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At least 19 recordsLinked to original sources
PubMed1992

[Malignant lymphomas in spleen--morphology and microenvironment].

The different entities of malignant lymphomas in the spleen exhibit characteristic stage-dependent infiltration patterns which, in conjunction with cytologic findings, may be employed for diagnostic purposes. These infiltration patterns result from complex interactions between neoplastic and non-neoplastic splenic cell populations which are only incompletely understood. These interactions are governed by intrinsic properties of the involved cell populations, e.g. surface receptors, proliferation activity, cytokine production, immunocompetence etc., as well as by extrinsic factors, e.g. splenic microanatomy and the behavior of splenic immunocompetent and accessory cells which are responsible for the highly organized splenic microenvironments.

Diagnosis, Differential↗
PubMed1985

Target cells and thymus microenvironment in the pathogenesis of thymic lymphomas in C57BL/Ka mice.

In C57BL/Ka mice, the induction of thymic lymphomas either by inoculation of radiation leukemia virus (RadLV) or by a split dose irradiation requires complex cellular events: Target cells are found among the population of thymic subcapsular blast cells, or, alternatively, of marrow or spleen prothymocytes; Progression of target cells to lymphoma growth requires a multi-step process, which occurs only within thymic microenvironment; Target cells are rapidly induced as "preleukemic" cells; After inoculation of RadLV, the initial events occur when target cells are in close association with cells of a specialized component of thymic epithelium, i.e., the so-called "nurse cells"; The leukemogenic agents induce damages to the thymic microenvironment itself; Lymphoma prevention by marrow grafting after irradiation results from mechanisms still unknown which inhibit the progression of "preleukemic" cells to neoplastic growth.

Animals↗
PubMed1993

The nonlymphoid microenvironment of reactive follicles and lymphomas of follicular origin as defined by immunohistology on paraffin-embedded tissues.

Twenty-five reactive lymph nodes, 10 palatine tonsils, and 72 B-cell non-Hodgkin's lymphomas (NHLs) of supposed follicular origin were investigated in an immunohistologic study of fixed, paraffin-embedded tissues using a panel of monoclonal antibodies reactive with antigens resistant against fixation and paraffin-embedding techniques together with polyclonal antibodies. The results concerning the microenvironmental organization of reactive lymphoid follicles confirmed that the distribution of CD21+ and CD23+ dendritic reticulum cells, vimentin+ fibroblastic reticulum cells, and CD68+ tingible-body macrophages is heterogeneous with reference to their immunostaining patterns and topographic localization within the germinal center and mantle zone. Moreover, a close microenvironmental similarity between the follicular lymphomas of supposed germinal center or mantle zone origin and their normal counterparts was noted. The study of the microenvironment of the B-zone small lymphocytic lymphoma cases, showing the same distribution patterns for the nonlymphoid cells as seen in mantle zone lymphomas, corroborated the supposed follicular origin of this unusual variant of small lymphocytic lymphoma. In conclusion, this study shows that monoclonal antibodies recognizing CD21, CD23, and CD68 antigens may be valuable additions to vimentin, S-100 protein, laminin, and type IV collagen antibodies for investigating the microenvironmental organization of lymphoid tissues in both normal and neoplastic conditions.

Biomarkers↗
PubMed2002

Chronic B cell malignancies and bone marrow microenvironment.

Chronic B-lymphoid malignancies depend upon supportive interactions within specific microenvironments. Follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) cells accumulate in the bone marrow (BM) where they receive survival or growth signals from by-stander cells. However, they deeply differ in their interaction with the microenvironment. We propose a model where FL and CLL recreate in the BM the microenvironment most suitable to their growth by 'importing' the normal cells that usually nurse them in secondary lymphoid organs. In contrast, MM takes advantage of the actual BM microenvironment by 'instructing' it through an abnormal activation state.

Bone Marrow↗
PubMed1998

Natural killer cell-derived large granular lymphocyte lymphoma of lung developed in a patient with hypersensitivity to mosquito bites and reactivated Epstein-Barr virus infection.

A 17-year-old female developed natural killer (NK) cell-derived large granular lymphocyte (LGL) lymphoma of the lung. She had a past history of hypersensitivity to mosquito bites (HMB). After an eight-year chronic, active Epstein-Barr virus (EBV) infection, she developed multiple lung lesions and pleural effusion. In the effusion, 60% of the cells were LGL. They were CD2+, 3-, 16+, 56+, 57+, 45RO+/RA + weak, and possessed strong NK activity. No rearrangement of T-cell-receptor genes was detected. From all these results, a diagnosis of NK-LGL lymphoma of the lung was made. EB virus DNA was detected in cells infiltrating the pleural effusion. The clonality of the LGLs was determined by Southern blot hybridization with the terminal repeat sequence of EB virus as a probe, and by chromosomal abnormalities. The patient died from respiratory failure. Necropsy of the lung revealed diffuse lymphoma composed of polymorphic cells with typical angiocentric lesions. Reportedly, lymphomas of NK lineage show predominantly extranodal involvement, and primary lung lesions are rare. In the pleural effusion of the present case, abnormally high levels of soluble Fas ligand, interleukin-10 and interferon gamma were detected. This hypercytokinemia, reflecting the microenvironment of lymphoma cells, may play a role in the progression of the lymphoma and organ injury in the lung.

Adolescent↗
PubMed1995

A multivariate study of non Hodgkin's lymphoma involving proliferation, apoptosis, bcl-2 and the microenvironment.

The study was carried out on 22 patients with non-Hodgkin's lymphoma (NHL) who had received sequential infusions of two thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). Cell cycle kinetic studies seemed to differentiate distinctly between low grade lymphoma (n = 8, LI = 2.6%) compared to that of intermediate grade (n = 9, LI = 13%, p = 0.0001) and high grade NHL (n = 5, LI = 16.3%, p = 0.0062). While the majority of 14 intermediate and high grade lymphomas had a high labeling index there were 3/14 patients with a LI of 5.5%, 5.5% and 4.1% respectively. A decrease in the rate of programmed cell death (PCD) or apoptosis due to the overexpression of bcl-2 has been implicated as the possible pathogenesis for follicular lymphoma. We determined the presence of bcl-2 protein immunohistochemically and apoptosis by in situ end labeling of DNA which detects cells in early stages of PCD not recognized morphologically. Nine NHL patients demonstrated PCD ranging from 1%-40%, while it was undetectable in 13/22 patients. Of these 13 cases, 6 showed the presence of bcl-2 expression. To understand the relationship of the microenvironment to the lymphoma cells, the presence of transforming growth factor beta (TGF-beta) was determined immunohistochemically. TGF-beta was present in all the cases where bcl-2 was present, except one. This study highlights some of the key biological features of NHL cells and their microenvironment.

Apoptosis↗
PubMed1977

Spontaneous and induced appearance of murine leukemia virus antigen containing cells in organ cultures of embryonic mouse thymus.

The potential of embryonic thymus organ cultures for studies on relations of endogenous MuLV, lymphoid cells and thymic microenvironment to lymphoma development were evaluated. Four main findings are reported. First, thymuses of 14-day-old CBA and AKR embryos could be maintained in organ cultures for at least 9 weeks with sustained production of lymphocytes. Lymphopoiesis in CBA and AKR thymuses were not grossly different. Secondly, an indirect immunofluorescence (IF) technique demonstrated spontaneous appearance of MuLV-antigen-containing cells in AKR, but not in CBA thymuses. Such spontaneous MuLV expression first occurred after 16 days of organ culture, thereafter infrequently and at random in individual thymus cultures. Thirdly, incubation of AKR and CBA thymuses in lymphoma extract containing AKR-type MuLV at initiation of organ cultures induced MuLV-antigen-containing cells. These were first detected after 7-14 days in culture, somewhat earlier and initially more frequently in AKR than in CBA thymuses. In the former, induction was accompanied by a clear reduction in the number of lymphocytes per thymus. Fourthly, iododeoxyuridine (IdUrd) treatment of AKR thymuses on cultute day 0, 3 or 7 decreased the number of lymphocytes per thymus and induced appearance of MuLV-antigen containing cells, assayed 8-20 days later. The IdUrd effect was most marked on day 0, and decreased sucessively on days 3 and 7. IdUrd had a much slighter effect on CBA thymuses, causing a lower reduction in cell numbers and inducing few MuLV-antigen cells. These main results clearly demonstrate the potential usefulness of the organ culture system for studied on leukemogenesis. It may be directly applied to answer several questions raised by detailed findings in our study.

Animals↗
PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗
PubMed2001

Variation in simian immunodeficiency virus env V1 region in simian AIDS-associated lymphoma.

Genetic variation of SIV env during the course of infection provides a large population pool that is continually shaped by selective forces in vivo and may influence the development of clinical disease. SAIDS-associated lymphoma (SAL) in the SIV-infected macaque is typically a clonal or oligoclonal mass of B cell origin, extranodal in anatomic distribution, in which SIV is restricted largely to infiltrating macrophages. To explore the degree of genetic variation in SIV env represented in SAL, a 480-bp DNA fragment containing the V1 region was PCR amplified from seven cases of SAL and from a nonneoplastic lymph node of an SIV-infected macaque. The nucleotide sequence of the V1 region was determined from at least 10 clones from multiple independent amplification reactions of each tissue. Overall, the degree of V1 variability within lymphomas was found not to be restricted but to resemble the heterogeneity reported in SIV-infected lymphoid and other tissues. V1 variation in the nonneoplastic lymph node was unexpectedly limited, perhaps related to the unusual disease condition associated with SAIDS in that animal. Unlike observations from SIV-infected tissues of animals without neoplastic disease, no increase was detected in the number of O- or N-linked glycosylation sites in the V1 regions isolated from lymphomas as compared with the original inoculum. These findings suggest that, within the microenvironment of the lymphoma, the immune evasion conferred by increased glycosylation may offer little selective advantage.

Algorithms↗
PubMed1996

Characterization of the AKR thymic microenvironment and its influence on thymocyte differentiation and lymphoma development.

The thymic stroma has long been implicated in AKR thymic leukaemia. In this study an extensive panel of monoclonal antibodies was used to investigate changes in the AKR thymic microenvironment, in parallel with thymocyte differentiation of normal (2 month), preleukaemic (5-7 month) and leukaemic (> 7 month) mice. We found select alterations in the thymic stroma, including a loss of isolated medullary antigens and changes in MTS 32, a mAb detecting an antigen on both thymocytes and stroma in the thymic cortex. Stromal alterations were accompanied by shifts in thymocyte differentiation and the appearance of the leukaemogenic mink cell focus-forming (MCF) murine leukaemia virus.

Analysis of Variance↗
PubMed1997

Loss of T cell receptor diminished tumorigenicity of thymocyte-derived lymphoma cells in the T cell receptor transgenic mice.

Mice with transgenic T cell receptor (TCR) recognizing H-Y male antigen developed spontaneous lymphomas originated from immature thymocytes, with the surface expression of transgenic TCR and CD4/CD8 co-receptors. During in vitro long-term culture (3 months) some lymphoma cell lines lost the surface expression of TCR and co-receptors. Interestingly, the proteins of transgenic receptor were expressed intracellularly but TCR was not detectable on the surface of the in vitro selected subline in contrast to TCR-positive parental cells maintained in vivo. TCR-negative subline has been found to be slowly growing in vivo (i.p. injection) and less tumorigenic (s.c. injection) than parental TCR positive lymphoma. It seems that the in vivo interactions of lymphoma cells with microenvironment preserve their TCR expression and endow with growth advantage, while the selected in vitro TCR-negative cells lose the tumorigenic potential.

Animals↗
PubMed2026

Integrated Genomic and Tumor Microenvironment Subtyping Improved Risk Stratification in Primary Central Nervous System Lymphoma.

Current prognostic models fail to capture the biological complexity of primary central nervous system lymphoma (PCNSL). We integrated whole-genome sequencing and multiplex immunofluorescence in 68 treatment-na&#xef;ve patients to define four genomic subtypes (C1, C2, C3, and C4) with divergent survival (C4 worst: median overall survival [OS], 26&#x2009;months). In parallel, a novel tumor microenvironment (TME) classification based on CD8+T/M2 macrophage ratio stratified patients into High (>&#x2009;1.5), Intermediate (0.8-1.5), and Low (<&#x2009;0.8) groups. Unexpectedly, the Intermediate TME group showed the poorest outcomes (5-year OS: 10%). Integration revealed a lethal subgroup (C4&#x2009;+&#x2009;Intermediate TME; 9.8% of cohort) with a median OS of 3.0&#x2009;months (hazard ratio&#x2009;=&#x2009;7.24, p&#x2009;=&#x2009;0.006). Prognostic nomograms incorporating these subtypes showed promising discriminative performance in internal validation (C-index >&#x2009;0.78), but external validation is needed. Together, these findings identify a high-risk biological subset and provide a hypothesis-generating framework for future biomarker-driven risk stratification and therapeutic discovery in PCNSL.

Humans↗
PubMed2003

Gene expression profiles of cutaneous B cell lymphoma.

We studied gene expression profiles of 17 cutaneous B cell lymphomas that were collected with 4-6 mm skin punch biopsies. We also included tissue from two cases of mycosis fungoides, three normal skin biopsies, and three tonsils to create a framework for further interpretation. A hierarchical cluster algorithm was applied for data analysis. Our results indicate that small amounts of skin tissue can be used successfully to perform microarray analysis and result in distinct gene expression patterns. Duplicate specimens clustered together demonstrating a reproducible technique. Within the cutaneous B cell lymphoma specimens two specific B cell differentiation stage signatures of germinal center B cells and plasma cells could be identified. Primary cutaneous follicular and primary cutaneous diffuse large B cell lymphomas had a germinal center B cell signature, whereas a subset of marginal zone lymphomas demonstrated a plasma cell signature. Primary and secondary follicular B cell lymphoma of the skin were closely related, despite previously reported genetic and phenotypic differences. In contrast primary and secondary cutaneous diffuse large B cell lymphoma were less related to each other. This pilot study allows a first glance into the complex and unique microenvironment of B cell lymphomas of the skin and provides a basis for future studies, which may lead to the identification of potential histologic and prognostic markers as well as therapeutic targets.

Adult↗
PubMed1999

Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas.

The suppression of apoptosis is one mechanism by which tumours become drug resitant. Extracellular signals from the germinal centre (GC) of secondary lymphoid tissue can rescue B cells from physiological- and chemotherapy-induced apoptosis. Such survival signals include CD40 receptor ligation, interleukin-4 (IL-4) receptor stimulation and the interaction of the integrin ligand VCAM-1 with its receptor. The GC environment was modelled in vitro by providing B lymphoma cells with these survival signals. JLP119 B lymphoma cells underwent apoptosis after exposure to the topisomerase II inhibitor etoposide and this was dramatically reduced when the cells were cultured in the GC system. CD40 receptor ligation resulted in increased levels of Bcl-XL. Etoposide diminished the binding between Bax and Bcl-XL but this was restored by IL-4 and VCAM-1 triggered signals. These data demonstrate combined effects of three microenvironmental signals on the Bcl-2 family and illustrate the potential importance of such signalling pathways in drug resistance of tumour cells.

Animals↗
PubMed2003

Follicular lymphoma with marginal zone differentiation: cytogenetic findings in support of a high-risk variant of follicular lymphoma.

AIMS: The pathogenesis and clinical significance of marginal zone differentiation in follicular lymphoma remains to be determined, although genetic alterations are likely to be important determinants of both. We therefore report the cytogenetic findings in three cases of follicular lymphoma with marginal zone differentiation studied by routine karyotyping and in-situ hybridization. METHODS AND RESULTS: The morphology and immunophenotype of each case was typical of follicular lymphoma displaying marginal zone differentiation. Karyotyping, performed on GTL-banded preparations of cell cultures derived from fresh lymph node tissue, revealed a complex karyotype in all three cases, including t(14;18)(q32;q21) and abnormalities associated with progression and/or transformation of follicular lymphoma. In addition, trisomy 3 was found in one case and translocations between the q27-29 region of chromosome 3 and chromosome 2 in the other two cases; the latter was identified only in subclones derived from less complex stem lines possessing t(14;18). In-situ hybridization, performed on sections cut from routinely processed paraffin-embedded tissue blocks, localized cells possessing these abnormalities of chromosome 3 to both the follicular and marginal zone components of two lymphomas studied in this way. CONCLUSIONS: Trisomy 3 and alterations involving the q27-29 region of chromosome 3 are implicated in the pathogenesis of de novo marginal zone lymphoma. Their presence in the current cases indicates that they may also be responsible for marginal zone differentiation in follicular lymphoma when cells harbouring these genetic alterations are exposed to the appropriate microenvironment. Our findings are consistent with follicular lymphoma with marginal zone differentiation as a high-risk variant of follicular lymphoma.

Aged↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by 24-666, a virus isolated from an AKR B cell lymphoma.

Injection of a nonlymphomagenic ecotropic virus 24-666 isolated from a B cell lymphoma of AKR origin into young AKR mice (1-60 days old) inhibited spontaneous T cell lymphoma development. The reduction in T cell lymphoma incidence (16/106-15%) was accompanied with the appearance of B cell lymphomas (16/106-34%) in older mice (500 days mean latency). Infection of newborn to 60-day-old AKR mice with 24-666 prevented changes in thymus subpopulations and expression of MuLV-related cell surface antigens, normally observed in the thymus of 5- to 6-month-old AKR mice prior to lymphoma development. Thymuses of 24-666-infected 9- to 12-month-old mice lacked recombinant dual tropic virus (DTV) expression and retained the thymus pattern of 2-month-old AKR mice. At 12 months after 24-666 administration a striking decrease in Thy1.1 level and in the CD4+ CD8+ population and an increase in CD4- CD8- cells and in mu+ B cells, predominantly Ly1+, were observed. The presence of B cells in these thymuses was also reflected in the high response of thymocytes to LPS blastogenesis accompanied by a decreased response to PHA. Although T cell lymphoma development was markedly reduced by 24-666 administration, the establishment of potential lymphoma cells (PLC) was not affected. Transfer of lymphoid cells from 12-month-old grossly normal 24-666-infected mice to the appropriate recipients resulted in a high incidence (64-80%) of B cell lymphoma development. Thus, 24-666 seems to act through interference with the establishment of DTV in the thymus, thereby preventing PLC promotion to overt T cell lymphomas. Lack of the favorable microenvironment for PLC development in the T cell pathway enables PLC development in the B cell pathway in older mice.

Aging↗