Ocular manifestations of central nervous system lymphoma

Primary intraocular lymphoma (PIOL) is a variant of primary central nervous system lymphoma in which lymphoma cells are initially present only in the eyes without evidence of disease in the brain or cerebrospinal fluid. Patients with PIOL are typically older adults who present with blurred vision and floaters. The ophthalmic examination characteristically shows a cellular infiltrate in the vitreous with or without the presence of subretinal infiltrates. Diagnostic evaluation for PIOL includes neuroimaging, cytologic examination of the cerebrospinal fluid, and a diagnostic vitrectomy with special handling of the vitreous specimen, if the former is nondiagnostic. Molecular and cytokine analyses are useful adjuncts to cytology for the diagnosis of PIOL. Recent molecular studies demonstrating viral DNA in the ocular lymphoma cells suggest a role for infectious agents in the pathogenesis of PIOL. To date, the best mode for treatment of PIOL or recurrent primary central nervous system lymphoma involving only the eyes remains undefined.     

Two Cases of Cerebral Involvement in Malignant Lymphoma (CD20+) That Responded to Combination Therapy with Rituximab and Cladribine

Cerebral involvement frequently occurs in association with progression or relapse of malignant lymphoma. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, the standard chemotherapy for malignant lymphoma, is an ineffective treatment for cerebral involvement because these drugs cannot cross the blood-brain barrier. Therefore, various alternative strategies have been attempted. Although high-dose methotrexate combined with whole-brain radiotherapy is widely used to treat primary central nervous system lymphoma, there is no standard therapy to treat cerebral involvement in malignant lymphoma. Furthermore, high-dose methotrexate in combination with whole-brain radiotherapy is not always effective, and high rates of neurotoxicity are often observed, particularly in the elderly. To expand the therapeutic options for central nervous system involvement in recent years, systemic chemotherapies, including rituximab, high-dose methotrexate, and other agents that act during the S, G2, and M phases of the cell cycle, have been attempted. In our hospital, cladribine, a purine analogue with a cytocidal effect on resting malignant cells (G0/G1 phase of the cell cycle), has been used in combination with rituximab, which exhibits antitumor effects on nodal and extranodal lesions of relapsed and/or refractory B cell lymphomas, particularly cerebral lesions. Here, we report 2 representative cases of patients who were treated with cladribine plus rituximab and survived for 30 months (died of sepsis) and 52 months (still alive), respectively. The outcomes of these cases suggest that cladribine plus rituximab combination therapy with whole-brain radiotherapy may be very useful as salvage therapy for secondary central nervous system lymphoma and as initial therapy for primary central nervous system lymphoma.Key Words: Cladribine, Rituximab, Cerebral involvement in malignant lymphoma, Purine analogue     

Primary central nervous system lymphoma: long-term survival following treatment with radiation and methotrexate

Primary lymphoma of the central nervous system is a rare disease with poor response to therapy. A 37-year-old man presented with primary cerebral lymphoma diagnosed by stereotactic brain biopsy. He was initially treated with whole brain irradiation but subsequently developed recurrent disease in the spinal cord manifested by paraplegia. Combined modality treatment with spinal cord irradiation, intrathecal methotrexate and 19 courses of high-dose systemic methotrexate with urinary alkalinization, resulted in stabilization of his neurologic status. No further disease progression has been observed and the patient remains free of disease 62 months after beginning chemotherapy. Methotrexate therapy may offer an effective means of treating recurrent primary central nervous system lymphomas.     

Diagnosis and management of primary intraocular lymphoma

Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma. The incidence of PIOL has increased in the past 20 years. PIOL often presents as chronic uveitis that is resistant to corticosteroid therapy. Diagnosing PIOL can be challenging and requires an expert pathologist. The treatment of PIOL is difficult because of its high recurrence rate and refractory nature. The objective for the future is to improve diagnostic techniques and therapeutic success while minimizing ocular toxicities.     

Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium

Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%-90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of Ig(H) or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.     

High‐resolution genomic copy number profiling of primary intraocular lymphoma by single nucleotide polymorphism microarrays

Primary intraocular lymphoma (PIOL) is a rare lymphoma. Because of difficulties in obtaining tissue samples, little is known about the disease's genetic features. In order to clarify these features, we carried out single nucleotide polymorphism array karyotyping of IOL using genomic DNA extracted from vitreous fluid. We analyzed 33 samples of IOLs consisting of 16 PIOLs, 12 IOLs with a central nervous system (CNS) lesion at diagnosis (IOCNSL), and five secondary IOLs following systemic lymphoma. All were B‐cell type. We identified recurrent copy number (CN) gain regions in PIOLs, most frequently on chromosome 1q followed by 18q and 19q. Chromosome 6q was the most frequent loss region. Although these CN gain regions of PIOL were in common with those of IOCNSL, loss of 6q22.33 containing PTPRK and 9p21.3 containing CDKN2A were more frequently deleted in IOCNSL. Large CN loss in 6q was detected in three of four PIOL patients who had early CNS development and short survival periods, whereas long‐term survivors did not have such deletions. There was a correlation between gain of the IL‐10 gene located on 1q and intravitreal interleukin‐10 concentration, which was higher in IOL than in benign uveitis. The results suggest that IOCNSL is a highly malignant form of PIOL that infiltrates into the CNS at an early stage. They also indicate that genetic differences between PIOL and primary CNS lymphoma need to be clarified.     

Eradication of tumor colonization and invasion by a B cell-specific immunotoxin in a murine model for human primary intraocular lymphoma

Human primary intraocular lymphoma (PIOL) is predominantly a B cell-originated malignant disease with no appropriate animal models and effective therapies available. This study aimed to establish a mouse model to closely mimic human B-cell PIOL and to test the therapeutic potential of a recently developed immunotoxin targeting human B-cell lymphomas. Human B-cell lymphoma cells were intravitreally injected into severe combined immunodeficient mice. The resemblance of this tumor model to human PIOL was examined by fundoscopy, histopathology, immunohistochemistry, and evaluated for molecular markers. The therapeutic effectiveness of immunotoxin HA22 was tested by injecting the drug intravitreally. Results showed that the murine model resembles human PIOL closely. Pathologic examination revealed that the tumor cells initially colonized on the retinal surface, followed by infiltrating through the retinal layers, expanding preferentially in the subretinal space, and eventually penetrating through the retinal pigment epithelium into the choroid. Several putative molecular markers for human PIOL were expressed in vivo in this model. Tumor metastasis into the central nervous system was also observed. A single intravitreal injection of immunotoxin HA22 after the establishment of the PIOL resulted in complete regression of the tumor. This is the first report of a murine model that closely mimics human B-cell PIOL. This model may be a valuable tool in understanding the molecular pathogenesis of human PIOL and for the evaluation of new therapeutic approaches. The results of B cell-specific immunotoxin therapy may have clinical implications in treating human PIOL.     

原发性中枢神经系统弥漫性大B细胞淋巴瘤临床病理诊断并相关文献复习（附4例）

目的:探讨原发性中枢神经系统弥漫性大B细胞淋巴瘤(primary central nervous system diffuse large B cell lymphoma,PCNS-DLBCL)的临床病理学特点。方法:对4例原发性中枢神经系统弥漫性大B细胞淋巴瘤的临床表现、大体、组织学特征及免疫组化等进行观察，并复习相关文献。结果:患者男性1例，女性3例，平均年龄56.25岁；病变均位于幕上，临床表现多样，MRI表现具有一定特异性。肿瘤细胞呈圆形、卵圆形，中等偏大，可见核仁，核分裂象多见，可见病理性核分裂，有坏死，肿瘤细胞亲血管生长形成淋巴细胞血管套。免疫组化示肿瘤细胞表达B细胞相关抗原，4例均表达CD20(+），Ki-67平均增殖指数为 70%。结论:原发性中枢神经系统弥漫性大B细胞淋巴瘤是一种罕见恶性肿瘤，预后差，诊断应结合临床资料及影像学检查，并需与多种良、恶性肿瘤相鉴别。目前治疗首选大剂量甲氨蝶呤为基础联合利妥昔单抗的化疗方案，辅以全脑放疗、自体干细胞移植等巩固治疗。     

原发性睾丸淋巴瘤及原发性中枢神经系统淋巴瘤研究进展：第19届欧洲血液学会年会报道

原发性睾丸淋巴瘤（PTL）是一类少见的结外淋巴瘤,进展迅速,预后不良.对于早期局限性病变,可联合应用以蒽环类为基础的化疗、利妥昔单抗、鞘内注射甲氨蝶呤后行对侧睾丸放疗等.中枢神经系统复发风险极高,鞘内注射甲氨蝶呤可能是最好的防治方法.原发性中枢神经系统淋巴瘤（PCNSL）是一种侵袭性淋巴瘤,预后较差,对现有非霍奇金淋巴瘤标准治疗方案均不敏感,甲氨蝶呤联合阿糖胞苷是目前的标准诱导方案.抗CD20单克隆抗体虽然脑脊液含量低,但仍有治疗效果.高剂量化疗联合自体造血干细胞移植缓解率高,3年总生存率可达87％.     

Primary intraocular lymphoma: a review

Primary intraocular lymphoma (PIOL) is a rare, non-Hodgkin lymphoma considered to be a subtype of primary central nervous system lymphoma. We describe a 65-year-old woman who presented to the Hematology/Oncology Clinic at Scripps Clinic, La Jolla, California, who was diagnosed with bilateral PIOL without systemic disease. She enjoyed a 16-month remission but ultimately recurred in the brain. We reviewed the literature and present a discussion of the diagnostic criteria for PIOL and current strategies for treating PIOL in immunocompetent patients.     

High‐dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma

In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high‐dose MTX on treatment‐naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high‐dose MTX (3.5 g/m²) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin‐10 concentration. Adverse events of intravitreal and systemic high‐dose MTX were mild and tolerable. With a median follow‐up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma‐free survival (CLFS) time was 51.1 months. Two‐year CLFS, which was the primary end‐point of the study, was 58.3% (95% confidence interval, 23.0–82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2‐year CLFS was 37.5% (95% confidence interval, 8.7–67.4%). In conclusion, systemic high‐dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).     

Challenges in the management of Burkitt's lymphoma

Burkitt's lymphoma and small noncleaved Burkitt's-like lymphoma are rare and are highly aggressive forms of non-Hodgkin's lymphoma that are characterized by dysregulation of the c-myc oncogene. Patients with human immunodeficiency virus (HIV) also appear to be at risk for developing Burkitt's lymphomas. Treatment options for Burkitt's lymphoma involve complex chemotherapy regimens that contain as many as 10 cytotoxic agents. Approximately 50%-80% of adult patients with Burkitt's lymphoma or small, noncleaved lymphoma can be cured with these intensive chemotherapy regimens, and in pediatric populations, the cure rate is even higher. However, a number of factors often compromise the outcome of patients with Burkitt's lymphoma. For instance, the high proliferation rate of Burkitt's lymphoma enhances the risk for tumor lysis syndrome, which results from metabolic imbalances, such as hyperuricemia, that occur as large numbers of malignant cells are lysed during cytotoxic chemotherapy. Standard treatment for tumor lysis syndrome includes adjustments in the chemotherapy regimen, vigorous hydration, administration of a uric acid synthesis inhibitor like allopurinol, and alkalinization. The administration of recombinant urate oxidase (rasburicase) also has been shown to provide effective prophylaxis against hyperuricemia in pediatric and adult patients with hematologic malignancies. The lifetime risk of developing central nervous system disease is 20%-30% for Burkitt's lymphoma. Consequently all chemotherapy regimens with activity in Burkitt's lymphoma utilize some form of central nervous system prophylaxis, such as systemic or intrathecal methotrexate or cytarabine. In the past, patients with HIV who developed Burkitt's lymphoma often received inadequate chemotherapy doses because of their immunosuppression. With the discovery of highly active antiretroviral therapy, the ability to treat and control Burkitt's lymphoma in patients with HIV has improved.     

Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report.

BACKGROUND: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. PATIENTS AND METHODS: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. RESULTS: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. CONCLUSION: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.     

Treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) describes a malignant non-Hodgkin's lymphoma (NHL) whose sole site of involvement is the central nervous system (CNS). The diagnosis of PCNSL must be differentiated from systemic NHL with metastasis to the CNS, which usually occurs late in the course of systemic disease. PCNSL accounts for approximately 4% to 7% of primary brain tumors, and its incidence has been increasing since the mid-1970s. Compared with other more common malignant primary brain tumors, PCNSL tends to be more amenable to radiotherapeutic and chemotherapeutic intervention. In this article, the authors review the standard treatment for upfront and recurrent PCNSL.     

Therapie von ZNS-Lymphomen

Primary central nervous system lymphoma (PCNSL) differs from nodal lymphoma with similar histological findings, usually diffuse large B-cell lymphoma, by its strong affinity for the central nervous system (CNS), aggressive course and unusual sensitivity to high-dose methotrexate (HDMTX). Thus, primary therapy of PCNSL is currently based on HDMTX but the optimal chemotherapy regimen has not yet been defined due to the rarity of this disease. In younger patients a cure should be the goal and thus intensified chemotherapy protocols should be considered. Whole brain irradiation does not prolong overall survival when used in primary therapy and thus should not be used routinely. Similar to PCNSL the infrequent CNS involvement of a systemic lymphoma, also called secondary CNS lymphoma, has a very poor prognosis. The scarce data suggest a role for HDMTX-based systemic chemotherapy and high-dose chemotherapy followed by stem cell transplantation for outcome improvement. Avoidance of late neurotoxicity is an important goal in the treatment of PCNSL.     

Treatment of relapsed central nervous system lymphoma with high-dose methotrexate.

PURPOSE: Over the past decade, high-dose methotrexate has emerged as the single most effective agent in the initial treatment of primary nervous system lymphoma. However, the majority of patients who respond initially to treatment relapse. The optimal management of these patients has not been determined. We performed a multicenter, retrospective study of high-dose methotrexate in patients with relapsed central nervous system lymphoma. EXPERIMENTAL DESIGN: Patients with relapsed disease were eligible if they achieved a complete response to initial treatment with methotrexate-based chemotherapy or received methotrexate after gross total resection or interstitial radiation. All of the patients were retreated with a regimen containing high-dose methotrexate (>/=3 g/m(2)). RESULTS: Twenty-two patients with a median age of 58 years were included in the study. Overall response rates were 91% to first salvage (20 of 22 patients) and 100% to second salvage (4 of 4 patients). Median survival was 61.9 months after first relapse (95% confidence interval, 42.1- infinity ) and 91.9 months overall (95% confidence interval, 47.2- infinity ). Toxicity was primarily hematologic with 10 episodes of grade 3 or 4 toxicity during 566 cycles of chemotherapy. CONCLUSIONS: These results indicate that high-dose methotrexate remains effective for relapsed central nervous system lymphoma in patients who initially respond to methotrexate and raise the possibility of deferring more toxic salvage regimens in this select group of patients.     

原发性中枢神经系统淋巴瘤的治疗

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,总体预后欠佳,主要治疗方法包括手术、放疗和化疗.立体定向活检术以其微创、便捷的优点,已经成为确诊PCNSL的常规方法.全脑放疗是多病灶性PCNSL的标准化治疗方法,可短期内延缓肿瘤进展.以大剂量甲氨蝶呤为基础的治疗方案大大改善了PCNSL的治疗效果,成为PCNSL的有效治疗措施.有效的综合治疗是延长PCNSL患者生存期和改善生命质量的关键.     

原发性中枢神经系统淋巴瘤的治疗进展

原发性中枢神经系统淋巴瘤（PCNSL）是一种少见疾病,至今尚无标准治疗方案。单纯放疗复发率高,生存期短。放疗宜在化疗结束后进行。化疗联合标准放疗明显降低了复发率,并延长了生存期,但神经毒性发生率高。老年患者易出现神经毒性,不建议放疗,应首选单纯化疗;年轻患者可将放疗作为难治复发时的二线治疗。目前,以大剂量甲氨蝶呤为主的化疗已成为PCNSL的一线治疗,大剂量阿糖胞苷为最常联合的药物。年轻患者可选用包含一些新药如甲基苄肼、替莫唑胺的化疗方案。替莫唑胺为老年患者一种有前途的新药。预防性鞘内化疗的必要性尚未达成共识。自体造血干细胞支持下的大剂量化疗对年轻的初发及复发PCNSL患者均有效。手术通常用于PCNSL诊断。糖皮质激素不宜在取得病理组织前使用。      

Primary central nervous system lymphomas

Opinion statement Primary central nervous system lymphoma (PCNSL) is widely regarded as one of the primary brain tumors most amenable to treatment. Although whole brain radiotherapy was the cornerstone of therapy for decades, recent work clearly indicates that chemotherapy has become the primary focus of treatment for this disease. The initial treatment of PCNSL for all patients, including the elderly, should be chemotherapy using a high-dose methotrexate-based regimen. Although cranial irradiation has often been combined with methotrexate, the unacceptably high incidence of late neurotoxicity, particularly in older patients, has caused many to eliminate radiotherapy, especially in those older than age 60 years. Emerging data support the validity of this approach, and the development of more efficacious chemotherapeutic regimens has been the focus of recent research.