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1.  Temporal Trends in Presentation and Survival for HIV-Associated Lymphoma in the Antiretroviral Therapy Era 
Background
Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era.
Methods
We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan–Meier curves and Cox proportional hazards.
Results
Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log10copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year.
Conclusions
HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes.
doi:10.1093/jnci/djt158
PMCID: PMC3748003  PMID: 23892362
2.  Clinical Analysis of 10 AIDS Patients with Malignant Lymphoma 
Cancer Biology & Medicine  2012;9(2):115-119.
Objective
This work summarizes the clinical features and treatment of 10 AIDS patients with malignant lymphoma.
Methods
A total of 10 AIDS patients with malignant lymphoma seen in Beijing Ditan Hospital since 2009 were enrolled. Clinical manifestations, pathological examinations, immunity levels, Epstein-Barr virus antibody examinations, complications, treatments, and outcomes were retrospectively analyzed.
Results
The main clinical manifestations of these patients included intermittent fever in 2 cases, neck masses and fever in 3 cases, auxiliary lymph node enlargement in 2 cases, and abdominal pain and bloating with fever in 3 cases. Up to 7 patients were pathologically diagnosed with diffuse large B cell lymphoma (DLBCL), and 3 patients were pathologically diagnosed with Burkitt’s lymphoma. Up to 8 patients had CD4 cell counts below 200/µL, and 2 patients had a level of more than 200/µL. Up to 7 patients were negative for EBV-IgM antibodies and 3 patients were not examined. Six patients underwent different chemotherapy and their prognoses were different. One patient with Burkitt’s lymphoma alternatively took CODOXM and IVAC for 3 turns after VP chemotherapy; 1 patient with liver metastasis took R-CHOP 5 times, then changed therapy regimen to R-MINE and MINE. One patient with adrenal DLBCL took CHOP 6 times. Three patients with DLBCL took CHOP 1 or 2 times. Four patients gave up treatment. Various infections and side effects occurred, including bone marrow suppression, gastrointestinal bleeding, and renal dysfunction during chemotherapy. Six patients took HAART, and 4 did not. Six patients died, whereas 3 patients got improved; and 1 patient was discharged.
Conclusions
AIDS patients with malignant lymphoma had various clinical manifestations, were immunocompromised, and had multiple metastases when they were admitted; they were already in the interim or late stage of lymphoma. Chemotherapy was not effective, and additional complications occurred. HAART failed to improve patient prognosis, and the overall prognosis was poor.
doi:10.3969/j.issn.2095-3941.2012.02.006
PMCID: PMC3643651  PMID: 23691465
acquired immunodeficiency syndrome (AIDS); malignant lymphoma; chemotherapy; HAART; prognosis
3.  The role of EBV in the pathogenesis of Burkitt’s Lymphoma: an Italian hospital based survey 
The exact worldwide incidence of Burkitt’s lymphoma is not known. There are three distinct clinical variants of Burkitt’s lymphoma, each manifesting differences in epidemiology, clinical presentation, morphology, biology and genetic features: the endemic (African), the sporadic (non-endemic), and the immunodeficiency-associated form. In particular, we reported data regarding Burkitt’s lymphoma incidence in the world and across different European countries. Finally, we described clinic-pathological data of 48 Burkitt’s lymphomas occurred in Italy from 2003 to 2013, in 4 different hospitals, two of which located in east side, and the other ones located in the west-coast. Forty Burkitt’s lymphomas occurs in children (age range 3–12), and 8 were adulthood Burkitt’s lymphomas (age range 18–87). In the pediatric group the Male:Female ratio (M:F) was of 4:1, whereas the group of the adult patients has a M:F of 1:1.67. Immunohistochemical detection of Latent Membrane Protein 1 (LMP1) expression and Epstein-Barr virus Encoded RNA (EBER) In Situ Hybridization (ISH) procedures have been performed. Lymphocyte B monoclonal spread has been demonstrated using a Polymerase Chain Reaction (PCR) based method to amplify Fragment Restriction FR1, FR2 and FR3 immunoglobulin heavy chains DNA fragments. Only 38 cases out of 48 were analyzed for LMP-1 showing various percentage of stained cells in 47.4% of the patients.
Considering ISH for EBER detection results: 1 out 2 (50%) adult analyzed cases was positive, with 50% of stained tumor cells (this patient was a 22 years old female, coming from Napoli);15 out 24 (62.5%) children analyzed Burkitt’s lymphomas resulted as positive for EBER;the overall positivity has been observed in 16/26 Burkitt’s lymphomas (61.53%).Finally, EBV has been detected in children and adult patients, one of them with deregulation of the oncogene c-MYC by chromosomal translocation.
doi:10.1186/1750-9378-9-34
PMCID: PMC4216353  PMID: 25364378
Burkitt’s lymphoma; Immunohistochemistry; In situ hybridization
4.  B-cell Lymphomas with Concurrent IGH-BCL2 and MYC Rearrangements Are Aggressive Neoplasms with Clinical and Pathologic Features Distinct from Burkitt Lymphoma and Diffuse Large B-cell Lymphoma 
B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as “double-hit” lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathological features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathological spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we performed case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32-91). Six patients had a history of grade 1-2 follicular lymphoma (FL); review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 months) was inferior to both BL (p=0.002) and IPI-matched DLBCL (p=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (p<0.0001), Mum1/IRF4 (p=0.006), Ki-67 <95% (p<0.0001), and absence of EBV-EBER (p=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen in most BL controls (p=0.001), and exhibited a higher number of chromosomal aberrations (p=0.0009). DHL is a high-grade B-cell neoplasm with a poor prognosis, resistance to multi-agent chemotherapy, and clinical and pathological features distinct from other high-grade B-cell neoplasms. Familiarity with the morphologic and immunophenotypic spectrum of DHL is important in directing testing to detect concurrent IGH-BCL2 and MYC rearrangements when a karyotype is unavailable. The aggressive clinical behavior and combination of genetic abnormalities seen in these cases may warrant categorization as a separate entity in future classifications and call for novel therapeutic approaches.
doi:10.1097/PAS.0b013e3181cd3aeb
PMCID: PMC3152212  PMID: 20118770
MYC; BCL2; diffuse large B-cell lymphoma; Burkitt lymphoma; cytogenetics; high-grade B-cell lymphoma
5.  Ran GTPase-Activating Protein 1 Is a Therapeutic Target in Diffuse Large B-Cell Lymphoma 
PLoS ONE  2013;8(11):e79863.
Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL) showed differential expression of Ran GTPase-activating protein 1 (RanGAP1) between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50) were RanGAP1+, while reactive lymphoid hyperplasia (n = 12) was RanGAP1+ predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180) with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95%) or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin’s lymphoma 91%). Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62) than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52) and healthy controls (0.55 ± 1.58 ng/mL, n = 75) (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test). In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035) and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030) along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon), a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.
doi:10.1371/journal.pone.0079863
PMCID: PMC3819250  PMID: 24223200
6.  Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas 
Journal of Clinical Oncology  2013;32(1):44-50.
Purpose
Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.
Patients and Methods
Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles.
Results
We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event–related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response.
Conclusion
The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.
doi:10.1200/JCO.2012.46.8793
PMCID: PMC3867644  PMID: 24043741
7.  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
8.  Primary pediatric gastrointestinal lymphoma 
Background:
Primary non-Hodgkin's lymphoma (NHL) of the gastrointestinal (GI) tract is the most common extranodal lymphoma in pediatric age group. Yet, the overall incidence is very low. The rarity of the disease as well as variable clinical presentation prevents early detection when the possibility of cure exists.
Materials and Methods:
We studied six cases of primary GI NHL in pediatric age group with reference to their clinical presentation, anatomic distribution and histopathologic characteristics.
Results:
All were males except one. Intestinal obstruction was the presenting feature in 50%. Half the cases showed ileocaecal involvement, while large bowel was involved in 16%. Histology showed four cases of diffuse large B-cell lymphoma (DLBCL), one case of Burkitt lymphoma, and one Burkitt-like lymphoma. Immunohistochemistry for Tdt, CD20, CD3, CD30, bcl2, bcl6 confirmed the morphological diagnosis.
Conclusion:
Pediatric GI lymphoma commonly involves the ileocaecal region and presents with intestinal obstruction. A higher prevalence of DLBCL is found compared to other series. A high proliferative index is useful in differentiating Burkitt-like lymphoma from DLBCL.
doi:10.4103/0971-5851.89786
PMCID: PMC3237187  PMID: 22174497
Gastrointestinal tract; non-Hodgkin's lymphoma; pediatric
9.  Unusual presentation of sporadic Burkitt’s lymphoma originating from the nasal septum: a case report 
Introduction
Burkitt’s lymphoma is a highly aggressive, small, non-cleaved B-cell non-Hodgkin's lymphoma. In the sporadic form of the disease that occurs in non-endemic areas around the world, most commonly in developed countries, patients usually present with an abdominal mass that frequently involves the ileocecal region of the bowel; ocular or orbital involvement is rare. Primary disease of the sinuses is uncommon and, to the best of our knowledge, that of the anterior septum has never been described. We report the diagnosis and successful management of Burkitt’s lymphoma originating from the nasal septum in a male patient.
Case presentation
An otherwise healthy 78-year-old Caucasian man who did not smoke cigarettes was admitted to our Ear, Nose and Throat outpatient clinic with the complaint of nasal obstruction due to left-sided nasal septal thickening. Paranasal computerized tomography revealed a well-circumscribed solid mass originating from his anterior nasal septum and obstructing his airway. The final diagnosis of Burkitt’s lymphoma was verified by immunohistochemical studies. Our patient had a good clinical outcome after chemoradiotherapy, with no problems reported to date in the second year of follow-up.
Conclusion
We provide what we believe to be the first report of a case of sporadic Burkitt’s lymphoma involving the nasal septum, and describe the efficacy of first-line chemotherapy. Being an original case report with broader clinical impact across more than one area of medicine, this case presentation has the potential to significantly advance our understanding of Burkitt’s lymphoma and we emphasize the need to include this disease in the differential diagnosis of patients presenting with a nasal septal mass.
doi:10.1186/1752-1947-7-60
PMCID: PMC3599746  PMID: 23497670
10.  EBV, HHV8 and HIV in B cell non Hodgkin lymphoma in Kampala, Uganda 
Background
B cell non Hodgkin lymphomas account for the majority of lymphomas in Uganda. The commonest is endemic Burkitt lymphoma, followed by diffuse large-B-cell lymphoma (DLBCL). There has been an increase in incidence of malignant lymphoma since the onset of the HIV/AIDS pandemic. However, the possible linkages of HHV8 and EBV to the condition of impaired immunity present in AIDS are still not yet very clearly understood.
Objectives
1. To describe the prevalence of Epstein-Barr virus, Human Herpes virus 8 and Human Immunodeficiency Virus-1 in B cell non Hodgkin lymphoma biopsy specimens in Kampala, Uganda.
2. To describe the histopathology of non Hodgkin lymphoma by HIV serology test result in Kampala, Uganda
Method
Tumour biopsies specimens from 119 patients with B cell non Hodgkin lymphoma were classified according to the WHO classification. Immunohistochemistry was used for detection of HHV8 and in situ hybridization with Epstein Barr virus encoded RNA (EBER) for EBV. Real time and nested PCR were used for the detection of HIV.
The patients from whom the 1991-2000 NHL biopsies had been taken did not have HIV serology results therefore 145 patients biopsies where serology results were available were used to describe the association of HIV with non Hodgkin lymphoma type during 2008-2009.
Results
In this study, the majority (92%) of the Burkitt lymphomas and only 34.8% of the diffuse large B cell lymphomas were EBV positive. None of the precursor B lymphoblastic lymphomas or the mantle cell lymphomas showed EBV integration in the lymphoma cells.
None of the Burkitt lymphoma biopsies had HIV by PCR. Of the 121 non Hodgkin B cell lymphoma patients with HIV test results, 19% had HIV. However, only 1(0.04%) case of Burkitt lymphoma had HIV. All the tumours were HHV8 negative.
Conclusions
The majority of the Burkitt lymphomas and two fifths of the diffuse large B cell lymphomas had EBV. All the tumours were HHV8 negative. Generally, the relationship of NHL and HIV was weaker than what has been reported from the developed countries. We discuss the role of these viruses in lymphomagenesis in light of current knowledge.
doi:10.1186/1750-9378-5-12
PMCID: PMC2907314  PMID: 20591151
11.  Childhood non-Hodgkin lymphomas in the United Kingdom: findings from the UK Children's Cancer Study Group. 
Journal of Clinical Pathology  1997;50(2):128-134.
AIM: To review the presenting clinical features and the histology of cases of non-Hodgkin lymphoma (NHL) entered into the United Kingdom Children's Cancer Study Group NHL Trial. METHODS: Sections of biopsy specimens from all cases entered into the trial were stained with Giemsa and haematoxylin and eosin. All cases were stained immunohistochemically for CD45, CD3, CD45RO, CD20, and CD30. Sections were stained with either naphthol AS-D chloroacetate esterase or KP1 (CD68) to identify granulocytic tumours. In a minority of cases, additional immunohistochemical stains were performed when necessary to establish the diagnosis. The sections were reviewed by three pathologists. RESULTS: Of 308 cases analysed, 293 were categorised as NHL. There was only one case of low grade lymphoma in the series. Over 80% of the cases fell into the categories Burkitt lymphoma (42.2%), lymphoblastic lymphoma (27.2%) and anaplastic large cell lymphoma (15.1%). Cases of Burkitt lymphoma presented most often with abdominal tumours mainly of the ileocaecal region. Tumours of the oropharynx and nasopharynx were also common in this group. Of the 84 lymphoblastic lymphomas, 56 were of the T-cell phenotype, 12 of the B-cell phenotype and 16 of indeterminate lineage. Most of the T-lymphoblastic lymphomas showed mediastinal or pleural involvement. Infiltration of the skin and soft tissues was seen in 25% of lymphoblastic lymphoma of B or indeterminate phenotype. Forty six children were diagnosed as having anaplastic large cell lymphoma, the majority being of T or indeterminate lineage. Most patients presented with lymphadenopathy but involvement of the bones, soft tissues or skin was seen in seven patients and of the mediastinum and lungs in five. CONCLUSION: Childhood non-Hodgkin lymphomas are almost all high grade and frequently extranodal. They fall mainly into the categories Burkitt lymphoma, lymphoblastic lymphoma and anaplastic large cell lymphoma. The separation of these subcategories can be made on the basis of morphology and immunohistochemical features. The anatomical distribution of these different categories of non-Hodgkin lymphoma is distinctive.
Images
PMCID: PMC499737  PMID: 9155693
12.  Diffuse large B-cell lymphoma of the uterus suspected of having transformed from a marginal zone B-cell lymphoma harboring trisomy 18: a case report and review of the literature 
The patient was a 72-year-old female with the chief complaint of abdominal fullness. A giant primary myoma of the uterine cervix was suspected, and total hysterectomy was performed. Based on a postoperative histopathological examination of the tumor a diagnosis of diffuse large B-cell lymphoma (DLBCL) was made in the uterus and a mass in the greater omentum was diagnosed as a marginal zone B-cell lymphoma (MZBCL). No flow-cytometry studies or chromosome or gene examinations were performed on a fresh specimen. The results of an examination of a paraffin block histopathology specimen by fluorescence in-situ hybridization (FISH) showed no mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) (18q21.1), B-cell lymphoma 2 (BCL2) (18q21.3), or BCL6 (3q27) split signals in either the uterus or the greater omentum, however, trisomy 18 was detected in approximately 50%-70% of the tumor cells in both the uterus and the greater omentum. Trisomy 18 was present in around 15-33% of the DLBCL cells and MZBCL cells. These findings suggested a strong possibility that the tumor cells in the uterus and greater omentum were the same clone and that transformation from MZBCL to DLBCL had occurred. Since DLBCLs that result from a transformation usually have a worse outcome than de novo DLBCLs, even when a DLBCL seems to have originated in the uterus the surrounding tissue should always be examined, and caution should be exercised in regard to transformation from a low-grade B-cell lymphoma to a DLBCL.
PMCID: PMC3843282  PMID: 24294388
Marginal zone lymphoma; diffuse large B-cell lymphoma; transformation; trisomy 18; uterus; greater omentum
13.  The Histological and Biological Spectrum of Diffuse Large B-cell Lymphoma in the WHO Classification 
Cancer journal (Sudbury, Mass.)  2012;18(5):411-420.
Diffuse large B cell lymphomas (DLBCL) are aggressive B-cell lymphomas that are clinically, pathologically and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been towards incorporation of clinical features, morphology, immunohistochemistry and ever evolving genetic data into the classification scheme. The 2008 WHO classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling (GEP) heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age, and include EBV-positive large B-cell lymphoma of the elderly. HHV-8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a “solid variant.” Two borderline categories were created; one deals with tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL. The second confronts the interface between Burkitt Lymphoma (BL) and DLBCL, so called “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma” in the 2008 classification. Most cases harbor both MYC and BCL2 translocations, and are highly aggressive. Another interesting entity is ALK+ DLBCL, which renders itself potentially targetable by ALK inhibitors. Ongoing investigations at the genomic level, with both exome and whole genome sequencing, are sure to reveal new pathways of transformation in the future.
doi:10.1097/PPO.0b013e31826aee97
PMCID: PMC3458515  PMID: 23006945
Diffuse large B-cell lymphoma; plasmablastic lymphoma; Burkitt lymphoma; double hit lymphoma; grey zone lymphoma; Hodgkin’s lymphoma; cutaneous lymphoma; central nervous system; immunophenotyping
14.  Double Hit Lymphoma – a Case of Unusual Response After Sequential Aggressive Chemotherapy and Review of the Literature 
Lymphomas with recurrent chromosomal breakpoints activating multiple oncogenes, including MYC, BCL2, and BCL6 are often referred to as “Dual Hit” or “Double Hit” lymphomas (DHL). In the updated classification for malignant lymphomas by the World Health Organization (WHO), the novel category of “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt’s lymphoma (BL)” was proposed in an attempt to create a (temporary) container for aggressive mature B-cell lymphomas that should not be diagnosed as either BL or DLBCL. DHL make up an important part of this novel WHO category, the other part representing heterogeneous cases of aggressive B-cell lymphoma that have features of BL. DHL are highly aggressive lymphomas with generally poor response to first line and salvage treatment. Limited data is available to guide therapeutic decisions, and despite aggressive measures including high dose (HD) chemotherapy followed by autologous hematopoietic cell transplantation (AHCT), outcome is unsatisfyingly poor. Herein, we report a case of a patient with DHL and review the relevant literature.
doi:10.4137/CCRep.S11393
PMCID: PMC4196880  PMID: 25336995
double hit lymphoma; diffuse large B cell lymphoma; autologous hematopoietic cell transplantation; myc; bcl2
15.  Overexpression of MicroRNAs from the miR-17-92 Paralog Clusters in AIDS-Related Non-Hodgkin's Lymphomas 
PLoS ONE  2011;6(6):e20781.
Background
Individuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined.
Methodology/Principal Findings
We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis.
Conclusion
Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs.
doi:10.1371/journal.pone.0020781
PMCID: PMC3116840  PMID: 21698185
16.  NODAL DIFFUSE LARGE B-CELL LYMPHOMAS IN CHILDREN AND ADOLESCENTS: IMMUNOHISTOCHEMICAL EXPRESSION PATTERNS AND C-MYC TRANSLOCATION IN RELATION TO CLINICAL OUTCOME 
Diffuse large B-cell lymphoma (DLBCL) is a very infrequent neoplasm in the pediatric age group; therefore there are very few studies on the immunophenotype or genetics of these cases. We studied a series of 16 patients with nodal DLBCL occurring in patients between 10 and 18 years of age. The cases were classified according to the 2008 World Health Organization classification criteria, with application of immunohistochemistry for the detection of CD10, BCL-6 and MUM1 proteins to divide the lymphomas into germinal center and non-germinal center types. In addition, TCL1, BCL-2 expression, and the Ki-67 proliferation index were evaluated by immunohistochemistry, and c-MYC and BCL-2 translocations were evaluated by FISH. All these parameters were correlated with clinical features and outcome. Our study revealed that centroblastic morphology and the germinal center type of DLBCL are more prevalent in these young patients (63%), with 37% containing a c-MYC translocation. Only one case showed a BCL-2 translocation, reflecting a double-hit case with features intermediate between DLBCL and Burkitt lymphoma. We found a higher frequency of BCL-2 expression than previously reported, with no direct influence on the outcome of the disease in univariate or multivariate analysis. The expression of TCL1 has not been specifically studied in nodal pediatric DLBCL before; we found a 31% incidence of TCL1 expression. MUM1 expression was observed in 44% of the cases and these positive cases showed a significant negative impact on clinical outcome. TCL1 is directly and significantly associated with the presence of c-MYC and a high proliferative index. The germinal center and non-germinal center subtypes showed significant differences for both overall survival and disease-free interval. C-MYC translocation was found in 37% of patients, and had a favorable impact on clinical outcome. We conclude that nodal pediatric and adolescent DLBCL are mainly of the germinal center type, with a generally good outcome in spite of the frequent expression of BCL-2 and the presence of c-MYC translocation. TCL1 expression seems to be associated with a good clinical outcome, while MUM1 expression predicts a poor clinical outcome.
doi:10.1097/PAS.0b013e3181bb9a18
PMCID: PMC2788112  PMID: 19816150
pediatric non-Hodgkin lymphoma; diffuse large B-cell lymphoma; TCL-1; germinal center-like DLBCL (GCB); non-germinal center-like DLBCL; c-MYC and BCL-2
17.  Classification of AIDS-related lymphoma cases between 1987 and 2012 in Japan based on the WHO classification of lymphomas, fourth edition 
Cancer Medicine  2014;3(1):143-153.
The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-naïve patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein–Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.
doi:10.1002/cam4.178
PMCID: PMC3930399  PMID: 24407967
AIDS-related lymphoma; antiretroviral therapy; Burkitt lymphoma; diffuse large B-cell lymphoma; Epstein–Barr virus
18.  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
19.  Ocular adnexal lymphoproliferative disorders in an ophthalmic referral center in Saudi Arabia 
Saudi Journal of Ophthalmology  2013;27(3):227-230.
Purpose
To study the pattern of ocular adnexal lymphoproliferative disorders (OALD) in an ophthalmic referral center in Saudi Arabia and to review their, histopathological characteristics with clinical correlation.
Methods
Retrospective chart review of 40 cases of patients who underwent incisional biopsy with the suspected diagnosis of periocular and/or adnexal lymphoid lesions over the period: 2000–2012 at the King Khaled Eye Specialist Hospital (KKESH), Riyadh, Saudi Arabia. The routine histopathologic slides are reviewed by a single pathologist to identify cases of Benign Reactive Lymphoid Hyperplasia (RLH), Atypical Lymphoid Hyperplasia and probable lymphoma. The identification of the specific types of lymphoma is performed at a tertiary general hospital: King Faisal Specialist Hospital and Research Centre (KFSH&RC).
Results
Forty patients are included with an age range of 11–91 years and a median of 36 years. The males constitute 70% and females 30% of the cases. The right eye and/or orbit are involved in 48%. The left eye is involved in 45% while a bilateral disease is found in 7.5%. The median duration of symptoms is 5 months. The site distribution is conjunctiva (42.5%), orbit (25%), lacrimal gland (12.5%), eyelid (10%), lacrimal sac (7.5%) and caruncle (2.5%). One case is excluded after histopathologic diagnosis of malignant melanoma. Diagnosis in the remaining 39 cases includes: RLH in 14 cases (35%), atypical lymphoid hyperplasia in three cases (9%), and lymphoma in 22 cases (56%). Classification of the lymphoma group is: extranodal marginal zone lymphoma (EMZL) in 9/22 cases (41%), diffuse large B cell lymphoma (DLBCL) in 4/22 cases (18%), Castelman’s disease in 3/22 cases (14%), Burkitt’s lymphoma in 2/22 cases (9%), follicular lymphoma and T cell-rich B cell lymphoma: one case each (4.5%).Two cases remain unclassified.
Conclusion
We have a wide age range which is comparable to other studies. Our results show male predominance and the commonest site of involvement is conjunctival, however if RLH cases are excluded, the commonest site for lymphoma is orbit/lacrimal gland in 45% followed by conjunctival in 23%. The commonest type of lymphoma is: EMZL in 41% followed by DLBCL in 18% then other types of lymphoma including follicular lymphoma.
doi:10.1016/j.sjopt.2013.07.003
PMCID: PMC3770215  PMID: 24227991
Lymphoma; Orbit; Adnexal; Lymphoid hyperplasia; Lacrimal
20.  Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma 
BMC Cancer  2010;10:517.
Background
Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a hallmark of cancer. To assay its extent in human lymphoma, methylation of 24 TSG was analyzed in lymphoma-derived cell lines as well as in patient samples.
Methods
We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated CD44 was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of CD44 and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.
Results
On average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that CD44 was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: CD44 was not methylated in MCL patients (0/11) whereas CD44 was frequently hypermethylated in BL patients (18/29). In cell lines with CD44 hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of CD44. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44+ lymphoma cells. CD44 hypermethylated, CD44- lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.
Conclusion
Our data show that CD44 is epigenetically regulated in lymphoma and undergoes de novo methylation in distinct lymphoma subtypes like BL. Thus CD44 may be a promising new epigenetic marker for diagnosis and a potential therapeutic target for the treatment of specific lymphoma subtypes.
doi:10.1186/1471-2407-10-517
PMCID: PMC2955612  PMID: 20920234
21.  Endocytoscopic findings of lymphomas of the stomach 
BMC Gastroenterology  2013;13:174.
Background
The gastric lesions of various lymphomas were observed at the cellular level using endocytoscopy.
Methods
Endocytoscopy and magnifying endoscopy with narrow band imaging (NBI) were performed in 17 patients with lymphomas of the stomach. The lesions consisted of 7 with low-grade mucosa-associated lymphoid tissue (MALT), 5 with gastric involvement by adult T-cell leukemia/lymphoma (ATLL), 4 with diffuse large B-cell lymphoma (DLBCL), and 1 with peripheral T-cell lymphoma.
Results
On conventional endoscopy, 9 were classified as having superficial spreading type, 7 were mass-forming type, and 1 was diffuse infiltrating type. Anti-H. pylori treatment was given in the 7 MALT lymphoma cases. NBI magnification endoscopy invariably showed dilatation or ballooning and destruction of gastric pits and elongation and distortion in microvessels. Endocytoscopy showed mucosal aggregation of interstitial cellular elements in almost all gastric lymphoma cases. The nuclear diversity in size and configuration was exclusively seen in gastric lymphomas other than MALT lymphoma, whereas the nuclei of MALT lymphoma cells were regular and small to moderate in size. Inter-glandular infiltration by lymphomatous cell elements was frequently observed in MALT lymphoma and DLBCL, but it was uncommon in peripheral gastric T-cell malignancies. Endocytoscopy could identify the disease-specific histology, the lymphoepithelial origin, as inter-glandular infiltration of cellular components in MALT lymphoma and the possibly related DLBCL cases. Complete regression (CR) was observed in 2 of the 7 MALT lymphoma patients. In the 2 patients with CR who underwent repeat endocytoscopy, the ultra-high magnification abnormalities returned to normal, while they were unchanged in those without tumor regression.
Conclusions
On endocytoscopy, intra-glandular aggregation of cellular components was invariably identified in lymphomas of the stomach. Nuclear regularity in size and configuration may indicate the cytological grade, differentiating the indolent low-grade from aggressive lymphoproliferative diseases. The inter-glandular infiltration seen on endocytoscopy can indicate the lymphoepithelial lesions seen in MALT lymphoma and related DLBCL. Endocytoscopy would be applicable for virtual histopathological diagnosis of different lymphoproliferative disorders and their clinical assessment during ongoing endoscopy.
doi:10.1186/1471-230X-13-174
PMCID: PMC3877966  PMID: 24369830
ATLL; DLBCL; Endocytoscopy; Gastric low-grade MALT lymphoma; H. pylori; Narrow band imaging
22.  Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell Non-Hodgkin’s Lymphoma: Results of the FAB/LMB 96 international study 
Clinical studies showed that advanced stage, high LDH, poor response to reduction therapy and combined bone marrow and central nervous system disease are significantly associated with a decreased event free survival (EFS) in pediatric mature B-NHL treated on FAB/LMB96. Although rearranged MYC/8q24 (R8q24) is characteristic of Burkitt Lymphoma (BL), little information is available on other cytogenetic abnormalities and their prognostic importance. We performed an international review of 238 abnormal karyotypes in childhood mature-B-NHL treated on FAB/LMB96: 76% BL, 8% Burkitt-like lymphoma, 13% diffuse large B-cell lymphoma (DLBCL). The main BL R8q24 associated chromosomal aberrations were +1q [29%], +7q and del(13q) [14% each]. The DLBCL appeared heterogeneous and more complex. Incidence of R8q24 [34%] was higher than reported in adult DLBCL. The prognostic value of cytogenetic abnormalities on EFS was studied by Cox model controlling for the known risk factors: R8q24, +7q and del(13q) were independently associated with a significant inferior EFS [HR: 6.1 (p=0.030), 2.5 (p=0.015), 4.0 (p=0.0003), respectively]. The adverse prognosis of R8q24 was observed only in DLBCL while del(13q) and +7q had a similar effect in DLBCL and BL. These results emphasize the significant biological heterogeneity and the development of cytogenetic risk adapted therapy in childhood mature-B-NHL.
doi:10.1038/leu.2008.312
PMCID: PMC2988438  PMID: 19020548
Childhood mature B-cell lymphoma; Burkitt lymphoma; DLBCL; cytogenetics; prognosis
23.  Primary esophageal Burkitt’s lymphoma: a rare case report and review of literature  
Esophageal lymphoma is a rare condition, accounting for less than 1% of all gastrointestinal lymphomas. Primary extra nodal esophageal lymphoma constitutes less than 0.2% cases of the total esophageal lymphomas. The definition of primary GI lymphoma has differed among authors. The etiology of the disease is unknown, with the role of Epstein-Barr virus being controversial. The common symptoms of patients with esophageal lymphoma include dysphasia, odynophagia, weight loss, chest pain or present as a result of complications. Burkitt’s lymphoma is one of the fastest growing human malignancies, with a 100% replication rate. Endemic, sporadic (non-endemic) and immunodeficient variants have been recognized. The diagnosis of Burkitt’s lymphoma relies on morphologic findings, immunophenotyping results, and cytogenetic features. Burkitt’s lymphoma is usually treated with LMB-96 protocol depending on the risk stratification. We present a case of primary esophageal Burkitt’s lymphoma, which has been successfully treated with LMB-96 protocol. An extensive review of literature did not reveal a single case of esophageal Burkitt’s lymphoma. To the best of our knowledge this is the first case report in the world literature with diagnosis of primary esophageal Burkitt’s lymphoma.
PMCID: PMC4185878  PMID: 25289138
Gastrointestinal (GI) lymphoma; Non-Hodgkin’s Lymphoma (NHL); Burkitt’s lymphoma (BL); Diffuse large B-cell lymphoma (DLBCL); COPADM
24.  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
25.  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

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