Development Of Malignant Lymphoma Research Articles

The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism

Obesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

Lymphknotenpathologie – ein Update

Immune suppression is a risk factor for malignant lymphoma development. Progress in medical science has increased the numbers of immunosuppressed patients due to organ transplantations or successful treatment of autoimmune diseases. Different forms of immune suppression and the respective lymphoma entities are discussed in this article. Another issue treated are gray zone lymphomas between Hodgkin's lymphoma and diffuse large B cell lymphoma. This category not only represents a diagnostic challenge but also represents more a true biological continuum.

FOXP3+ regulatory and TIA‐1+ cytotoxic T lymphocytes in HIV‐associated Hodgkin lymphoma

Human immunodeficiency virus (HIV) infects CD4(+) lymphocytes, leading to a development of malignant lymphomas, such as HIV-associated Hodgkin Lymphoma (HIV-HL). This study aimed to assess the differences in cellular composition of the inflammatory reactive background of HIV-HLs. We examined infiltrating T lymphocytes, specifically regulatory T cells, cytotoxic cells, Epstein-Barr virus (EBV) related antigens and HIV-receptor CCR5. In all HIV-HL cases, Hodgkin and Reed-Sternberg (HRS) cells showed EBER1 expression, LMP-1 staining positivity and EBNA-2 staining negativity, except for one case which showed LMP-1 staining negativity. Our histological findings indicate the percentage of CD8(+) , TIA-1(+) lymphocytes was significantly higher in HIV-HL than in non-HIV-HL cases (P < 0.05). On the other hand, the percentage of CD4(+) , FOXP3(+) lymphocytes was significantly lower in HIV-HL than in non-HIV-HL cases (P < 0.05) but present. The percentage of CCR5(+) lymphocytes was significantly lower in HIV-HL than in non-HIV-HL cases (P < 0.05). Usually, CD4(+) and CCR5(+) lymphocytes are reported to be rarely detected in HIV-associated non-Hodgkin lymphomas, but the presence of CD4(+) and/or FOXP3(+) lymphocytes may be implicated in the pathogenesis of HL. In addition, although additional CD8(+) lymphocytes are probably not EBV-LMP specific cytotoxic T-cells, these lymphocytes may also well be involved in the pathogenesis of HIV-HL.

Expression of HAT1 and HDAC1, 2, 3 in Diffuse Large B-Cell Lymphomas, Peripheral T-Cell Lymphomas, and NK/T-Cell Lymphomas

BackgroundIt has generally been proven that histone acetylation and deacetylation are involved in the malignant transformation. To date, however, this has rarely been studied in cases of malignant lymphoma.MethodsWe studied nine cases of reactive lymphoid hyperplasia, 78 cases of diffuse large B-cell lymphoma (DLBCL), 13 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 cases of extranodal NK/T-cell lymphoma, nasal type (NKTCL). Thus, we attempted to elucidate the associations of the degree of the expression of histone acetyltransferase 1 (HAT1), histone deacetylase (HDAC) 1, HDAC2, and HDAC3 with the clinical behaviors of above malignant lymphomas using the immunohistochemistry and a western blot analysis.ResultsThe degree of the expression of HAT1 was higher in cases of DLBCL, PTCL-NOS or NKTCL as compared with reactive lymphoid hyperplasia (p<0.05). The degree of the expression of HAT1 was correlated with that of HDAC1 in cases of DLBCL or NKTCL (p<0.05). The degree of the expression of HAT1 and HDAC1 was correlated with a poor survival in cases of DLBCL or PTCL-NOS (p>0.05).ConclusionsHAT1, HDAC1, and HDAC2 play a critical role in the development of malignant lymphomas. Both HAT1 and HDAC1 might be indicators for a poor prognosis in cases of DLBCL as cooperating factors.

A Case of Mikulicz's Disease Complicated by Malignant Lymphoma: A Postmortem Histopathological Finding

A 66-year-old Japanese man with an 11-year history of Mikulicz's disease (MD) received continuous corticosteroid administration. At age 58, a left renal pelvic mass was identified and diagnosed as an IgG4-related inflammatory pseudotumor. The patient underwent an operation to remove the tumor. Subsequently, he contracted repeated pulmonary infections and eventually died of severe gastrointestinal bleeding. Autopsy revealed systemic lymph node swelling and infiltration in some organs, and diffuse large B-cell lymphoma (DLBCL) was diagnosed. These findings suggest that an IgG4-related disease can be causally related to the development of malignant lymphoma through the occurrence of mucosa-associated lymphoid tissue lymphoma.

Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syndrome

ObjectiveThe development of non-Hodgkin's lymphoma (NHL) confers a high risk of mortality in primary Sjögren's syndrome (pSS) patients, but the sensitivity and specificity of proposed lymphoma predictors are insufficient for...

Risk of malignant lymphoma in patients with inflammatory bowel diseases: A Dutch nationwide study

Immune suppressant medications such as thiopurines and anti-tumor necrosis factor agents are important for maintaining disease control in most patients with inflammatory bowel diseases (IBDs); however, their use has been associated with the development of malignant lymphoma. The purpose of this Dutch nationwide study was to estimate the relative risk of malignant lymphoma in IBD patients. IBD patients who developed a lymphoma between 1997 and 2004 were identified using the Dutch National Database of PALGA. Data from confirmed cases were collected from individual hospitals, including data on Epstein-Barr virus (EBV). The age-adjusted 8-year incidence of malignant lymphoma in the Netherlands was retrieved from the Central Bureau of Statistics. Forty-two hospitals were visited and 285 matches evaluated in the total cohort of 17,834 IBD patients. Forty-four lymphomas were observed, resulting in a relative risk of 1.27 (95% confidence interval [CI]: 0.92-1.68). Only 19 of 44 patients (43%) were exposed to azathioprine/6-mercaptopurine (AZA/6-MP). Remarkably, 92% of patients (11/12) with EBV-positive lymphoma used AZA/6-MP, in contrast to only 19% patients (4/21) with EBV-negative lymphoma, suggesting a strong relation between EBV-positive lymphoma and thiopurine use. This nationwide study does not suggest a significant overall increased risk for lymphoma in IBD patients. A distinct correlation between EBV-positive lymphoma and AZA/6-MP use was observed.

Patients with Systemic Lupus Erythematosus (SLE) Having Developed Malignant Lymphomas. Continuing Complete Remission of Lymphoma Following Chemotherapy, but Not of SLE

AbstractAbstract 5098 Intoduction:The development of malignant lymphomas, generally of the non-Hodgkin type (NHL), and with a preference to diffuse large cell B lymphomas (DLCBL), in systemic lupus erythematosus (SLE), has been proven and analyzed in an exhaustive recent literature. The combination of germline and somatic mutations, persistent immune overstimulation and the impairment of immune surveillance facilitated by immunosuppressive drugs, is thought to be at the origin of the increased lymphoma genesis. However the treatment and course of such affected patients is less known, and prognosis is generally estimated as poor. Materials: Out of 258 patients with complete/incomplete lupus and secondary antiphospholipid syndrome (APS) seen and treated at the institutional Day Hospital between 1982 and 2009, 6 developed lymphomas (4 DLCBL, 1 Hodgkin's and 1 indolent lymphocytic lymphoma). Results:The first 5 patients were treated with chemotherapy and achieved continuous complete remissions (CCR) with a follow-up comprised between 18 and 172 months. One patient achieved complete remission (CR) of both diseases. In the other 4 lupus serology (ANA, APA) persisted, with occasional lupus flares and vascular complications. Conclusion:While eradication of the last cancer stem cell is tantamount to cure in neoplastic disease, persistent autoantigenic overstimulation may contribute to the refractoriness of autoimmunity. The implications of these results for the increasing utilization of hematopoietic stem cell transplantation for severe autoimmune diseases (SADS), with lupus as a paradigm, are extensively discussed elsewhere (1).(1) Rossi E, Catania G, Grassia L, and Marmont AM. Patients with systemic lupus erythematosus (SLE) having developed malignant lymphomas. Continuing complete remission of lymphoma following high-dose chemotherapy, but not of SLE. (submitted for publication) Disclosures:No relevant conflicts of interest to declare.

IgG4-related Sclerosing Disease

An elevated serum titer of immunoglobulin G4 (IgG4), the least common (3% to 6%) of the 4 subclasses of IgG, is a surrogate marker for the recently characterized IgG4-related sclerosing disease. The syndrome affects predominantly middle-aged and elderly patients, with male predominance. The patients present with symptoms referable to the involvement of 1 or more sites, usually in the form of mass lesions. The prototype is IgG4-related sclerosing pancreatitis (also known as autoimmune pancreatitis), most commonly presenting as painless obstructive jaundice with or without a pancreatic mass. Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, but practically any organ-site can be affected, such as retroperitoneum, aorta, mediastinum, soft tissue, skin, central nervous system, breast, kidney, prostate, upper aerodigestive tract, and lung. The patients usually have a good general condition, with no fever or constitutional symptoms. Common laboratory findings include raised serum globulin, IgG, IgG4, and IgE, whereas lactate dehydrogenase is usually not raised. Some patients have low titers of autoantibodies (such as antinuclear antibodies and rheumatoid factor). The disease often shows excellent response to steroid therapy. The natural history is characterized by the development of multiple sites of involvement with time, sometimes after many years. However, the disease can remain localized to 1 site in occasional patients. The main pathologic findings in various extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, accompanied by atrophy and loss of the specialized structures of the involved tissue (such as secretory acini in pancreas, salivary gland, or lacrimal gland). The relative predominance of the lymphoplasmacytic and sclerotic components results in 3 histologic patterns: pseudolymphomatous, mixed, and sclerosing. Immunostaining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). The lymph nodes show multicentric Castleman disease-like features, reactive follicular hyperplasia, interfollicular expansion, or progressive transformation of germinal centers, with the unifying feature being an increase in IgG4+ plasma cells on immunostaining. The nature and pathogenesis of IgG4-related sclerosing disease are still elusive. Occasionally, the disease can be complicated by the development of malignant lymphoma and possibly carcinoma.

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Aging and DNA polymerase beta deficiency (beta-pol(+/-)) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load in mice. Folate deficiency (FD) has been shown to induce DNA damage repaired via the base excision repair (BER) pathway. We anticipated that FD and BER deficiency would interact to accelerate aberrant crypt foci (ACF) formation and tumor development in beta-pol haploinsufficient animals. FD resulted in a significant increase in ACF formation in wild type (WT) animals exposed to 1,2-dimethylhydrazine, a known colon and liver carcinogen; however, FD reduced development of ACF in beta-pol haploinsufficient mice. Prolonged feeding of the FD diet resulted in advanced ACF formation and liver tumors in wild type mice. However, FD attenuated onset and progression of ACF and prevented liver tumorigenesis in beta-pol haploinsufficient mice, i.e. FD provided protection against tumorigenesis in a BER-deficient environment in all tissues where 1,2-dimethylhydrazine exerts its damage. Here we show a distinct down-regulation in DNA repair pathways, e.g. BER, nucleotide excision repair, and mismatch repair, and decline in cell proliferation, as well as an up-regulation in poly(ADP-ribose) polymerase, proapoptotic genes, and apoptosis in colons of FD beta-pol haploinsufficient mice.

Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas

Chronic autoimmune or pathogen-induced immune reactions resulting in lymphoid neogenesis are associated with development of malignant lymphomas, mostly extranodal marginal zone B-cell lymphomas (MZBCLs). In this review we address (i) chemokines and adhesion molecules involved in lymphoid neogenesis; (ii) the autoimmune diseases and pathogens which are associated with development of B-cell lymphomas; (iii) the molecular mechanisms involved in the initiation and progression of MZBCL; and (iv) 'potential' mouse models for MZBCL.

Leydig Cell Tumor and Malignant Lymphoma in a Patient with Nonclassical 21-Hydroxylase Deficiency

A 46-year-old man was admitted in our hospital with hypoglycemia; his FPG was 43 mg/mL. Five years earlier, he underwent simultaneous surgeries for an adrenal adenoma, a benign Leydig cell tumor (LCT), and a malignant lymphoma. Based on the laboratory results, he was diagnosed as congenital adrenal hyperplasia (CAH) due to nonclassical 21-hydroxylase deficiency (21-OHD). On immunohistochemistry analysis using the antibody against adrenal-specific 11beta-hydroxylase antibody, the LCT showed both properties as a testicular cell and as an adrenal cell. The genetic background of 21-OHD might contribute to the development of malignant lymphoma. Such as a case of LCT and malignant lymphoma in a patient with 21-OHD seems to be rare.

Defective control of Epstein-Barr virus-infected B cell growth in patients with X-linked lymphoproliferative disease

We studied the cellular function and lymphokine production of T cells from patients with X-linked lymphoproliferative disease (XLP) when activated by the challenge with Epstein-Barr virus (EBV) infection. We used an assay system in which T cells were stimulated with membrane antigens of autologous EBV-infected B lymphoblastoid cell lines (B-LCL) and we examined cellular and humoral factors derived from the stimulated T cells which control the growth of EBV-infected B-LCL. Immunoglobulin secretion from the autologous B-LCL was suppressed with radiosensitive suppressor cells in the patients with XLP. The degree of suppression was correlated with the immunoglobulin levels in the serum of the patients with acquired hypogammaglobulinaemia (P less than 0.05). In addition, T cells from the patients with XLP failed to produce interferon-gamma (IFN-gamma) (P less than 0.001). Moreover, the T cell supernatants from the patients with XLP were less potent to inhibit the B-LCL growth. This diminished inhibition of the B-LCL growth was correlated well with the decreased concentration of IFN-gamma in the T cell supernatants. These findings suggest that suppressor cells may be activated in the patients with the hypogammaglobulinaemia phenotype of XLP, but the frequent development of B cell lymphoma in hypogammaglobulinaemia indicate that immunoglobulin suppression may not exert enough pressure on the in vivo growth of EBV-infected B cells. The defective secretion of IFN-gamma may be, at least partially, responsible for the abnormal cytotoxic T cell and natural killer activities found in the patients with XLP, and may indicate the clinical evaluation about the preventive injection of IFN-gamma against the development of malignant lymphoma.

Effects of Dietary Antioxidant Supplementation on the Development of Malignant Lymphoma and Other Neoplastic Lesions in Mice Exposed to Proton or Iron-Ion Radiation

Malignancy is considered to be a particular risk associated with exposure to the types of ionizing radiation encountered during extended space flight. In the present study, two dietary preparations were evaluated for their ability to prevent carcinogenesis in CBA mice exposed to different forms of space radiation: protons and highly energetic heavy particles (HZE particles). One preparation contained a mixture of antioxidant agents. The other contained the soybean-derived Bowman-Birk protease inhibitor (BBI), used in the form of BBI Concentrate (BBIC). The major finding was that there was a reduced risk of developing malignant lymphoma in animals exposed to space radiation and maintained on diets containing the antioxidant formulation or BBIC compared to the irradiated animals maintained on the control diet. In addition, the two different dietary countermeasures also reduced the yields of a variety of different rare tumor types observed in the animals exposed to space radiation. These results suggest that dietary supplements could be useful in the prevention of malignancies and other neoplastic lesions developing from exposure to space radiation.

Viral Elimination Reduces Incidence of Malignant Lymphoma in Patients with Hepatitis C

Purpose A high prevalence of malignant lymphoma among patients with hepatitis C virus (HCV) infection has been reported. The aim of this retrospective study was to determine the incidence of malignant lymphoma and the relationship between malignant lymphoma and viral elimination in patients with HCV. Method We studied 501 consecutive HCV-infected patients who had never received interferon therapy and 2708 consecutive HCV-infected patients who received interferon therapy. Results In the non-interferon group, the cumulative rates of malignant lymphoma development were 0.6% at the 5th year, 2.3% at the 10th year, and 2.6% at the 15th year. The cumulative rates of malignant lymphoma development in interferon-treated patients with sustained virologic response were 0% at the 5th year, 0% at the 10th year, and 0% at the 15th year. The cumulative rates of malignant lymphoma development with persistent infection were 0.4% at the 5th year, 1.5% at the 10th year, and 2.6% at the 15th year. The malignant lymphoma development rate was higher in patients with persistent infection than in patients with sustained virologic response ( P = .0159). The hazard ratio of lymphomagenesis in 1048 patients with sustained virologic response was significantly lower than in patients with persistent infection (hazard ratio: 0.13; P = .049). Conclusion Our retrospective study is the first to determine the annual incidence of malignant lymphoma among patients with HCV at 0.23%. Our results indicate that sustained virologic response induced by interferon therapy protects against the development of malignant lymphoma in patients with chronic HCV.

Clinical implication of distinction from clinical features and treatment outcome of malignant lymphoma in Korean childhood and young adult

18534 Background: The Clinicopathologic features of malignant lymphomas vary to geography and differ to age. The goal of this study was to find the implication of distinction from biology, clinical features and treatment outcome of malignant lymphoma in childhood and young adult. Methods: We analysed the clinical features including age, gender, histologic type, and treatment outcome of 294 children and young adults during 13-year period (from May 1993 to November 2005) in Samsung medical center and compared our study to all age group and western childhood and adolescence group on clinical features or treatment outcome in malignant lymphoma. Results: Median age at diagnosis was 20.7 years (range: 0.1–30.1 years). Male to female ratio was 1.37:1, Of 294 cases, there were 248 cases of non-hodgkin’s lymphoma (NHL) (84.3%) and 44 cases of hodgkin’s disease (HD) (15%). This rate was significantly different to rate of all age group (HD= 5.3%) (p=0.001). Of 248 cases of non-hodgkin’s lymphoma, 134 cases (54.0%) were B-lineage and 113 cases (45.6%) were T- or NK-cell lineage. Our study group had higher rates of T- or NK-cell NHL compared to all age group (p=0.001) and western group (p=0.001). Among 248 cases of NHL, the most common histologic type was diffuse large cell lymphoma (DLBL) in our study group. Burkitt’s lymphoma (BL) was the most common histologic types in Western study group. 5-year survival rate (5YSR) was 80.4% and was superior for BL and was inferior for NK/T cell lymphoma. However male T-LBL patients had better outcome in western study group. NHL and T-cell NHL had significantly worse outcomes than HD and B-cell NHL (p=0.049, 0.001, respectively). Comparing age-groups 0–10, 10–20 and 20–30, 5YSR was inferior for the oldest patients only in NHL-, T-cell NHL- and T-cell LBL-groups. Conclusions: Our study suggested environmental and genetic factor was associated with the development of malignant lymphoma. No significant financial relationships to disclose.

Development of malignant lymphoma subsequent to breast cancer

The development of malignant lymphoma following breast cancer has not been described before. Here we report the development of malignant lymphoma at the ipsilateral chest wall subsequent to the surgical treatment of breast cancer. A 48-year-old woman underwent modified radical mastectomy due to breast carcinoma. Tamoxifen (10 mg twice daily) was given 3 years after the operation and continued for about 3 years. The patient was well until she recently (17 years after the initial operation) noted a small lump at her left anterior chest wall near the axilla. The local tumour mass was initially assumed to be a local recurrent lesion of breast cancer. Excisional biopsy was performed and eventually was histologically diagnosed to be malignant lymphoma. In view of the therapeutic implication, the development of second malignancy should not be mistaken as a progression of the known primary malignancy. Only with the awareness of such entity, can the prompt diagnosis and proper treatment be achieved.

Sick Leave due to Depressive Disease: Not a Risk Factor for the Development of Malignant Lymphoma

For unknown reasons the incidence of non-Hodgkin's Lymphomas (NHL) has increased during the last decades. Conditions with impaired immune functions have been associated with an increased risk of malignant lymphomas. Interactions between the central nervous, immune, and endocrine systems have been recently identified, and the potential physiological importance of these interactions is being explored. In this prospective cohort study the potential association between an increasing incidence of depressive disorders and the development of malignant lymphoma is being explored. The participants were part of the Swedish manpower on sick leave between 1988 and 2000 with depressive disease for more than two weeks were followed until a diagnosis of lymphoid malignancy, death, emigration, or end of follow-up period. The final cohort included 87,677 individuals with 373,135 years of follow-up. There were 80 cases of NHL, chronic lymphocytic leukemia (CLL), and Hodgkin lymphoma (HL) with 70 cases expected. The first year of follow-up showed a slightly increased risk of NHL, which most probably can be interpreted as initial symptoms of lymphoma. We conclude that the increase in the incidence of malignant lymphomas observed during the last decades seems not to be associated with a concurrent increase of depressive disorders.

Lymphomatoid Papulosis Associated with Recurrent Cutaneous T-Cell Lymphoma

Introduction: Lymphomatoid papulosis is a chronic benign disease which may be associated with malignant lymphomas. This case illustrates the relapsing and remitting nature of both lymphomatoid papulosis and its potential of developing cutaneous T-cell lymphoma and narrowband ultraviolet B (NB-UVB) phototherapy as a new modality of treatment of early-stage mycosis fungoides in these patients. Clinical Picture: A 44-year-old woman has had recurrent crops of papules and nodules of lymphomatoid papulosis on the limbs for 15 years. Histological features are consistent with the type B lesions of lymphomatoid papulosis. Eight years after the initial onset of these lesions she developed cutaneous T-cell lymphoma (mycosis fungoides). Since then, she has had recurrence of mycosis fungoides following the cessation of phototherapy, but had no evidence of systemic involvement. Treatment: The lesions of lymphomatoid papulosis responded to intermittent courses of oral methotrexate. Mycosis fungoides was treated with oral psoralen and ultraviolet A phototherapy with good response. Unfortunately, the lesions relapsed whenever phototherapy was discontinued. The most recent recurrence of mycosis fungoides was treated with NB-UVB therapy. Outcome: The papules of lymphomatoid papulosis continue to appear but she remains free of lesions of mycosis fungoides, 10 months after cessation of NB-UVB therapy. Conclusion: Long-term surveillance is essential in all cases of lymphomatoid papulosis as accurate predictors for the development of malignant lymphoma in these individuals are still lacking.

B cells under influence: transformation of B cells by Epstein–Barr virus

Epstein-Barr virus (EBV) is an extremely successful virus, infecting more than 90% of the human population worldwide. After primary infection, the virus persists for the life of the host, usually as a harmless passenger residing in B cells. However, EBV can transform B cells, which can result in the development of malignant lymphomas. Intriguingly, the three main types of EBV-associated B-cell lymphoma - that is, Burkitt lymphoma, Hodgkin lymphoma and post-transplant lymphomas - seem to derive from germinal-centre B cells or atypical survivors of the germinal-centre reaction in most, if not all, cases, indicating that EBV-infected germinal-centre B cells are at particular risk for malignant transformation.