Extranodal Diffuse Large B-cell Lymphoma Research Articles

Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large b-cell lymphomas of the thyroid – A study of 21 cases

Context: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored. Objective: Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations. Design: A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data. Results: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups....

Diffuse large B-cell lymphoma of the thyroid: Seven cases with review of the literature from India

Background: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of nonHodgkin's lymphoma globally with frequent extra nodal involvement. There is sporadic data available on thyroid DLBCL in Indian population and hence we undertook this retrospective observational study at Kidwai Memorial Institute of Oncology, a tertiary care oncology center in India to analyze the clinico biological features of this disease. Methodology: A total of 7 consecutive cases diagnosed as DLBCL by appropriate lymph node biopsy with evidence of thyroid involvement on fine-needle aspiration cytology of thyroid or thyroid histopathology (following thyroidectomy) were confirmed by immunohistochemistry (WHO classification) between January 2008 and September 2013 were included in this study. Results: A total of 7 patients were included in the study. Median age was 65-years (range: 50-72 years), and all were females. Six out of seven were in stage IIAE and one was in stage IVAE. The distribution according to the international prognostic index was as follows: 3 were in low risk, 1 in low-intermediate, 2 in high-intermediate and 1 in high risk group. Regarding treatment, 5 received CHOP, 1 received COP and 1 received no treatment. 5 patients received radiotherapy. 2 patients underwent subtotal thyroidectomy. Of the 6 patients who received chemotherapy ΁ radiotherapy, 4 had complete response 1 was lost to follow-up at 3 months and 1 alive with no disease at 32 months), 2 had partial response. The median survival was 15 months (3-32 months). Conclusions: Extranodal thyroid DLBCL presents common in elderly age group and in females. A multimodality treatment approach is used to treat this entity and may improve survival compared with unimodality approach.

Prognostic Impact of Extranodal Diffuse Large B-Cell Lymphoma in the Era of Immunochemotherapy and PET/CT Staging

Background:Extranodal disease is common in diffuse large B-cell lymphoma (DLBCL), and involvement of more than one extranodal site is associated with a worse outcome. 18F-fluorodeoxyglucose PET/CT (PET/CT) is the current state-of-the-art for staging of DLBCL, and has shown to be much more sensitive for the detection of extranodal involvement than a stand-alone CT scan. Therefore, a re-evaluation of the clinical significance of extranodal disease among PET/CT staged DLBCL patients is warranted.Patients and Methods:We retrospectively included patients from Aalborg (2007-2012), Copenhagen (2009-2012), and British Columbia (2011-2012) in the present study. The inclusion criteria were, i) newly diagnosed DLBCL, ii) R-CHOP or R-CHOP like first-line treatment, and iii) PET/CT staging. The written PET/CT files were reviewed for disease stage and extranodal sites of involvement. The relationship between number of involved sites, extranodal locations and outcome were assessed with simple Cox regression analyses. Extranodal locations with p<0.1 in univariate analysis were entered in a multivariable Cox regression analysis together with the following International Prognostic Index (IPI) factors: age > 60 years, elevated LDH, ECOG performance score >1.Results:A total of 444 patients with a median age of 65 years (range 16-90) and a male:female ratio of 1.3 were included in the study. Of these patients 28% (n=98) had Ann Arbor stage I disease, 16% (n=72) stage II disease, 16% (n=71) stage III disease, and 46% stage IV disease (n= 203). LDH was elevated in 51% (n=224), and 17% (n=74) had ECOG performance status >1. B-symptoms were present in 37% (n=164) and 26% (n=114) had a bulky mass =/> 10 cm. With a median follow-up of 2.4 years (range 0.5-6.5) in patients still alive at the time of analysis, the 3-year OS and PFS were 73% and 69%, respectively. Extranodal disease was diagnosed in 286 (64%) of the patients. The anatomic locations of extranodal disease and their relations to outcome are shown in Table I. Figure 1A and B show the PFS and OS curves when patients are grouped according to the number of involved extranodal sites. Patients with one or two extranodal sites of involvement had similar outcome (3-year PFS 68% vs. 70%), whereas all patients with involvement of more than three extranodal sites progressed.Conclusions:Extranodal involvement is diagnosed in more than half of all newly diagnosed DLBCL patients staged with PET/CT. Bone/bone marrow involvement was the most common site and associated with a worse outcome. Thus, detection of these lesions with PET/CT is clinically important. The presence of extranodal disease is generally associated with a worse outcome, but our data suggest that the optimal cut-off for prognostication in PET/CT staged patients may be more than two sites rather than more than one site, as according to the IPI.Abstract 1630 Table1:Extranodal DLBCL and their relationship with outcome in PET/CT staged patients treated with R-CHOP. Empty boxes represent variables not included in multivariate models.SiteFrequency, n (%)HR, univariateHR, multivariatePFSOSPFSOSLung33 (7%)1.56, p=0.0021.46, p=0.26Not significantLiver34 (8%)2.39, p=0.0012.43, p=0.002Not significantNot significantBone/bone marrow (PET/CT)127 (29%)2.49, p<0.0012.53, p<0.0011.77, p=0.0071.66, p=0.03Bone marrow indolent NHL (biopsy)28 (6%)0.86, p=0.700.94, p=0.87Bone marrow DLBCL (biopsy)43 (10%)2.55, p<0.0012.66, p<0.001Not significantNot significantGastrointestinal35 (8%)1.27, p=0.431.02, p=0.96Kidney13 (3%)2.10, p=0.061.63, p=0.29Not significantSoft tissue and muscle46 (10%)1.18, p=0.581.17, p=0.64Paranasal sinus15 (3%)1.57, p=0.281.69, p=0.25Pleural fluid16 (4%)2.82, p=0.0053.23, p=0.0032.43, p=0.022.53, p=0.02Testicular13/252 (5%)2.42, p=0.221.81, p=0.41Female genitals10/192 (5%)3.38, p=0.0063.76, p=0.003 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Features of and Treatment Outcome of Neurolymphomatosis: Single Institutional Experience over 7 Years

Abstract Introduction: Neurolymphomatosis (NL) is an extremely rare neurological manifestation of non-Hodgkin lymphoma (NHL) in which peripheral nerve infiltration of lymphoma cells is a dominant feature both clinically and pathologically. Previously, we reported a high frequency of NL as a relapse disease of intravascular large B cell lymphoma (IVL), although NL could present as an initial disease as well as relapsed disease in other types of NHL. In addition, the clinical features and treatment outcomes of NL are largely unknown. However, the recent increase in use of PET/CT in lymphoma has facilitated the diagnosis of NL. Here, we report our experience with NL at our hospital over the period from January 2006 to July 2014. Methods: We reviewed the clinical records at the Hematology/Oncology Department of Kameda Medical Center. The diagnosis of NL required: 1) clinical symptoms and neurological examination findings related to the cranial or spinal nerves; and 2) histological confirmation of malignant lymphoma cells within the peripheral nerve, nerve root/plexus, or cranial nerve; or 3) CT/MRI demonstration of nerve enhancement and/or enlargement of peripheral nerve(s) or nerve root that were also demonstrated by the accumulation of FDG by FDG-PET/CT. Patients with stomach limited mucosa-associated lymphoid tissue (MALT) lymphoma and leukemic infiltration of peripheral nerve due to acute leukemia were excluded from the study. Results: Over the past 7 years, there were 514 patients diagnosed with NHL. Among them, we identified 9 patients (1.8%) diagnosed as having NL. The patients consisted of 2 men and 7 women with a median age of 72 years (range: 63 – 83 years). All 9 patients were histologically diagnosed as a diffuse large B-cell lymphoma (DLBCL). NL occurred as part of the presenting disease in 3 patients and as a relapse disease in the remaining 6 patients. 4 NL patients presented as a relapse disease of IVL, 2 as a relapse disease of nodal DLBCL, and 3 as a concomitant extranodal DLBCL (stomach, ileum, and uterus). CD5 was positive in 7 cases (78%). Diagnosis of NL was made by neurological findings, enlargement and enhancement of affected cranial or peripheral nerves by MRI, and FDG-uptake of affected nerve demonstrated by PET/CT in all patients. Autopsy also confirmed the lymphoma infiltration in 1 patient. The affected nerves included the lumbosacral nerve (5 patients), brachial plexus (2 patients), peroneal nerve (1 patients), cranial nerves (4 patients), especially oculomotor nerve (2 patients), trigeminal nerve (2 patients). Cerebrospinal fluid cytology was positive in 4 cases (44%). All 9 patients received a treatment regimen including high-dose methotrexate (MTX) in addition to rituximab containing systemic chemotherapy. Six patients received involved nerve irradiation, 4 patients at relapse and 2 at presentation. Neurological symptoms of the all patients responded promptly. Six patients subsequently developed CNS involvement despite the prophylactic use of high-does MTX. Six patients died due to progressive NL with a median of 11.3 months after NL development. Three patients are still alive 8, 9, and 92 months from the diagnosis. Two patients received autologous stem cell transplantation (auto-SCT), one survived for more than 7 years but the other relapsed 4 months after auto-SCT and being treated with radiation and chemotherapy. Conclusions: NL occurs in a minority of patients (1.8%) and can present in diverse ways, both at initial diagnosis of lymphoma or after treatment. All of them were DLBCL and 78% were CD5-positive. IVL is a most common type of lymphoma subtype in which develop NL. Contemporary imaging techniques including MRI and PET/CT, can often detect relevant neural involvement. Prognosis remains poor once patient developed NL despite the use of high-dose MTX and rituximab containing aggressive chemotherapy included auto-SCT. Only involved nerve irradiation was effective for the relief of neurologic symptoms. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.

Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored. Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations. A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data. Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively. Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.

Abstract 5192: Mutational analysis of primary central nervous system lymphoma

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal diffuse large B-cell lymphoma (DLBCL). Little is known about the genomic basis of tumorigenesis in PCNSL partly explained by the rarity of biological material available for research studies. PCNSL patients display poor outcomes compared to systemic DLBCL and it is still unclear whether this is linked to the organ-specific microenvironment or reflects a specific, aggressive, intrinsic biological behavior. To our knowledge, the mutational landscape of PCNSL has never been investigated Experimental design: We analyzed 9 paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Then, we performed focused sequencing in 28 additional PCNSL tumors to validate somatic genomic alterations and better estimate their incidence. Mutational data were correlated with copy number variations (CNV) identified by SNP and CGH arrays and clinical data. Results: We identified recurrent somatic mutations in genes involved in key signalling pathways such as NFκB (i.e. MYD88, CD79B, TBL1XR1), B cell differentiation (i.e. ETV6, EBF1, IRF4) and cell cycle control (i.e. BTG1, PIM1). We found somatic mutations on MYD88 (38%), CD79B (30%), TBL1XR1 (22%) or ETV6 (16%) genes and described bi-allelic inactivation of TBL1XR1 and ETV6 genes. Interestingly, the correlation with the outcome showed a significant negative impact of TBL1XR1 mutation on survival in a multivariate analysis. Conclusions: The present study showed that PCNSLs have high genetic heterogeneity and that their mutational patterns display similarities with extracerebral DLBCL, particularly of the ABC subtype, suggesting shared underlying biological mechanisms. These results provide new insights into the mutational landscape of PCNSL and potential targets for therapeutic strategies. This work benefited from the LOC study group network (réseau national de centres experts des lymphomes primitifs du SNC, INCa). Citation Format: Aurélie Bruno, Blandine Boisselier, Karim Labreche, Yannick Marie, Marc Polivka, Anne Jouvet, Clovis Adam, Dominique Figarella-Branger, Catherine Miquel, Anne Vital, Caroline Houillier, Carole Soussain, Karima Mokhtari, Romain Daveau, Khê Hoang-Xuan. Mutational analysis of primary central nervous system lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5192. doi:10.1158/1538-7445.AM2014-5192

Is adding rituximab to CHOP regimen beneficial to patients with extranodal diffuse large B-cell lymphoma? A retrospective study.

e19511 Background: Adding rituximab to CHOP regimen led to significant improvement in diffuse large B-cell lymphoma (DLBCL) treatment outcomes, but its role in case of extranodal DLBCL remains cont...

Relapsed or refractory extranodal DLBCL treated with lenalidomide: A single center study.

e19517 Background: Approximately one third of Diffuse Large B-cell Lymphoma (DLBCL) arise in tissue different from the lymph node and they are usually termed as extranodal DLBCL. Patients (pts.) wi...

The diversity of diffuse large B-cell lymphoma in extranodal sites: overview and update

Extranodal lymphomas are a diverse group of low and high grade neoplasms of B-, T-, and NK-cell lineage, each with characteristic sites of origin, morphology, immunophenotype, genetic features, patterns of spread, and prognosis. The diversity is sometimes seen even within a single histologic type of lymphoma. This phenomenon is especially striking in the category of diffuse large B-cell lymphoma (DLBCL). DLBCLs as classified in the WHO Classification are clinically and pathologically heterogeneous (Swerdlow et al. 2008; Stein et al. 2008). Since the publication of the most recent edition of the WHO Classification of tumours of haematopoietic and lymphoid tissues (Swerdlow et al. 2008), a number of advances in the understanding of these lymphomas have been made. This review provides an overview of extranodal DLBCLs and describes recent updates regarding these lymphomas.

Improved survival with rituximab-based chemoimmunotherapy in older patients with extranodal diffuse large B-cell lymphoma

Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, we investigated the relative benefits of adding rituximab to CHOP chemotherapy in diffuse large B-cell lymphoma (DLBCL) of extranodal origin, and found similar advantage for nodal and extranodal lymphomas. Hazard ratio for overall survival was 0.64 for nodal, and 0.70 for extranodal DLBCL. Hazard ratios for lymphoma-related death were 0.62 and 0.57, respectively. The advantage was largest for DLBCL of the spleen, liver and lung. Conversely, it was not evident for thyroid or testicular lymphomas. Compared with nodal DLBCL, spleen was the only site with significantly better prognosis after R-CHOP.

Intravascular Natural Killer Cell Lymphoma Mimicking Mycosis Fungoides

Intravascular lymphoma is a rare entity. Most cases constitute a variant of extranodal diffuse large B-cell lymphoma, and only 10% of the published cases are of T-cell or histiocytic origin. Even fewer cases of intravascular natural killer (NK) cell lymphoma have been reported. To date, only the intravascular lymphoma of B-cell linage is recognized as a distinct entity by the WHO Classification. Here, we report the clinical, morphological, immunohistochemical, and molecular findings of a 72-year-old male patient with intravascular NK-cell lymphoma of the skin who initially presented with red skin efflorescences suspicious of mycosis fungoides. A skin biopsy revealed large cell infiltrates of NK/T-cell phenotype (CD3ε, CD4, CD8, CD56, and TIA-1), which were localized strictly intravascularly and which were positive for Epstein-Barr virus nucleic acid EBER (Epstein-Barr virus-encoded small RNA). Molecular studies revealed a germline configuration for the T-cell receptor consistent with the possibility of an NK-cell origin. At the beginning, the disease appeared to be limited to the skin with no sign of bone marrow involvement or leukemic dissemination. Chemotherapy was initiated; however, the patient subsequently developed meningiosis lymphomatosa with recurrent epileptic episodes and bone marrow infiltration with pancytopenia 7 months after primary admission. Finally, the patient passed away in a septic shock.

Risk of diffuse large B-cell lymphoma after solid organ transplantation in the United States.

Non-Hodgkin lymphoma arising in the context of immunosuppression is an important adverse outcome after solid organ transplantation. Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed subtype of post-transplantation non-Hodgkin lymphoma, but few studies of transplant recipients have examined subtype-specific risks. Therefore, we examined DLBCL risk in the Transplant Cancer Match Study, including registry-based cancer ascertainment among 96,615 solid organ transplants performed from 2000 to 2008. We determined standardized incidence ratios (SIRs) and 95% confidence intervals comparing DLBCL risk in transplant recipients with that in the general population, and used multivariable Poisson regression models to assess the impact of potential risk factors. We identified 321 incident cases of DLBCL, over 12 times more than expected based on general population rates (SIR = 12.6, 95% confidence interval = 11.2-14.0). SIRs were highest in young recipients and those receiving a lung or pancreas/kidney-pancreas transplant, and were greatly elevated for extranodal DLBCLs at the site of the transplantation compared with other sites. DLBCL risk was highest in the first year following transplantation, and SIRs for early-onset DLBCL risk were elevated in association with Epstein-Barr virus-negative serostatus and use of polyclonal antibody induction therapy. In conclusion, associations between recipient and transplant factors and post-transplantation DLBCL risk suggest a complicated interrelationship among multiple risk factors and timing of disease.

Sites of extranodal involvement are prognostic in patients with diffuse large B‐cell lymphoma in the rituximab era: An analysis of the Surveillance, Epidemiology and End Results database

Approximately a third of the patients with diffuse large B-cell lymphoma present with extranodal involvement. Our study aims to identify primary extranodal sites of disease associated with prognosis in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era. A secondary objective is to describe epidemiological and clinical characteristics of patients with extranodal DLBCL. We included adult patients from the Surveillance, Epidemiology and End Results (SEER) database (2004-2009) in whom DLBCL was the first malignancy diagnosed. Extranodal primary sites were divided into 12 groups according to the topography code reported by SEER. Multivariate overall survival (OS) analyses were performed using Cox proportional-hazard regression models adjusted for age, sex, race, and stage. From a total of 25,992 adult DLBCL patients included in our analysis, 32% presented with extranodal primary sites. Gastrointestinal tract (34%), head/neck (H&N; 14%), and skin/soft tissue (11%) were the most common. In comparison with nodal DLBCL, patients with extranodal involvement were older (with exception of skeletal sites) and presented with earlier stages. In the multivariate analysis, sites associated with worse OS rates were gastrointestinal (Hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.15-1.33; P <0.001), pulmonary (HR 1.59, 95% CI 1.38-1.83; P <0.001), and liver/pancreas (HR 1.58, 95% CI 1.35-1.85; P <0.001), whereas H&N was associated with better survival (HR 0.79, 95% CI 0.70-0.89; P <0.001). In this population-based study, primary extranodal sites of involvement are associated with distinct outcomes in patients with DLBCL. Gastrointestinal, pulmonary, and liver/pancreas sites had a significant worse outcome than nodal sites.

Intravascular large B-cell lymphoma with prominent cutaneous manifestation — case report

Abstract Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) characterized by selective growth of neoplastic cells within the vascular lumen. IVLBCL involves all types of organs and mostly is associated with poor prognosis, but patients with cutaneous variant have significantly better survival. In this article we report a case of 80-year-old woman with prominent cutaneous manifestation of intravascular large B-cell lymphoma.

Extranodal diffuse large B-cell lymphoma: Experience from a tertiary care oncology center in South India

Aims: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL) with frequent extra nodal (EN) presentation. The overall occurrence of lymphomas has been increasing; however, those of EN-NHL have been increasing much more rapidly. There is limited data found on EN-DLBCL in the Indian population and hence we carried out this retrospective observational study of primary EN-DLBCL at our center in Southern India. Materials and Methods: A total of 90 consecutive cases diagnosed as EN-DLBCL (according to the standard criteria) by tissue biopsy confirmed by immunohistochemistry between 2007 and 2011 were included. Staging workup including computed tomography of neck, thorax and abdomen and pelvis, bone marrow aspiration and biopsy was done and International Prognostic Index (IPI) calculated. Staging was according to Cotswold's modification of Ann Arbor. The actuarial survival analysis was performed by Kaplan-Meier. Data were analyzed using the SPSS (version 16) statistical software. Results: The median age in this study was 49 years (18-88) with results showing EN-DLBCL to be 1.36 times more common in males. Advanced stages were seen in 15 subjects (16.6%) and bulky disease in 13 subjects (14.4%). CD20 was positive in 89 (98.8%) while 32 had high serum lactate dehydrogenase. According to the IPI most were low-risk-56 (66.6%). Overall response rate for the various combination chemotherapies was 85.7% with complete response in 62.3%. The overall survival range spanned from 2 to 123 months. Univariate analysis showed only bulky disease was associated with inferior survival. Conclusions: EN-DLBCL was present at an early age compared to nodal DLBCL, present more often in early stage and low IPI score. Chemoimmunotherapy with radiotherapy to the EN or bulky site is the standard treatment at present.

The role of tumor-associated macrophages on serum soluble IL-2R levels in B-cell lymphomas.

Interkeukin-2 receptor (IL-2R) is comprised of three different subunits (α, β, and γ chain) and is expressed on B cells and NK cells besides T cells. CD25 is also known as the IL-2Rα chain on cell membranes, while soluble IL-2R (sIL-2R) is generated by the proteolytic cleavage of the IL-2Rα chain. Levels of sIL-2R in sera are monitored as a marker of disease activity in patients with lymphoma. However, elevated serum sIL-2R levels are also found in inflammatory diseases, such as infectious diseases. Levels of sIL-2R in sera are thought to reflect tumor burden in adult T-cell leukemia/lymphoma due to the expression of CD25 on tumor cells. Conversely, sIL-2R is thought to be mainly derived from activated T cells infiltrating tumor tissues in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) because lymphoma cells except for a subtype of DLBCL are mainly negative for CD25. Matrix metalloproteinase-9, a protease capable of cleaving the membrane bound IL-2Rα chain, is mainly produced by tissue-associated macrophages. Increased macrophages in tumor tissues are reported to be associated with poor prognosis, especially in Hodgkin's lymphoma. We found increased macrophages in DLBCL and FL compared with reactive lymphoid hyperplasia as well as a positive correlation between the levels of sIL-2R in sera and the number of macrophages in tumor tissues in FL and extranodal DLBCL.

Differences In Clinical-Biological Features and Outcome Between Diffuse Large B-Cell Lymphomas Of HIV-Infected and Non-HIV-Infected Patients Treated With RCHOP In The CART Era

BackgroundThe use of combination antiretroviral therapy (CART) has improved the prognosis of HIV-related diffuse large B cell lymphoma (DLBCL). In the pre-CART era, HIV-infected individuals usually presented DLBCL of primary extranodal origin and advanced stage, unlike non-HIV-infected individuals. In the CART era, studies conducted before the introduction of immunochemotherapy pointed outcomes of HIV-infected patients to be approaching those of non-HIV-infected patients. Recently, studies have reported the lack of influence of HIV-infection in the prognosis of Burkitt's lymphoma treated with immunochemotherapy. Nevertheless, there is scarce information comparing the clinical presentation and outcome of DLBCL treated with immunochemotherapy between non-HIV-infected patients and HIV-infected patients in CART era. MethodsWe retrospectively studied two series of DLBCL patients treated with RCHOP; 81 HIV-infected patients included in a Spanish multicentre trial and 84 non-HIV-infected patients diagnosed in our institution between 2002 and 2010. Demographic, HIV-infection, and DLBCL data on each case were collected. DLBCL cases were classified in nodal and extranodal according to a previously reported definition (JCO 2005). Continuous and categorical variables are presented using descriptive statistics. Survival analyses were performed using the Kaplan-Meier method, and compared using the log-rank test. P-values of less than 0.05 were considered statistically significant. ResultsThe median follow-up of HIV-infected patients was 6.5 years and of non-HIV-infected patients was 4.6 years. Non-HIV-infected patients were older at the time of DLBCL diagnosis than HIV-infected patients, median age (range) 62 years (24-80) and 44 years (24-74) respectively; (P<0.001). HIV-infected series had a higher percentage of males (81%) than non-HIV-infected (52%); (P<0.001). There were differences between HIV-infected patients and non-HIV-infected patients regarding the following features: B-symptoms (53% vs. 26%; P<0.001), III and IV Ann Arbor stages (71% vs. 52%; P=0.011), and ECOG performance status higher than 2 (51% vs. 26%; P=0.001). There was a trend for more HIV-infected patients (61%) to have high LDH levels at DLBCL diagnosis than non-HIV-infected patients (45%); P=0.057. On the other hand, the percentage of patients with intermediate-high/high International Prognostic Index, two or more extranodal involvement, and bulky disease was similar in both HIV-infected and non-HIV-infected patients. No differences were observed between HIV-infected and non-HIV-infected series in terms of nodal and extranodal presentation. HIV-infected patients were classified according to the time of CART onset; before immunochemotherapy (69%) and concomitantly with RCHOP (31%). More patients receiving CART prior to immunochemotherapy presented undetectable viral load at lymphoma diagnosis (43%) than patients to whom CART was initiated with DLBCL treatment (4%); P=0.001. Time of CART onset had no effect on the presentation of the remaining clinical features, as well as in CD4-lymphocyte counts at DLBCL diagnosis. Non-HIV-infected patients tended to have a better complete response (CR) rate than HIV-infected patients (81% vs. 69%; P=0.071). Within HIV-infected patients the time of CART onset did not influence the achievement of CR to RCHOP. The overall survival (OS) was better in non-HIV-infected patients (5-year OS 74%; 95%CI: 64-84%) than in HIV-infected patients (5-year OS 56%; 95%CI: 45-67%); P=0.009. No differences in disease free survival (DFS) were observed between HIV-infected (5-year DFS 72%; 95%CI: 60-84%) and non-HIV-infected patients (5-year DFS 73%; 95%CI: 62-84%). In HIV-infected patients time of CART onset neither had impact in OS nor in DFS. Nodal and extranodal DLBCL cases showed similar OS and DFS. ConclusionsIn the CART era, DLBCL of HIV-infected patients still have aggressive features but the incidence of extranodal involvement equalizes that of non-HIV-infected patients. The prognosis of DLBCL treated with RCHOP is worse in HIV-infected than in non-HIV-infected patients.Supported in part by grants EC11-041 and RD12/0036/0029 RTICC from Instituto Carlos III, Spain. Disclosures:No relevant conflicts of interest to declare.

Clinical Significance of sIL-2R Levels in B-Cell Lymphomas

Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas.

Intravascular Large B-cell Lymphoma Transformed from a Mantle Cell Lymphoma: A Case Report and Literature Review

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal diffuse large B-cell lymphoma (NHL) characterized by the presence of neoplastic lymphocytes only in the lumina of small vessels and capillaries. Although studies have shown an association of IVLBCL with other lymphomas, its relationship with mantle cell lymphoma has not been reported. Here we report a rare case of a 76 year-old male with intravascular transformation of mantle cell lymphoma in the adrenal glands. Histopathological examination of the adrenal mass biopsy revealed two cell populations within the fibrovascular tissue – a diffuse and infiltrative small lymphoid cell population and an unexpected large neoplastic cell population. Immunohistochemistry (IHC) for the small lymphoid cells are positive for CD5, CD20, and cyclin D1, with the t(11;14)(q13;q32) chromosomal rearrangement on cytogenetic analysis by interphase fluorescence in situ hybridization (FISH), characteristic for mantle cell lymphoma. The large cells are positive for CD5, CD20 and CD79a and negative for cyclin D1 on IHC, demonstrating exclusive localization within small capillaries by CD34 staining, evident of IVLBCL. In addition, FISH analysis revealed that the large cells also have the t(11;14)(q13;q32) mantle cell lymphoma rearrangement. To our knowledge, the present study provides the first reported case of IVLBCL transformation from mantle cell lymphoma and supports the hypothesis that IVLBCL may arise by transformation from other lymphomas.

Primary mediastinal large B-cell lymphoma segregating in a family: exome sequencing identifies MLL as a candidate predisposition gene

AbstractPrimary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) accounting for 2% to 4% of all non-Hodgkin lymphomas. We report a family of 3 siblings with PMBCL and their cousin with extranodal DLBCL. The histopathological characteristics of lymphomas of all 4 patients are similar, implying post–germinal center differentiation and growth deregulation by other mechanisms than BCL2-mediated inhibition of apoptosis and suggesting a shared biological background. We aimed to identify the genetic defect underlying lymphoma susceptibility in this family using exome sequencing and linkage analysis. The only variant segregating in all 4 patients and not reported in genetic databases was 5533C>A (His1845Asn) in the MLL gene. To our knowledge, this is the first time when familial clustering of PMBCL is reported. Although we propose MLL as a candidate predisposition gene for this condition, this finding needs to be validated in additional cases.