In high-grade ‘starry-sky’ non-Hodgkin’s lymphoma (NHL), particularly Burkitt’s lymphoma (BL), large numbers of apoptotic tumour cells are engulfed by infiltrating tumour-associated macrophages (TAM). In situ studies suggest that in starry-sky TAM in a xenograft model of BL various tumour-promoting, trophic, angiogenic, tissue remodelling, and anti-inflammatory pathways are activated. Furthermore, apoptotic cells have been shown to activate expression of tumour-promoting matrix metalloproteinases in macrophages. This work investigates the hypothesis that apoptotic cells or factors released from apoptotic cells induce additional aspects of the starry-sky TAM signature, which serve to promote tumour growth. Macrophages at different stages of maturation, cultured in vitro in the presence of large numbers of apoptotic cells, were shown to differ in phenotype, giving credibility to the hypothesis. Less mature mouse bone marrow-derived macrophages (BMDM) were better at migrating towards apoptotic cells, whereas mature BMDM were better at phagocytosing them. Lactoferrin, which is released from cells undergoing apoptosis and inhibits the migration of neutrophils, was selected as a candidate mediator in the activation of macrophages by apoptotic cells. Lactoferrin was shown to bind viable human and murine monocytes and macrophages, however only high concentrations, which are unlikely to be physiologically or clinically relevant, were found to affect expression of starry-sky TAM genes or reduce classically-activated macrophage cytotoxicity. The direct effect of apoptotic cells on macrophage activation was assessed. Mature BMDM were not used for these studies as their development in vitro in a highly apoptotic environment was judged likely to bias their activation state toward that of TAM, therefore macrophages were first classically-activated with IFN-γ and LPS. This reduced the expression of many starry-sky TAM genes, including several genes associated with responses to apoptotic cells. However, classical activation did not inhibit apoptotic cell engulfment, but rather enhanced it. Co-culture with apoptotic cells, but not viable cells, increased the gene expression of Gas6, Mrc1, Cd36, Timp2, and Pparg, and the latter was dependent on direct interaction with macrophages rather than factors released from apoptotic cells. Furthermore, classically-activated macrophages were found to induce apoptosis in lymphoma cells, and although pre-co-culture of the macrophages with apoptotic cells did not reduce their ability to induce apoptosis, it enhanced tumour cell growth. Macrophage deficiency of IL-4Rα or galectin-3 did not affect classically-activated macrophage responses to apoptotic cells. However, classical activation of galectin-3 deficient macrophages appeared to restore the decreased ability of galectin-3 deficient, untreated macrophages to phagocytose apoptotic cells. Because of the unique new method of laser-capture microdissection by which starry-sky TAM signatures were established, direct comparisons with expression databases of tissue and in vitro cultured macrophages were not possible, but indirect comparisons suggest starry-sky TAM activation reflects the activation phenotype of a mixture of tissue macrophages. Furthermore, it highlighted phagocytosis as one of the most important pathways activated by starry-sky TAM. Together the results presented here suggest apoptotic lymphoma cells can shape TAM activation signatures in starry-sky NHL, even when macrophages are pre-activated to induce apoptosis in lymphoma cells. This is important when considering the consequences of anti-cancer therapies that induce apoptosis or aim to redirect phagocyte activation.

The clinicopathological feature of primary cutaneous lymphomas according to WHO/EORTC classification and their relationship to EBV in Taiwan has never been reported. This retrospective study collected the patients with cutaneous lymphomas from 1990 and 2006. The morphology, EBER in situ hybridization and immunohistochemistry of primary cutaneous lymphomas were studied to reclassify based on the WHO/EORTC classification. A total of 54 patients were included. Twenty-nine were primary cutaneous lymphomas and 25 were secondary cutaneous lymphomas. The age ranged from 21 to 86 years old (mean 62 years old). Twenty-one (72.4%) were primary cutaneous T-cell and NK-cell lymphoma, including 5 extranodal NK/T-cell lymphoma, nasal type (17.2%), 5 primary cutaneous peripheral T-cell lymphoma, unspecified (17.2%), 4 mycosis fungoides (13.8%), 1 Sezary syndrome, 3 primary cutaneous anaplastic large cell lymphoma, 2 primary cutaneous small-medium CD4+ T-cell lymphoma and 1 subcutaneous panniculitis-like T-cell lymphoma. Eight cases were primary cutaneous B-cell lymphoma (27.6%) including 3 cutaneous marginal zone B-cell lymphoma (10.3%), 3 cutaneous follicle center B-cell lymphoma (10.3%), and 2 diffuse large B-cell lymphoma, leg type (6.9%). Seventeen cases were secondary cutaneous T-cell and NK -cell lymphoma. Eight cases were secondary cutaneous B-cell lymphoma. All primary and secondary extranodal NK/T-cell lymphoma, nasal type, were positive for EBER, however, one of them (10%) without both angiocentric growth pattern and necrosis in histomorphological examination. This is the first clinicopathological study of cutaneous lymphoma according to recent WHO/EORTC classification in Taiwan. In comparison with the Western countries, mycosis fungoides is less common whereas primary extranodal NK/T-cell lymphoma, nasal type, and peripheral T-cell lymphoma, unspecified, is more common in Taiwan. EBER in situ hybridization study is helpful in the diagnosis of extranodal NK/T-cell lymphoma, nasal type, especially in tumor without both angiocentric growth pattern and necrosis.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

The efficacy of therapeutic modalities for non-Hodgkin’s lymphoma have been tested and improved throughout the 19th century through various series of drug trials aimed at eliminating cellular malignancies, first through chemotherapy treatment, and more recently through immunotherapy. While to an extent successful in eliminating cancerous lesions and affected cells, chemotherapy treatments have shown to influence the induction of new malignancies, through genetic mutation, as well as unwanted toxic effects of systemic poisoning. The purpose of this thesis is to compare treatment methods in terms of their biomolecular activity, precision of intended results, and possible drawbacks, as well as their application to specific populations of Non-Hodgkin lymphoma diagnoses, including Follicular and Diffuse Large B-Cell lymphomas. In the following sections on contributing factors specific to Diffuse Large B-Cell lymphomas and Follicular lymphoma, elements of disease prognosis will be analyzed from a molecular and clinical point of view. This includes a focus on the impact of genetic mutation, the immunohistochemical evidence these changes present, as well as the variances in immune cell functionality, and finally a description of symptoms with direction to specific underlying causes. An analysis of standard of care chemotherapy, and monoclonal antibody treatments will then be provided for each occurrence. The second segment will discuss novel techniques being developed for the treatment of lymphoma including but not limited to new monoclonal antibodies, synthetic lethality modulation, inhibition of selected chemokine receptors, DNA vector immunization for production of internal host antibodies, concepts of cell mediated bispecific antibody induced destruction, and new generations of Immunomodulatory drugs. With the recent development of cost effective sequencing technology, included is a discussion of the shift towards personalized medicine treatments, targeting appropriate phenotypic specific populations for optimal results, as it relates to therapies for Diffuse Large B-Cell lymphoma and Follicular lymphoma.

Case Report: Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive tumor of B cells that can arise almost anywhere in the body. It is the most common type of non-Hodgkin lymphoma in adults. We report a case of double hit lymphoma, a rare subtype that has an abnormal MYC and BCL2 gene translocation and occurs in about 5% of DLBCLs. A 58-year-old male with a 15-year smoking history presented with abdominal pain accompanied by weight loss of 20 lbs, night sweats, poor appetite, and fatigue. CT angiogram showed posterior mediastinal mass 3.5x5.6x12.8 cm, massive lymphadenopathy in the retroperitoneum surrounding aorta 10.5x5.2x11cm and a large left upper quadrant mesenteric mass measuring 7.2x10.2x13.6 cm. Left abdominal mass was biopsied and pathology showed DLBCL. FISH showed double hit lymphoma. Bone marrow biopsy and aspiration was negative for involvement. LV EF was 61% per ECHO. Patient underwent PET/CT, which showed extensive adenopathy in the inferior neck, chest, and abdomen, as well as a retroperitoneal mass extending into T10-11 extradural space. International Prognostic Index (IPI) for DLBCL categorized the patient as having a poor prognosis and in the high-intermediate risk group with a 4 year overall survival of 55% and 4 year progression-free survival of 53%. The PET scan results showing multiple extranodal sites was a factor in calculating his prognosis. MRI T spine with contrast showed direct invasion of T9, 10, 11, and 12. Urgent chemotherapy was started with DA-R-EPOCH. Our case demonstrates how imaging predicts the aggressiveness of DLBCL biology. The PET scan is very important in determining the extent of disease and the stage to allow for risk stratification of patients with DLBCL.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare and unique subtype of Hodgkin's lymphoma (HL), accounting for approximately 5% of HL. On histology, NLPHL presents with “popcorn cells” composed of lymphocytic and histiocytic cells that express CD20 and CD45, unlike the pathognomonic Reed-Sternberg cells in classic HL (cHL) that express CD15 and CD30. Such differences in histopathology may require alternative treatment approaches. We present a rare case of NLPHL with atypical features at presentation with excellent response to treatment regimen used in Non Hodgkin’s Lymphoma (NHL). A 36-year-old male presented with acute onset back pain. He also noted multiple gradually enlarging lumps in his neck, axilla, and anterior chest wall for a few months. He mentioned significant constitutional symptoms including fatigue, weight loss, and drenching night sweats. No evidence of end-organ damage was present, except significant hypercalcemia suggestive of hypercalcemia of malignancy. An excisional biopsy of his axillary lymph node confirmed the diagnosis of NLPHL with immuno-stains that were positive for CD20, CD45 and negative for CD15 and CD30. PET scan demonstrated extensive tumor burden in the skeletal system, including the sternum, and multi-stationary lymphadenopathy. Splenomegaly with lymphomatous infiltration was also present. He was assigned stage IV based on the Ann Arbor staging system. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated with a goal of 6 cycles, differing from ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen that is used for cHL. Interval PET scan post 4 cycles of R-CHOP showed no evidence of residual disease. PET scan after 6 cycles demonstrated a complete response (CR), including resolution of hypermetabolic uptake in the spleen, lymph nodes and bones. NLPHL is often considered indolent in clinical courses but with a tendency for multiple late relapses compared to cHL. It still maintains a favorable prognosis. In contrast to cHL, NLPHL less frequently presents with constitutional symptoms, increased tumor burden, or at an advanced stage, which is associated with a worse prognosis. Our patient had multiple features that are unusual in NLPHL such as hypercalcemia, extensive bony involvement with hypermetabolic lytic lesions and significant constitutional symptoms. The clinical conundrum with this rare subtype is whether to treat with HL vs NHL regimens. Literature and the guidelines recommend a conservative approach for low stage NLPHL with observation vs radiation vs single agent rituximab (used in NHL!). Advanced stages require multi-agent regimens ranging from one end of the spectrum with ABVD (used in cHL) to the other end with R-CHOP and its variants (used in NHL). Our patient with a rare subtype of HL had a very unusual and aggressive presentation with CR to R-CHOP demonstrating that rituximab based regimens should be the mainstay of treatment.

Marek’s disease (MD) of chickens is an economically important, contagious, neoplastic disease caused by Gallid herpesvirus type 2. All chicken are susceptible to MDV infection and neoplastic transformation, but, only susceptible genotypes develop gross lymphomas. Lymphomas regress in resistant genotypes from 21 days post infection (dpi). The central aims of this study were to understand the mechanisms of non-MHC associated genetic resistance and the molecular pathways of neoplastic transformation. We hypothesized that, a) in resistant chickens at 21 dpi the tissue microenvironment is compatible with cell mediated immunity but in susceptible lines antagonistic to cell mediated immunity, b) resistant genotypes present immunogenic peptides on their MHC class I which while the peptides presented by susceptible genotypes do not induce CTL immunity resulting in tumor progression. We used inbred, MHC homozygous MD resistant (L6) and susceptible (L7) chickens and reductionist methods to test our hypotheses. Our results indicated that the tumor microenvironment is pro T-regulatory in both resistant and susceptible genotypes, and, the host immune response (pro Th-1 in resistant and pro Th-2/T-reg in susceptible) influences the tumor regression or progression. Statistical analysis of MHC class I bound peptides from resistant and susceptible genotypes confirmed that they present the same peptides and perhaps genes outside the MHC locus play an important role in determining resistance. Next, using Systems Biology tools like genomics, proteomics, Gene Ontology modeling and pathway analysis we compared the transcriptome and proteome of neoplastically transformed cells (CD30hi) and non-neoplastically transformed cells (CD30lo) which are the two components of tumor microenvironment. We demonstrated that: a) in situ, CD30lo cells are pre-neoplastic and the proteome involved in transformation and potential mechanisms that may be controlled by MDV oncogene Meq; b) Meq can drive a feed forward loop that induces CD30 transcription and overexpression, increased CD30 signaling, which then activates NFêB and, in turn, increases Meq transcription; c) Meq transcriptional repression or activation from the CD30 promoter generally correlates with a polymorphism in the CD30 promoter between MD-resistant and -susceptible chicken genotypes and so a herpesvirus has evolved to utilize NFêB as a direct transcriptional activator for its oncogene.

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