Epidemiology of Primary CNS Lymphoma

In the beginning of the nineties the National Cancer Institute Surveillance, Epidemiology, and End Results Program calculated the incidence of primary central nervous system non-Hodgkin's lymphoma (PCNSL) as 1:100000. The incidence of PCNSL has been increasing since the seventies in immunocompetent patients. The main increase, however, is taking place since the mid-eighties and is due to the increase of immunodeficieny and immunosuppression. The risk is 2–6% in AIDS patients according to clinical data and will probably further increase with the length of survival in these patients. Transplant patients carry a risk of 1–5% to develop a PCNSL. The risk is 1–2% for renal, and 2–7% for cardiac, lung or liver transplant recipients. Patients with congenital immune deficiency have a risk of 4%. PCNSL may also present as a secondary malignancy.     

Solitary primary CNS lymphoma: long term survival following total resection

Primary non-Hodgkin's CNS lymphoma is rare, constituting 0.3–1.5% of all intracranial neoplasms in patients without AIDS. In the past 10 years the incidence has tripled in this population. The role of surgery is commonly limited to obtaining adequate tissue for diagnosis. This has precluded the evaluation of total surgical resection for a surgically accessible solitary lesion. We have encountered a 36-year-old healthy white male with primary CNS lymphoma who is HIV-negative and who has survived over five years disease free after total surgical resection of his lymphoma.     

Differential micro-RNA expression in primary CNS and nodal diffuse large B-cell lymphomas

Most primary CNS lymphomas (PCNSL) are diffuse large B-cell lymphomas (DLBCL). However, clinical behavior and prognosis differ considerably from those for nodal DLBCL (nDLBCL), and their pathogenesis is still not fully understood. Micro-RNAs (miRNAs) have been associated with cancer development and progression. We investigated a large miRNA panel for differential expression in PCNSL and nDLBCL, to determine new mechanisms potentially involved in PCNSL pathogenesis. Using paraffin-embedded biopsy specimens from 21 HIV-negative patients with newly diagnosed PCNSL (n = 11) and nDLBCL (n= 10), we measured the expression of 365 miRNA species by quantitative real-time PCR using low-density PCR arrays. We found that 18 miRNAs were differentially expressed: median expression levels of 13 miRNAs were 2.1-13.1 times higher in PCNSL, and median expression levels of 5 miRNAs were 2.6-3.3 times higher in nDLBCL. MiRNAs upregulated in PCNSL were associated with the Myc pathway (miR-17-5p, miR-20a, miR-9), with blocking of terminal B-cell differentiation (miR-9, miR-30b/c), or with upregulation by inflammatory cytokines (miR-155). Putative tumor-suppressor miRNAs (miR-199a, miR-214, miR-193b, miR-145) were downregulated in PCNSL. There was no overlap of miRNAs dysregulated in PCNSL with those differentially expressed between immunohistologically defined germinal center B cell-like (GCB) and non-GCB types or, apart from miR-9, with miRNAs known to be overexpressed in human brain. We conclude that PCNSL exhibits a distinct pattern of miRNA expression compared with nDLBCL. This argues for the involvement of different molecular mechanisms in the pathogenesis of these two lymphoma types.     

High-dose methotrexate for elderly patients with primary CNS lymphoma

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.     

Epigenetic silencing of multiple genes in primary CNS lymphoma

Epigenetic silencing of functionally important genes is important in the development of malignancies and is a source of potential markers for molecular detection. Primary central nervous system lymphoma (PCNSL) is an increasingly common tumor that has not been extensively examined for changes in promoter region methylation. We examined 14 tumor suppressor genes in 25 cases of PCNSL using methylation-specific PCR. Methylation was observed in DAPK (84%), TSP1 (68%), CRBP1 (67%), p16(INK) (4a) (64%), p14(ARF) (59%), MGMT (52%), RARbeta2 (50%), TIMP3 (44%), TIMP2 (42%), p15(INK) (4b) (40%), p73 (28%), hMLH1 (12%), RB1 (8%) and GSTP1 (8%). Promoter methylation of p14(ARF), p16(INK) (4a) and MGMT was correlated with loss of expression by immunohistochemical staining. The methylation of many of these genes in PCNSL is similar to that reported in other high-grade B-cell lymphomas. All 25 cases of PCNSL had methylation of at least 2 genes. Methylation of DAPK, p16(INK) (4a) or MGMT was found in 96% of the tumors, suggesting simple marker strategies to detect circulating methylated DNA in serum that might facilitate early tumor detection. Our study provides insight into the epigenetic alterations in PCNSL and provides potential biomarkers of disease.     

Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma

In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain “prognostic groups”. However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0–124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series.     

On point in primary CNS lymphoma

Primary CNS lymphoma (PCNSL) is an aggressive brain tumor that represents a significant challenge both to elucidate its biological pathogenesis as well as to develop definitive precision medicines with minimal collateral toxicity. We highlight the key issues in diagnosis and treatment and focus on emerging technologies, current options among consolidation strategies, and biological agents. We anticipate that further development of molecular diagnostics and molecular imaging approaches that elucidate minimal residual disease in brain parenchyma, leptomeninges, intraocular compartments and even bone marrow will greatly impact the delivery and timing of cytotoxic and biological therapies. Implementation of these approaches is likely essential to clarify ongoing discrepancies in the interpretation of clinical trial results that currently are based on relatively unrefined definitions of response. While the results of early phase investigations involving ibrutinib and the IMiD agents, lenalidomide, pomalidomide, as well as avadomide, strongly support the hypothesis that the B-cell receptor (BCR) pathway, involving MYD88 and CD79B and NF-kB activation, is critical to the pathogenesis of PCNSL, much work is needed to elucidate mechanisms of resistance. Similarly, development of strategies to overcome immunosuppressive mechanisms that are upregulated in the tumor microenvironment is a high priority. Finally, ongoing evidence supports the hypothesis that the blood-brain barrier represents a significant impediment to efficient brain tumor penetration of novel therapeutic agents and innovative strategies of drug delivery remain essential to further improve outcomes.     

Immunophenotypic profile of CNS lymphoma: A review of eighteen cases

Summary The cell surface antigenic phenotype of 18 cases of central nervous system (CNS) large-cell lymphoma (14 primary, four secondary) was examined by an immunoperoxidase technique using antibodies that identify B cell restricted and associated antigens. All cases were shown to be of B cell origin by virtue of the expression of monotypic immunoglobulin (Ig) (16 IgM, two IgG) and the pan B cell antigen B1 ( CD20). A panel of monoclonal antibodies directed against B cell restricted and associated activation antigens including B5, Blast-1, Blast-2 (CD23), BB1, interleukin 2 receptor (IL2R, CD25), T9 (transferrin receptor) and TNK-TAR (4F2) was used on 12 of the cases. The majority expressed T9 and TNK-TAR. Blast-1 was expressed by less than half the cases and Blast-2 and B5 by one of 12 cases each. This is in contrast to 10 non-CNS diffuse large cell lymphomas where B5 and Blast-1 were present on all cases. This study confirms previous observations that primary CNS large cell lymphomas are of B cell derivation. Moreover, the differences in expression of B cell activation antigens on CNS large cell lymphomas as compared to non-CNS lymphomas raise the possibility that a subset of neoplastic B cells may have unique tropism for the CNS.Supported by a fellowship of the Association of Brain Tumor Research, the Narragansett Foundation and the Anne Blittner and James Smith Funds.Supported by PHS grant 5K08 CA 01105-01. Awarded by National Cancer Institute, DHHS and by National Institute of Health Grant CA 40216.     

Primary CNS lymphoma as second malignancy in a case of carcinoma larynx treated with chemoradiation

A 66-year-old male was diagnosed as carcinoma larynx in the year April 2004. He was treated with concurrent chemoradiation and remained disease free for three consecutive years. After 3 years he suddenly complained of giddiness and seizures. Magnetic Resonance Imaging of brain showed features of primary CNS lymphoma (PCNSL) which was confirmed by histopathology test. To the best of our knowledge PCNSL as second malignancy in a case of carcinoma of head and neck has not been reported till date. The PCNSL in this patient may have resulted from depressed immunity due to previous radiotherapy. Whatever may be the predisposing cause, this case is most probably the first reported case of PCNSL in a patient of squamous cell carcinoma of larynx.     

Cognitive functions in primary CNS lymphoma after single or combined modality regimens

The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.     

The value of bone marrow biopsy for staging of patients with primary CNS lymphoma

BackgroundIn patients with presumed primary CNS lymphoma (PCNSL), a systemic manifestation is found only in a small minority. Although bone marrow biopsy (BMB) is recommended for staging, its diagnostic value is unclear.MethodsA retrospective analysis of 392 patients with presumed PCNSL from 3 university hospitals and 33 patients with secondary CNS lymphoma (SCNSL) and initial CNS involvement from a multicenter Germany-wide prospective registry was performed.ResultsA BMB was performed and documented in 320/392 patients with presumed PCNSL; 23 had pathologic results. One harbored the same lymphoma in the brain and bone marrow (BM), 22 showed findings in BM discordant to the histology of brain lymphoma; n = 12 harbored a low-grade lymphoma in the BM, the other showed B-cell proliferation but no proof of lymphoma (n = 5), monoclonal B cells (n = 3), or abnormalities not B-cell-associated (n = 2). In the group of SCNSL with initial CNS manifestation, 32/33 patients underwent BMB; 7 were documented with bone marrow involvement (BMI); 1 had concordant results in the brain and BM with no other systemic manifestation. Six had additional systemic lymphoma manifestations apart from the brain and BM.ConclusionsIn only 2 out of 352 (0.6%) patients with CNS lymphoma (320 presumed PCNSL and 32 SCNSL), BMB had an impact on diagnosis and treatment. While collected in a selected cohort, these findings challenge the value of BMB as part of routine staging in presumed PCNSL.     

Clinical characteristics of non-hodgkin's lymphoma as a second primary tumor: a population-based survey

Data from 29, 845 patients with lymphomas, 981 of whom had lymphoma as a second primary tumor, registered in the Surveillance Epidemiology and End Results (SEER) program in the U.S.A. between 1973 and 1986 were analyzed. The characteristics of the 274 patients with lymphoma as a second tumor who had received chemotherapy and/or radiotherapy for their primary tumor (SEP PT) were compared with 675 patients with second primary lymphomas who had no prior treatment (SEP NT) and with patients with single lymphomas (SIP). Patients with SEP PT disease had a significantly higher percentage of intermediate and high-grade tumors (80%) compared to those with SEP NT or SIP tumors (73% and 72%, respectively). The survival of all patients with SIP tumors did not differ from those with SEP tumors, but the median survival of those with SEP PT disease was shorter than for SEP NT disease. This was most probably due to the high percentage of intermediate and high-grade lymphomas in the SEP PT group. This was statistically significant in the group treated by combined chemotherapy and radiotherapy but not in those treated by a single modality alone. These findings relating to a worse prognosis in patients with SEP PT lymphoma are in line with our previous observations of a poor survival in patients with other multiple primary tumors.     

Primary CNS Lymphoma: Findings Outside the Brain

In addition to the brain parenchyma and the leptomeninges, primary central nervous system lymphoma (PCNSL) can involve the posterior parts of the eye with ocular lymphoma in up to 20% of patients and lead to systemic dissemination of lymphoma in 7–8% of patients. Ocular lymphoma is diagnosed by slit lamp examination and requires treatment by ocular irradiation. However, the clinical significance of systemic dissemination, which occurs mainly in the end stage of the disease, appears to be disputable. Extensive systemic staging at the time of initial presentation proved to be unrewarding in the vast majority of studies. So far, only 10 patients have been reported with occult systemic lymphoma at time of initial presentation, and systemic lymphoma determined the course of the disease in none of them. Thus, initial staging procedures for patients with biopsy-confirmed PCNSL can be restricted to regular blood tests, including HIV testing, and slit lamp examination of the eye.     

Hemorrhage and VEGF Expression in a Case of Primary CNS Lymphoma

Hemorrhage at presentation in primary CNS lymphoma is exceedingly rare. We describe a patient with primary CNS lymphoma who presented with seizures and was found to have an intracerebral hemorrhage which prompted a cerebral angiogram. Ultimately pathologic evaluation of the lesion revealed a highly cellular B-cell lymphoma with marked hypervascularity and intense expression of vascular endothelial growth factor (VEGF). A review of four other recent cases of primary CNS lymphoma at our institution revealed less-intense VEGF immunoreactivity. This is the first report of VEGF expression in primary CNS lymphoma. The potential significance of VEGF expression with respect to the biology of this tumor is discussed.     

Primary central nervous system lymphoma: a role for adjuvant chemotherapy

Summary Sixteen immunocompetent patients, 10 of whom were previously reported, with primary non-Hodgkins lymphoma of the central nervous system (PCNSL) were treated and followed longitudinally by the Neurooncology Service at the University of California, San Francisco (UCSF) and the University of California, San Diego (UCSD). After undergoing surgery (biopsy or resection), these patients received radiation therapy (RT) with hydroxyurea (HU) followed by adjuvant chemotherapy with the combination of procarbazine, CCNU, and vincristine (PCV) as previously reported. All patients ultimately died of progressive recurrent PCNSL. Toxicity using the HU + RT followed by PCV schedule was tolerable. Median and quartile survival data (41 and 65 months, respectively) suggest efficacy for this chemotherapy schedule and further emphasizes a role for adjuvant chemotherapy in the primary treatment of PCNSL.     

High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma

We conducted a prospective Phase II study of high-dose methotrexate (HD-MTX) and rituximab with deferred whole brain radiotherapy in patients with newly diagnosed B-cell primary central nervous system lymphoma with a primary objective of evaluating progression-free survival (PFS). Forty patients (25 men; 15 women), ages 18–93 years (median 61.5), were treated. All patients received biweekly HD-MTX/rituximab (8 g/m²/dose; 375 mg/m²/dose) for 4–6 cycles (induction) and following best radiographic response, with every 4 weeks HD-MTX (8 g/m²/dose) for 4 cycles (maintenance). Neurological and neuroradiographic evaluation were performed every 4 weeks during induction therapy and every 8 weeks during maintenance therapy. All patients were evaluable. A total of 303 cycles of HD-MTX (median 8 cycles; range 4–10) was administered. HD-MTX/rituximab-related toxicity included 16 grade 3 adverse events in 13 patients (32.5%). Following induction, 8 patients (20%) demonstrated progressive disease and discontinued therapy; 32 patients (80%) demonstrated a partial (8/40; 20%) or complete (24/40; 60%) radiographic response. At the conclusion of maintenance therapy (6–10 months of total therapy), 28 patients (70%) demonstrated either a partial (1/28) or complete (27/28) response. Overall, survival of these 28 patients ranged from 11 to 80 months (median 33.5). Survival in the entire cohort ranged from 6 to 80 months with an estimated median of 29 months. Overall, PFS ranged from 2 to 80 months (median 21.0). HD-MTX/rituximab and deferred radiotherapy demonstrated similar or better efficacy similar to other HD-MTX-only regimens and reduced time on therapy on average to 6 months.     

原发于上颌窦非霍奇金淋巴瘤15例临床分析

目的对原发于上颌窦非霍奇金淋巴瘤的临床、病理、治疗及预后结合文献进行分析。方法经手术后病理确诊为原发于上颌窦非霍奇金淋巴瘤15例在本院行放疗和化疗的综合治疗。放疗采用60Co-γ线或6MV~8MV高能X线,原发灶放疗中位剂量为56Gy,颈部放疗剂量为50Gy,颈部预防放疗剂量为44Gy。放射治疗前后行CHOP、COPP、COMP、BACOP等方案化疗2个~6个周期。结果5年生存率为53.4%。死亡8例,均死于远处转移。结论上颌窦非霍奇金淋巴瘤需行放射治疗和全身化疗,有条件时给予鞘内预防化疗。     

肺癌细胞间黏附分子-1的表达及其意义

目的　探讨肺癌组织 ICAM- 1与血清 s ICAM- 1的表达及其意义。方法　应用 EL ISA与免疫组化方法检测 6 8例肺癌血清 s ICAM- 1与组织 ICAM- 1表达水平。结果　癌组织 ICAM- 1表达呈阳性 7例、强阳性 19例、阴性 4 2例 ,与正常肺组织比较差异有显著性 (P <0 .0 2 5 ) ;淋巴结转移组 ICAM- 1表达阳性率高于无转移组 (P <0 .0 1) ;腺癌 ICAM- 1阳性表达率高于鳞癌 (P<0 .0 1)。肺癌血 s ICAM- 1浓度高于对照组 (P<0 .0 1) ,淋巴结转移组s ICAM- 1浓度高于无转移组 (P<0 .0 1)。 TNM分期、组织 ICAM- 1表达与血 s ICAM- 1浓度呈正相关 (P<0 .0 1)。根治术后血 s ICAM- 1浓度低于姑息术后 (P<0 .0 1)。结论　血清 s ICAM- 1水平可以反映肺癌组织的 ICAM- 1表达变化 ,并与肿瘤负荷和疾病进展相关 ,s ICAM- 1检测可作为肺癌的一项血清学动态观察指标     

The utility of body FDG PET in staging primary central nervous system lymphoma

(18)F-Fluorodeoxyglucose (FDG) PET has become an important tool in the management of non-Hodgkin's lymphoma (NHL), but its role in the evaluation of primary CNS lymphoma (PCNSL) has not been established. We investigated the ability of body FDG PET to detect systemic disease in the staging and restaging of PCNSL. The records of 166 PCNSL patients seen at Memorial Sloan-Kettering Cancer Center were examined. Forty-nine patients who underwent body FDG PET for staging of PCNSL were identified. Clinical data were reviewed to determine FDG PET results and their influence on therapy. Body FDG PET disclosed a systemic site of malignancy in 15% of patients. NHL was found in 11% of all patients, 7% of patients at diagnosis, and 27% of patients at CNS relapse. Four percent had a second systemic neoplasm. Workup with conventional staging did not reveal systemic disease, and in 8% of patients, body FDG PET was the only abnormal diagnostic exam suggestive of lymphoma. FDG PET findings altered patient treatment and resulted in additional chemotherapy, surgery, or radiotherapy. Our findings suggest that FDG PET may be more sensitive than conventional body staging and may disclose higher rates of concomitant systemic disease at PCNSL diagnosis. Body FDG PET may be an important noninvasive adjunct to conventional PCNSL staging, and its utility should be evaluated prospectively.