Nodular lymphocyte predominant hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma : endpoints of a spectrum of one disease?

In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis

High-grade endometrial stromal sarcoma presenting in a 28-year-old woman during pregnancy: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, soft tissue sarcomas have not prevously been reported as a complication during pregnancy.</p> <p>Case presentation</p> <p>A 28-year-old Caucasian woman was diagnosed with a transperitoneal sarcoma during pregnancy. Morphological, immunohistochemical, chromosomal and mutational analyses pointed towards a high-grade endometrial stromal sarcoma. Although surgery and chemotherapy are possible during pregnancy, we were unable to perform these in this case.</p> <p>Conclusion</p> <p>The potential to treat gynecological cancer during pregnancy should always be assessed individually.</p

Assessment of the Microbiota in Microdissected Tissues of Crohn's Disease Patients

The microbiota of the gastrointestinal tract is frequently mentioned as one of the key players in the etiopathogenesis of Crohn's disease (CD). Four hypotheses have been suggested: the single, still unknown bacterial pathogen, an abnormal overall composition of the bowel microbiota (“dysbiosis”), an abnormal immunological reaction to an essentially normally composed microbiota, and increased bacterial translocation. We propose that laser capture microdissection of selected microscopic structures, followed by broad-range 16S rRNA gene sequencing, is an excellent method to assess spatiotemporal alterations in the composition of the bowel microbiota in CD. Using this approach, we demonstrated significant changes of the composition, abundance, and location of the gut microbiome in this disease. Some of these abnormal findings persisted even after macroscopic mucosal healing. Further investigations along these lines may lead to a better understanding of the possible involvement of the bowel bacteria in the development of clinical Crohn's disease

Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas

Morphologic and molecular-genetic analysis of MALT lymphomas

The marginal zone (MZ) is a distinct micro-anatomic compartment of the B-follicle, well developed in those secondary lymphoid organs where an abundant influx of antigens is known to occur (spleen, mucosa-associated lymphoid tissue and the mesenteric lymph nodes. The MZ comprises a particular subset of lymphoid cells indicated as MZ B-cells, which play an essential role in the rapid humoral immune response to T-cell-independent antigens, such as polysaccharides of encapsulated bacteria (Hemophilus influenza, Neisseria Meningitidis en Streptococcus pneumoniae). The latter is possible because of the capacity of MZ B-cells to rapidly proliferate upon antigen encounter and differentiate into short-living plasma-cells, which are responsible for the rapid release of low-affinity IgM antibodies and thus first-line defence against the pathogen. As such, until the age of 2 years, when the MZ is finally known to be fully developed, infants remain susceptible to infections with capsulated bacteria. Also, splenectomized individuals are notoriously susceptible to infections with these bacteria. MZ lymphomas (MZL) represent a group of non-Hodgkin lymphomas related to the MZ. They are morphologically marked by the presence of lympho-epithelial lesions as well as the presence of reactive B-follicles located within the neoplastic proliferation. Dependent upon their location, MZL are subdivided into 3 entities by the WHO: splenic MZL, nodal MZL lymphoma and extranodal MZL (or MALT lymphoma). Whether these 3 MZL represent 3 variants of one and the same disease or whether they represent 3 distinct clinico-pathological entities is still a matter of debate. Growing evidence indicates that MZL are associated with chronic inflammation, such a bacterial infections (Helicobacter pylori, Borrelia burgdorferi, Campylobacter jejuni, Chlamydia psittaci), viral infections (Hepatis C), or autoimmune disease (Sjögren syndrome, Hashimoto thyroiditis). The evolution from a reactive, polyclonal to a malignant, monoclonal B-cell population is related to the occurrence of genetic aberrations, which make the lymphoproliferation independent of antigenic stimulation. Although the stomach, lung, salivary and lachrymal glands are the most common site of involvement, MALT lymphomas may be encountered in virtually every organ of the human body. In 10 up to 50%, the gastric MALT lymphoma is associated with the genetic aberration t(11;18)(q21;q21). The latter juxtaposes the API2 gene (11q21) next to the MALT1 gene (18q21), resulting in the expression of an abnormal API2-MALT1 fusion protein. The API2-MALT1 fusion-transcript will always comprise the N-terminal API2 region with three intact BIR (baculovirus inhibitor of apoptosis protein repeat) domains and the C-terminal MALT1 region containing an intact caspase-like domain. This translocation is less frequently observed in non-gastric MALT lymphomas. Other MALT lymphoma-related translocations are t(1;14)(p22;q32) and t(14;18)(q32;q32), thereby bringing BCL10 and MALT1 respectively under control of the IGH-gene enhancer, resulting in a massive BCL10 and MALT1 overexpression. The precise role of the API2-MALT1 fusion protein as well as the role of BCL10 and MALT1 overexpression in the pathogenesis of MALT lymphomas is not yet fully understood. Knock-out mice with targeted disruption ofstatus: publishe

Dysplasia (or intraepithelial neoplasia) and neoplasia without dysplasia in the digestive tract

cancer of the digestive tract is a major medical problem associated with considerable morbidity and mortality. Surgery remains the only curative treatment. Despite the development of new chemotherapeutic and radiotherapy regimens, the prognosis of advanced cancer remains limited. early detection and treatment are essential in the management of these cancers. early detection relies on the identification of precancerous or premalignant lesions, i.e. lesions that do not yet show features of invasion. These have been called dysplasia and can be identified by morphology. Three factors have an impact on the subsequent therapeutic strategy: macroscopy results, type and number of biopsies and histology results. A lesion may be either flat or elevated. Biopsies can be obtained randomly or in targeted lesions and the ratio of positive biopsies to total number of samples taken is an important determinant in the risk of finding a malignancy. Specific cytological and architectural features allow distinction between low- and high-grade lesions, but not all neoplastic lesions show these features

The pathogenesis of MALT lymphomas: where do we stand?

Mucosa-associated lymphoid tissue (MALT) lymphoma is a heterogeneous form of a B-cell non-Hodgkin's lymphoma with extranodal location. The gastrointestinal tract is the most common site of disease, but involvement of multiple other organ systems has been documented. Four translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32), are specifically associated with MALT lymphoma. Remarkably, the genes targeted by at least three of these translocations are involved in one and the same pathway, leading to the activation of nuclear factor-kappaB (NF-kappaB). This review presents MALT lymphoma as a model of how sustained inflammation increases the risk of genotoxic insults and how these genetic events initiate oncogenesis.status: publishe

The dynamics of the B follicle: understanding the normal counterpart of B-cell-derived malignancies

The repertoire of B cells secreting antibodies with unique antigen-binding specificities is produced at two stages: a primary B-cell repertoire is formed in the bone marrow through immunoglobulin gene rearrangements, whereas a secondary B-cell repertoire is generated in the peripheral lymphoid organs (spleen, lymph nodes and mucosa-associated lymphoid tissue) through somatic hypermutation and class-switch recombination upon antigen encounter. The latter events take place within highly specialized histological structures, designated B follicles, which are composed of distinct microanatomical compartments namely the follicle centre, lymphocytic corona and marginal zone. Each compartment comprises a particular subset of B cells, characterized by unique properties, thereby reflecting the complexity and variability in the spectrum of defence mechanisms against invading pathogens. The past years have spawned an avalanche of new data and information that encompasses both the structure and function of each compartment and its B cells. This review incorporates up-to-date information on peripheral B-cell differentiation into a challenging working model, thereby pointing to the structural and functional imprint of both the T-cell-dependent and T-cell-independent immune response on the B follicle. As such, this article aims to form an excellent base for a better understanding of the normal counterpart of B-cell-derived haematological malignancies (leukemias and lymphomas).status: publishe

Splenic marginal zone lymphoma-like features in API2-MALT1 transgenic mice that are exposed to antigenic stimulation

Recently, we described a transgenic mouse model to analyze the effect of the API2-MALT1 fusion-protein in vivo. Our results showed that the expression of API2-MALT1 is not sufficient to induce the development of lymphoma masses. Here, we demonstrate that immunization with Freund's complete adjuvant led to the loss of compartmentalization of the splenic white pulp in API2-MALT1 transgenic mice, resulting in a splenic marginal zone lymphoma-like lymphoid hyperplasia of a peculiar B-cell subset that disappeared as soon as the antigenic stimulation faded away. These data indicate an effect of API2-MALT1 expression on the normal immune response.status: publishe

A cheesy diagnosis

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