原发纵隔B细胞淋巴瘤研究进展

 【摘要】　新的WHO分类将原发纵隔B细胞淋巴瘤（PMBCL）归为弥漫大B细胞淋巴瘤（DLBCL）的一个独立亚型,其在发病机制、病理组织学、分子遗传学及临床特点等多个方面均与其他类型的DLBCL有所不同,与霍奇金淋巴瘤及纵隔灰区淋巴瘤又有着密切地联系,为加深临床医师对PMBCL的认识,就近年来的相关研究进行综述。     

Posttransplant primary CNS lymphoma

The records and neuro-imaging studies of 8 cases of posttransplant primary CNS lymphoma (PT-PCNSL) diagnosed at Mayo Clinic Rochester between 1970 and 1998 were reviewed retrospectively. All patients received organ transplantation. Patients who had hematologic transplantation were not included in the analysis. The median and mean age of the 4 men and 4 women was 45 years (range, 34 to 50 years). The median duration of symptoms before diagnosis was 36 days (range, 5 to 98 days). At diagnosis, the neurologic examination was focally abnormal in 6 of 8 patients. Compared with the initial computed tomographic study, MRI showed 25 additional brain lesions. Only 43.7% of lesions enhanced with contrast agent; of those that did, all but one were heterogeneous. Ependymal contact occurred in 5 patients. MRI lesion burden increased proportionally to the interval between scans. Diagnostic tissue was obtained by stereotactic biopsy from 6 patients and by open biopsy from 2. Hemorrhage occurred in the biopsy area in 4 patients who had stereotactic biopsy and 2 died (all had normal coagulation studies). Slides available for review (7 patients) showed that the tumors were of CD20-positive lineage and were positive for Epstein-Barr virus, using in situ hybridization. Six patients died. Median survival for the cohort was 13 weeks. PT-PCNSL has clinical and imaging features distinct from typical PCNSL. In our series, (1) PT-PCNSL presented nonspecifically and progressed rapidly, (2) stereotactic brain biopsy had significant morbidity, and (3) despite multimodal therapy, survival was poor.     

Non-enhancing primary CNS lymphoma

Journal of Neuro-Oncology -     

原发中枢神经系统淋巴瘤治疗进展

 【摘要】　原发性中枢神经系统淋巴瘤（PCNSL）是原发于脑、眼和脊髓的结外淋巴瘤,发病率低,老年患者多见,因其在庇护所内恶性侵袭性生长,使得治疗困难,预后不良。目前PCNSL尚无标准治疗方法,有效的治疗一般采用化疗和放疗联合的措施。手术不能完全切除病灶,仅起到诊断作用。大剂量甲氨蝶呤（HD-MTX）是最有效的药物,大剂量阿糖胞苷是常用的药物之一。PCNSL对放疗高度敏感,但单纯放疗有效维持时间短,对60岁以上患者可导致严重的远期神经毒性,影响预后,故主张延迟放疗。大剂量化疗联合自体干细胞移植通过提高剂量化疗可以克服肿瘤细胞耐药,提高药物生物利用度,替代全脑放疗,减少神经毒性。新药替莫唑胺、利妥昔单抗等对PCNSL取得一定效果,值得进一步研究。     

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.     

肝脾T细胞淋巴瘤的研究进展

肝脾T细胞淋巴瘤（HSTCL）是一种罕见的特殊类型的侵袭性外周T细胞淋巴瘤,主要表现为发热、盗汗、体重减轻及腹痛,多累及脾、肝和骨髓,通常无淋巴结肿大。因HSTCL具有异质性及侵袭性,其预后极差。目前有关HSTCL治疗的文献多数出自个案报告,缺乏随机前瞻性试验,因此暂无统一的一线疗法,大剂量化疗诱导联合异基因造血干细胞移植的方案目前较受认可。由于此病罕见且研究相对较少,本文回顾相关文献将HSTCL的病因、发病机制、临床表现及诊断治疗做一综述。     

Prophylactic intrathecal chemotherapy in primary CNS lymphoma

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.     

Post-treatment T1 shortening in primary CNS lymphoma

The incidence of primary central nervous system lymphoma (PCNSL) has increased over the past two decades. The MR imaging appearance of PCNSL plays a central role in the initial diagnosis, management and follow-up of patients. The purpose of this study was to describe the presence and frequency of the pre-contrast T1 hyperintensity (T1h) that is sometimes identified in the region of enhancing neoplastic disease following treatment of PCNSL. We also explored possible causes for this phenomenon that, to the best of our knowledge, has not been previously described. The MR imaging and relevant medical records of 221 patients with pathologically confirmed PCNSL were retrospectively reviewed. Only patients with both treatment and follow-up imaging at our institution were eligible for inclusion in the study. Patients with evidence of post-procedural blood products (pre-contrast bright T1 lesions) prior to the initiation of therapy were excluded. Out of 221 patients, 119 met the eligibility criteria and were included in this investigation. Following treatment, 75 patients (63 %) developed pre-contrast T1h not attributable to blood products. All patients with this finding had been treated with methotrexate chemotherapy. The development of pre-contrast T1h following treatment for PCNSL is common. The hyperintense T1 signal in these patients may be caused by the biochemical response of tumor cells to treatment. To assess the prognostic significance of this novel finding, additional studies focusing on disease recurrence and patient survival are warranted.     

Ocular involvement in patients with primary CNS lymphoma

To describe the demographics, clinical characteristics, and treatment outcomes in patients with primary CNS lymphoma (PCNSL) with ocular involvement. A retrospective chart review was conducted on 61 patients who were diagnosed with PCNSL from January 2000 to October 2008 at the Asan Medical Center, Seoul, Korea. Among 46 patients who underwent ophthalmologic examination, 13 (28%) showed intraocular involvement. Mean age at diagnosis was 52.8 years, and 54% of patients were female. Diagnosis of PCNSL was made by vitrectomy (1 patient) or brain biopsy and/or CSF cytology (12 patients). In 4 (31%) patients, ocular symptoms preceded CNS symptoms. The most common ocular symptom was decreased visual acuity. Nine patients showed bilateral involvement. Intraocular findings included retinal infiltrative lesions (3 eyes), vitritis/vitreous opacity (5 eyes), or both (14 eyes). In addition to systemic chemotherapy and/or radiotherapy, vitrectomy and/or intravitreal methotrexate was utilized in 8 patients. Mean survival duration was 32.2 months (range 2–120 months). Although rare, the number of patients with PCNSL seems to be increasing in Korea. Early detection and dedicated treatment of intraocular lymphoma may result in improved visual outcome.     

Pathogenesis and management of primary CNS lymphoma

Primary CNS lymphoma (PCNSL), a rare variant of extranodal non-Hodgkin's lymphoma, may cause various neurological symptoms and signs. The best therapeutic strategy is still a matter of debate. High-dose methotrexate (HD-MTX) is the most active compound and should be used as the backbone for any chemotherapy applied. Several other chemotherapeutic drugs have been assessed in combination with HD-MTX, but no standard has yet been defined. Whole-brain radiotherapy is active against PCNSL, but typically does not confer long-lasting remission and is associated with significant neurotoxicity in many patients. The recently published G-PCNSL-SG1 trial has shown that consolidating whole-brain radiotherapy after HD-MTX-based chemotherapy does not prolong overall survival and may therefore be deferred. Combined systemic and intraventricular polychemotherapy, or high-dose chemotherapy followed by stem cell transplantation may offer cures to younger patients. Improving treatment regimens without adding significant (neuro-)toxicity should be the focus of ongoing and future studies.     

Recent advances in the treatment of follicular lymphoma

The success of anti-CD20 monoclonal antibody therapy for follicular lymphoma has encouraged efforts to identify new target molecules, and a new generation of more potent antibodies is now being developed, targeting either CD20 or other molecules. At the same time, other agents that were developed to treat other kinds of malignancies have turned out to be effective against this disease. In both treatment approaches, using either antibodies or chemical compounds, data on such trials are accumulating. In this mini-review these agents are introduced, and it is noted that clinical trials of these new agents are also ongoing in Japan.     

CNS involvement in primary mediastinal large B-cell lymphoma.

PURPOSE: The risk of CNS involvement by non-Hodgkin's Lymphoma (NHL) has been associated with bone marrow and/or testicular involvement; however, it was recently reported that the number of extranodal sites is a more reliable predictor of CNS disease. Because primary mediastinal thymic large B-cell lymphoma (PMLCL) has a high propensity for involving extranodal sites, we investigated the frequency and pattern of CNS involvement in PMLCL. PATIENTS AND METHODS: The medical records of 219 patients with aggressive NHL, consecutively entered onto protocols at the National Cancer Institute between 1987 and 1998, were retrospectively reviewed. RESULTS: Twenty-three patients (11%) had clinical and pathologic features of PMLCL. These patients were young (median age, 29 years), female (61%), and presented with massive mediastinal adenopathy (70%). Extranodal disease occurred at presentation in 70% and at relapse in 93% of patients and involved contiguous intrathoracic structures and/or distant sites, including the lungs, kidneys, liver, adrenals, ovaries, pancreas, and bone. Six patients (26%) developed CNS involvement, two (9%) at presentation and four (27%) at relapse. All had extranodal disease, but only one had bone marrow involvement. Parenchymal and leptomeningeal CNS disease occurred in four and three patients, respectively. CONCLUSION: CNS involvement in PMLCL is associated with extranodal involvement other than bone marrow and may reflect the unique biology of this disease. The propensity to involve the CNS parenchyma raises the concern that intrathecal prophylaxis may not be effective and suggests that CNS imaging should be considered in patients with extranodal disease.     

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.     

Therapeutic management of primary CNS lymphoma in immunocompetent patients

The best therapeutic management in primary CNS lymphomas remains to be defined because of the small size and short follow-up of retrospective series, the methodological pitfalls and limited number of prospective studies, and the paucity of randomized trials. The purpose of this article is to analyze, discuss and summarize the current therapeutic approaches, namely chemotherapy or radiotherapy as exclusive treatment, combined treatment, most commonly used drugs, intrathecal chemotherapy and consolidation radiotherapy and to provide recommendations for ordinary clinical practice. Some important therapeutic issues such as the management of intraocular lymphomas, elderly patients and patients without histological diagnosis, as well as the relevance of salvage therapy as a playground for the evaluation of new drugs are also analyzed. Finally, the main open questions as well as current and expected investigation trends are discussed.     

High-dose methotrexate for primary CNS lymphoma in the elderly

Primary central nervous system lymphoma (PCNSL) in the immunocompetent patient reaches a peak incidence in the sixth and seventh decades of life. This retrospective study reviewed the efficacy and tolerability of high-dose methotrexate (HDMTX) in an elderly patient population. Between May 1995 and September 1998, ten consecutive elderly patients with histologically proven PCNSL were treated with HDMTX. The median age was 72.5 years and eight patients (80%) were older than 70 years. HDMTX was well tolerated with no episodes of grade 4 toxicity nor febrile neutropenia. Toxicity included grade 3 nausea (1), grade 2 mucositis (2), and grade 2 asymptomatic elevation of liver transaminases (2). Grade 1 toxicity occurred in three patients with nausea, diarrhea, and mild reversible elevation in serum creatinine in one patient each. Six patients had a complete response and three patients achieved a partial response, giving an overall response rate of 90% (95% confidence interval, 56%-100%). The median overall survival for the cohort was 36 months (range 4-43 months). In summary, HDMTX is well tolerated in this elderly population with PCNSL and achieves response rates and median survival comparable with other chemotherapy or radiotherapy regimens.     

Therapeutic management of primary CNS lymphoma in immunocompetent patients

The best therapeutic management in primary CNS lymphomas remains to be defined because of the small size and short follow-up of retrospective series, the methodological pitfalls and limited number of prospective studies, and the paucity of randomized trials. The purpose of this article is to analyze, discuss and summarize the current therapeutic approaches, namely chemotherapy or radiotherapy as exclusive treatment, combined treatment, most commonly used drugs, intrathecal chemotherapy and consolidation radiotherapy and to provide recommendations for ordinary clinical practice. Some important therapeutic issues such as the management of intraocular lymphomas, elderly patients and patients without histological diagnosis, as well as the relevance of salvage therapy as a playground for the evaluation of new drugs are also analyzed. Finally, the main open questions as well as current and expected investigation trends are discussed.     

Update on the management of primary CNS lymphoma

Primary central nervous system (CNS) lymphoma is a non-Hodgkin's lymphoma restricted to the nervous system. The incidence of this lymphoma is rising in the immunocompetent population but may be decreasing in patients with the acquired immune deficiency syndrome (AIDS) due to the introduction of highly active antiretroviral therapy. A periventricular, diffusely enhancing lesion on magnetic resonance imaging (MRI) is suggestive of primary CNS lymphoma, but a stereotactic biopsy is needed to make a definitive diagnosis. Concurrent leptomeningeal and ocular involvement is common in this brain tumor. Because primary CNS lymphoma is exquisitely sensitive to steroids, these drugs should be withheld until tissue is obtained for diagnosis. Age and performance status are important prognostic factors, regardless of specific treatment. Methotrexate in high doses is the single most effective chemotherapeutic agent for primary CNS lymphoma. It substantially improves survival when combined with radiation therapy and is better than radiotherapy alone as a single agent. Multimodality treatment results in delayed cognitive neurotoxicity, particularly in older patients. New treatment protocols have focused on the use of chemotherapy alone.