原发中枢神经系统恶性淋巴瘤的诊断及治疗

目的:探讨原发中枢神经系统恶性淋巴瘤(PCNSL)的临床、影像学表现,治疗方案选择和预后. 方法: 对24例PCNSL的诊断、治疗过程、预后进行回顾性分析. 结果: PCNSL的临床表现以颅内压增高、局灶占位性病变损伤症状为主,肿瘤可单发或多发;肿瘤影像学缺乏特异性,确诊依靠病理学诊断. 结论: PCNSL恶性度高,预后不良,手术全切率低;对确诊病例采用个体化的手术方案结合术后放、化疗是治疗本病的关键,可显著延长患者生存时间.     

原发性中枢神经系统淋巴瘤临床病理及免疫组化研究

[目的]探讨原发性中枢神经系统恶性淋巴瘤(PCNSI。)的病理学特点。[方法]收集10例PCNSL病人的临床资料，并进行病理形态及免疫组化分析。[结果]PCNSL病理形态及免疫组化结果提示均为B细胞性淋巴瘤，其中8例为弥漫性大B细胞淋巴瘤，2例为小淋巴细胞性淋巴瘤。[结论]PCNSL是少见的颅内肿瘤，绝大部分为B细胞性，其亲血管性常形成血管袖套状结构。免疫组化在诊断与鉴别诊断中起着重要作用。     

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.     

Primary central nervous system lymphoma with systemic metastasis: Case report and review

Summary Primary central nervous system lymphoma (PCNSL) almost always remains confined to the nervous system. We report a patient with well documented PCNSL who responded to treatment, but subsequently developed pathologically confirmed systemic metastases without repeated local failure 35 months after initial diagnosis. In a review of the world's literature we identified 5 other cases of PCNSL with histologically confirmed antemortem systemic metastases and a total of 62 cases of central nervous system (CNS) lymphoma in some way associated with extraneural lymphoma. These cases are classified and discussed. Clinicians caring for PCNSL patients must remain alert to the possibility of systemic metastasis, especially as local control of PCNSL improves.     

Meeting report: primary central nervous system lymphoma: standards of care and future perspectives

A standard of care for patients with primary central nervous system lymphoma (PCNSL) has not been defined. Current controversies concern, amongst others, the role, dose and timing of radiotherapy, the role of intrathecal chemotherapy and the delineation of age-specific standards of care. Given the strong clinical trial activities for PCNSL in Germany, the PCNSL conference held in Tubingen aimed at comparing the diverging trial strategies in Germany and at exploring the options for joint activities of the various PCNSL study groups in the near future.     

Classification,Pathogenesis and Molecular Pathology of Primary CNS Lymphomas

Classification, pathogenesis and molecular pathology of primary central nervous system lymphomas (PCNSL) pose major clinico-pathologic problems. Application of histopathologic classification schemes developed for nodal lymphomas, i.e. the Kiel Classification and the Working Formulation, is not reliable and clinically not relevant for PCNSL. The more recent REAL Classification will simplify subtyping of PCNSL, but reliability and clinical significance remain to be determined. There are virtually no experimental data on whether PCNSL develop outside of the brain, or whether they arise from polyclonal lymphoproliferations within the brain. Mutations of oncogenes and tumor suppressor genes have been analyzed in only a few tumors, and their type and frequency is essentially unknown. In conclusion, compared with both neuroectodermal brain tumors and nodal lymphomas, and given the increasing incidence and clinical impact of PCNSL, there is a remarkable lack of histopathologic consensus as well as a surprising shortage of pathogenetic and molecular genetic information.     

原发中枢神经系统恶性淋巴瘤的诊断及治疗

目的：探讨原发中枢神经系统恶性淋巴瘤（PCNSL）的临床、影像学表现,治疗方案选择和预后。方法：对24例PCNSL的诊断、治疗过程、预后进行回顾性分析。结果：PCNSL的临床表现以颅内压增高、局灶占位性病变损伤症状为主,肿瘤可单发或多发;肿瘤影像学缺乏特异性,确诊依靠病理学诊断。结论：PCNSL恶性度高,预后不良,手术全切率低;对确诊病例采用个体化的手术方案结合术后放、化疗是治疗本病的关键,可显著延长患者生存时间。     

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.     

Incidence, clinical features, treatment and outcome of primary central nervous system lymphoma in Norway

The incidence of primary central nervous system lymphoma (PCNSL) has been reported to increase in some parts of the world, while being stable in other regions. In an attempt to characterize the incidence rate, clinical features, treatment, outcome, and prognostic factors of PCNSL in Norway, we report our experience in a large unselected series of patients. Clinical features, histological diagnosis, radiological findings, treatment, and outcome of all patients diagnosed with PCNSL in Norway in the years 1989-1998 were registered. During the 10-year period 58 new cases of histologically verified PCNSL were registered in Norway. The annual incidence rate of PCNSL was on average 1.34 cases per million people with a non-significant increasing trend (p=0.069). For patients diagnosed before death (n=45) the estimated survival following histological diagnosis was 55%, 47%, and 23% at 1, 2, and 5 years, respectively. In Cox-regression analysis age, WHO performance status and treatment had independent prognostic impact on survival. In the studied decade, there was a non-significant trend towards increased incidence of PCNSL, perhaps due to increased availability of diagnostic imaging, especially magnetic resonance imaging.     

A case with coincidental diagnosis of primary central nervous system lymphoma and lymph node sarcoidosis

Primary central nervous system lymphoma (PCNSL) is rare. Clinical and histological differential diagnosis of systemic lymphoma and sarcoidosis continues to be a challenge. The first case report in the German and English literature of PCNSL and synchronous sarcoidosis is presented. Synchronous mediastinal lymphadenopathy suggestive of non-Hodgkin’s lymphoma (NHL) or sarcoidosis was noted. Both conditions require alternative therapeutic and prognostic considerations to PCNSL. A regime of intrathecal and adjuvant systemic chemotherapy led to transient clinical improvement prior to the patient’s demise through overwhelming sepsis and multiorgan failure. Post mortem findings confirmed synchronous PCNSL with mediastinal lymph node sarcoidosis.     

Epstein–Barr virus (EBV)-associated primary central nervous system lymphoma: is incidence of EBV expression associated with median survival time?

The frequency and clinical features of Epstein–Barr virus (EBV)-associated primary central nervous system lymphoma (PCNSL) in elderly patients were investigated in this study. Thirty-three PCNSL cases were enrolled in the retrospective study. Biopsies were performed, and tissue was embedded in paraffin and sectioned. In-situ hybridization of EBV-encoded small RNAs was then conducted. Specimens were scored as having one of three possible results: negative (no EBV-positive cells), slightly positive (<50% EBV-positive cells), and strongly positive (>50% EBV-positive cells). Fifteen cases were negative for EBV expression. Sixteen cases were slightly positive, and two cases (68 and 79 years of age) were strongly positive. The incidence of strongly positive EBV expression in PCNSL was 6.1%. The incidence of strongly positive EBV expression in PCNSL patients ≥65 years of age was 13%. Median survival time differed significantly among PCNSL patients treated with high-dose methotrexate and radiotherapy. Importantly, the strongly EBV-positive PCNSL cases had the worst outcomes, and the EBV-negative PCNSL cases had the best outcomes. These results suggest that EBV infection may affect the treatment outcome of PCNSL. In the future, examination of EBV expression in PCNSL patients who receive individualized treatment may be useful.     

Pathology and genetics of primary central nervous system and intraocular lymphoma

Ongoing studies based on gene expression profile analysis using microarrays have provided preliminary evidence for significant molecular distinctions between primary central nervous system lymphoma (PCNSL) and nodal lymphomas of the large B-cell type. The application of array-based comparative genomic hybridization techniques attempts to identify genomic distinctions between PCNSL and nodal lymphomas and to identify the molecular markers that relate to prognosis. It is possible that insights gained from these studies will facilitate the development of targeted therapies, which address the fundamental genetic mutations that drive PCNSL and intraocular lymphoma growth.     

Primary brain lymphomas in patients with a prior or concomitant malignancy

The increased incidence of second malignancies among cancer survivors is well documented. Thus, differential diagnosis between metastatic spread from a prior malignancy and the occurrence of a new neoplasm should be considered. This isparticularly difficult for brain lesions due to their poor prognosis that often discourages diagnostic work-up. In some cases diagnosisof a second primary neoplasm, such as primary central nervoussystem lymphomas (PCNSL), could change the therapeutic managementand the prognosis. About 8% of PCNSL occurs as a second malignancy.Homogeneous and intense tomographic enhancement, deep location of lesions and dramatic response to corticosteroids are suggestive for PCNSL and should be carefully considered before the startof treatment for cerebral lesions. Prognosis and standard management of brain metastases and PCNSL are almost completely different. In addition, while treatment of brain metastases oftenhas a palliative purpose the goal in PCNSL treatment is the cure.Four patients with PCNSL as a second malignancy are reported and literature is reviewed. Diagnosis of PCNSL changes the strategyof treatment which could have a critical therapeutic and prognosticimpact.     

原发性中枢神经系统淋巴瘤的诊断和治疗

原发性中枢神经系统淋巴瘤(PCNSL)是一种较罕见的中枢神经系统恶性肿瘤,其生物学行为具有侵袭性,临床无典型性,病理形态存在异质性,影像表现多样性,依靠病理免疫组织化学及分子生物学方可确诊.各种以大剂量甲氨蝶呤为基础的治疗方案,改善了PCNSL的治疗效果,并成为PCNSL的标准治疗措施,患者的生存率较单用放疗得以显著地提高.早期诊断并进行有效的综合治疗是延长PCNSL患者生存期和改善生活质量的关键.     

Rapid detection of the MYD88 L265P mutation for pre- and intra-operative diagnosis of primary central nervous system lymphoma

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease-specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra-operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra-operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real-time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real-time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra-operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild-type MYD88 was detected in 16 cases. Although two of the 16 cases with wild-type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.     

Expression of signal transducer and activator of transcription 3 (STAT3) in primary central nervous system diffuse large B-cell lymphoma: a retrospective analysis of 17 cases

Most primary central nervous system lymphomas (PCNSL) occurring in immunocompetent patients are diffuse large B-cell lymphomas (DLBCL), characterized by poor prognosis. An activated B-cell (ABC) origin of PCNSL has been postulated based on bcl-6 and MUM-1 expression by majority of these tumors. ABC DLBCL has been functionally subdivided using gene expression profiling and immunohistochemical analysis into STAT3-high and STAT-3 low subsets. A potentially crucial difference between STAT3-high and STAT3-low ABC DLBCL is in the expression of bcl-2 family members. STAT3-high cases are generally bcl-2 low and STAT3-low cases show higher expression of bcl-2. Further mechanisms such as activation of nuclear factor-kappa B (NF-κB) activation seem to be responsible for upregulation of bcl-2 in ABC subtype of DLBCL with an adverse outcome. As deregulation of STAT-3 pathway is known to play a critical role in ABC DLBCL and majority of the PCNSL are of the ABC subtype we studied the immunohistochemical expression of STAT-3 proteins in PCNSL along with other traditional markers (CD10, bcl-6, MUM-1 and bcl-2) in 17 cases of PCNSL occurring in immunocompetent patients. Despite lack of STAT3 expression in all our cases, majority (70%) of the patients with bcl-2 positive PCNSL had an adverse outcome similar to that reported in systemic lymphomas of ABC subtype. Based on our observations we propose that PCNSL represents a distinct subset of ABC diffuse large B-cell lymphomas with low STAT3 expression and perhaps mechanisms other than interaction of STAT-3 and NF-κB pathways may play a role in upregulation of bcl-2 in PCNSL. To the best of our knowledge expression of STAT-3 protein in PCNSL which represents a distinct anatomical subset of ABC DLBCL with a dismal prognosis has not been studied before.     

原发性中枢神经系统淋巴瘤的影像学特点及治疗

原发性中枢神经系统淋巴瘤是一种比较罕见的结外原发非霍奇金淋巴瘤（NHL）,其细胞来源多为弥漫大B淋巴细胞,淋巴细胞影像学表现为单发或多发的深部脑实质、脑室周围或脑膜等处的病变。其治疗尚无标准方案,目前多采用放化疗结合的综合治疗。化疗采用以大剂量MTX为主的方案,全脑放疗已被公认为治疗PCNSL的有效手段。但最佳的化疗方案组合、MTX最佳剂量及放疗剂量仍无定论。我们收治一例原发性中枢神经系统淋巴瘤,于外院行肿瘤切除术,术后予阿糖胞苷加大剂量MTX化疗6程后残留,现经多学科讨论后认为应予辅助放疗加替莫唑胺维持化疗。现患者已完成放疗,替莫唑胺维持化疗中。本文就此病例的影像特点及治疗进行讨论。     

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.     

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.