Updates on Primary Central Nervous System Lymphoma

Purpose of Review

Primary central nervous system lymphoma (PCNSL) is an aggressive malignancy confined to the brain, spinal cord, leptomeninges, and eyes. Due to its rarity, there is a paucity of randomized trials and a varied approach to its management in the oncologic community. This review summarizes recent literature guiding current clinical practice.

Recent Findings

The presentation, work up, and management of PCNSL are discussed. Induction therapy incorporates a methotrexate-based chemotherapy regimen and is generally followed by a consolidation regimen including high dose chemotherapy (with or without autologous stem cell rescue). Whole brain radiation therapy (WBRT) is a potential additional consolidation strategy. Management of relapsed and refractory disease poses a special challenge due to poor outcomes. Immunotherapy and targeted treatments are promising novel strategies for recurrent/refractory patients.

Summary

Currently, there is little consensus in the management of PCNSL. Treatment recommendations should be tailored to the individual patient, with consideration for risk of neurotoxicity. New, exciting strategies are in development and when feasible, enrollment in a clinical trial should be considered.

     

中枢神经系统原发性恶性淋巴瘤──附24例临床光镜、电镜及免疫组化研究

本文报告２４例原发于中枢神经系统的恶性淋巴瘤（ＭＬＣＮＳ）。以光镜、电镜和免疫组化进行观察，所得结果与临床资料、随访等对比分析，发现该瘤早、中期瘤细胞围血管分布，并沿Ｖｉｒｃｈｏｗ－Ｒｏｂｉｎ（ＶＲ）间隙扩展；晚期病变弥漫，但不均匀，无滤泡形成，瘤细胞彼此不粘聚。免疫标记及电镜检查，多数为Ｂ细胞起源，少数为组织细胞起源。临床以颅内压增高症状为主，病程多较短。ＣＴ示单灶，少数为多灶病变，呈高密、等密或疏密混合块影，周围可见轻度水肿带，常拟诊为胶质瘤或转移瘤而手术。随访结果表明，该瘤预后差，多于短期内死亡，且较颅外相同的组织学类型更差。另就病因、起源及病理鉴别诊断作了讨论。     

原发性中枢神经系统淋巴瘤诊治进展

原发性中枢神经系统淋巴瘤(primarycentralnervoussystemlymphoma,PCNSL)是原发于脑、眼和脊髓的非霍奇金氏淋巴瘤,临床上较罕见,近数十年来发病率逐渐上升。PCNSL多见于老年患者,病理类型、预后因素和治疗方案有别于全身性非霍奇金淋巴瘤(NHL)。PCNSL病理类型以弥漫大B细胞为主,年龄和(performancestatus)PS是最重要的预后因素,预后较全身性NHL差。目前PCNSL尚无标准治疗方法,一般采用化疗和放疗联合的治疗措施。手术仅起到诊断作用。PCNSL对放疗高度敏感,但单纯放疗有效维持时间短。化疗在治疗PCNSL中不可缺少,但CHOP方案对PCNSL无效。大剂量甲氨蝶呤(HD-MTX)是最有效的药物,大剂量阿糖胞苷(HD-AraC)是常用的药物之一。因此,现阶段PCNSL采用含HD-MTX或/和HD-AraC等的联合化疗,同时鞘内注射MTX、AraC和地塞米松(DXM)。放疗疗效差,放疗应在化疗结束后进行。联合化、放疗对60岁以上患者可造成严重的远期神经毒性,对老年患者可选择单纯化疗和延迟放疗的治疗方法。自体造血干细胞支持下超大剂量化疗疗效优于历史对照。新药Temozolomide、Temozolomide联合美罗华、Topotecan、放射免疫治疗药物Y90标记CD20单抗等对PCNSL取得一定效果,值得进一步研究。     

Pituitary Stalk Thickening and Primary Central Nervous System Lymphoma

We report a 14-year-old girl in whom a diagnosis of primary central nervous system lymphoma was confirmed while receiving growth hormone (GH) for GH deficiency, detected after presenting with short stature. MRI revealed an enhancing and thickened pituitary stalk with absence of the normal bright signal in the posterior pituitary. Regular MRI surveillance detected progression of the neurohypophyseal changes 13 months into GH treatment. Biopsy confirmed this to be B-cell large cell lymphoma. This case highlights the diagnostic and management challenges inherent in treating such children.     

Ongoing Protocols for Non-AIDS Primary Central Nervous System Lymphoma

The optimal treatment for primary central nervous system lymphoma (PCNSL) remains undefined. In this paper, we review the main multi-institutional ongoing protocols for PCNSL. Most of the current protocols evaluate the efficacy of combination high-dose methotrexate-based chemotherapy and brain irradiation in phase II studies. Some trials focus on chemotherapy alone as initial treatment, in order to minimize long-term cognitive sequellae. Because old age appears as a major predisposing factor for combined RT and CT neurotoxicity some specific protocols have been proposed to this particular population.     

原发性中枢神经系统淋巴瘤研究进展

原发性中枢神经系统淋巴瘤(Primary Central Nervous System Lymphoma,PCNSL)是一种比较罕见的结外淋巴瘤。好发于免疫缺陷的人群中。但近年来在免疫力正常人群中发病率不断增加,目前其发病机制仍有争论。其病理形态与颅外淋巴瘤相似,病理类型一般为中高度恶性非霍奇金淋巴瘤(NHL),多为弥漫型大B细胞来源,来源于T细胞的比较少见。影像学表现为单发或多发的深部脑实质或血管周围病变及脑膜等处的病变。CT平扫呈圆形或卵圆形等密度占位病变,边界相对清楚,周围有水肿带,应与胶质瘤、脑膜瘤、转移瘤鉴别。脑脊液淋巴细胞亚群的流式分析能够对诊断脑膜淋巴瘤有所帮助。在临床表现方面与其它颅内肿瘤无明显差异。放化疗综合治疗有可能提高治愈率。化疗采用以MTX为主的化疗,全脑放疗已被公认为治疗PCNSL的有效手段。放、化疗的顺序在一定程度上可能影响患者的生存期,目前推荐采用先放后化的治疗方法。预后取决于多种因素如年龄、确诊时间、病变部位、肿瘤组织类型、治疗措施的选择、患者有否免疫抑制状态等。     

A New Xenograft Model of Primary Central Nervous System Lymphoma

The management of primary lymphoma of the central nervous system (PCNSL) remains controversial and patients' outcome dismal. In order to investigate new selective therapeutic strategies in a controlled system, a reproducible model of PCNSL in nude rats was developed and characterized. Human B lymphoma cells (BL2) were implanted in the brain frontal area in New Zealand nude rats through a silastic device sealed to the skull. Fifteen and 30 days post-implantation, animals were sacrificed. An autopsy was performed. Representative brain sections were cut and examined for the presence of lymphoma. Immunohistochemistry was performed for proliferation (MIB1-Ki67), a B-cell marker (L26-CD20), a T-cell marker (UCHL1-CD45RO).The analysis of the brains showed tumor growth in 88% of the rats. No mortality was observed. At autopsy no extracerebral, spinal or cerebellar metastasis were found. Microscopically the brain tumors appeared non-encapsulated, highly vascularized, with a characteristic perivascular and diffuse lymphomatous spread in the parenchyma. Immunohistochemistry showed a marked positivity of the tumor cells for L26. Tumor cells were negative for UCHL1. Mean proliferation rate was 30%. The device was well tolerated and caused no local infection. Controlled studies on PCNSL in animal models are lacking. This PCNSL model in nude rats reproduces the histology and location of human CNS lymphoma. Tumor dimensions are within the resolution limits of CT and MRI and therefore suitable for stereotactic therapy. This model provides a tool to test new chemo and radiotherapeutical strategies in a controlled fashion.     

Management of Immunocompetent Patients With Primary Central Nervous System Lymphoma

Primary central nervous system (CNS) lymphoma (PCNSL) is a non-Hodgkin lymphoma that arises within and is confined to the CNS. Recent data have suggested an increasing incidence in immunocompetent individuals, with a peak of incidence between 60 and 70 years of age. Patients with PCNSL present mostly with symptoms of increased intracranial pressure. The clinical management of these patients remains controversial, and the optimal treatment for patients with PCNSL has not yet been defined. Surgery, even if macroscopically radical, does not improve survival because of the multifocal and infiltrative nature of PCNSL; furthermore, the deep location of most of these tumors makes patients susceptible to serious and irreversible neurologic sequelae. Corticosteroids have a specific role in the treatment of patients with PCNSL, whose disease is sensitive to them as a chemotherapeutic agent. PCNSL is an extremely radiation-sensitive neoplasm; whole-brain radiation therapy plus corticosteroids was the first modality of treatment for patients with this neoplasm until 10 years ago, with a low cure rate and a high local recurrence rate. PCNSL is also a chemosensitive neoplasm; while the optimal choice, sequence, and combination of appropriate agents for efficacious treatment of patients with PCNSL has yet to be determined. An essential component of therapy must include an adequate drug delivery behind a normal blood-brain barrier. Methotrexate is the agent with the most proven activity in PCNSL. Combined-modality therapy has improved survival, but relapse is still common, and late neurologic toxicity is a significant complication, especially in older patients, who represent the majority of immunocompetent patients with PCNSL.     

Advances in the Therapy of Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma (NHL) confined to the nervous system. The management of PCNSL is quite different from the usual treatment of either primary brain tumors or systemic NHL. First-generation chemotherapy regimens used successfully in systemic NHL are ineffective in PCNSL, in large part due to the existence of the blood-brain barrier. Whole-brain radiation therapy (WBRT) results in high response rates but rapid relapse, and this treatment is associated with delayed neurotoxicity in patients with PCNSL. The addition of methotrexate-based chemotherapy has improved survival and lessened toxicity for this patient population. Fundamental issues that remain unresolved in PCNSL include identification of the optimal chemotherapy regimen for newly diagnosed and relapsed PCNSL, the role of WBRT and intrathecal chemotherapy in the treatment of PCNSL, and the optimal management of intraocular lymphoma. Finally, the optimal clinical study design for this rare disease has yet to be defined and implemented.     

34例原发性中枢神经系统恶性淋巴瘤临床分析

目的:分析免疫功能正常的中国人原发性中枢神经系统淋巴瘤(PCNSL)的临床资料,探讨PCNSL的临床特征,评价大剂量甲氨蝶呤(HD-MTX)加全脑放疗(WBRT)治疗PCNSL的疗效。方法:回顾性分析34例经病理证实的PCNSL患者的临床资料以及治疗效果,Kaplan-Meier法分析患者生存期。结果:34例PCNSL患者中B细胞淋巴瘤31例(91.2%),T细胞淋巴瘤3例(8.8%);所有患者治疗后评价完全缓解率(CR)41.2%,2年生存率60.2%;病理类型和是否接受HD-MTX加放疗是影响PCNSL生存期的主要原因(P<0.05)。结论:PCNSL以颅内高压为主要表现,B细胞亚型占绝对优势,具有独特的预后因素,HD-MTX联合放疗是PCNSL有效的治疗方法。     

31例原发性中枢神经系统恶性淋巴瘤临床分析

目的：分析免疫正常的原发性中枢神经系统恶性淋巴瘤患者的临床表现、影像学特点和病理表现并探讨其诊断、治疗方法方法：回顾分析1995年7月至2006年6月经病理证实的31例原发中枢神经系统恶性淋巴瘤病例的临床、实验室检查、影像学、病理结果及治疗效果．18例采用手术＋放疗＋化疗方法．5例单纯手术；台疗、其中化疗CH（）P方案11例，替尼泊苷（VM26）＋司莫司汀（me-CCNU）7例结果：原发性中枢神经系统恶性淋巴瘤临床表现复杂，无特异性，主要为颅内压增高和神经功能缺损为主，误诊率高脑脊液检查无阳性结果．31倒均为B细胞淋巴瘤31倒中获随访24例．随访时间6～98个月，其中手术＋放疗＋化疗组中位生存期20个月，单纯手术组中位生存期10个月结论：原发性中枢神经系统恶性淋巴瘤缺乏特异性临床表现，术前难以确诊，预后不良病理检查是确诊的唯一方法。应采取综合治疗手术的主要目的是解除肿瘤引起的颅内高压，单纯手术后，短时间内复发．应该采取手术、放疗、化疗综合治疗．这是延长生存期和改善生存质量的关键     

Primary Central Nervous System Lymphoma: From Clinical Presentation to Diagnosis

Immunocompetent patients with primary central nervous system lymphoma (PCNSL) present with a median age of 55 years, immunosuppressed patients with a median age of 40 years. They show a broad range of signs and symptoms. Symptoms of increased intracranial pressure and personality change are most frequent, followed in frequency by ataxia and hemiparesis. The median time from onset of symptoms to diagnosis is 3–5 months in immunocompetent patients and 2 months in immunodeficient patients. The time to diagnosis can be considerably longer in patients with slowly developing personality change or fluctuating symptoms due to spontaneous or steroid-induced remission of so-called sentinel lesions. Native CT scans show iso- or hyperdense lesions with homogenous contrast enhancement. T1-weighted MRI scans show hypointense and T2-weighted scans hyperintense lesions. The definitive diagnosis of PCNSL requires biopsy. In some cases, however, the definitive diagnosis may exclusively be made by the demonstration of malignant B-lymphocytes in the cerebrospinal fluid.     

原发性中枢神经系统淋巴瘤的MRI 诊断

 目的 评价MRI在诊断原发性中枢神经系统淋巴瘤中的作用。方法 回顾性分析7例经病理证实的原发性中枢神经系统淋巴瘤的MRI表现。结果 本组病例均为B细胞型非霍奇金淋巴瘤，其中单发5例，多发2例。MRI表现为均匀的长T1、长T2信号，病灶内无明显坏死囊变灶，瘤周水肿相对较轻，占位效应轻，中线结构移位不明显，增强后病灶呈明显均匀性强化。结论 原发性中枢神经系统淋巴瘤无典型的MRI表现，发病部位相对较深，肿瘤大小与占位效应不成比例，增强时病灶实质均匀性强化且无坏死囊变，最后确诊有赖于病理的免疫组化检查。     

原发中枢神经系统淋巴瘤17例临床分析

目的:原发性中枢神经系统淋巴瘤(PCNSL)是一种较少见的中枢神经系统恶性肿瘤.近年发病率有逐年增高的趋势,本文探讨其临床特点、诊治方案及临床疗效.方法:总结1999年9月～2007年12月收治的17例患者(男性8例,女性9例,年龄19～80岁),均经病理证实为B细胞来源非霍奇金淋巴瘤.全部患者接受放疗,其中15例放疗后接受化疗等综合治疗.结合文献对原发性中枢神经系统淋巴瘤患者的临床特点、病理学检查、影像学表现、治疗及预后进行回顾性分析.结果:本病以中老年人多见,发病急,病程短,病情进展快.临床表现复杂,颅内高压为主要临床表现之一.头颅CT以及MRI检查显示中枢侵及额叶多见,CT扫描多表现为较高密度肿块,MRI显示T1加权像多呈低信号,T2加权像多呈高信号.CT和MRI增强扫描病灶多呈均匀明显强化,可单发或多发,极少发生出血、钙化或囊变.PCNSL主要起源于B细胞,包括手术、放疗、化疗和免疫治疗的综合治疗效果较好.17例患者随访7～65个月,中位时间17个月,平均生存23.9个月.1、3年生存率分别为76.5%和23.5%,5年生存率仅有5.9%.结论:PCNSL是一组异质性肿瘤,侵袭性强,预后差,伴脊髓侵犯者则预后更差.其临床、影像学表现复杂多变,无特异性,术前诊断困难.确诊主要依靠病理检查,三维立体定向穿刺活检(定向活检)可显著提高诊断效率.其病程短,疗效不理想,最佳治疗方案是手术加放疗、化疗的联合治疗.虽然对放射及化学药物治疗敏感,但缺乏共识方案,较全身及其他部位淋巴瘤预后差.中等剂量放疗加足疗程化疗是有效的治疗方法,增加放射剂量未能改善肿瘤控制.综合治疗是提高本病疗效的关键.