Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n ¼ 29) and whole-exome sequencing (n ¼ 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P ¼ 0.006 and P ¼ 0.01) and CDKN2A homozygous deletion (P ¼ 0.02 and P ¼ 0.01) were significantly associated with shorter progression-free survival and overall survival.Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-kB signaling pathway, which may be promising targets for future therapeutic strategies.

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Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.

Traditionally, the most widely used criteria for response assessment in glioblastoma have been Macdonald and the Response Evaluation Criteria In Solid Tumors (RECIST). Recently, new criteria addressing contrast enhancement and fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity have been defined (the Response Assessment in Neuro-Oncology criteria) to better evaluate the effect of antiangiogenic therapy. Whether FLAIR/T2 imaging could also be helpful to refine RECIST criteria remains unresolved. This study proposed the RECIST + F criteria and compared the 4 methods (Macdonald, RECIST, RANO, and RECIST + F) to determine their agreement in identifying response and progression of recurrent glioblastomas to irinotecan-bevacizumab. Patients with recurrent glioblastoma treated with second-line irinotecan-bevacizumab were eligible. Clinical status, corticosteroid dose, and 1-dimensional and 2-dimensional measurements of tumor contrast enhancement and FLAIR hyperintensity were retrospectively assessed. Response and progression were determined according to each set of criteria. Seventy-eight patients were included. Response rates ranged from 34.2% with RECIST + F to 44.7% with Macdonald criteria. Agreement among the 4 methods in determining response and type of progression was high (kappa statistic > 0.75). One-third of patients exhibited nonenhancing progression with stable or improved contrast enhancement. Median progression-free survival was predicted by RECIST, at 13.6 weeks; RECIST + F, 12.3; Macdonald, 12.7; and RANO, 11.7 (P = .840). Intra- and interobserver correlations were high for both contrast enhancement and FLAIR hyperintensity measurements. There was a strong concordance among the different methods in determining response and progression to irinotecan-bevacizumab. Criteria integrating FLAIR hyperintensity tended, however, to reduce response rates and progression-free survival compared with criteria considering only contrast enhancement. The 1-dimensional approach appeared to be as valid as the 2-dimensional approach.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a treatable brainstem encephalitis recently described by Pittock et al. [1]. We report a case with clinical, radiological, and pathological signs of CLIPPERS but with final diagnosis of type B primary central nervous system lymphoma (PCNSL).In March 2010, a 33-year-old man with unremarkable personal history was first seen in the internal medicine unit for isolated vomiting with weight loss of 5 kg. The clinical and paraclinical examinations were unremarkable. In June, he was admitted to our unit for subacute gait ataxia, dysphagia, and binocular diplopia. Clinical examination revealed bilateral sixth nerve palsy and gait ataxia with pyramidal signs. Brain magnetic resonance imaging (MRI) showed hyperintense lesions on T2-weighted and fluidattenuated inversion recovery (FLAIR) sequences within the pons, medulla, and upper cervical cord, with enhancement after gadolinium administration. Cerebrospinal fluid (CSF) analysis showed elevated levels of proteins (1.10 g/l) with normal electrophoretic pattern and without abnormal cell count (2/mm 3 ). Extensive laboratory investigations were normal. Whole-body fluorodeoxyglucose positron emission tomography (FDG-PET), and labial salivary gland biopsies were negative, including aquaporin-4 water channel and onconeural antibodies. Biopsy of pons revealed perivascular lymphocyte infiltrates without any findings of sarcoidosis, lymphoma, glioma, or lymphomatoid granulomatosis (Fig. 1d). CLIPPERS syndrome was suspected, and the patient was treated for five consecutive days with 1,000 mg intravenous methylprednisolone followed by oral prednisone 60 mg (1 mg/kg/day) every day, with dramatic recovery except for persistence of moderate gait ataxia. In August 2010, a second brain MRI showed a reduction in the number and size of brainstem lesions. Localized proton magnetic resonance spectroscopy (MRS) examination showed a slight decrease of N-acetyl-aspartate/creatine (NAA/Cr) ratio (1:52) and an increase in choline/creatine (Cho/Cr) ratio (1:58) in the brain and medulla (Fig. 1a). The dose of steroids was reduced by 10 mg/week until 30 mg/ day was reached. In September 2010, he complained of numbness in all four limbs with worsening gait ataxia. A third brain MRI showed enlargement of the pontine lesions with necrosis. The MRS showed a slightly elevated Cho/ NAA ratio, as well as strong resonance of lipids and lactates (Fig. 1b). The patient was then treated with 1,000 mg intravenous methylprednisolone for 5 days; this was followed by double-filtration plasmapheresis. Because no further clinical improvement was observed, monthly intravenous cyclophosphamide was added. In October, the fourth brain MRI revealed radiological progression of brainstem lesions with the appearance of gadoliniumenhanced lesions localized close to the left lateral ventricle.

The role of prophylactic intrathecal chemotherapy in the treatment of primary central nervous system lymphoma remains controversial. We report a retrospective single center study of a cohort of 69 patients with primary central nervous system lymphoma who had been treated with a regimen that combined high intravenous doses of Methotrexate, CCNU, procarbazine and methylprednisolone. Before 2000, patients systematically received intrathecal prophylaxis including Methotrexate, cytarabine, and hydrocortisone delivered either by intraventricular or lumbar injection along with the systemic chemotherapy (group A, n = 39). After this date, the procedure was changed and intrathecal chemotherapy was withdrawn from the protocol (group B, n = 30). The median age and Karnofsky index were comparable in both groups. At the time of analysis, we found no significant difference between patients with and without intrathecal prophylaxis in terms of objective response rate, patterns of relapse, progression-free survival or overall survival. In our study, intrathecal prophylaxis withdrawal from a high dose intravenous Methotrexate-based chemotherapy regimen did not influence disease control and outcome of primary central nervous system lymphoma. Further studies prospectively investigating the role of intrathecal chemoprophylaxis are warranted for this disease.

The treatment strategy for AIDS-PCNSL in the HAART era tends to become similar to that of the immunocompetent population. In the absence of randomized trials devoted to AIDS-PCNSL, most current national comprehensive cancer network guidelines recommend the use of high-dose methotrexate-based chemotherapy combined or not with whole-brain radiotherapy as initial treatment in addition to HAART. The objective for the future would be that prognosis of AIDS-PCNSL catch up with that of the immunocompetent patients with special attention to systemic and neurocognitive tolerance of the treatments.

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