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A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability. more...

This work reports a rare case of meningeal lymphoma revealed by a bilateral exophthalmos and takes stock of this association. primary meningeal lymphoma is a very rare localization of lymphoma and its revelation by an exophthalmia is even rarer, despite the multitude of radiological aspects the role of imaging essentially MRI is essential for early diagnosis, the assessment of extension and control after a suitable treatment. more...

Restricted diffusion in the optic nerve detected with MRI has been previously reported in infarction and inflammation but not in infiltrative neoplasm. We report a 44-year-old man with recently diagnosed non-Hodgkin B-cell lymphoma who developed an acute left optic neuropathy. MRI showed no evidence of brain parenchymal or meningeal lymphoma but did show restricted diffusion in the intraorbital portion of the affected optic nerve. Despite treatment with corticosteroid, standard chemotherapy, and orbital X-irradiation, visual function did not improve. The restricted diffusion persisted on a follow-up MRI performed 4 months after the onset, a phenomenon that is atypical for infarction. Perhaps, this persisting imaging abnormality in lymphomatous optic neuropathy reflects the dense cellularity of the neoplasm. more...

With the widespread use of highly active antiretroviral therapy (HAART) the incidence of systemic non-Hodgkin lymphoma (NHL) in patients infected with the Human Immunodeficiency Virus (HIV) has declined. HAART has also modified the clinical manifestations of these tumors, with a lower frequency of involvement of the central nervous system (CNS). Currently, the frequency of meningeal involvement at the time of diagnosis of NHL in HIV-infected patients varies between 3% and 5%. These figures are similar to those observed among immunocompetent hosts. The diagnosis of meningeal lymphoma relies in clinical findings, imaging techniques, and cerebrospinal fluid (CSF) examination. Flow cytometry is a diagnostic technique with a higher sensitivity and specificity than conventional cytology for the diagnosis of meningeal lymphoma. However, flow cytometry is not yet considered to be the gold standard for this purpose. Until recently, most experts recommended neuromeningeal prophylaxis for all HIV-infected patients with aggressive NHL. However, at present this prophylaxis is recommended only in patients with higher risk of CNS relapse according to different sites of involvement, stage and histological subtype. There are different regimens of prophylaxis and treatment for meningeal lymphoma. The drugs most commonly used for this purpose are methotrexate and cytosine arabinoside. However, there are other alternatives such as liposomal cytosine arabinoside that requires fewer spinal taps for drug administration and whose results are very promising. In summary, in the context of an effective HAART, HIV infected patients with NHL have a frequency of CNS involvement by lymphoma similar to that found among immunocompetent hosts. Consequently, indications and regimens for CNS prophylaxis in HIV-infected patients with NHL should not be different than those employed in the general population. Universal CNS prophylaxis should be reserved for the few patients unable to receive an effective HAART. more...

Meningeal involvement (MI) by non-Hodgkin's lymphoma (NHL) was seen in 38/602 patients (6.3%). In relation to histologic subtype the frequency of MI was: Follicular small cleaved and mixed cell 2/128 (1.6%), small lymphocytic and diffuse small cleaved cell 2/83 (2.4%), large cell and immunoblastic 13/295 (4.5%), small noncleaved cell 6/31 (19%), lymphoblastic 15/66 (23%). Risk factors that predict for MI were, besides histologic subtype, age under 40 yr, clinical stage IV, site of involvement (bone marrow, bone, skin gastrointestinal tract), and a poor response to initial therapy. In a Cox multivariate model encompassing the intermediate and high grade malignancy groups of the Working Formulation (WF), the 3 most important risk factors were histology, age, and stage. The estimated 1-yr probability of MI for combinations of the 3 risk factors was: 3 risk factors (61%), 2 risk factors (15-28%), 1 risk factor (4-8%), 0 risk factor (1.5%). At the diagnosis of MI, 84% of the patients had evidence of advanced systemic NHL, and the median survival after MI was 10 wk. CNS prophylaxis with whole-brain irradiation and intrathecal chemotherapy can only be recommended in patients with 2 or 3 risk factors. Improvement of the systemic chemotherapy might be the most important factor for prevention of MI in NHL. more...

Primary meningeal lymphoma is a rare clinical entity. Central nervous system infiltration by systemic lymphoma should always be excluded. Diagnosis can be difficult, and prognosis is usually poor. Most are of B-cell origin. We present the case of a young man with a primary meningeal lymphoma of T-cell origin. He was treated with systemic chemotherapy with high-dose methotrexate and cytarabine and intraventricular chemotherapy. He had a clinical improvement and a complete remission, with a long overall survival. There is no standard treatment for this rare disease. Traditionally, treatment has been based in craniospinal radiation therapy and intrathecal chemotherapy, with poor overall results. More recently, systemic chemotherapy with high-dose methotrexate has been advocated, which could avoid the long-term toxicity of craniospinal radiation therapy, and could improve the prognosis of these patients. more...

BACKGROUND Central nervous system involvement is a common manifestation of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected individuals. The purpose of this study was to review the frequency and pattern of neurologic manifestation of lymphoma in a cohort of HIV-infected individuals with systemic NHL. METHODS Sixty-two patients with HIV-associated systemic NHL received infusional cyclophosphamide, doxorubicin, and etoposide. Five patients with lymphomatous meningitis at presentation received whole brain radiation therapy plus intrathecal chemotherapy (ITC). Of the remaining 57 patients, prophylactic ITC was recommended only for those patients with lymphomatous bone marrow involvement and/or high grade histology (N = 31). RESULTS Thirteen patients (21%) had histologically documented (N = 6) or presumed (N = 7) central nervous system involvement, including 7 patients (11%) with meningeal lymphoma discovered either at presentation (N = 5) or soon after diagnosis (N = 2), and 6 patients (10%) with cerebral mass lesions at the time of disease recurrence consistent with parenchymal brain involvement. Five of six parenchymal brain recurrences occurred in the setting of progressive systemic disease. Four of 7 patients (57%) with meningeal lymphoma detected at presentation (N = 5) or within 3 months of presentation (N = 2) responded to therapy and survived > 1 year. Of the 26 patients assigned to receive no prophylactic ITC, no patient developed an isolated meningeal recurrence and 1 patient developed an isolated parenchymal brain recurrence. CONCLUSIONS The findings of the current study suggest that in patients with HIV-associated systemic lymphoma, meningeal lymphoma is potentially curable, parenchymal brain recurrence usually occurs in the setting of uncontrolled systemic disease, and prophylactic ITC may not be necessary for patients with intermediate grade histology and uninvolved bone marrow. Cancer 1999;86:1840–7. © 1999 American Cancer Society. more...

A 57-year-old man who presented with leptomeningeal lymphoma was reported. The lymphoma cells in the cere-brospinal fluid were large in size, had atypical nuclei and contained many azurophilic granules in their pale cytoplasm, all of which were consistent with malignant lymphoma of large granular lymphocytes (LGL). Immunohistochemically, tumor cells were positive for cyto-plasmic CD3, UCHL-1, and CD56, markers of natural killer (NK)cells. Epstein-Barr virus encoded small RNA (EBER) was detected in tumor cells by in situ hybridization. No evidence of parenchymal central nervous system or systemic tumor was identified, although at autopsy microscopic lympuoma involvement was found in the pituitary gland and kidney. To our knowledge this is the first autopsy case report of primary meningeal LGL lymphoma. more...

Meningeal involvement in patients with AIDS-related non-Hodgkin lymphoma (ARL) is common; it confers a dismal prognosis, and therapy usually involves frequent lumbar punctures. In 137 individuals with ARL in the era of highly active antiretroviral therapy (HAART), 22 had meningeal involvement at more...

Summary We report the case of a 21-year-old man in whom intracranial localization was discovered during initial staging at the onset of Hodgkin's disease (HD). The patient was treated by surgical excision, irradiation and chemotherapy and 50 months after completion of therapy is in remission with no evidence of HD. A brief review of the literature regarding 48 patients with intracranial Hodgkin's disease is presented. more...

Platinum (Pt) levels in plasma and cerebrospinal fluid (CSF) in patients with malignant glioma were determined after initiation of selective intraarterial chemotherapy with a combination of VP-16 (etoposide) and CDDP (cisplatin), and were compared with the CSF Pt levels in patients with metastatic brain tumors after intravenous or intracarotid administration of VP-16 and CDDP. CSF Pt levels were also compared for various administration routes, doses, CSF sampling routes and blood-CSF barriers in metastatic brain tumor. Changes in the blood-CSF barrier to CDDP during treatment in a patient with meningeal lymphoma and in a patient recovering from surgical removal of a metastatic brain tumor were also examined by periodic administration of CDDP. All CSF samples were taken through Ommaya reserviors placed in the anterior horn of the lateral ventricle or the postoperative cavity. The mean peak CSF/plasma total Pt ratio (T/T ratio) and the mean CSF total Pt/plasma ultrafiltrable Pt ratio (T/U ratio) were highest (15.0% and 24.4%, respectively) following selective intraarterial infusion of CDDP in patients with malignant glioma, followed by intravenous infusion in meningeal carcinomatosis (11.5% and 18.9%), intracarotid administration (5.4% and 8.7%) and intravenous infusion (60 mg/m2 2.5% and 100 mg/m2 2.9%; and 60 mg/m2 3.5% and 100 mg/m2 7.7%) in patients with the solid type of metastatic brain tumor. In CSF obtained from the postoperative cavity in cases of metastatic brain tumor, T/T and T/U ratios were extremely high (40.9% and 62.4%). However, the CSF Pt level even after selective intraarterial administration of CDDP in malignant glioma was 0.51-1.64 micrograms/ml total Pt and 0.43-1.08 micrograms/ml ultrafiltrable Pt. Even the CSF level obtained from the postoperative cavity was 1.0-4.7 micrograms/ml total Pt. These low levels of total and ultrafiltrable Pt are considered not to be cytotoxic to disseminated cells in the CSF space and to normal brain cells. As for changes in the blood-CSF barrier, repeated administration of CDDP showed that the rate of entry of Pt into the CSF decreased in parallel with improvements apparent on CT scans in the patient with meningeal lymphoma, and also showed that the blood-CSF barrier to Pt was gradually repaired after the metastatic brain tumor had been removed. more...

The MRI demonstrated a T1-weighted isointense and T2weighted hyperintense extra-axial homogeneously enhancing mass over the right frontotemporal convexity associated with marked oedema and midline shift. The histopathology demonstrated extensive necrotising granulomatous inflammation with acid-fast bacilli identified on Ziehl-Neelsen staining. The specimen culture polymerase chain reaction test was positive for Mycobacterium tuberculosis. Cerebral tuberculoma is an uncommon manifestation of central nervous system (CNS) tuberculosis (TB) and presents in only 15% to 30% of all CNS TB. It appears as localised tuberculous masses histologically characterised by granulomatous caseating necrosis. While most are intraparenchymal, extra-axial tuberculomas are rare but well-recognised variants of cerebral tuberculoma. Meningeal tuberculomas, as reported here, are rarer, with only 12 cases reported in the English literature. Diagnosis of both intraparenchymal and extra-axial tuberculomas radiologically is often difficult, with cases commonly misdiagnosed initially as a neoplasm. en-plaque meningiomas. The MRI appearance is variable, with hypointensity or isotensity on T1weighted and hypointensity, isointensity or hyperintensity on T2-weighted MRI. Similar to meningioma, tuberculomas enhance strongly on gadolinium contrast. In addition, an unremarkable clinical history and a negative TB screening investigation do not eliminate the possibility of tuberculoma. In recent years, magnetic resonance spectroscopy has been reported to be able to differentiate extra-axial tuberculoma radiologically. Both neurosarcoidosis and CNS lymphoma can have similar radiological appearance, being isointense and hyperintense on T1-weighted and T2-weighted MRI respectively with gadolinium enhancement. MRI findings of neurosarcoidosis include periventricular and white matter lesions, multiple intracerebral lesions and leptomeningeal enhancement. Angiotensin-converting enzymes are commonly normal in neurosarcoidosis. Meningeal lymphoma may result from dissemination of aggressive lymphoma more...

Diffuse large B-cell lymphoma of the meninges is a particularly rare form of primary CNS lymphoma. We report a case of a 63-year-old woman found to have primary meningeal lymphoma (PML) with dural and leptomeningeal involvement whom we treated with multiple cycles of intra-arterial (IA) methotrexate, intravenous (IV) etoposide phosphate, and IV cyclophosphamide after reversible osmotic blood-brain barrier disruption (BBBD). Improvement was evident on gadolinium-enhanced brain MRI one month into therapy. At 67 months post-diagnosis there is no evidence of CNS disease. After completing her therapy regimen, she remained disease-free for 34 months, when stage IV diffuse large B-cell lymphoma was discovered in her left adrenal gland and right thigh. Following six cycles of rituximab and CHOP treatment, she is presently in complete remission. IA methotrexate and reversible osmotic BBBD without radiation therapy may be an effective therapy for treating PML. more...

Primary meningeal lymphomas are rare. Here, we discuss a case of a 59 year old female who underwent an operation to remove a dural based frontal mass that was thought to be meningioma preoperatively. Histopathological assessment revealed the tumour to be a meningeal MALT lymphoma with amyloid deposition. Dural lymphomas may mimic meningiomas and subdural hematomas radiologically. Distinction of a primary meningeal MALT lymphoma from a lymphoplasmacytic meningioma may be difficult based solely on morphological grounds and ancillary tests are often necessary. References 1. Menniti A, Moschettoni L, Liccardo G, et al. Low-grade primary meningeal lymphoma: case report and review of the literature. Neurosurg Rev 2005; 28: 229–33. 2. Venkataraman G, Rizzo KA, Chavez JJ, et al. Marginal zone lymphomas involving meningeal dura: possible link to IgG4related diseases. Mod Pathol 2011; 24: 355–66. 3. Kulkarni KM, Sternau L, Dubovy SR, et al. Primary dural lymphoma masquerading as a meningioma. J Neurophthalmol 2012; 32: 240–2. more...

Introduction: Central nervous system (CNS) manifestation accounts for dismal prognosis in patients diagnosed with systemic diffuse large B-cell lymphoma (DLBCL). Myc rearrangement, deletions encompassing the CDKN2A (a.k.a. INK4a/ARF) or ATM gene loci as well as NF-kB-hyperactivating mutations are frequently detected in primary and secondary CNS-tropic lymphoma, however, investigations that functionally link these lesions to CNS involvement in adequate in vivo model systems are missing. Methods: We generated primary Eµ-myc transgenic mouse lymphomas with and without distinct naturally occurring NF-kB mutations (within genes encoding for MyD88, CD79B, A20, IkBζ, IkBε or BIRC3) or deletions at the INK4a/ARF and ATM loci by retroviral gene transfer and crossbreeding to the respective knockout strains. A subset of the lymphomas was subjected to gene expression profiling and whole-exome sequencing (WES). Wild-type recipient mice propagated with lymphoma cells via tail vein injection were monitored for systemic lymphoma development, the time at which the brain was isolated and examined regarding lymphoma infiltration. Results: Underlining Myc's role as a putative co-driver of CNS involvement, we found in about 40% of primary Eµ-myc lymphomas (with no additional exogenous lesions) meningeal lymphoma manifestations, and transplantation of the same individual lymphomas into numerous recipients reproduced the CNS lymphoma status. Gene set enrichment analysis of genome-wide transcriptome profiles indicated NF-kB hyperactivation in the CNS-tropic lymphoma group, suggesting that constitutive NF-kB signaling may promote CNS-prone pathogenesis in vivo. Transplantation of Eµ-myc transgenic hematopoietic stem cells expressing a variety of NF-kB-activating mutants in myeloablated recipient mice resulted in a significant acceleration of Eµ-myc -driven lymphomagenesis, with some, but not all of these mutants conferring a CNS-tropic lymphoma phenotype. Global NF-kB suppression in CNS-tropic Eµ-myc lymphomas via the NF-kB-antagonizing IkBΔN super-repressor did not fully abrogate lymphoma infiltration of the brain, suggesting that additional factor(s) must contribute. Accordingly, targeted ablation of the INK4a/ARF and ATM loci robustly enhanced CNS tropism of Eµ-myc lymphomas. Conclusions: The Eµ-myc mouse lymphoma model is well-suited to genetically dissect and rebuild components of DLBCL-like CNS tropism. We identified CDKN2A or ATM deletions as critical determinants of CNS tropism in vivo. Our systematic analyses of different NF-kB mutants - so far rather recognized as functionally interchangeable - indicated that only distinct NF-kB mutants contribute to CNS tropism in B-cell lymphomas. WES data, results from compound genotypes (e.g. combining ATM deletions with an NF-kB-activating mutation), and the impact of the host's cellular immune status will be reported at the meeting. Our findings underscore the need for functional analyses of oncogenic network contexts, and provide important insights into candidate target lesions for personalized CNS-directed therapies in DLBCL patients in the future. Disclosures No relevant conflicts of interest to declare. more...

Primary meningeal lymphoma is a rare occurrence. We present a case of an immunocompetent patient operated on for a fronto-parietal lesion similar to a meningioma, which the histological examination diagnosed as a mucosa-associated lymphoid tissue (MALT)-type lymphoma. She received no further post-operative treatment and after 36 months showed no evidence of disease. In a review of the literature, we identified 14 similar cases of MALT lymphoma pre-operatively diagnosed as meningioma. Recognition of this rare meningeal location of a lymphoma involving the central nervous system is useful for a proper diagnosis and adequate treatment. more...

We report on a patient with spontaneous remission of a third-nerve palsy who was subsequently found to have meningeal lymphoma. Initial magnetic resonance images (MRI) showed bilateral enhancement of the third nerves. Follow-up MRI 7 months later, without treatment, showed complete resolution. One year after initial presentation, the patient developed multiple lumbosacral radiculopathies and examination of a nerve root biopsy specimen disclosed a B-cell lymphoma. Serial cerebrospinal fluid analyses over the previous year showed occasional atypical cells, later found to resemble closely the biopsy cell type. We conclude that meningeal lymphoma may have a protracted course, with spontaneous remission of both clinical and neuroimaging findings. more...

Secondary central nervous system lymphoma (SCNSL) refers to lymphoma that initially involves the lymph nodes and, occasionally, extranodal sites, and only subsequently disseminates to the central nervous system (CNS). Many studies have reported the incidence of CNS involvement in patients with non-Hodgkin’ s lymphoma (1–6). Critical review of these early series is limited by the inclusion of all lymphoma histologies, the discrepancies between old and new lymphoma classifications, the lack of modern imaging modalities, the inclusion of patients with epidural involvement, and the inclusion of patients who received a variety of, and often substandard, chemotherapy regimens. In these large series of unselected patients with non-Hodgkin’s lymphoma, approx 5–11% of patients had CNS involvement. Incidence was very low in patients with follicular center, small lymphocytic, and other indolent lymphomas, but incidence was relatively high in patients with diffuse histology, (especially lymphoblastic and Burkitt’ s lymphoma), young age, poor performance status, more advanced-stage disease, and extranodal involvement (1–7). more...

Wilkening et al 1 described the unusual history of a formerly healthy immunocompetent white woman initially presenting with an S1 syndrome with lymphocytic pleocytosis in the CSF, leading to the misdiagnosis of meningoradiculitis. Repeated spinal MRI disclosed an epidural mass lesion, and histological examination of the tumour biopsy confirmed the diagnosis of primary spinal lymphoma of Burkitt's type. The authors emphasise that in every case with suspected meningoradiculitis including neuroborreliosis, meningeal lymphoma should be considered as an important differential diagnosis. In view of the occasionally difficult diagnosis of primary meningeal lymphoma we briefly present the clinicopathological report of a primary malignant lymphoma with almost selective involvement of the spinal roots: A woman aged 65 years without known systemic … more...

Abstract 3477 Background: There is a paucity of molecular information regarding the phenotype of relapsed aggressive CNS lymphoma, a condition for which there are few effective treatment options and, as a consequence, patient survival is often short. To test our hypothesis that the molecular properties of CNS lymphoma at relapse are distinct from those at diagnosis we pursued two parallel lines of investigation: 1) the genomic analysis of relapsed aggressive CNS lymphomas in comparison to newly diagnosed specimens and 2) the generation of novel CNS lymphoma cell lines derived from recurrent meningeal lymphomas isolated from the cerebrospinal fluid. We hypothesize that this approach will facilitate the identification of the underlying molecular determinants of tumour progression, novel genome-based biomarkers and therapeutic targets. Methods: We compared genome copy number using high-resolution array comparative genomic hybridization (array-CGH) and used bioinformatics to study a carefully selected cohort of tumours comprised of 10 newly-diagnosed primary CNS lymphomas (large B-cell) and 7 relapsed/refractory CNS lymphomas (5 large B-cell, 2 of transformed histology). We evaluated copy number aberrations that occurred in the tumour cohort as a whole as well as those that occur predominantly in relapsed cases. In addition, we established five novel lymphoma cell lines from relapsed cases, three of which were derived from meningeal lymphomas isolated from the cerebrospinal fluid and expanded upon intracranial implantation in NSG mice as patient-derived xenografts. Results: There was a trend for an increase in the proportion of copy number losses involving the short arm of chromosome 6 as well as overall gains on chromosome 12 among the relapsed cases. Significant DNA copy number gains for STAT6 were noted in 4/7 relapsed cases. We observed a significant number of deletions present in between 50–90% of newly diagnosed tumors that were absent in CNS lymphomas at relapse, suggestive of complex genomic remodeling during tumour evolution. In addition, a region with potential prognostic implications was identified at chromosome 19p.13.3 that was deleted in 57% of relapsed tumors but not in newly diagnosed cases. Three of the five relapsed large cell cases exhibited significant deletions, including one focal homozygous deletion, at chromosome 4q23.3–4q23.5, a region not previously shown to be deleted in large cell lymphoma (Lenz et al., PNAS, 2008). Both chromosomes 14 and 22 have copy number aberrations that occur in > 80% of all tumours as well as high frequency focal aberrations that appear linked to either good or poor prognosis. Significantly, the MTAP and CDKN2A genes at 9q21 are homozygously co-deleted in 18% of poor prognosis or relapsed patients. Notably, each of the orthotopic xenografts exhibited an ABC immunophenotype and were diffusely infiltrative with meningeal tropism. In fact, CNS metastasis to the meninges was recapitulated when the lymphoma cells were implanted in flank and spontaneously metastasized to brain, within three months post injection. In vitro chemotaxis assays demonstrated responsiveness of human meningeal lymphoma cells to CXCL-13 and SDF-1, chemokines postulated to contribute to the CNS tropism of NHL. Importantly, genomic aberrations identified in the parent tumours were retained when the relapsed meningeal lymphomas were serially passaged by intracranial implantation as xenografts, as evidenced by array-CGH. Conclusions: We believe that this study represents the first analysis of the biologic and genetic properties of relapsed CNS lymphoma. This analysis provides the first direct evidence that chemokines previously shown to be expressed in the CNS lymphoma microenvironment direct chemotaxis of meningeal lymphoma cells isolated from patients. This result is suggestive of a molecular mechanism which may be essential to CNS tropism. In addition, we have established the first in vivo model system of CNS lymphoma which retains the genomic properties of relapsed, refractory disease and which has significant potential for preclinical testing of novel therapeutic strategies. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures: No relevant conflicts of interest to declare. more...

CSF beta-glucuronidase, polyamines and carcinoembryonic antigen (CEA) were analyzed in 16 patients with meningeal carcinomatosis from solid tumor in systemic organs, 27 with benign brain lesions, 18 with primary brain tumors, 14 with metastatic brain tumors and 5 with leptomeningeal dissemination of other malignant diseases. Beta-glucuronidase levels in all cases of meningeal carcinomatosis, meningeal gliomatosis and meningeal lymphoma were higher than 100 micrograms/dl/hr; on the other hand, levels in all cases of benign brain lesions were below 100 micrograms/dl/hr. Levels of beta-glucuronidase and polyamines were not high in the cases with positive cytology after tumor resection. Polyamine levels were below 0.05 nmol/ml in all cases after resection of the metastatic brain tumor. Cystic fluid of malignant tumors showed high levels of beta-glucuronidase and polyamines. On the other hand, the levels of polyamines in the cystic fluid of benign tumor were low, although the levels of beta-glucuronidase were high. Some cases of meningeal carcinomatosis with high levels of serum CEA did not show high levels of CSF CEA. For metastatic brain tumors, the cases with intraparenchymal tumors, especially with dural attachment showed high levels of beta-glucuronidase and CEA preoperatively, but they returned to normal after surgery. In cases of meningeal carcinomatosis treated by intrathecal chemotherapy with methotrexate (MTX) and cytosine arabinoside (Ara-C), CSF beta-glucuronidase reflected the neurological status better than the cell count decreased rapidly following chemotherapy and beta-glucuronidase was considered as a useful CSF marker in cases of meningeal carcinomatosis to monitor the course of the disease. The same situation was observed in CSF CEA and CEA was also considered as a useful marker when CEA levels in CSF are higher than those in serum. more...

We describe the case of a woman in whom a Ki-1 lymphoma confined to the meninges developed nearly 4 years after complete remission of a Hodgkin lymphoma. The neurological symptoms appeared in two stages. The first, marked by multi-radicular impairment, cleared almost completely within a few months. The second, a year after the beginning of the first, manifested with a syndrome of meningeal irritation, which quickly led to death. We discuss the clinical course and the possible relationship between Hodgkin lymphoma and Ki-1 lymphoma. more...

A 50-year-old woman with a history of pyrexia of unknown origin, weight loss and constitutional symptoms was diagnosed with intravascular large B-cell lymphoma. The trephine biopsy confirmed the presence of CD19, CD20, CD79a large lymphoid cells, with prominent nucleoli, lodged intraluminally. Initial staging with [F]-fluorodeoxyglucose (FDG) combined positron emission tomography – computed tomography (PET/ CT) demonstrated left axillary nodal disease and diffuse increased bone marrow uptake. She was treated with six cycles of R-CEOP (rituximab, cyclophosphamide, epirubicin, vincristine and prednisolone). Early PET-CT re-staging after two cycles of R-CEOP demonstrated a complete metabolic response and bone marrow examination demonstrated complete remission. In view of high-risk disease, consolidation treatment with carmustine, etoposide, cytarabine and melphalan (BEAM) chemotherapy plus autologous stem cell transplantation was undertaken in first remission. The transplant course was uncomplicated with neutrophil engraftment on day 12. Routine restaging at 3 months post-transplant with a bone marrow examination showed no evidence of lymphomatous infiltration. On clinical review 2 weeks later, she was asymptomatic except for a several-day history of a vague intermittent headache. A routine PET-CT at this time demonstrated striking intense uptake in the spinal canal extending from L1 to L5 levels. There was further intense uptake in subcentimetre right axillary lymph nodes, and further focal bony uptake in the right clavicle, sternum, humeri and femora, without abnormality on CT bony windows. Subsequent lumbar puncture revealed heavy infiltration with lymphocytes confirming meningeal lymphoma recurrence. Treatment with salvage chemotherapy was undertaken, with an early re-staging PET study after one cycle demonstrating a complete metabolic response. Intravascular large B-cell lymphoma is a rare subtype of diffuse large B-cell lymphoma. It is characterised by the presence of lymphoma cells in the lumina of small vessels resulting in highly variable end-organ involvement and clinical presentation. It has a very poor prognosis, partly reflecting frequent delays in diagnosis and initiation of therapy due to its unusual presentation. This case demonstrates the utility of functional imaging with PET-CT throughout disease management, including initial staging, early re-staging and response to therapy, which resulted in the early diagnosis of disease recurrence, allowing prompt institution of appropriate salvage chemotherapy. more...

A 64-year-old woman was admitted because of progressive paraplegia. She had a history of unexplained blindness which had developed gradually 1 year earlier. The contrast-enhanced CT showed a small mass at the sella turcica. The funduscopy showed merely atrophic discs. The lumbar puncture revealed marked pleocytosis (cell count: 10.4 x 10(9)/l) and a diagnosis of meningeal lymphoma was made by the cytology of the cerebrospinal fluid. No lymphomatous lesions were detected outside of the central nervous system (CNS) and the patient received whole brain irradiation together with intrathecal chemotherapy. However, there was no improvement in vision or other neurological activities. Eventually the patient died of interstitial pneumonia 2 months after admission. The autopsy revealed a residual B-cell lymphoma existing only in the leptomeninges of medulla oblongata. The optic nerves were atrophic macroscopically and massive gliosis was seen microscopically. In addition, cytomegalovirus infection was observed in the lungs and adrenal glands but not in the CNS. This patient must have had a primary meningeal lymphoma. The mechanism of the visual loss of this patient is discussed. more...

The clinical value of CSF beta-glucuronidase assay in the differential diagnosis of chronic meningitis had been investigated over the past 20 years. Significant (P < .001), often marked, elevation of the enzyme level was found in the first sample submitted in 29 of 30 cases of neoplastic meningitis, irrespective of treatment (mean, 324 units), and in 12 of 14 untreated cases with meningeal lymphoma (mean, 174 units). On the other hand, untreated patients with chronic meningitis of other etiologies had significantly lower of other etiologies had significantly lower levels of enzyme elevation, eg, leukemic meningitis (mean, 46 units), fungal meningitis (mean, 41 units), and tuberculous meningitis (mean, 79 units). In the few cases of chronic meningitis studied during appropriate therapy, a tendency toward a decrease in enzyme activity was noted, thus offering further diagnostic support. In our opinion, the finding of a marked elevation of beta-glucuronidase activity in a patient with chronic meningitis is presumptive evidence of neoplastic etiology. more...

The clinical features of 34 patients with Burkitt's lymphoma diagnosed at the American University Medical Center (AUMC) are described. Ages ranged between 3 and 20 years (median, 7 years). Seventy-three percent of the patients were younger than 8 years. Three cases occurred among siblings. The primary site of disease at presentation was the abdomen, 23 patients; jaw, 6; jaw and abdomen, 2; Waldeyer's ring, 2; and mediastinum, 1. Of those who had abdominal disease, the involvement was diffuse and extensive in abdomen and pelvis in 9, apparently confined to the ileocecal region in 5, mesenteric nodes and small intestine in 5, large intestine in 1, and ovary in 3. One patient presented with paraplegia. The bone marrow was studied in 19 patients; it was positive in 5 and suspicious in 2. None had frank leukemia. CSF was studied in 4 patients at presentation and was negative. Eight patients developed meningeal lymphoma during the course of the disease. Liver involvement was documented in 3 patients. Peripheral lymphadenopathy was observed at presentation in 11 patients (9, neck; 2, inguinal + axillary). In contrast to African Burkitt's, the majority of our patients presented with abdominal disease, and in contrast to the American form, our patients were younger with a median age similar to that of African Burkitt's. Thirty percent of the patients had jaw tumor at presentation--a figure intermediate between the African and the American Burkitt's. more...

Two cases of malignant lymphoma of the leptomeninges in dogs are described. Both involved the subarachnoid space overlying the cerebrum and cerebellum and in one dog there was infiltration of neoplastic lymphocytes into the leptomeninges of the cervical spinal cord and nerve roots. These cases appeared to represent primary meningeal lymphoma, except that lymphoma was present in an ovary of one of the dogs and here the meningeal lymphocytes were demonstrated to be B cells by the peroxidase-antiperoxidase method for cytoplasmic immunoglobulin. Meningeal lymphoma, primary or metastic, is rare in dogs. The differential diagnosis is discussed and includes reticulosis, sarcomatosis of the meninges, and the diffuse spread of an oligodendroglioma in the subarachnoid space. A tentative diagnosis of meningeal lymphoma in these cases could be made by examination of the cerebrospinal fluid cells. more...

Before the introduction of the central nervous system (CNS) prophylaxis in acute lymphoblastic leucaemia (ALL) in childhood the incidence of meningeal leucaemia was about 50%. Now it is only 10%, but extension to the meninges might become more frequent in the near future, due to a better patient survival Simultaneous the incidence of meningeal metastases from certain types of malignant lymphoma, such as mediastinal T-cell lymphoma in children and young adults and in hystiocytic lymphoma stage IV, is increasing. Breast cancer, lung cancer and melanoma are the solid tumors which may cause meningeal involvement. The symptoms have been described in the previous paper by Swen. It is the purpose of our paper to discuss the treatment of meningeal metastases and specially the role of the ventriculostomy system (V.S.) of Ommaya (O.S.). Finally the pharmacology and toxicity of MTX will be considered. more...

CLM developed in 60 of 526 patients (11%) with SCLC seen at the NCI between August 1969 and June 1980. Life table analysis revealed an overall 25% risk of CLM at 3 years. CLM was diagnosed during all phases of the patients' clinical course, but the majority (83%) were cases diagnosed at the time of progressive systemic disease. Univariate log rank analysis indicated that pretreatment factors associated with the development of CLM included: involvement of the brain, spinal cord, bone marrow, liver or bone; extensive disease; and male sex. Patients who did not obtain a complete response to systemic therapy were at greater risk of developing CLM than complete responders. Multivariate analysis of these factors indicated that liver metastases were most strongly associated with the time to development of CLM, followed in order of importance by bone and CNS metastases. Patients usually presented with signs and symptoms reflecting involvement of multiple areas of the neuraxis including the cerebrum, cranial nerves and spinal cord; 51 of the 60 patients had intracerebral metastases and 27 had spinal cord lesions during their clinical course. Autopsy features including focal or diffuse involvement of the leptomeninges with infiltration of the Virchow-Robin spaces were similar to meningeal lymphoma and leukemia, except that CLM was rarely the sole manifestation of CNS tumor. Median survival following the diagnosis of CLM was 7 weeks. However, most deaths were attributed to systemic disease, and treatment with intrathecal chemotherapy and irradiation often provided palliation. With the increased awareness of this complication, an antemortem diagnosis increased from 39% prior to 1977, to 88% of patients after 1977. more...

Summary The optimal treatment of meningeal lymphoma is not at all standardized, but from this abbreviated review emerges at least two important concepts which may be applied to provide effective therapy. First, patients with the histologic subtypes of histiocytic, undifferentiated or convoluted cell, and the anatomic distribution of marrow involvement might warrant prophylactic therapy to the CNS. The use of intrathecal therapy in conjunction with cerebral radiation much like the prophylaxis for meningeal leukemia may be indicated in this group and has been suggested by Young et al. (31). Similarly, Levitt et al. (14) have proposed prophylaxis particularly for diffuse histiocytic lymphoma with marrow involvement. CNS complications developed in 35% (6/17) of such patients. This issue, however, is not resolved and Sweet et al. (27) have not observed a comparable frequency of CNS relapse. Secondly, in patients with established meningeal lymphoma the intrathecal drugs are either untested (thiotepa) or of limited effect (methotrexate and cytosine arabinoside). In the series of Young et al. (31), 80% of patients treated for CNS lymphoma and coming to autopsy demonstrated histologic evidence of persistent disease. A new therapeutic approach to CNS lymphoma is therefore justified and the use of multiple intrathecal drugs in sequence may avoid development of tumor cell resistance. In addition, the The role of radiation therapy as primary treatment or combined with systemic and/or intrathecal chemotherapy is undetermined at present although the general tendency is to apply both modalities with some risk of adverse effects. Specifically identified mass lesions are effectively treated with localized radiation therapy but irradiation of the entire central nervous system (cerebral hemispheres and spinal cord) would be associated with a major compromise of marrow reserve. The sequential interdigitation of chemotherapy with radiation would appear to be an important area of future study. more...

CRYPTOCOCCAL meningitis is a frequently described complication of malignant lymphoma. A patient with nodular, poorly differentiated lymphocytic lymphoma (a B-cell neoplasm) had a notable alteration in mental status. Examination of the CSF showed characteristic cryptococcal organisms, but also was believed to demonstrate CNS involvement with lymphoma. A T-cell rosetting assay proved clinically useful by identifying the atypical lymphocytes as T cells rather than neoplastic B cells. Report of a Case A 69-year-old man first came to the Minneapolis Veterans Administration Hospital in April 1973 with leg edema secondary to obstruction of the inferior vena cava. Laparotomy revealed a 12-cm mass. The histopathologic diagnosis was nodular, poorly differentiated lymphocytic lymphoma (PDLL). Several abdominal nodes were involved and a bone marrow biopsy specimen was positive for lymphoma. The patient was treated with cyclophosphamide and lomustine, with complete clinical response. However, two subsequent relapses required further therapy. The second relapse occurred in May more...

• Facial nerve paralysis developed in a man with tumor-stage mycosis fungoides (MF). Mastoidectomy disclosed that MF had involved the mastoid and middle ear. Meningeal lymphoma, confirmed by the finding of Sezary cells in the CSF, was subsequently established. Autopsy disclosed MF lymphoma in the leptomeninges, medulla, spinal cord, and cranial nerves. A unique feature was the formation of a communicating hydrocephalus. Case reports of 23 patients with MF of the CNS, including 21 autopsies, are reviewed. Practically all had tumor-stage or erythrodermic MF. Atypical mononuclear cells were found ante mortem in the CSF in eight patients. In contrast to other CNS lymphomas, bone marrow involvement was uncommon. Cranial, especially facial, nerve paralyses were often premonitory signs of meningeal lymphomas. Patients with MF having such symptoms should have cytologic examination of the CSF. ( Arch Dermatol 1983;119:311-318) more...