A PCR analysis of bcl-2 gene rearrangement in nodal and extranodal non-hodgkins-lymphoma (nhl) - some unusual observations in saudi patients

Non-Hodgkin's lymphoma (NHL) is the most common malignancy referred to our institute which is the largest tertiary referral cancer centre in Saudi Arabia, The proportion of follicular low grade NHL appears to be extremely small in this population (<5% of all NHL). To date, there is no data available regarding any correlation between bcl-2 gene rearrangement and different cell types of nodal and extranodal NHLs in Saudi patients. We used a sequential polymerase chain reaction (PCR) technique to determine the frequency of bcl-2/J(H) recombination occurring via the major breakpoint region (mbr) in 16 GI tract NHLs including 4 MALT lymphomas and 13 follicular (nodal) NHLs. The results showed only 2/13 (15%) nodal follicular NHLs with bcl-2/J(H) fusion DNA whereas 9/16 (56%) of the extranodal NHLs with at least 2 of them exhibiting MALT characteristics were positive for the bcl-2 gene rearrangement. A breakdown of the proportion of extranodal NHLs of different cell types showing bcl-2 rearrangement via mbr was as follows: 5/8 diffuse large non-cleaved cell (DLNCC), 1/3 diffuse small cleaved cell (DSCC), 1/1 follicular small cleaved cell (FSCC) and 2/4 MALTs. The PCR amplified bcl-2/J(H) fusion DNA from 5 randomly selected tumors (2 MALTs, 1 DLNCC, 1 DSCC and 1 nodal follicular lymphoma) were cloned and sequenced. All 5 of them showed different bcl-2/J(H) N-regions confirming the clonality of each tumor sample. The data indicating a very low incidence of bcl-2 translocation in nodal follicular NHLs and a surprisingly high incidence of it in extranodal NHLs are intriguing, and quite contrary to the findings in Western patients. These unusual observations warrant further studies and may suggest that different genetic events are involved in the development of extranodal NHLs including MALT and follicular center-cell NHLs in Saudi patients.     

Primary duodenal follicular lymphoma successfully treated with rituximab

Non-Hodgkin’s lymphoma (NHL) of the gastrointestinal (GI) tract is the most common extranodal lymphoma, accounting for approximately 40% of all extranodal NHLs. Initial treatment of duodenal lymphoma includes surgery, chemotherapy and radiotherapy, alone or in combination. Here, we present a case of stage I primary duodenal follicular lymphoma (FL) showing a complete response after rituximab therapy. Rituximab alone can be an effective alternative treatment for duodenal FL.     

Central nervous system involvement in indolent lymphomas.

BACKGROUND: Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. PATIENTS AND METHODS: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. RESULTS: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1-9 years for treated patients (median 2 years). Three patients died of CNS disease. CONCLUSIONS: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.     

Primary extranodal lymphomas of stomach: clinical presentation,diagnostic pitfalls and management

Gastrointestinal lymphoma is the most common form of extranodal lymphoma, accounting for 30%–40% of cases. The most commonly involved site is the stomach (60%–75% of cases), followed by the small bowel, ileum, cecum, colon and rectum. The most common histological subtypes are diffuse large B-cell lymphoma (DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT). Helicobacter pylori infection has been implicated in the pathogenesis of MALT gastric lymphoma, but its role in gastric diffuse large B-cell non-Hodgkin's lymphoma (NHL) is controversial. The therapeutic approach for patients with gastric NHL has been revised over the last 10 years. Conservative treatment with anthracycline-based chemotherapy alone or in combination with involved-field radiotherapy has replaced gastrectomy as standard therapy in cases with DLBCL. Additionally, MALT lymphomas are mainly treated with antibiotics alone, which can induce lasting remissions in those cases associated with H. pylori infection. Nevertheless, various therapeutic aspects for primary gastric lymphomas are still controversial and several questions remain unanswered. Among others, the role of rituximab, consolidation radiotherapy as well as H. pylori eradication in histological aggressive subtypes warrants better clarification.     

A prospective analysis of circulating saturated and monounsaturated fatty acids and risk of non‐Hodgkin lymphoma

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non‐Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre‐diagnosis red blood cell (RBC) specimens in the Nurses’ Health Study (NHS) and Health Professionals Follow‐Up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T‐NHL), B cell NHL (B‐NHL) and three individual B‐NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B‐NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0 and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T‐NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B‐NHLs other than CLL/SLL and for VLCSFA and MUFA with T‐NHL suggest an influence of fatty acid metabolism on lymphomagenesis.     

Adhesion of Follicular Lymphoma Cells to Lymphoid Germinal Centers—A Potential Mechanism of Tumor Cell Homing Following Autologous Transplantation

Follicular non-Hodgkin's lymphomas (NHL) generally present as disseminated diseases with infiltration of lymphoid organs, bone marrow (BM), as well as peripheral blood (PB). These lymphoma cells may recapitulate the behavior of normal germinal center (GC) B cells, some of which remain in follicles and others which have the capacity to migrate. Normal activated B cells and follicular lymphoma cells bind to GCs in vitro and this interaction is mediated by VLA-4 on the lymphoid cell and VCAM-I on follicular dendritic cells. Since the dissem inated nature of follicular NHLs may be related to the ability of PB and BM cells to recirculate through lymphoid tissues, we examined the adhesive characteristics of follicular lymphoma cells isolated from thesesite. Cells from 10 of 14 cases of follicular NHL involving PB or BM bound to normal GCs. Neoplastic GCs could similarly support the binding of PB or BM derived follicular NHL cells. This interaction was inhibited by monoclonal antibodies directed against VLA-4 and VCAM-1. These studies may provide insight into the clinical behavior of these diseases. More importantly the homing and adhesion of lymphoma cells is likely to be relevant to the use of PB and BM as a source of hematopoietic stem cells following high dose ablative therapy.     

Die Rolle der Strahlentherapie bei seltenen extranodalen Non-Hodgkin-Lymphomen

Extranodal non-Hodgkin lymphoma (NHL) accounts for approximately 30% of NHLs. Extranodal NHLs are mainly located in the skin (mainly T-cell NHL), stomach, small intestines, tonsils and central nervous system (CNS mainly B-cell lymphoma). Uncommon sites represent the orbit, salivary glands, nasal cavity, paranasal sinuses, thyroid gland, lungs, bladder, breast, female genital tract, testes, bone and extradural space. Stage, localization and histology are crucial for the decision of treatment modality. As, in contrast to nodal NHL, extranodal NHLs are more frequently diagnosed in stages I/II, radiotherapy (RT) plays a significant role in the treatment of extranodal NHLs. In general, in patients with low grade NHL involved-field radiotherapy (IF-RT) alone with 30?C40?Gy is recommended. Excellent local control is achieved by IF-RT resulting in high disease-free and overall survival rates. In cases of high grade lymphoma, induction chemotherapy is followed by consolidating IF-RT (36?C40?Gy). The localization and histology are predictors for local control, disease-free and overall survival.     

Non-Hodgkin's lymphoma: the old and the new

During the past decade we have witnessed a number of changes in the field of non-Hodgkin lymphoma (NHL), including new entities added to the classification as well as a better understanding of the biology of diffuse large B-cell lymphoma (DLBCL). An understanding of the epigenetics of NHL is also contributing new agents for the management of this disorder. It has become increasingly clear that DLBCL is a biologically and clinically heterogeneous cell type. Two major categories are now recognized: germinal center B cell and activated B-cell (ABC) types. The former is associated with a good prognosis while the latter is known to have a more adverse outcome. With the use of routine immunohistochemical stains, these two types can be identified. The ABC type is known to be NFK-B dependent. NFK-B is a therapeutic target for bortezomib which is being investigated as treatment for this subtype of DLBCL. Several major changes in the classification will be discussed among which the most important are the recognition of so-called borderline entities. One of the two most common of these is the borderline DLBCL/Burkitt tumor (DLBCL/BL) which has features of both DLBCL and Burkitt's lymphoma. Many of the cases in this DLBCL/BL category contain a translocation of MYC as well as BCL2, so-called "double-hit lymphomas" which have a very aggressive clinical behavior. The second common borderline entity is the mediastinal grey zone NHL (MGZL) which has pathological features intermediate between primary mediastinal B-cell lymphoma and nodular sclerosing Hodgkin lymphoma (NSHL). Overlapping clinical features include young age, male predominance, and localized mediastinal presentation. Anecdotal reports suggest MGZL is relatively resistant to Hodgkin-based chemotherapy. Epigenetic therapy represents a new concept. Histone deacetylase inhibitors (HDACi)and DNA methyltransferase inhibitors constitute a promising new class of antineoplastic agents. They modify the expression of genes related to cancer development. In this review, we discuss the role of HDACi in lymphomagenesis as well as in treatment. To understand the benefits of HDACi in lymphoma treatment, we must appreciate the crucial interplay between BCL6, p53, and STAT3. The STAT3 oncogene is involved in the ABC type of DLBCL, an unfavorable and frequently therapy-refractory lymphoma. STAT3 can be effectively suppressed by several HDACi. We will summarize the results of recent trials with HDACi such as romidepsin, panobinostat and valproic acid that have shown significant preliminary activity in recurrent and refractory lymphomas. Their future role in front-line management remains to be determined.     

Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas.

Clonally related composite lymphomas of Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL) represent models to study the multistep transformation process in tumorigenesis and the development of two distinct tumors from a shared precursor. We analyzed six such lymphomas for transforming events. The HLs were combined in two cases with follicular lymphoma (FL), and in one case each with B-cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). In the HL/FL and HL/MCL combinations, BCL2/IGH and CCND1/IGH translocations, respectively, were detected in both the HL and NHL. No mutations were found in the tumor suppressor genes FAS, NFKBIA and ATM. The HL/DLBCL case harbored clonal replacement mutations of the TP53 gene on both alleles exclusively in the DLBCL. In conclusion, we present the first examples of molecularly verified IgH-associated translocations in HL, which also show that BCL2/IGH or CCND1/IGH translocations can represent early steps in the pathogenesis of composite HL/FL or HL/MCL. The restriction of the TP53 mutations to the DLBCL in the HL/DLBCL case exemplifies a late transforming event that presumably happened in the germinal center and affected the fate of a common lymphoma precursor cell towards development of a DLBCL.     

A systematic overview of radiation therapy effects in non-Hodgkin's lymphoma

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for non-Hodgkin's lymphoma (NHL) is based on data from seven randomized trials. Moreover, data from 17 prospective studies, 22 retrospective studies and 27 other articles were used. In total, 73 scientific articles are included, involving 13,305 patients. The results were compared with those of a similar overview from 1996 including 14,137 patients. The conclusions reached can be summarized as follows: Indolent lymphomas. Data indicate that one-third to one-half of patients with indolent lymphoma in stage I are cured by radiotherapy (follow-up more than 15 years). Addition of chemotherapy to radiotherapy does not indicate any improvement in overall outcome. Optimal radiation dose is not defined and extended field is not superior to involved field. Aggressive localized lymphomas. Data indicate that half of the patients in stage I are cured by radiotherapy alone. Although randomized and non-randomized studies favour combined modality treatment with chemotherapy followed by radiotherapy instead of radiotherapy or chemotherapy alone in localized disease, no firm conclusions can be drawn. Conflicting data have been published on the value of radiotherapy towards bulky disease and no firm conclusions can be drawn. Optimal dose for radiation alone or after chemotherapy has not been established. Total body irradiation (TBI). The value of TBI for treatment of NHL has not been proven. There is no proof that fractionated TBI in conjunction with high-dose chemotherapy is superior to chemotherapy regimens alone. Primary CNS lymphomas. Data show that radiotherapy induces a response of short duration and is associated with major neurotoxicity, especially in elderly patients. High-dose methotrexate therapy seems to lead to longer survival than radiotherapy alone. No randomized trials have been performed. There is fairly good support for primary chemotherapy including high-dose methotrexate followed by radiotherapy in patients below 60 years. To minimize the risk of neurotoxicity of combined modality treatment it has been proposed to use chemotherapy alone and delay radiotherapy for relapse, especially in patients above 60 years, or use it in chemotherapy-resistant disease. Optimal chemotherapy regimen is not defined and the role of radiotherapy remains to be determined. Head and neck lymphomas. There is some support for combined modality treatment with chemotherapy and radiotherapy for aggressive lymphomas in Waldeyer's ring with limited disease. There are sparse data supporting radiotherapy alone in localized indolent lymphomas in salivary glands. Radioimmunotherapy (RIT). Radioimmunotherapy is a new treatment modality with systemic radiation for patients with advanced NHL, where conventional external beam radiotherapy plays only a minor role. Several phase I and II studies with RIT have documented promising results. A variety of monoclonal antibodies, radionuclides and study designs with both myeloablative and non-myeloablative approach have resulted in high response rates in patients with recurrent or refractory NHL. One randomized clinical trial is published, showing superior therapy results with radiolabelled antibody compared with the corresponding unlabelled antibody.     

Non-Hodgkin lymphoma in Chile: a review of 207 consecutive adult cases by a panel of five expert hematopathologists

The distribution of subtypes of non-Hodgkin lymphoma (NHL) in Latin America is not well known. This Chilean study included 207 consecutive cases of NHL diagnosed at five cancer centers in the capital, Santiago, and one center in Vi?a del Mar. All cases were reviewed and classified independently by five expert hematopathologists according to the 2001 World Health Organization classification of NHL. A consensus diagnosis of NHL was reached in 195 of the 207 cases (94%). B-cell lymphomas constituted 88% of NHL, and diffuse large B-cell lymphoma (DLBCL, 38.5%) and follicular lymphoma (25.1%) were the most common subtypes. There was a high frequency of marginal zone B-cell lymphoma (10.3%), as well as of extranodal natural killer (NK)/T-cell lymphoma, nasal type (2.6%) and adult T-cell leukemia/lymphoma (0.5%). Extranodal presentation was seen in 74 of the 195 cases (38%) and the most common extranodal presentation was in the stomach (37.6%). The most common gastric lymphoma was DLBCL (54.5%) followed by mucosa-associated lymphoid tissue (MALT) lymphoma (41%). Overall, the frequency of NHL subtypes in Chile is between that reported in Western and Eastern countries, which is probably a reflection of the admixture of ethnicities as well as the environment and socioeconomic status of its population.     

Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin's lymphoma.

PURPOSE: To explore the safety and therapeutic activity of combination anti-B-cell monoclonal antibody therapy in non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Twenty-three patients with recurrent B-cell lymphoma received anti-CD22 epratuzumab 360 mg/m(2) and anti-CD20 rituximab 375 mg/m(2) monoclonal antibodies weekly for four doses each. Sixteen patients had indolent histologies (15 with follicular lymphoma) and seven had aggressive NHL (all diffuse large B-cell lymphoma [DLBCL]). Indolent patients had received a median of one (range, one to six) prior treatment, with 31% refractory to their last therapy and 81% with high-risk Follicular Lymphoma International Prognostic Index scores. Patients with DLBCL had a median of three (range, one to eight) prior regimens (14% resistant to last treatment) and 71% had high intermediate-risk or high-risk International Prognostic Index scores. All patients were rituximab na?ve. RESULTS: Treatment was well tolerated, with toxicities principally infusion-related and predominantly grade 1 or 2. Ten (67%) patients with follicular NHL achieved an objective response (OR), including nine of 15 (60%) with complete responses (CRs and unconfirmed CRs). Four of six assessable patients (67%) with DLBCL achieved an OR, including three (50%) CRs. Median time to progression for all indolent NHL patients was 17.8 months. CONCLUSION: The full-dose combination of epratuzumab with rituximab was well tolerated and had significant clinical activity in NHL, suggesting that this combination should be tested in comparison with single-agent treatment.     

High-grade transformation of low-grade non-Hodgkin's lymphomas: mechanisms of tumor progression.

In the natural history of low-grade non-Hodgkin's lymphomas (NHL) a prolonged indolent phase of the disease may be followed by clinical progression toward intermediate and high-grade disease. The abrupt appearance of diffuse large cell lymphoma (DLL) in patients with low-grade NHL is usually associated with an accelerated clinical course and shorter time of survival. The histologic transformation has been described for chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and lymphoma of mucosa-associated lymphoid tissue (MALT). Although the histological transformation of low-grade lymphomas are relatively frequent, the clonal relationship between the two neoplasms and pathogenetic mechanisms underlying the progression of the disease are widely debated. In this review, we will focus on the possible relationship between the low-grade and the transformed high-grade NHLs and genetic lesions that may be associated with the histologic transformation and clinical progression of the disease.     

Recent progress in the treatment of malignant lymphoma

The present state of the art and developments in the treatment for Hodgkin's disease (HD), follicular lymphoma (FL), MALT lymphoma, and aggressive non-Hodgkin's lymphoma are reviewed. Four courses of ABVD therapy (ABVd therapy in Japan) followed by involved-field irradiation (IFRT), and 6 to 8 courses of ABVD (ABVd in Japan) are the current state art of the therapy for early stage HD and advanced stage HD, respectively. High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is also the state of the art for refractory or relapsed HD within 1 year after complete remission (CR) produced by polychemotherapy. The prognosis of the patients with 3 or more International Prognostic Scores (IPS) is poor. New intensified polychemotherapy or auto-HSCT as up-front setting is under randomized phase III clinical trial in Europe and the USA. There is no state of the art therapy for indolent lymphoma including FL, or MALT. Promising results were reported from clinical studies using new anti-lymphoma drugs such as rituximab, iibritumomab, or purine analogs (cladribine and fludarabine), and auto-HSCT with effectively purged stem cells or allogeneic HSCT. These therapeutic strategies hold a possibility of cure for indolent lymphomas. Antibiotic treatment for Helicobacter pylori-positive localized gastric MALT lymphoma is the state of the art therapy. However, there is no standard therapy for advanced stage MALT lymphoma. Risk adapted therapy using the International Prognostic Index is essential for the treatment of aggressive NHL. Three courses of CHOP followed by IFRT for localized aggressive NHL and 8 courses of CHOP for the low-risk group of advanced stage aggressive NHL are the state of the art therapies, respectively. High-dose chemotherapy with auto-HSCT is also the state of the art for sensitive relapse patients with aggressive NHL. Although some clinical studies suggested that high-dose chemotherapy with auto-HSCT as up-front setting for high-intermediate or high-risk group aggressive NHL is more effective than conventional chemotherapy, the efficacy remains to be determined. The development of new therapeutic strategies with combined use of molecular targeting drugs such as rituximab, or new anti-lymphoma drugs such as purine analogs, and HSCT is desired for more effective therapy for refractory lymphomas.     

Immunologic markers in non-Hodgkin's lymphoma

The majority of non-Hodgkin's lymphomas (NHLs) are of B-cell lineage, with less than 20% of cases being of T-cell lineage. The B-cell NHLs phenotypically correspond to normal cells in the mid stages of normal differentiation. More specifically, by their expression of B-cell activation antigens, these tumors are the neoplastic counterparts of normal activated B cells. The follicular lymphomas--including the small cleaved, mixed small and large cell, and large cell types, as well as the small noncleaved cell (Burkitt's) lymphomas--represent malignant expansions of normal germinal center B cells by their expression of pan-B cell antigens, B-cell activation antigens, and CD10 (CALLA). The diffuse lymphomas also correspond to normal activated B cells. The small lymphocytic lymphomas express the low-affinity IL-2 receptor and CD5, both of which are induced on normal B cells following mitogen stimulation. The other diffuse B-cell NHLs similarly express activation antigens and resemble "transformed" B cells. The T-cell NHLs generally correspond to normal activated CD4+ T cells. These tumors--which include most peripheral T-cell lymphomas, cutaneous T-cell lymphomas, and HTLV-I-associated adult T-cell leukemias/lymphomas--express antigens induced on activated T cells, including IL-2 and transferrin receptors (CD25 and CD71, respectively), as well as HLA-DR. The lymphoblastic lymphomas, which are generally of T-cell lineage, phenotypically correspond to stages of intrathymic differentiation, often by their coexpression of CD4 and CD8, as well as expression of CD1. It remains controversial whether the immunophenotype of lymphoblastic lymphoma differs significantly from T-cell acute lymphoblastic leukemia. Since immunologic heterogeneity of NHL was first observed, attempts have been made to employ the data as a prognostic variable. Early studies suggested that lineage derivation or expression of markers of proliferating cells affected outcome in NHL. However, these reports were often retrospective, included various histologies, and did not treat patients uniformly. More recent prospective studies with relatively uniformly treated patients, predominantly involving DLCL, suggest that certain immunologically defined subgroups may have significantly different clinical outcomes. However, additional clinical studies will be necessary before treatment options are based upon immunologic markers.     

Epstein‐Barr virus and risk of non‐Hodgkin lymphoma in the cancer prevention study‐II and a meta‐analysis of serologic studies

Epstein‐Barr virus (EBV) causes rare, malignant lymphomas. The role of EBV in other non‐Hodgkin lymphomas (NHLs) remains unclear, but mildly reduced immune function could lead to reactivation of EBV and subsequent NHL. We examined the association between prospectively‐collected plasma EBV antibodies and NHL risk in the Cancer Prevention Study‐II (CPS‐II) Nutrition Cohort and conducted a meta‐analysis of our and published results. The CPS‐II study included 225 NHL cases and 2:1 matched controls. No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen (EA‐D) diffuse and BZLF1‐encoded replication activator antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (ORs) for EBV nuclear antigen‐1 and viral capsid antigen (VCA)‐p18 were elevated but not statistically significant. In the meta‐analysis, both EA (summary OR = 1.52, 95% confidence interval (CI): 1.16–2.00) and VCA (summary OR = 1.20, 95% CI: 1.00–1.44) were positively associated with NHL risk. These results suggest EBV may be associated with a wider spectrum of NHL subtypes, but further study is needed to confirm and fully understand these associations.     

Etiology and pathogenesis of AIDS-related non-Hodgkin's lymphoma

The incidence of NHL is greatly increased in HIV-infected individuals; malignant lymphoma is the second most common neoplasm that occurs in association with AIDS. The vast majority of neoplasms are clinically aggressive, monoclonal B-cell neoplasms that exhibit Burkitt's, immunoblastic, large cell, or transitional histopathology. Approximately 80% arise systemically (nodal or extranodal) and 20% arise as primary CNS lymphomas. A small proportion of neoplasms are body cavity-based, primary effusion lymphomas that are uniquely associated with KSHV infection. Recently, HIV-associated polymorphic lymphoproliferative disorders have been described as well. AIDS-related NHLs appear to exhibit distinctive clinical characteristics according to their histopathology and anatomic site of origin. Factors that contribute to lymphoma development include HIV-induced immunosuppression, impaired immune surveillance, cytokine release and deregulation, and chronic antigenic stimulation. This environment is associated with the development of oligoclonal B-cell expansions. The appearance of NHL is characterized by the presence of a monoclonal B-cell population that displays a variety of genetic lesions, including, for example, EBV infection, MYC gene rearrangement, BCL6 gene rearrangement, P53 mutations and deletions, and RAS gene mutations. The number and type of genetic lesions vary somewhat among AIDS-related NHLs according to their histopathologic category and anatomic site of origin. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of AIDS-related NHLs. Further work is necessary to develop a complete understanding of the etiology and pathogenesis of NHL in the setting of HIV infection. AIDS-related NHL is an important biologic model for investigating the development and progression of high-grade NHLs and NHLs that develop in immunedeficient hosts.     

Type Distribution of Lymphomas in Lebanon: Five-Year Single Institution Experience

Background: Lymphomas represent the fifth most frequent cancer in Lebanon. However, little is knownconcerning epidemiologic characteristics and distribution of lymphoid neoplasms according to the 2008 WHOclassification. Materials and Methods: We conducted a retrospective study of lymphoma cases diagnosed from2008 till 2012 at Hôtel-Dieu de France University Hospital. Results: A total of 502 new cases of lymphoma werediagnosed at our institution during a five year period: 119 cases (24%) were Hodgkin lymphomas (HL) and 383cases (76%) were non-Hodgkin lymphomas (NHL). HLs were equally distributed in both sexes with a meanage at diagnosis of 30 years. Among NHL, 87% (332 cases) were B cell lymphomas, 9% (34 cases) were T celllymphomas and 4%(17 cases) were classified as precursor lymphoid neoplasms. Among B cell lymphomas,44% (147 cases) were diffuse large B cell lymphomas (DLBCL), 20% (65 cases) follicular lymphomas and 8%(27 cases) mantle cell lymphomas. DLBCL were equally distributed in both sexes with a mean age of 58 years.Follicular lymphomas were characterized by a male predominance (57%) and a mean age of 60 years. Mantlecell lymphomas showed a pronounced male predominance (85%) with a mean age of 60 years in men and 70years in women. Some 72% of patients having T cell lymphomas were men, with a mean age of 57 years in menand 45 years in women, while 65% of patients having precursor lymphoid neoplasms were women with a meanage of 22 years in women and 30 years in men. Conclusions: The lymphoma subtype distribution in Lebanon isunique when compared to other countries from around the world. In fact, Hodgkin and follicular lymphomasare more frequent than in most Far Eastern, European and American countries, while T-cell lymphomas andDLBCL are less frequent.     

Expression of inhibitor of apoptosis proteins in B-cell non-Hodgkin and Hodgkin lymphomas

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) inhibit apoptosis by binding specific caspases, and possibly by other mechanisms. Eight IAPs have been identified in humans, of which cIAP1, cIAP2, and XIAP are well known. IAPs are being investigated as potential treatment targets in cancer patients. METHODS: cIAP1, cIAP2, and XIAP were assessed in lymphoma cell lines, 240 B-cell non-Hodgkin lymphoma (NHL) tumors, and 40 Hodgkin lymphoma (HL) tumors. RESULTS: All IAPs were expressed in most NHL and all HL cell lines. In NHL tumors, cIAP1 was expressed in 174 (73%), cIAP2 in 115 (48%), and XIAP in 37 (15%). cIAP1 was positive in all precursor B-cell lymphoblastic lymphoma/leukemia (LBL) and nodal marginal zone B-cell lymphoma (MZL), over 90% of follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), and approximately 50% to 60% of myeloma, Burkitt lymphoma (BL), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), small lymphocytic lymphoma/ chronic lymphocytic leukemia (SLL/CLL), extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT-lymphoma), splenic MZL, and mantle cell lymphoma. cIAP2 was positive in all MALT-lymphoma, over 90% of precursor B-cell LBL (94%), most BL (75%), LPL/WM (71%), and SLL/CLL (67%), and approximately 40% to 60% of follicular lymphoma, myeloma, and DLBCL. XIAP was positive most cases of precursor B-cell LBL (57%) and approximately 30% to 40% of nodal MZL, BL, and DLBCL. In HL tumors, cIAP1 was positive in 30 (75%), cIAP2 in 27 (68%), and XIAP in 23 (58%), and did not correlate with histologic type. CONCLUSIONS: Differential expression of IAPs in B-cell lymphomas suggests differences in pathogenesis that may have implications for novel treatment strategies targeting IAPs.