Marginal zone lymphomas (MZLs) are a heterogeneous group of neoplasms that resemble the normal B-cell populations of the marginal zone of a lymph node. It includes three different subtypes, nodal, splenic, and extra -nodal, each, with overlapping features and yet unique characteristics. Nodal Marginal Zone lymphoma (NMZL) accounts for only 1% of all Non-Hodgkin Lymphoma (NHL). Marginal Zone lymphoma with plasmacytic differentiation is not very common. We report a unique case of Nodal marginal zone lymphoma initially presenting with lymphocytosis and lymphadenopathy, work up indicating low grade lymphoma, subsequently developing hyper viscosity syndrome due to symptomatic IgM monoclonal gammopathy. A 68 year old female was noted to have persistent leukocytosis with lymphocytic predominance after completing treatment for a urinary tract infection. Clinical exam revealed bilateral axillary adenopathy. CT scan of neck, chest, abdomen and pelvis revealed axillary, mediastinal and retroperitoneal adenopathy with splenomegaly. Chronic lymphocytic leukemia (CLL) was suspected and work up initiated. Peripheral blood Flow-cytometry revealed 24% small B-cells with surface kappa light chain restriction consistent with mature B-cell lymphoma or leukemia without typical immune phenotype of CLL. Lab reported significant elevation of total protein at 10 g/dl. Workup for para-proteinemia consistent with IgM level over 5000 mg/dl, with serum viscosity of 8. Axillary lymph node excisional biopsy reported marginal zone lymphoma with plasmacytic differentiation. Bone marrow biopsy demonstrated 42% monoclonal B-cells without co-expression of CD5 and CD23. FISH studies positive for duplication 1q and Molecular testing negative for MYDD88 mutation. Decision was made to initiate chemo therapy with R-CVP for a total of six cycles. Her treatment course was complicated by symptomatic hyper viscosity syndrome necessitating therapeutic plasmapheresis. Patient successfully completed chemo immunotherapy with normalization of blood counts, resolution of palpable adenopathy and splenomegaly. Nodal marginal lymphoma (NMZL) originates from nodal mono-cytoid or marginal zone B cells and the pathogenesis usually involves acquired mutations in oncogenes and tumor suppressor genes involving MLL2, PTTPRD, NOTCH2, and KLF2 genes. The median age is round 70 years with slight male predominance. The clinical picture varies and usually includes generalized lymphadenopathy along with B symptoms and infrequently with mild monoclonal gammopathy (any immunoglobulin subtype-IgM uncommon). Marginal Zone lymphoma with plasmacytic differentiation is not as common and shares immuno-histochemical features with lympho-plasmacytic lymphoma (LPL). They both express B cell markers CD19, CD20, and CD22) and not CD5, CD10 or CD23. Clinically, NMZL is more likely to present with prominent lymphadenopathy, while LPL can exclusively affect the marrow without extramedullary involvement. IgM levels in NMZL tend to be lower than in LPL, typically lower than 1000 mg/d. MYD88 mutation is very common in LPL, and can be seen in 10-15% NMZL. The presence of IgM monoclonal gammopathy increases the serum viscosity which can lead to serious neurologic and ophthalmologic complications. Treatment involves emergent plasmapheresis. Our case highlights a less common NHL, presenting with significant paraproteinemia and developing hyper viscosity syndrome with impressive response to plasmapheresis and chemo immunotherapy.

Background: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. Methods: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998–2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. Results: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20–74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Background: Although lymphoma is one of the most common malignancies in dogs, remission rates and survival times remain stagnant. Treatment with a multi-agent chemotherapy protocol induces remission for less than one year and the majority of patients relapse. Fewer than 25% of dogs live longer than two years with the currently available treatments. Targeted immunotherapy using checkpoint molecule blockade of PD-1 and PD-L1 shows promise for various types of human cancer, including relapsed/refractory lymphoma; however, little is known regarding the role of these checkpoint molecules in canine lymphoma. Objectives: To determine the patterns of expression of mRNAs encoding PD-1 and its ligands PD-L1 and PD-L2 in lymphoma and reactive lymphoid hyperplasia controls. Methods: Retrospective: formalin-fixed paraffin-embedded (FFPE) tissue from dogs with untreated lymphoma (n=10) and reactive lymphoid hyperplasia (n=10). Prospective: fine-needle aspirates (FNAs) from dogs with untreated lymphoma (n=10) and reactive lymphoid hyperplasia (n=10). Total RNA was extracted, and expression of PD-1, PD-L1, and PD-L2 was measured using qRT-PCR analysis of random-primed cDNA. Checkpoint molecule expression levels were determined using the 2^∆∆CT method. Lymphoma immunophenotype was assessed using immunohistochemical analysis of CD3 and CD79a (FFPE) and review of patient medical records (FNA). Data analysis included Wilcoxon ranksum tests, Dunn's procedure of multiple comparisons, Kruskal-Wallis tests, and regression within an ANOVA. Significance at P < 0.05. Results: PD-1, PD-L1, and PD-L2 expression (normalized internally to 18S rRNA) was lower in lymphoma compared to reactive lymphoid hyperplasia (FFPE); the difference was significant for PD-1 and PD-L2. PD-1 and PD-L2 expression was lower in lymphoma compared to reactive lymphoid hyperplasia (FNA); the difference was significant for PD-1. PD-1, PD-L1, and PD-L2 expression was lower in B cell lymphoma compared to reactive lymphoid hyperplasia (FFPE); this difference was significant for PD-1 and PD-L2. PD-1 and PD-L2 expression was lower in B cell lymphoma compared to reactive lymphoid hyperplasia (FNA); the difference was significant for PD-1. The higher relative abundance of PD-L1 vs PD-1 and PD-L2 vs PD-1 was significantly different between lymphoma and reactive lymphoid hyperplasia (FFPE and FNA). Conclusions: In this study, checkpoint molecule expression was not upregulated in canine lymphoma relative to canine reactive lymphoid hyperplasia, suggesting a limited application of PD-1 and PD-L1 blockade in canine lymphoma. The ligand:receptor relative abundance imbalances reflect the lower PD-1 expression relative to PD-L1 and PD-L2 in lymphoma. Although these results do not suggest that checkpoint inhibitors would be useful for treatment, they give insight into the mechanisms of unchecked lymphocyte proliferation in canine lymphoma. / Master of Science / Lymphoma, a cancer of the white blood cells in the body, is one of the most common malignancies in dogs. Although treatment with a multi-agent chemotherapy protocol results in high remission rates, the remission duration is usually less than one year, with the majority of patients relapsing. In an effort to improve remission rates and survival times, scientists have been working to develop therapeutic interventions that target specific points in the development and replication cycle of a cancer cell. One such strategy, targeting checkpoint molecules programed death (PD)-1 and PD-L1, has shown promise for several different types of human cancers, including lymphoma. PD-1 is a receptor on T cells, which together with its ligands, PD-L1 and PD-L2, decreases lymphocyte function when activated. This is a protective mechanism, acting to inhibit sustained harmful inflammation in a normal healthy dog. Some cancers have taken advantage of this pathway, increasing expression of PD-L1 or L-L2 in order to evade detection by the immune system. To date, little is known regarding the role and expression of these immune checkpoint molecules in dogs with lymphoma. We sought to evaluate if PD-1, PD-L1 and PD-L2 expression is significantly increased in canine lymphoma compared to reactive lymphoid hyperplasia controls. Tissue samples were collected from two sources. Cytology samples of lymphoma and reactive lymphoid hyperplasia were collected by fine needle aspiration from clinical patients. Formalin fixed paraffin embedded tissue samples of lymphoma and reactive lymphoid hyperplasia were collected from the archived tissue bank. Using a molecular analysis technique called quantitative reverse transcription PCR (qRT-PCR) we measured the amount of messenger RNA (mRNA) encoding PD-1 and its ligands PD-L1 and PD-L2 in lymphoma and in reactive lymphoid hyperplasia controls. In our results we did not observe an upregulation in the expression of checkpoint molecules in canine lymphoma relative to canine reactive lymphoid hyperplasia. This suggests there may be a limited therapeutic application for PD-1 and PD-L1/PD-L2 blockade in canine lymphoma. Although these results do not suggest that checkpoint inhibitors would be useful for treatment, they give insight into the mechanisms of unchecked lymphocyte proliferation in canine lymphoma.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

<p>Lymphomas are a heterogeneous group of neoplasias originating from B- or T-lymphocytes. In this thesis, we determined the genetic and immunophenotypic characterization of DLBCL and their prognostic impact. Moreover, genomic alterations associated with the transformation to DLBCL from Hodgkin lymphoma (HL) and follicular lymphoma (FL) were elucidated. </p><p>In order to outline the impact of cytogenetic as well as immunophenotypic prognostic markers in DLBCL, we firstly studied a series of 54 DLBCL tumors using comparative genomic hybridization (CGH) and we identified several frequently occurring chromosomal imbalances. Loss of 22q was more often found in the diagnostic tumors with a more advanced clinical stage, while gain of 18q21 was more commonly identified in relapses. Secondly, we correlated the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 with clinical parameters in a series of 173 de novo DLBCL patients. Patients with a germinal center (GC) phenotype displayed a better survival than the non-GC group. Expression of bcl-6 and CD10 was correlated with a better survival while bcl-2 expression was associated with a poor prognosis.</p><p>In approaching the HL transformation, two novel B-cell lines (U-2932 and U-2940), derived from patients with DLBCL following HL, were characterized. Interestingly, a translocation with materials from 2q and 7q as well as loss of material on 6q was found in both cell lines. For FL transformation, we assessed chromosomal alterations in a panel of 28 DLBCL patients with a previous history of FL. The DLBCL tumors displayed more chromosomal imbalances compared to FL tumors. Loss of 6q16-21 and gain of 7pter-q22 were more commonly found in the DLBCL counterparts, suggesting the chromosomal location of putative genes that may be involved in the transformation process.</p>

Lymphomas are a heterogeneous group of neoplasias originating from B- or T-lymphocytes. In this thesis, we determined the genetic and immunophenotypic characterization of DLBCL and their prognostic impact. Moreover, genomic alterations associated with the transformation to DLBCL from Hodgkin lymphoma (HL) and follicular lymphoma (FL) were elucidated. In order to outline the impact of cytogenetic as well as immunophenotypic prognostic markers in DLBCL, we firstly studied a series of 54 DLBCL tumors using comparative genomic hybridization (CGH) and we identified several frequently occurring chromosomal imbalances. Loss of 22q was more often found in the diagnostic tumors with a more advanced clinical stage, while gain of 18q21 was more commonly identified in relapses. Secondly, we correlated the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 with clinical parameters in a series of 173 de novo DLBCL patients. Patients with a germinal center (GC) phenotype displayed a better survival than the non-GC group. Expression of bcl-6 and CD10 was correlated with a better survival while bcl-2 expression was associated with a poor prognosis. In approaching the HL transformation, two novel B-cell lines (U-2932 and U-2940), derived from patients with DLBCL following HL, were characterized. Interestingly, a translocation with materials from 2q and 7q as well as loss of material on 6q was found in both cell lines. For FL transformation, we assessed chromosomal alterations in a panel of 28 DLBCL patients with a previous history of FL. The DLBCL tumors displayed more chromosomal imbalances compared to FL tumors. Loss of 6q16-21 and gain of 7pter-q22 were more commonly found in the DLBCL counterparts, suggesting the chromosomal location of putative genes that may be involved in the transformation process.

Primary gastrointestinal lymphoma is the most common type of extra-nodal lymphoma, representing about 30%-50% of all extra-nodal involvement. The stomach is the most common site, with the colon and rectum accounting for a minority of occurrences. Primary colorectal lymphoma is uncommon, representing only 0.3% of all large intestinal malignancies and approximately 3% of gastrointestinal (GI) lymphomas, with the majority of these being B-cell non-Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common subtype. We present a case of an 85-year-old male who presented with symptoms suggestive of bowel obstruction, who, after further evaluation, was diagnosed with primary non-Hodgkin lymphoma of the colon, DLBCL subtype.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / As research into the treatment of cancers improves patient’s chances for survival, the number of cancer survivors continues to increase. These patients are often treated with chemotherapy and radiation regimens that can increase their risk for cancers and other complications such as heart disease later on. Patients with Hodgkin’s lymphoma tend to be younger than patients with other cancers. Current treatment regimens lead to cures in many Hodgkin’s lymphoma patients with many long term survivors. However, these treatments place survivors at risk for numerous complications, most importantly other cancers and heart disease. Organizations such as the American Cancer Society recommend regular screening and surveillance by a patient’s doctor to detect these potential complications. To assess the factors that affect a patient’s follow‐up care we sent a survey to 365 Hodgkin’s Lymphoma survivors in Arizona and asked them about their specific follow‐up care. The survivors were identified using the Arizona Cancer registry, and 49 (13.4%) responded to our survey. However, of the 365 letter invitations that were sent out, 118 were returned undeliverable leading to a corrected response rate of 19.8%. Of the respondents 93% reported they were getting follow up care. We also looked at patient satisfaction with their care as a second outcome, 34 (72.3%) of the patients stated that they were strongly satisfied with their follow‐ up care. In order to assess physician‐patient communication, we asked patients if they had received a written follow‐up care plan. Of the respondents to this question, 14 (29.7%) noted that they had received a written follow up care plan. These two outcomes were stratified to various demographic factors (age, gender, education status, etc.) to determine if any of these caused a statistically significant difference in a patient’s satisfaction or whether or not they had received a written follow‐up plan. Due to the low number of responders, no statistically significant difference was found. Future studies are needed to further determine whether or not these sorts of demographic factors play a significant role but we believe studies like this are important as cancer survivorship continues to increase.