Primary central nervous system lymphomas—New pathological developments

Summary Primary central nervous system lymphomas (PCNSL) show increased incidence both in immunocompromised high-risk groups and in the general population. They are extranodal diffuse non-Hodgkin's lymphomas with a morphology similar to systemic lymphomas, but differ in their biological and molecular behaviour. The majority are large B-cell variants of high-grade malignancy; low-grade subtypes and T-cell lymphomas are rare; up to 50% remain unclassified according to the New Working Formulation and updated Kiel classification. Monoclonality of immunoglobulin receptor gene rearrangement can be diagnostically useful. The pathogenesis of PCNSL is obscure. Epstein-Barr virus (EBV) genome/proteins expression in two-thirds of HIV-related PCNSL but only in 15% of those in immunocompetent patients suggest different EBV latency stages in both types; human herpesvirus type 6 does not appear to play a pathogenic role. Comparison of expression patterns of integrin chains and adhesion molecules are very similar for PCNSL and nodal lymphomas suggesting that they are not selective mediators of lymphoma cell homing to the brain. In HIV-negative PCNSL they appear not to be influenced by EBV. Studies of protooncogenes (bcl-1 and bcl-2 genes) revealed no rearrangement in PCNSL, suggesting that they are not involved in the pathogenesis of PCNSL that probably do not differ cytogenetically from nodal B-cell lymphomas. Since most of the currently known molecular parameters are probably not the primary pathogenic events, the molecular genetics and pathogenesis of PCNSL are still to be elucidated.     

Differential expression of chemokines, chemokine receptors, cytokines and cytokine receptors in diffuse large B cell malignant lymphoma

Host immunity, particularly T cell immunity (Th1/Th2 balance), plays an important role in clinicopathological features of malignant disease. However, the T cell immunity has not been fully investigated in patients with lymphoid malignancies. Recent studies suggested the important role of dysregulation of the endogenous immune system in lymphomagenesis. The relationships between cytokines/chemokines and their receptors, are important in determining the selectivity of local immunity. To investigate differences in the endogenous immune system of diffuse large B cell lymphoma (DLBL), we performed gene expression profiling using cDNA microarrays of cytokines/chemokines and their receptors. We studied 5 cases each of primary central nervous system lymphomas (PCNSL), extranodal and nodal lymphomas. PCNSL exhibited diffuse down-regulated profiles, compared to normal peripheral blood lymphocytes. While extranodal and nodal lymphomas also exhibited diffuse down-regulated profiles, some genes displayed up-regulated profiles. Hierarchical clustering analysis separated PCNSL and extranodal lymphomas into distinct groups based on their gene expression profiles, as well as extranodal and nodal, but not PCNSL and nodal. PCNSL exhibited significantly lower expression of BLC/BCA-1 and CCR-3 (Th2 type), and higher expression of IL-8 and MIP-1beta (Th1 type) than extranodal lymphomas. Immunohistochemistry and RT-PCR revealed frequent CCR-3 and BLC/BCA-1 expression in extranodal lymphomas, compared with PCNSL. Our results provide new insights into the pathogenesis of each DLBL. A better understanding of the immune response in each DLBL could help in the design of novel therapeutic strategies based on cytokines/chemokines and their receptors.     

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.     

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.     

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma

Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16 vs 0.42; odds ratio 0.26, CI(95%): 0.09-0.74; P=0.005), suggesting a protective function of the G allele. These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.     

Primäre Zentralnervensystemlymphome (PZNSL)

Primary central nervous system lymphoma (PCNSL) comprises about 2?% of intracranial tumors. The vast majority of these tumors are diffuse large B-cell lymphomas; however, PCNSL differs from nodal lymphoma with a similar histopathology by its strong affinity for the CNS with infrequent systemic involvement, by its usually aggressive course and unusually high sensitivity to high-dose methotrexate (HDMTX). Thus, HDMTX represents the backbone of current therapy although the optimal treatment protocol for PCNSL has not yet been established due to the paucity of occurrence. Age and general condition of the patient are the most important prognostic factors. In younger patients curing is the goal and can probably be achieved in a fraction of patients by application of intensified chemotherapy protocols. In the elderly, however, a cure is mostly not possible and therapy optimization is still urgently needed. To spare patients with PCNSL the potentially devastating consequences of delayed treatment-related CNS toxicity is an important goal.     

Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma

BackgroundWhile there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease.Patients and methodsWe reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology.ResultsWhile PCNSL tumors usually express a BCL6+, MUM1+ ‘activated, germinal center’ immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses.ConclusionsThere is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease.     

Prognostic factors in primary central nervous system lymphomas

Efforts to identify survival predictors in primary central nervous system lymphoma (PCNSL) have produced isolated, unconfirmed observations in small retrospective and prospective series. Age and performance status are two unanimously accepted prognostic factors. These and other independent predictors of survival were used by the International Extranodal Lymphoma Study Group (IELSG) to establish a prognostic scoring system able to distinguish risk groups in PCNSL. The IELSG score will improve further with better knowledge of these malignancies, especially with the inclusion of molecular and pharmacogenetic variables able to identify lymphomas with different chemosensitivities or degrees of aggressiveness. In the years ahead, a well-established prognostic score will allow the separation of patients into risk groups, which could result in the application of risk-tailored therapeutic strategies.     

Array-based DNA methylation profiling of primary lymphomas of the central nervous system

Background  

Although primary lymphomas of the central nervous system (PCNSL) and extracerebral diffuse large B-cell lymphoma (DLBCL) cannot be distinguished histologically, it is still a matter of debate whether PCNSL differ from systemic DLBCL with respect to their molecular features and pathogenesis. Analysis of the DNA methylation pattern might provide further data distinguishing these entities at a molecular level.     

Selection of surrogate marker genes in primary central nervous system lymphomas for radio-chemotherapy by DNA array analysis of gene expression profiles

Primary central nervous system lymphomas (PCNSLs) are extra nodal B-cell non-Hodgkin's lymphomas with primary manifestation in the brain, and their incidence has been increasing among both immunocompetent and immunocompromised populations. Samples of oligodendroglioma (n=5), glioblastoma (n=7), PCNSL (n=6), and normal brain (n=3) were studied (total of 21 samples) using cDNA array technology. The hierarchical clustering algorithm was used to obtain a phylogenetic tree, and it revealed a striking feature: PCNSL was clearly separated. The genes encoding laminin receptor 2, thioredoxin peroxidase, and elongation factor-1 were selected as specific genes in PCNSL by principal component analysis (PCA). When Mann-Whitney tests were performed to identify genes responsible for the differences between responders and non-responders to the treatment schedule for PCNSL, 76 known genes were found to show significantly different expression patterns between the two groups at the P<0.01 level. The two groups were clearly separated by the re-clustering method using the selected genes related to response to chemo-radiotherapy. This is the first report describing the gene expression profiles of PCNSL. In conclusion, accumulation of data with respect to the expression profiles of PCNSL specimens, clinicopathological data, susceptibility to treatment, and outcome will provide information for identifying optimal therapeutic modalities for individual patients and novel therapeutic targets.     

Insights into the biology of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare variant of non-Hodgkin lymphoma that is confined to the central nervous system. Biologic studies of PCNSL are challenging to conduct because the disease is rare and available tissue material is sparse. However, in recent years there has been progress in the understanding of PCNSL biology, largely as the result of multicenter studies using modern molecular techniques. Recent studies may improve insight into the pathogenesis of PCNSL and increase the chances of identifying prognostic factors and novel therapeutic targets. This review discusses recent advances in PCNSL biology, including immunologic and genetic risk factors, and focuses on the molecular alterations important in central nervous system lymphomagenesis.     

Primary cutaneous lymphomas other than mycosis fungoides.

Primary cutaneous lymphomas present in and are confined to the skin with no evidence of extracutaneous disease. The skin is the second most common extranodal site involved by primary lymphoma; 50% are mycosis fungoides (MF)-type cutaneous T-cell lymphoma, with the remainder being peripheral T-cell lymphoma (25%) and B-cell lymphoma (25%). The diagnosis of non-MF primary cutaneous lymphomas differs from that of nodal lymphomas: (1) presentation in the skin more often predicts outcome than histology, (2) immunophenotyping and immunogenotyping studies show differences in chromosomal translocations, cell-surface antigen expression (T-cell receptor [TCR] and immunoglobulin [Ig] heavy and light chains), and oncogene expression, (3) involvement of structural compartments of the skin (epidermis, periadnexal or adventitial dermis, interstitial dermis, and subcutis) aids differential diagnosis in place of nodal architecture, and (4) cytokine and extracellular matrix environments may influence behavior of cutaneous lymphomas. Diagnosis often requires coordinated evaluation of clinical history, immunohistochemistry on paraffin and frozen sections of skin biopsies, and molecular analysis. Classification of primary cutaneous lymphomas by a combined histologic type and clinical behavior is useful.     

Primary Soft Tissue Lymphomas: Description of Seven Cases and Review of the Literature

The present study describes a series of primary soft tissue lymphomas, including immunohistochemical characterization by tissue microarray and cytogenetic profiling. Formalin-fixed, paraffin-embedded tissue samples were collected from patients who underwent soft tissue biopsy. Cases were selected according to the definition of primary soft tissue lymphoma as a lymphoid malignancy arising in soft tissues without evidence of other nodal or extranodal localization for a period of at least 6 months. Our series comprised seven patients with a mean age of 72 years. There were three diffuse large B-cell lymphomas (DLBCLs); one B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma; one DLBCL derived from follicular lymphoma; one ALK-negative anaplastic large cell lymphoma; and one follicular lymphoma. Immunohistochemical and molecular profiles were consistent with the histological diagnoses. The present study contributes to our knowledge about uncommon presentation of lymphoid neoplasms and confirms previously published clinical-pathological data. We present, for the first time, the complete immunohistochemical profile and molecular cytogenetic studies of these lymphoid neoplasms. A rare case of a primary soft tissue ALK-negative anaplastic large cell lymphoma is described in detail.     

Different spatial distribution between germinal center B and non-germinal center B primary central nervous system lymphoma revealed by magnetic resonance group analysis

Background

MRI group analysis is a powerful tool for elucidating pathological conditions in the brain that are challenging to reveal from single subject analysis. This research aimed to elucidate special distribution characteristics of primary central nervous system lymphoma (PCNSL) within the brain with respect to molecular marker expression patterns.

Methods

MR images from 100 treatment-naive PCNSL patients were collected and registered onto averaged standard anatomical MRI (MNI152). Gadolinium-enhanced lesions were extracted, and a lesion frequency map was created. Lymphoma subtypes were classified as germinal center B (GCB) or non-GCB by immunohistochemistry in 90 patients.

Results

A PCNSL frequency map showed that these tumors tended to occur around the lateral, third and fourth ventricles. Moreover, GCB (27 cases) and non-GCB (63 cases) PCNSL frequency maps showed GCB lymphomas located at the upper tegmentum and cerebellum around the fourth ventricle, while non-GCB lymphomas tended to occupy the anterior fornix. These differences were significant and confirmed by the existence of voxels with P values <.05 (random permutation analysis with voxel-wise Fisher'' exact test). This is the very first report to address phenotypical and spatial distributional differences between GCB and non-GCB PCNSL using an MR group analytical method.     

Pathology of extra-nodal non Hodgkin lymphomas

In the management of extra-nodal lymphomas it is important to determine whether the tumour has disseminated and whether lymph nodes are involved. Some extra-nodal lymphomas may be the result of random spread of nodal lymphoma. Specific homing, however, determines the site of many extra-nodal lymphomas, as exemplified by cutaneous T-cell lymphomas, which seem to be derived from skin-homing T-cells and mucosa-associated lymphoid tissue lymphomas that show features of the mucosal immune system. Enteropathy-associated T-cell lymphoma is derived from mucosal T-cells in patients with coeliac disease. Immunological sanctuary accounts for the localisation of primary brain, eye and testicular lymphoma. Mantle cell lymphoma frequently causes tumours in the gastrointestinal tract. Random biopsies have shown that a high proportion of patients with this lymphoma have extensive occult involvement of the gastrointestinal tract at the time of first diagnosis. Follicular lymphoma occurs at both nodal and extra-nodal sites, but uncommonly at both sites at the same time. Extra-nodal follicular lymphomas frequently lack t(14;18)(q32;q21) and do not express bcl-2, which are characteristics of the nodal disease. At extra-nodal sites, follicular lymphoma is more likely to be curable than nodal follicular lymphoma. The behaviour of extra-nodal lymphomas cannot be assumed to follow that of their nodal counterparts.     

Primary central nervous system T-cell lymphoma in aids patients: case report and literature review

According to the published data, most primary central nervous system lymphomas (PCNSLs) are B-cell lymphomas; primary T-cell lymphomas are rare. In a search of the MEDLINE database, we found only 6 cases of primary T-cell PCNSL. Here, we present the case of a 43-year-old man with AIDS, not on highly active antiretroviral therapy, who presented with focal neurologic symptoms and was found on magnetic resonance imaging to have multiple brain lesions. A biopsy showed T-cell lymphoma, and the patient was subsequently treated with whole-brain radiation, to marked clinical response. Reported cases from the literature of primary T-cell PCNSL in AIDS patients are summarized in this review.     

Study of radiolabeled indium-111 and yttrium-90 ibritumomab tiuxetan in primary central nervous system lymphoma

BACKGROUND: Therapeutic options for refractory or recurrent primary central nervous system lymphoma (PCNSL) are limited. The blood-brain barrier makes many agents used in systemic lymphomas ineffective in CNS lymphomas. The objective of this study was to determine whether intravenous radioimmunotherapy using anti-CD20 antibody can be delivered to PCNSL. METHODS: This was a single-institution prospective study. Indium-111 ibritumomab tiuxetan was used for imaging and dosimetry. Yttrium-90 ibritumomab tiuxetan at doses of 0.3 to 0.4 mCi/kg were subsequently given for the treatment of recurrent or refractory PCNSL. 111In data were used to estimate radiation doses to lesions delivered by 90Y ibritumomab tiuxetan therapy. RESULTS: Six patients (4 men, 2 women) with a median age of 60 years and median Karnofsky performance status of 70 received both indium-111 and yttrium-90 ibritumomab tiuxetan. The median absorbed dose delivered to the CNS lymphoma was 701 cGy compared with 70 cGy to normal brain. The median progression-free and overall survival times were 6.8 weeks and 14.3 weeks, respectively. CONCLUSIONS: The results from this study suggest that it may be feasible to deliver radiolabeled monoclonal anti-CD20 antibodies as a component of therapy for 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.     

Gender and time differences in initial location and histological grade of non-Hodgkin's lymphomas in Southern Sweden

In accordance with international data, non-Hodgkin's lymphomas (NHL) in the Southern Health Care Region of Sweden were more common in men than in women and there was an inreasing incidence for both genders in the 1980s and 1990s. A study of the years 1983 and 1992, i.e. the beginning and the end of a 10-year period, was carried out. Case records for 94% of all adults diagnosed in 1983 and 1992 (220 men and 171 women) were reviewed. The sites of the lymphomas and malignancy grade (Kiel classification) were recorded. Comparisons were made between the genders and between the two years studied. Among 170 men with nodal lymphomas, 49 were localized (stage I-II) in lymphoid tissue regional to the respiratory tract, 18 were localized elsewhere and 103 were generalized (stage III-IV). The corresponding sites in 138 women were 28, 33 and 77, respectively (p = 0.002), implying a predominance of stage I-II lymphomas regional to the respiratory tract in men and a larger number of localized lymphomas elsewhere, mostly abdominal/retroperitoneal with or without inguinal engagement in women. High-grade nodal lymphomas were more common in 1992 (54%) than in 1983 (34%, p = 0.01), suggesting an increasing number of mainly high-grade lymphomas. For extranodal lymphomas (50 in men and 33 in women), no clear differences were observed for gender and the years studied. Risk factors, e.g. occupational hazards, are probably different for men and women. The gender differences in initial nodal location suggest that initial lymphoma sites may be related to different risk factors. Epidemiologic studies where both malignancy grade and initial lymphoma locations are taken into account may be helpful in defining risk factors.     

原发性中枢神经系统淋巴瘤预后相关因素研究进展

 原发性中枢神经系统淋巴瘤（PCNSL）是一种少见的结外恶性淋巴瘤,好发于免疫缺陷人群,但近年来在免疫功能正常人群中发病率逐年提高。其临床治疗缓解期短,易复发,预后不佳。研究发现PCNSL的预后相关因素包括：年龄、体力状态、放化疗的方式、初治对糖皮质激素的反应、组织病理和分子生物学标志等。