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1.  Differential micro-RNA expression in primary CNS and nodal diffuse large B-cell lymphomas 
Neuro-Oncology  2011;13(10):1090-1098.
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.
doi:10.1093/neuonc/nor107
PMCID: PMC3177663  PMID: 21803762
micro-RNA; Myc; primary CNS lymphoma
2.  Primary central nervous system B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma 
B cell lymphoma with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma (DLBCL/BL) is a new lymphoma entity which is recognized in the current World Health Organization (WHO) classification (2008). We report a case of a primary central nervous system lymphoma (PCNSL) with findings consistent with DLBCL/BL. It is characterized by a very aggressive clinical course, and a widespread multifocal involvement of the CNS. Our case shows that a DLBCL/BL can manifest in the CNS alone without any systemic involvement.
PMCID: PMC3267488  PMID: 22295149
Lymphoma; central nervous system
3.  Array-based DNA methylation profiling of primary lymphomas of the central nervous system 
BMC Cancer  2009;9:455.
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.
Methods
Using an array-based technology we have assessed the DNA methylation status of 1,505 individual CpG loci in five PCNSL and compared the results to DNA methylation profiles of 49 DLBCL and ten hematopoietic controls.
Results
We identified 194 genes differentially methylated between PCNSL and normal controls. Interestingly, Polycomb target genes and genes with promoters showing a high CpG content were significantly enriched in the group of genes hypermethylated in PCNSL. However, PCNSL and systemic DLBCL did not differ in their methylation pattern.
Conclusions
Based on the data presented here, PCNSL and DLBCL do not differ in their DNA methylation pattern. Thus, DNA methylation analysis does not support a separation of PCNSL and DLBCL into individual entities. However, PCNSL and DLBCL differ in their DNA methylation pattern from non- malignant controls.
doi:10.1186/1471-2407-9-455
PMCID: PMC2807878  PMID: 20025734
4.  Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma 
Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.
doi:10.1084/jem.20031074
PMCID: PMC2194208  PMID: 12975453
gene expression profiling; microarray; outcome prediction; PMBL; DLBCL
5.  Successful Treatment of Primary Central Nervous System Lymphoma without Irradiation in Children: Single Center Experience 
Journal of Korean Medical Science  2012;27(11):1378-1384.
Primary CNS lymphoma (PCNSL) is a very uncommon disease in children, and usually treated by chemotherapy, combined with focal or craniospinal radiotherapy (RT). However, adverse effects of RT are a concern. We evaluated the outcomes of childhood PCNSL, treated with systemic and intrathecal chemotherapy, but without RT. For fifteen years, six patients among 175 of non-Hodgkin lymphoma were diagnosed as PCNSL in Seoul National University Children's Hospital and we analyzed their medical records retrospectively. Their male:female ratio was 5:1, and median age was 10.1 yr. The primary sites were the sellar area in three patients, parietal area in one, cerebellum in one, and multiple areas in one. Their pathologic diagnoses were diffuse large B-cell lymphoma in three patients, Burkitt lymphoma in two, and undifferentiated B-cell lymphoma in one. Five were treated with the LMB96 treatment protocol, and one was treated with the CCG-106B protocol. None had RT as a first-line treatment. One patient had a local relapse and received RT and salvage chemotherapy, without success. No patient had treatment-related mortality. Their estimated 5-yr event-free and overall survival rates were both 83.3%. In conclusion, PCNSL is a rare disease in childhood, but successfully treated by chemotherapy without RT.
doi:10.3346/jkms.2012.27.11.1378
PMCID: PMC3492674  PMID: 23166421
Primary CNS Lymphoma; Children; Irradiation
6.  Multicenter retrospective analysis of 581 patients with primary intestinal non-hodgkin lymphoma from the Consortium for Improving Survival of Lymphoma (CISL) 
BMC Cancer  2011;11:321.
Background
Primary intestinal non-Hodgkin lymphoma (NHL) is a heterogeneous disease with regard to anatomic and histologic distribution. Thus, analyses focusing on primary intestinal NHL with large number of patients are warranted.
Methods
We retrospectively analyzed 581 patients from 16 hospitals in Korea for primary intestinal NHL in this retrospective analysis. We compared clinical features and treatment outcomes according to the anatomic site of involvement and histologic subtypes.
Results
B-cell lymphoma (n = 504, 86.7%) was more frequent than T-cell lymphoma (n = 77, 13.3%). Diffuse large B-cell lymphoma (DLBCL) was the most common subtype (n = 386, 66.4%), and extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) was the second most common subtype (n = 61, 10.5%). B-cell lymphoma mainly presented as localized disease (Lugano stage I/II) while T-cell lymphomas involved multiple intestinal sites. Thus, T-cell lymphoma had more unfavourable characteristics such as advanced stage at diagnosis, and the 5-year overall survival (OS) rate was significantly lower than B-cell lymphoma (28% versus 71%, P < 0.001). B symptoms were relatively uncommon (20.7%), and bone marrow invasion was a rare event (7.4%). The ileocecal region was the most commonly involved site (39.8%), followed by the small (27.9%) and large intestines (21.5%). Patients underwent surgery showed better OS than patients did not (5-year OS rate 77% versus 57%, P < 0.001). However, this beneficial effect of surgery was only statistically significant in patients with B-cell lymphomas (P < 0.001) not in T-cell lymphomas (P = 0.460). The comparison of survival based on the anatomic site of involvement showed that ileocecal regions had a better 5-year overall survival rate (72%) than other sites in consistent with that ileocecal region had higher proportion of patients with DLBCL who underwent surgery. Age > 60 years, performance status ≥ 2, elevated serum lactate dehydrogenase, Lugano stage IV, presence of B symptoms, and T-cell phenotype were independent prognostic factors for survival.
Conclusions
The survival of patients with ileocecal region involvement was better than that of patients with involvement at other sites, which might be related to histologic distribution, the proportion of tumor stage, and need for surgical resection.
doi:10.1186/1471-2407-11-321
PMCID: PMC3160411  PMID: 21798075
intestine; non-Hodgkin lymphoma; prognosis; histopathology
7.  Gastrointestinal lymphomas in a North American population: clinicopathologic features from one major Central-Midwestern United States tertiary care medical center 
Diagnostic Pathology  2012;7:76.
Background
Gastrointestinal (GI) lymphomas are very common types of extranodal lymphomas, and we hypothesize there are regional differences in subtype, distribution in the GI tract, and epidemiological features among the different populations.
Methods
We retrospectively evaluated the clinical, molecular and histologic features of North American primary and secondary GI lymphomas diagnosed from 2000–2009 seen at our institution. We utilized immunohistochemistry and fluorescence in situ hybridization to further evaluate a subset of the gastric lymphomas.
Results
Extranodal marginal zone lymphomas of mucosal associated lymphoid tissue (MALTs) and diffuse large B cell lymphomas (DLBCLs) were the most common subtypes of GI lymphomas. Select gastric DLBCLs (N = 6) and MALTs (N = 13) were further examined for API2-MALT1 and IGH translocations, and P16 and P53 protein expression. Gastric MALTs showed frequent API2-MALT1 (38%) but not IGH translocations (0%), and the DLBCLs showed neither translocation. Expression of P16 and P53 proteins and the proliferative index were compared between high grade gastric lymphomas (gastric DLBCLs) and low grade gastric lymphomas (gastric MALTs). P53 overexpression (P = 0.008) and a high proliferation index [Ki-67] (P = 0.00042) were significantly associated with gastric DLBCL, but no statistically significant difference was observed in P16 expression (p = 0.108) between gastric DLBCL and gastric MALT.
Conclusion
Our study revealed that GI lymphomas from a Central-Midwestern North American population showed differences and similarities to non-North American cohorts. In addition, API2-MALT1, P16 and P53 abnormalities occurred frequently in gastric lymphomas from this North American population.
Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1415505838687793
doi:10.1186/1746-1596-7-76
PMCID: PMC3537672  PMID: 22742986
Gastrointestinal lymphoma; Secondary versus primary; Molecular features; Locations
8.  Extranodal marginal zone lymphoma of the dura mater with IgH/MALT1 translocation and review of literature 
Journal of Hematopathology  2008;1(2):131-137.
Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma involving brain, intraocular structures and spinal cord, without evidence of systemic disease. The majority of PCNSLs are diffuse large B-cell type. We encountered a rare case of primary dural marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) with extension into the brain in a 59-year-old man. A magnetic resonance imaging scan showed a 22-mm tumor located in the left posterior temporal lobe extending from the dura. Histopathology revealed a lymphoplasmacytic infiltration of the dura and the brain parenchyma in a perivascular pattern. Immunohistochemical and in situ hybridization studies showed a B-cell phenotype with kappa light chain restriction. Fluorescent in situ hybridization study showed a t(14;18)(q32;q21) with immunoglobulin heavy-chain/MALT1 fusion. The molecular study for immunoglobulin heavy-chain gene rearrangement by polymerase chain reaction showed a clonal gene rearrangement.
doi:10.1007/s12308-008-0005-9
PMCID: PMC2713483  PMID: 19669212
Primary CNS; MALT lymphoma; FISH; t(1418); MALT1 translocation; Dura
9.  Commentary on the WHO classification of tumors of lymphoid tissues (2008): “Gray zone” lymphomas overlapping with Burkitt lymphoma or classical Hodgkin lymphoma 
Journal of Hematopathology  2009;2(2):89-95.
The 2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues has introduced two new categories of high-grade B-cell lymphomas: entities in which features of diffuse large B-cell lymphoma (DLBCL) overlap with Burkitt lymphoma (DLBCL/BL) or classical Hodgkin lymphoma (DLBCL/HL). The DLBCL/BL category encompasses cases that resemble Burkitt lymphoma morphologically, but have one or more immunophenotypic or molecular genetic deviations that would exclude it from the BL category; conversely, some cases have immunophenotypic and/or genetic features of BL, but display cytologic variability unacceptable for BL. Many of the cases in the DLBCL/BL category contain a translocation of MYC as well as either BCL2 or BCL6 (so-called double-hit lymphomas) and have a very aggressive clinical behavior. The DLBCL/HL category encompasses lymphomas that exhibit the morphology of classical Hodgkin lymphoma but the immunophenotype of DLBCL, or vice versa. Most DLBCL/HL cases described present as mediastinal masses, but this category is not limited to mediastinal lymphomas. These new categories acknowledge the increasing recognition of cases that display mixed features of two well-established diseases. Whether the existence of such cases reflects shortcomings of our current diagnostic armamentarium or a true disease continuum in which such hybrid or intermediate neoplasms actually exist remains to be determined.
doi:10.1007/s12308-009-0039-7
PMCID: PMC2725285  PMID: 19669187
Burkitt; Diffuse large B-cell lymphoma; Hodgkin lymphoma; Gray zone lymphoma
10.  Commentary on the WHO classification of tumors of lymphoid tissues (2008): “Gray zone” lymphomas overlapping with Burkitt lymphoma or classical Hodgkin lymphoma 
Journal of Hematopathology  2009;2(2):89-95.
The 2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues has introduced two new categories of high-grade B-cell lymphomas: entities in which features of diffuse large B-cell lymphoma (DLBCL) overlap with Burkitt lymphoma (DLBCL/BL) or classical Hodgkin lymphoma (DLBCL/HL). The DLBCL/BL category encompasses cases that resemble Burkitt lymphoma morphologically, but have one or more immunophenotypic or molecular genetic deviations that would exclude it from the BL category; conversely, some cases have immunophenotypic and/or genetic features of BL, but display cytologic variability unacceptable for BL. Many of the cases in the DLBCL/BL category contain a translocation of MYC as well as either BCL2 or BCL6 (so-called double-hit lymphomas) and have a very aggressive clinical behavior. The DLBCL/HL category encompasses lymphomas that exhibit the morphology of classical Hodgkin lymphoma but the immunophenotype of DLBCL, or vice versa. Most DLBCL/HL cases described present as mediastinal masses, but this category is not limited to mediastinal lymphomas. These new categories acknowledge the increasing recognition of cases that display mixed features of two well-established diseases. Whether the existence of such cases reflects shortcomings of our current diagnostic armamentarium or a true disease continuum in which such hybrid or intermediate neoplasms actually exist remains to be determined.
doi:10.1007/s12308-009-0039-7
PMCID: PMC2725285  PMID: 19669187
Burkitt; Diffuse large B-cell lymphoma; Hodgkin lymphoma; Gray zone lymphoma
11.  AIDS-related primary central nervous system lymphoma: a Norwegian national survey 1989–2003 
BMC Cancer  2008;8:225.
Background
Primary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989–2003.
Methods
We identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry (by law recording all cases of cancer in Norway) and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases (by law recording all cases of AIDS in Norway).
Results
Twenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989–2003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1–2.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy.
Conclusion
This is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.
doi:10.1186/1471-2407-8-225
PMCID: PMC2525658  PMID: 18684320
12.  Selective central nervous system tropism of primary central nervous system lymphoma 
Primary Central nervous system lymphoma (PCNSL) is most frequently a diffuse large B cell lymphoma (DLBCL), which is confined to the Central nervous system (CNS). We performed an experiment in which lymphoma cells from a PCNSL patient were implanted subcutaneously in an athymic mouse. The lymphoma cells were shown to home to the CNS with histologic evaluations of the brain showing multiple large B cells in blood vessels consistent with intravascular large B cell lymphoma (IVL). We did not find any evidence of lymphoma at the site of implantation or other locations. The findings are consistent with highly selective tropism of PCNSLforthe CNS and its vasculature.
PMCID: PMC2993226  PMID: 21151389
Lymphoma; central nervous system; tropism
13.  Epstein-Barr Virus-Induced Gene 3 (EBI3): A Novel Diagnosis Marker in Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma 
PLoS ONE  2011;6(9):e24617.
The distinction between Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), two types of mature aggressive B-cell lymphomas that require distinct treatments, can be difficult because of forms showing features intermediate between DLBCL and BL (here called BL/DLBCL). They can be discriminated by the presence of c-myc translocations characteristic of BL. However, these are not exclusive of BL and when present in DLBCL are associated with lower survival. In this study, we show that Epstein-Barr virus-induced gene 3 (EBI3) is differentially expressed among BL and DLBCL. Analysis of gene expression data from 502 cases of aggressive mature B-cell lymphomas available on Gene Expression Omnibus and immunohistochemical analysis of 184 cases of BL, BL/DLBCL or DLBCL, showed that EBI3 was not expressed in EBV-positive or -negative BL cases, whereas it was expressed by over 30% of tumoral cells in nearly 80% of DLBCL cases, independently of their subtypes. In addition, we show that c-myc overexpression represses EBI3 expression, and that DLBCL or BL/DLBCL cases with c-myc translocations have lower expression of EBI3. Thus, EBI3 immunohistochemistry could be useful to discriminate BL from DLBCL, and to identify cases of BL/DLBCL or DLBCL with potential c-myc translocations.
doi:10.1371/journal.pone.0024617
PMCID: PMC3169615  PMID: 21931777
14.  Primary central nervous system lymphoma in Japan: Changes in clinical features, treatment, and prognosis during 1985–2004 
Neuro-Oncology  2008;10(4):560-568.
We have conducted nationwide surveys of primary central nervous system lymphoma (PCNSL) treated since 1985. In the present study, we newly collected data between 2000 and 2004 and investigated changes in clinical features and outcome over time. A total of 739 patients with histologically proven PCNSL undergoing radiotherapy were analyzed. Seventeen institutions were surveyed, and data on 131 patients were collected. These data were compared with updated data that were previously obtained for 466 patients treated during 1985–1994 and 142 patients treated during 1995–1999. Recent trends toward decrease in male/female ratio, increase in aged patients, and increase in patients with multiple lesions were seen. Regarding treatment, decrease in attempts at surgical tumor removal and increases in use of systemic chemotherapy and methotrexate (MTX)–containing regimens were observed. The median survival time was 18, 29, and 24 months for patients seen during 1985–1994, 1995–1999, and 2000–2004, respectively, and the respective 5-year survival rates were 15%, 30%, and 30%. In groups seen during 1995–1999 and during 2000–2004, patients who received systemic or MTX-containing chemotherapy had better prognosis than those who did not. Multivariate analysis of all patients seen during 1985–2004 suggested the usefulness of MTX-containing chemotherapy as well as the importance of age, lactate dehydrogenase level, and tumor multiplicity as prognostic factors. Thus, this study revealed several notable changes in clinical features of PCNSL patients. The prognosis improved during the last 10 years. Advantage of radiation plus chemotherapy, especially MTX-containing chemotherapy, over radiation alone was suggested.
doi:10.1215/15228517-2008-028
PMCID: PMC2666229  PMID: 18559969
brain neoplasm; chemotherapy; lymphoma; primary CNS lymphoma; radiotherapy
15.  Molecular pathology of lymphoma 
Eye  2012;27(2):180-189.
Ocular lymphomas can be divided into intraocular lymphomas and ocular adnexal lymphomas. The vitreoretinal lymphoma—usually a diffuse large B-cell lymphoma (DLBCL) of high-grade malignancy—is the most common lymphoid malignancy arising in the eye, while the extranodal marginal zone B-cell lymphoma (EMZL), an indolent often recurrent tumour, occurs most frequently in the ocular adnexal tissue. The two lymphoma subtypes differ significantly in their clinical presentation, subsequent course and outcome as well as in their underlying morphological, immunophenotypical and genetic features. The molecular processes involved in DLBCL and EMZL development are complex, and include chromosomal translocations, mutations caused by aberrant somatic hypermutation, sporadic somatic mutations, and copy number alterations, characterized by deletions and amplifications. These lead to alterations in particular signalling pathways, which in turn activate transcription factors, such as nuclear factor NF-κB. This review provides an overview of the histological features of DLBCL and EMZL, and discusses the current insights into the molecular mechanisms underlying the development of these tumours, when they occur systemically and particularly when they arise in ocular tissues.
doi:10.1038/eye.2012.247
PMCID: PMC3574248  PMID: 23222560
ocular adnexal lymphoma; extranodal marginal zone lymphoma; diffuse large B-cell lymphoma; ABC DLBCL; GCB DLBCL; vitreoretinal lymphoma
16.  Novel Therapies for Aggressive B-Cell Lymphoma 
Advances in Hematology  2012;2012:302570.
Aggressive B-cell lymphoma (BCL) comprises a heterogeneous group of malignancies, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and mantle cell lymphoma (MCL). DLBCL, with its 3 subtypes, is the most common type of lymphoma. Advances in chemoimmunotherapy have substantially improved disease control. However, depending on the subtype, patients with DLBCL still exhibit substantially different survival rates. In MCL, a mature B-cell lymphoma, the addition of rituximab to conventional chemotherapy regimens has increased response rates, but not survival. Burkitt lymphoma, the most aggressive BCL, is characterized by a high proliferative index and requires more intensive chemotherapy regimens than DLBCL. Hence, there is a need for more effective therapies for all three diseases. Increased understanding of the molecular features of aggressive BCL has led to the development of a range of novel therapies, many of which target the tumor in a tailored manner and are summarized in this paper.
doi:10.1155/2012/302570
PMCID: PMC3318210  PMID: 22536253
17.  Clinical features and survival outcomes of patients with diffuse large B-cell lymphoma: analysis of web-based data from the Korean Lymphoma Working Party Registry 
Blood research  2013;48(2):115-120.
Background
This study aimed to survey the clinical spectrum of diffuse large B-cell lymphoma (DLBCL) in terms of epidemiology, pathologic subtypes, stage, and prognostic index as well as treatment outcomes.
Methods
In 2007-2008, 13 university hospitals evenly distributed in the Korean peninsula contributed to the online registry of DLBCL at www.lymphoma.or.kr and filed a total of 1,665 cases of DLBCL recorded since 1990.
Results
Our analysis showed a higher prevalence of DLBCL in male than in female individuals (M:F=958:707), and extranodal disease was more common than primary nodular disease (53% vs. 47%). Among the 1,544 patients who had been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP (R-CHOP) therapy with or without radiation, 993 (63.9%) were alive, with 80% free of disease, 417 were dead (26.8%), with 13% free of disease, and 144 (9.3%) were lost to follow-up, with 23% free of disease. Age below 60 years, stage at diagnosis, international prognostic index (IPI) score regardless of age, and addition of rituximab to CHOP therapy in low- and low-intermediate-risk groups according to IPI scores significantly increased survival duration.
Conclusion
The epidemiology, clinical spectrum, and biological behavior of DLBCL in Korea are similar to those observed in Western countries, and the advent of rituximab improved survival.
doi:10.5045/br.2013.48.2.115
PMCID: PMC3698396  PMID: 23826580
Diffuse large B-cell lymphoma; Epidemiology; Survival; Rituximab; CHOP regimen
18.  Primary diffuse large B-cell lymphoma in the anterior hard palate: A rare case report with review of literature 
Diffuse large B-cell lymphomas (DLBCLs) are defined as neoplasms of large transformed B cells, i.e. with nuclear diameter more than twice that of a normal lymphocyte. These account for 30-40% of all adult non-Hodgkin's lymphomas (NHL). Intraoral lymphomas are relatively rare and often difficult to diagnose in clinical settings. In this case report, we describe a case of primary DLBCL affecting the anterior part of the hard palate of an elderly male patient. DLBCL of anterior part of hard palate is yet to be reported in the English literature, even though DLBCL cases involving the posterior palate have been recorded, thus making the present case to be first of its kind. Emphasis has also been given on the subclassification, differential diagnosis and prognostic antibody factors determining the outcome of DLBCL.
doi:10.4103/0973-029X.131927
PMCID: PMC4065424  PMID: 24959047
Anterior hard palate; diffuse large B-cell lymphoma; non-Hodgkin's lymphoma
19.  Primary lymphoma of the lacrimal sac: an EORTC ophthalmic oncology task force study 
The British Journal of Ophthalmology  2006;90(8):1004-1009.
Aim
To define the clinical and histopathological characteristics of primary lacrimal sac lymphoma in a predominantly white population.
Methods
Specimens of lacrimal sac lymphoma and follow up data were solicited from members of the Ophthalmic Oncology Task Force of the European Organization for Research and Treatment of Cancer (EORTC) and the European Ophthalmic Pathology Society (EOPS). Specimens were stained with haematoxylin and eosin and an immunohistochemical panel against leucocyte antigens was applied. Diagnosis was reached by consensus of five experienced pathologists according to the World Health Organization classification system. The histopathological findings were correlated with the clinical data.
Results
Of 15 primary lacrimal sac lymphomas, five (33%) were diffuse large B cell lymphoma (DLBCL), five (33%) were extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma), three were classified as “transitional MALT lymphoma,” being in transition from MALT lymphoma to DLBCL, and two were unclassified B cell lymphomas. Nine of the patients were female, and the median age at the time of diagnosis was 71 years (range 45–95 years). The most frequent presenting symptoms were epiphora (85%), swelling in the region of the lacrimal sac (79%), and dacryocystitis (21%). All but one patient presented in stage I. Systemic spread occurred in three of nine patients (33%). The 5 year overall survival was 65%.
Conclusions
DLBCL and MALT lymphoma are equally common in the lacrimal sac in contrast with the remaining periorbital and/or orbital region where MALT lymphoma predominates.
doi:10.1136/bjo.2006.090589
PMCID: PMC1857190  PMID: 16672329
ocular lymphoma; lacrimal sac; MALT lymphoma
20.  Gall Bladder and Extrahepatic Bile Duct Lymphomas: Clinicopathological observations and biological implications 
Lymphomas of the gall bladder and extrahepatic bile ducts are exceedingly rare. We present the clinicopathological features of 19 cases from our files; 14 patients had primary lymphoma (13 involving gall bladder and one involving common hepatic duct), while five had systemic lymphoma on further work-up. Most patients presented with symptoms mimicking cholecystitis. The most common primary lymphoma types were diffuse large B-cell lymphoma (DLBCL), extranodal marginal zone lymphoma (EMZL), B-lymphoblastic lymphoma (B-LBL) and follicular lymphoma (FL). Two cases had features of lymphomatous polyposis, one a case of FL and the second a case of mantle cell lymphoma (MCL), with disease limited to the mantle zones, so-called in situ MCL. Other rare lymphoma subtypes not previously described in this site included the extracavitary variant of primary effusion lymphoma (PEL) and plasmablastic lymphoma (PBL). Patients with DLBCL and EMZL were older (mean age 75.8 years) than those with other subtypes (mean age 47 years) and more likely to have gallstones (60% vs. 12.5%). A comprehensive literature review revealed 36 primary gall bladder and 16 primary extrahepatic bile duct lymphomas. When compared to primary gall bladder lymphomas, those involving the extrahepatic bile ducts present at a younger age (47 years vs. 63 years) usually with obstructive jaundice, and are less often associated with gallstones (17% vs. 50%) or regional lymph node involvement (6% vs. 31%). In conclusion, primary lymphomas of the gall bladder and extrahepatic bile ducts show a broad spectrum of disease types, but in many respects mirror the spectrum of primary lymphomas of the gastrointestinal tract.
doi:10.1097/PAS.0b013e3181e9bb8b
PMCID: PMC2929270  PMID: 20679881
lymphoma; gallbladder; bile duct; hepatic duct; cystic duct; cholecystitis; cholelithiasis; extranodal; intestinal follicular lymphoma; in situ mantle cell lymphoma; HHV-8/KSHV; plasmablastic lymphoma; primary effusion lymphoma; lymphomatous polyposis
21.  Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell–like diffuse large B cell lymphoma 
To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell–like (ABC), germinal center B cell–like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch μ (Sμ) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sγ and other illegitimate switch recombinations. Sequence analysis revealed ongoing Sμ deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase–dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Sμ in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.
doi:10.1084/jem.20062041
PMCID: PMC2137913  PMID: 17353367
22.  Statin Use and Prognosis in Patients With Diffuse Large B-Cell Lymphoma and Follicular Lymphoma in the Rituximab Era 
Journal of Clinical Oncology  2009;28(3):412-417.
Purpose
Statins have antilymphoma properties but have also been shown to inhibit the binding of rituximab to the CD20 antigen, resulting in reduced antitumor activity of rituximab in vitro. The clinical impact of statin use on the outcome of lymphoma patients treated with a rituximab-containing regimen is unknown.
Patients and Methods
Consecutive patients with newly diagnosed, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were enrolled onto a registry and observed prospectively. The impact of statin use on patients' outcomes was analyzed.
Results
Two hundred twenty-eight patients with DLBCL and 293 patients with FL were enrolled from September 2002 through June 2007; 21% of patients with DLBCL and 19% of patients with FL were on statins at diagnosis, and 20% and 17% remained on statins during lymphoma treatment, respectively. All patients with DLBCL and 39% of patients with FL received initial therapy containing rituximab. The median follow-up time was 47 months (range, 13 to 80 months). Statin use had no impact on the overall response rate (P = .67), overall survival (P = .76), or event-free survival (EFS) in patients with DLBCL (hazard ratio [HR] = 0.85; 95% CI, 0.43 to 1.68). Statin use at diagnosis was associated with improved EFS in patients with FL (HR = 0.45; 95% CI, 0.26 to 0.77), including subgroups treated with rituximab or a rituximab-containing regimen (HR = 0.38; 95% CI, 0.14 to 1.07) and patients who were observed only (HR = 0.38; 95% CI, 0.17 to 0.84).
Conclusion
The concurrent use of statins during the treatment of patients with DLBCL and FL in the rituximab era did not adversely affect outcome. The apparent benefit of statin therapy on FL outcome requires further studies.
doi:10.1200/JCO.2009.23.4245
PMCID: PMC2815703  PMID: 20008638
23.  Post-transplantation primary central nervous system lymphoma: A case report and review of the literature 
Background:
Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that can develop within months to years after transplantation, and imaging often reveals multiple lesions with homogeneous or ring enhancement. The clinical and imaging presentation of PT-PCNSL can often be nonspecific and present a diagnostic challenge.
Case Description:
A 56-year-old woman presented to a tertiary university emergency room with altered mental status 15 months after undergoing renal transplantation. On brain MRI, she was found to have three rim-enhancing mass lesions, and biopsy revealed PT-PCNSL.
Conclusion:
There has been a steady increase in the number of patients living following organ transplantation in the United States and an increasing likelihood that PT-PCNSL will increasingly be encountered in neurosurgical practice. We present here a case of PT-PCNSL and a brief review of the relevant clinical characteristics, treatment options, and prognosis of PT-PCNSL.
doi:10.4103/2152-7806.85471
PMCID: PMC3205489  PMID: 22059125
Primary central nervous system lymphoma; transplantation
24.  18F-FDG PET in the Diagnosis and Treatment of Primary Central Nervous System Lymphoma 
BioMed Research International  2013;2013:247152.
This paper summarizes the usefulness and limitation of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) in the diagnosis and treatment of primary central nervous system lymphoma (PCNSL). The 18F-FDG uptake in typical PCNSL is about 2.5 times higher than that in the normal gray matter, and the tumor can usually be identified visually. The 18F-FDG uptake pattern and value provide useful information for differentiating PCNSL from other enhancing malignant brain tumors especially glioblastoma (GB). The 18F-FDG uptake in typical PCNSL is usually homogenous, and the uptake value is significantly higher than that in GB. However, 18F-FDG PET often fails to show the presence of tumor in the brain as 18F-FDG uptake is faint in atypical PCNSL such as disseminated or nonenhancing lesions. 18F-FDG PET is also useful for evaluating the treatment response at a very early stage after the initial treatment. Pretreatment and posttreatment 18F-FDG uptake values may have a prognostic value in patients with PCNSL. In conclusion, 18F-FDG PET is very useful in the diagnosis of typical PCNSL and can differentiate PCNSL from other malignant brain tumors. However, the usefulness of 18F-FDG PET is limited in the diagnosis of atypical PCNSL.
doi:10.1155/2013/247152
PMCID: PMC3703402  PMID: 23844359
25.  Unfavourable prognosis of patients with trisomy 18q21 detected by fluorescence in situ hybridisation in t(11;18) negative, surgically resected, gastrointestinal B cell lymphomas 
Journal of Clinical Pathology  2004;57(4):360-364.
Background: The most frequent cytogenetic alteration in gastrointestinal (GI) B cell lymphoma (BCL) is t(11;18)(q21;q21). GI B cell non-Hodgkin lymphomas lacking this translocation vary in their biology and clinical outcome. The t(11;18) negative subgroup shows increased numerical changes of chromosome 18, although its clinical relevance remains unknown.
Methods: Thirty surgically resected primary GI BCLs were examined—11 low grade marginal zone mucosa associated lymphoid tissue (MALT) lymphomas, four marginal zone lymphomas with diffuse large BCL (DLBCL), and 15 de novo DLBCLs. Chromosome 18 aberrations were examined using interphase fluorescence in situ hybridisation. Trisomy 18 was studied applying a centromere 18 probe and a dual colour probe for the MALT1 gene at 18q21.
Results: Using the MALT1 probe, only one marginal zone MALT lymphoma had a break apart pattern, indicating t(11;18) or variants. In the GI BCLs lacking MALT1 breaks, trisomy 18q21 was seen in seven patients (four with complete trisomy 18 and three with partial trisomy of 18q21). Trisomy 18q21 was found in two of 10 low grade MALT lymphomas and five of 19 GI BCLs with large cell component. Six of 17 patients with trisomy 18q21 presented with ≥stage II and one of 12 with stage I disease. Trisomy 18q21 was associated with significantly shorter disease specific survival in the whole group and GI BCLs with large cell component, but not in the low grade group.
Conclusions: Trisomy 18q21, including MALT1, may be associated with advanced tumour stage and may be a predictor of poor outcome in surgically resected primary GI BCLs.
doi:10.1136/jcp.2003.012369
PMCID: PMC1770281  PMID: 15047736
gastrointestinal B cell lymphoma; fluorescence in situ hybridisation analysis; trisomy 18q21

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