnosis. Fifty-two patients met these criteria and were enrolled.ResultsThe 3-year overall survival (OS) and failure-free survival rates were 69.7% and 45.6%, respectively, with a median follow-up duration of 36.2 months. OS of patients with low apparent diffusion coefficient (ADC) was lower than those with higher ADC. Multivariate analysis revealed that old age (>60 yr) [hazard ratio (HR), 20.372; P=0.001], Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 (HR, 10.429; P<0.001), higher lactate dehydrogenase (LDH) levels (HR, 7.408; P=0.001), and low ADC (HR, 0.273; P=0.009) were associated with lower OS. We modified the conventional prognostic scoring system using low ADC, old age (>60 yr), ECOG PS ≥2, and higher LDH. The risk of death was categorized as high (score 3-4), intermediate-2 (score 2), intermediate-1 (score 1), and low (score 0), with three-year OS rates of 33.5%, 55.4%, 88.9%, and 100%, respectively.ConclusionADC demonstrated significant prognostic value for long-term survival in patients with newly diagnosed PCNSL. Low ADC was an independent unfavorable prognostic factor, suggesting that ADC obtained from MRI can improve the current prognostic scoring system.

Apparent diffusion coefficient as a valuable quantitative parameter for predicting clinical outcomes in patients with newly diagnosed primary CNS lymphoma.

e14532 Background: Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma (NHL). Although, there are various treatment options for PCNSL which include methotrexate based chemotherapy and whole brain radiotherapy (WBRT), half of the patients who initially achieved complete response experience disease relapse. Accordingly, we attempted to identify novel prognostic factors using MRI in patients with newly diagnosed PCNSL. Methods: We retrospectively evaluated 672 patients who were diagnosed with central nervous system (CNS) cancers between January 2011 and May 2018. Enrollment criteria were i) pathologic diagnosis of CNS lymphoma, ii) no evidence of systemic involvement, iii) no evidence of human immunodeficiency virus-1 infection or other immunodeficiencies, and iv) available magnetic resonance imaging (MRI) examinations at diagnosis. Fifty-two patients met these criteria and were enrolled. Results: Patients with low apparent diffusion coefficient (ADC) showed inferior overall survival (OS) compared to those with high ADC. Patients with a hyperintense signal on T2-weighted image and homogenous enhancement showed better failure-free survival (FFS), while patients with low ADC and necrosis showed poor FFS. In the multivariate survival analysis, old age ( &gt; 60) (hazard ratio (HR) 20.372, p= 0.001), Eastern Cooperative Oncology Group performance status ((ECOG PS) ≥ 2 (HR 10.429, p &lt; 0.001), higher levels of lactate dehydrogenase (LDH) (HR 7.408, p= 0.001), and low ADC (HR 0.273, p= 0.009) were associated with inferior OS, while ECOG PS ≥ 2 (HR 10.319, p= 0.021), presence of necrosis (HR 6.372, p= 0.008), and low ADC (HR 0.226, p= 0.020) were unfavorable factors for FFS. Conclusions: We conclude that ADC, a characteristic MRI finding, had significant prognostic value for long-term survival in our study of patients with newly diagnosed PCNSL Specifically, low ADC was an independent unfavorable prognostic factor, suggesting that ADC measurements through non-invasive MRI can improve the current prognostic scoring system.

Quantitative imaging biomarkers of CNS lymphoma and its correlation with genotypic markers.

e14520 Background: Central nervous system (CNS) lymphoma can be divided into primary CNS lymphoma (PCNS) versus secondary involvement of the CNS in systemic lymphoma. Traditionally radiology-pathology correlation is needed to accurately stage these entities, but the invasive nature of intracranial biopsies can add to patient morbidity. As such, there is an unmet need for noninvasive imaging biomarkers of CNS lymphoma. We aim to assess whether quantitative imaging analysis can characterize improve diagnostic specific and identify underlying genomic alterations in CNS lymphoma. Methods: 42 cases of CNS lymphoma (26 males, 16 females) were reviewed. Inclusion criteria required MRI (1.5Tesla or 3.0Tesla) of the brain and time-concordant histopathologic evaluation (i.e. MRI obtained within 72 hours of histologic evaluation) confirming diagnosis of CNS lymphoma. 19 patients met the inclusion criteria: 16 patients with large B-cell and 3 patients with T-cell lymphoma. All diagnoses were confirmed by evaluating biopsies through morphological and immunohistochemical analysis. MRI studies included T1-weighted pre- and post-contrast images, T2-weighted images and diffusion weighted images. Quantitative analysis included 3D-volumetric and textural analysis. Results: In B-cell lymphoma, mean patient age was 57 (22-91) while in T-cell lymphoma mean age of diagnosis was 43 (20-59). On MRI, all cases of CNS lymphoma (B- and T-cell) demonstrated enhancement. All T-cell lymphoma lesions were intra-axial and demonstrated homogeneous enhancement. Meanwhile, B-cell lymphomas demonstrated variable pattern of enhancement (homogenous; reticulonodular; subcortical U-fiber; peripheral). 80% (4/5) patients tested for MYC alterations demonstrated peripheral enhancement. 70% (7/10) tested for BCL2 expression demonstrated homogenous enhancement; while BCL2 &amp; MYC dual-expression was noted in the remaining 30% (3/10) with MRI showing peripheral enhancement. All CNS lymphomas demonstrated restricted diffusion with variable ADC range: 292-980. 84.2% (16/19) of the cases were intra-axial while 15.2 (3/19) were extra-axial (all of which were B-cell lymphoma). Conclusions: Our study shows all lymphomas enhance and demonstrate variable degree of restricted diffusion. Patients with Myc-alterations or dual-expression of BCL2-MYC showed peripheral enhancement, while isolated BCL2 expressed tumors showed homogeneous enhancement.

Effectiveness of digital PCR for MYD88L265P detection in vitreous fluid for primary central nervous system lymphoma diagnosis.

Primary central nervous system lymphoma (PCNSL) is a rare type of primary extranodal lymphoma (PEL). MYD88L265P mutation has been observed in up to 75% of PCNSL cases, however, the validity and sensitivity of digital PCR in detecting this mutation remains to be elucidated. A total of 44 PCNSL patients, 15 diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS) patients and 13 other PEL patients were enrolled in the present study. The abilities of reverse transcription quantitative PCR (RT-qPCR) and droplet digital PCR (ddPCR) to detect the MYD88L265P mutation in cerebral spinal fluid (CSF) samples were compared. The results suggested that ddPCR showed superior mutation detection sensitivity when compared with RT-qPCR (58 vs. 15%; P<0.05). The MYD88L265P mutation was significantly associated with increased MYD88 protein overexpression in PCNSL brain tissue samples (P<0.05). Analysis of MYD88L265P mutation status in CSF and vitreous fluid samples using ddPCR may be a promising technique for minimally invasive confirmation of PCNSL diagnosis.

Psychiatric Disturbance As a Presenting Symptom in Central Nervous Lymphoma

Background: Central nervous system (CNS) lymphoma manifests as a highly aggressive non-Hodgkins lymphoma, either confined to the central nervous system or secondary to spread of systemic diffuse large B cell lymphoma. Rising incidence of CNS lymphoma has been observed, especially in elderly populations. Presentation depends on the burden and location of disease, with a varying spectrum of symptoms ranging from headaches and cognitive changes to focal neurological deficits and seizures. Neuropsychiatric presentation of CNS lymphoma has been seen and anecdotally reported but appears to be under-represented in the literature. In this retrospective review of patients with CNS lymphoma at MCA we report a cohort of patients who presented with primarily neuropsychiatric symptomsMethods: After receiving IRB approval, we retrospectively identified 135 patients with ICD 9 and 10 codes consistent with CNS lymphoma, seen at Mayo Clinic Arizona, between 1998-2018. Symptoms identified prior to presentation with the CNS component of the lymphoma were recorded with attention to those with depression, anxiety, agitation, psychosis, disinhibition, and apathy. Patients with long term premorbid psychiatric disease or symptoms that developed later in the course as a result the stressors of disease and treatment were excluded.Results: A total of 19 out of 136 patients (14%) were noted to have primarily neuropsychiatric symptoms prior to diagnosis of CNS lymphoma. Symptom onset to diagnosis of PCNSL ranged from 3 weeks to 11 months. The average age was 65, and 47% of subjects were male. Depression, apathy, agitation and features of parkinsonism were the most common neuropsychiatric symptoms identified, with psychosis and disinhibition being the least frequent. The majority of these patients had frontal lobe lesions (42%), although several also had multifocal disease at time of diagnosis. Improvement of neuropsychiatric disease was not explicitly discussed or noted in the treatment and post-treatment notes. In fact, we found it notable that follow up notes generally did not comment on these psychiatric symptoms at all, and there was no clear management plan separate from treating the disease process.Parkinsonian features were observed in 5 patients (26%), with onset range from 2 weeks to 29 months prior to PCNSL diagnosis. The associated lesions were mostly deep basal ganglia or corpus callosum except in one case of left parietal lobe tumor. Notably, all patients had resolution of their parkinsonism with treatment of the lymphoma.Conclusions: Neuropsychiatric symptoms are a rare but noteworthy presentation of CNS lymphoma, distinct from cognitive changes that have been previously described with this condition. There is an increasing awareness of neurological illness presenting as pure psychiatric disturbance, prompting exclusion of organic disease, particularly in elderly patients who present with new psychiatric complaints. DisclosuresNo relevant conflicts of interest to declare.

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66-Year-Old Woman With Falls and Confusion

Frequency, Risk Factors and Mortality Effect of Venous Thromboembolism in Adult Patients with Central Nervous System Lymphoma

Background: Venous thromboembolism (VTE) is an established complication of cancer, with a high incidence in patients with both lymphoma (5-15%) and gliomas (15-20%). There is minimal data describing the incidence of VTE in patients with CNS lymphoma. Known VTE risk factors including obesity, immobility, and hospitalization are present in those with central nervous system (CNS) lymphoma; however, concern for bleeding complications limits the use of pharmacologic prophylaxis. The aim of this study is to characterize the frequency of VTE in adult patients with CNS lymphoma treated at a large academic medical center.Methods: The University of California, San Francisco (UCSF) Cancer Registry was queried for all cases of adult CNS lymphoma diagnosed from 2008-2014. Chart review was performed and patients were excluded if the primary treatment occurred elsewhere. Demographics, histology, treatment and mortality data were examined. The presence of VTE was defined by radiographic evidence of a pulmonary embolism (PE) or deep vein thrombosis (DVT).Results: 134 cases of adult CNS lymphoma were reported at UCSF between 2008-2014; 18 patients were excluded. The average follow up time was 3.8 years from date of diagnosis. The mean age at diagnosis was 63. Of the 116 patient included in the study, 77 (66%) were identified as having Primary CNS Lymphoma and 39 (34%) had Secondary CNS Lymphoma including the following subtypes: Diffuse Large B-cell, Burkitt's, Mantle cell, Marginal zone, and NK cell lymphoma.There were 34 cases of VTE (29.3%): 12 were PE and 22 were DVT, 32 (94%) patients were hospitalized at the time of VTE diagnosis. Twenty eight (82%) were symptomatic. Ten (29%) were line-associated VTE. Fifty percent of VTE cases occurred during cycle 1 (18%) or cycle 2 (32%) of chemotherapy and 27 patients (79%) received systemic steroids within 30 days of VTE diagnosis. The median time from diagnosis of CNS lymphoma to VTE was 70 days.Confounding variables including age at diagnosis, race, sex, smoking history and histology were studied and no difference was found between the VTE and non-VTE groups. Notably, body mass index was significantly higher in the VTE group (29.85, 95% CI: 26.5-33.2) as compared to the non-VTE group (25.66, 95% CI: 24.76-26.55, p=0.019). There was a trend toward shorter time to death after the diagnosis of CNS lymphoma in the VTE group (382 days, 95% CI: 106-657) vs. the non-VTE group (699 days, 95% CI: 348-1049, p= 0.18). There was no difference in overall survival (log rank p=0.09).Conclusions: Here we report a remarkably high frequency of VTE (29%) in CNS Lymphoma patients treated at a large academic center. While there was no difference in age, sex, race, smoking history or histology, those who developed VTE did have a significantly greater BMI. Because many patients receive eight cycles of high dose methotrexate as treatment for CNS Lymphoma, our determination that half of the VTE episodes occurred during the first two cycles may be useful in defining the optimal timing of VTE prophylaxis in this high risk population. Most (82%) of the VTE reported in this study were symptomatic, which suggests VTE may have a significant impact on quality of life. There was a trend toward shorter time to death after diagnosis of CNS lymphoma in the VTE group, suggesting VTE may affect mortality. Larger, prospective studies are needed to characterize the timing and incidence of VTE in patients with CNS Lymphoma, but this study reports one of the largest single institution experiences in the literature. DisclosuresRubenstein:Genentech: Research Funding; Celgene: Research Funding.

Contribution of cerebrospinal fluid sCD19 levels to the detection of CNS lymphoma and its impact on disease outcome

AbstractFlow 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.

How I treat CNS lymphomas

AbstractThe pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

Clinical value of MRS and DWI in the diagnosis of central nervous system lymphoma

Objective To investigate the diagnostic value of magnetic resonance imaging (MRI) ordinary scan and functional imaging in primary central nervous system lymphoma.Methods 20 primary central nervous system lymphoma patients underwent MRI scan,enhanced scan and the MRS,DWI scan.The image features of primary central nervous system lymphoma MRI scan and strengthen scan were analyzed.The ADC values of each region of interest,NAA/Cho,NAA/Cr,Cho/Cr,Lip/Cr and ADC values were measured and compared.Results Lesions showed slightly longer T1 signal,etc.or slightly longer T2 signal,GD-DTPA enhanced scan,16 lesions were significantly enhaneed uniformity lesions inhomogeneous enhancement.Lymphoma parenchyma Cho/NAA,Cho/Cr and Lip/Cr values were significantly higher than peritumoral edema.The peritumoral edema Cho/NAA,Cho/Cr and Lip/Cr values were significantly higher than the contralateral control area,the differences were statistically significant(t =2.595,3.900,4.697,2.800,3.167,all P ＜ 0.05).The tumor substance of mean ADC value was (0.551 ± 0.088)mm2/s,the peritumoral edema average ADC value was (0.932 ±0.141)mm/s,the contralateral control area mean ADC value was (0.799 ± 0.081) mm2/s,tumor parenchyma ADC values significantly higher than peritumoral edema,the peritumoral edema ADC values were significantly higher than the contralateral control area,the differences were significant (t =10.251,3.657,all P ＜0.05).Conclusion In the diagnosis of primary central nervous system lymphoma,magnetic resonance ordinary scan,MRS and DWI has a high value. Key words: Lymphoma; Central nervous system; Magnetic resonance imaging

Diagnosis of primary cerebral lymphomas: possible value of PCR testing in equivocal cases requiring rebiopsy

Introduction. Rebiopsy rates as high as 12% have been reported in previous studies of Primary Central Nervous System Lymphoma (PCNSL). This can lead to secondary operations, increasing risks of morbidity to the patient and costs for the NHS. Polymerase Chain Reaction (PCR) testing for clonality in haematological malignancies has been applied to cases of lymphoma outwith the central nervous system (CNS), but is less commonly used in the diagnosis of CNS lymphomas. Clonality in B- and T-cell populations may indicate the presence of malignancy. We aimed to identify factors to reduce the rebiopsy rate in PCNSL. Methods. We examined a cohort of 102 suspected cerebral lymphoma cases biopsied at Frenchay Hospital, Bristol over a 10-year period (2000–2010). Clinical data, including age, sex, location, pre-biopsy steroid use, the need for rebiopsy and histological diagnosis, were collected. We retrospectively reviewed rebiopsied cases and they subsequently underwent PCR testing for clonality. Results. Overall, 96/102 (94%) cases achieved a histological diagnosis after one or more biopsies. 81/96 (84%) of these were lymphomas involving the brain and 15/96 (16%) were spinal lymphomas. The majority of these were B-cell lymphomas (95/96 (99%)), with one case of peripheral T-cell lymphoma (1/96 (1%)). Due to insufficient histological evidence of PCNSL after the first biopsy, 9/102 (9%) of cases had required rebiopsy. In 7/9 (78%) of these cases, we undertook PCR testing for clonality on tissue from the first biopsy. We found 3/7 (43%) cases were monoclonal for B or T populations, raising the possibility of PCNSL. Conclusions. We recommend that all CNS lymphoproliferative lesions be assessed by haematopathologists, with the inclusion of PCR testing particularly in equivocal cases. This would reduce the number of patients going for rebiopsy and reduce the patient morbidity and costs for the NHS.

CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma

AbstractEstablishing the diagnosis of focal brain lesions in patients with unexplained neurologic symptoms represents a challenge. The goal of this study is to provide evidence supporting functional roles for CXC chemokine ligand (CXCL)13 and interleukin (IL)-10 in central nervous system (CNS) lymphomas and to evaluate the utility of each as prognostic and diagnostic biomarkers. We demonstrate for the first time that elevated CXCL13 concentration in cerebrospinal fluid (CSF) is prognostic and that CXCL13 and CXCL12 mediate chemotaxis of lymphoma cells isolated from CNS lymphoma lesions. Expression of the activated form of Janus kinase 1 supported a role for IL-10 in prosurvival signaling. We determined the concentration of CXCL13 and IL-10 in CSF of CNS lymphoma patients and control cohorts including inflammatory and degenerative neurologic disease in a multicenter study involving 220 patients. Bivariate elevated CXCL13 plus IL-10 was 99.3% specific for primary and secondary CNS lymphoma, with sensitivity significantly greater than reference standard CSF tests. These results identify CXCL13 and IL-10 as potentially important biomarkers of CNS lymphoma that merit further evaluation and support incorporation of CXCL13 and IL-10 into diagnostic algorithms for the workup of focal brain lesions in which lymphoma is a consideration.

A Systematic Approach to the Diagnosis of Suspected Central Nervous System Lymphoma

Central nervous system (CNS) lymphoma can present a diagnostic challenge. Currently, there is no consensus regarding what presurgical evaluation is warranted or how to proceed when lesions are not surgically accessible. We conducted a review of the literature on CNS lymphoma diagnosis (1966 to October 2011) to determine whether a common diagnostic algorithm can be generated. We extracted data regarding the usefulness of brain and body imaging, serum and cerebrospinal fluid (CSF) studies, ophthalmologic examination, and tissue biopsy in the diagnosis of CNS lymphoma. Contrast enhancement on imaging is highly sensitive at the time of diagnosis: 98.9% in immunocompetent lymphoma and 96.1% in human immunodeficiency virus-related CNS lymphoma. The sensitivity of CSF cytology is low (2%-32%) but increases when combined with flow cytometry. Cerebrospinal fluid lactate dehydrogenase isozyme 5, β2-microglobulin, and immunoglobulin heavy chain rearrangement studies have improved sensitivity over CSF cytology (58%-85%) but have only moderate specificity (85%). New techniques of proteomics and microRNA analysis have more than 95% specificity in the diagnosis of CNS lymphoma. Positive CSF cytology, vitreous biopsy, or brain/leptomeningeal biopsy remain the current standard for diagnosis. A combined stepwise systematic approach outlined here may facilitate an expeditious, comprehensive presurgical evaluation for cases of suspected CNS lymphoma.

An Approach to Improve the Diagnosis of Primary CNS Lymphoma Using Conventional and Advanced Imaging Techniques

The incidence of central nervous system (CNS) lymphoma is increasing, and it is important to raise this suspicion preoperatively because lymphomas will need only stereotactic biopsy for tissue typing as compared with a more extensive resection in other forms of brain tumors. Moreover, if the diagnosis of CNS lymphoma is unknown preoperatively, inadvertent administration of preoperative corticosteroids can lead to a false biopsy histopathologic interpretation. The imaging appearance of CNS lymphoma depends on the immunity status of the patient and can be confused easily with CNS infection, glioma, or metastasis. This CME activity emphasizes that the use of more advanced imaging techniques now has an important role in diagnosing CNS lymphoma, and, therefore, helps to avoid unnecessary, extensive surgical procedures needed to obtain a more accurate diagnosis. This review article will concentrate not only on how the diagnostic radiologist can use conventional and advanced imaging techniques to diagnose CNS lymphoma, but also how these techniques can help in the follow-up management of CNS lymphoma.