Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm showing morphologic and immunophenotypic evidence of histiocytic differentiation. The vast majority of previously reported HSs are now ...generally recognized to be misdiagnosed examples of non-Hodgkin lymphomas, predominantly diffuse large B-cell lymphoma or anaplastic large cell lymphoma. The recognition of such tumors parallels the development and widespread use of immunohistochemical techniques, along with the development of molecular genetic methods to detect immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangement. The 2001 World Health Organization (WHO) definition of HS requires the absence of clonal B/T-cell receptor gene rearrangements. However, the 2008 WHO classification no longer strictly requires the absence of clonal immunoglobulin heavy chain (IGH) or TCR gene rearrangement for the diagnosis of HS. Recent studies demonstrated that HSs that occur subsequent to or concurrent with B- or T-lymphoblastic lymphoma/leukemia or mature B-cell neoplasms generally show clonal IgH and/or TCR gene rearrangement. These findings suggest the possibility of transdifferentiation of the two otherwise morphologically and immunohistochemically distinctive neoplasms. In addition, a recent study suggested clonal IG gene rearrangements may be detected at a high frequency in sporadic HS, indicating that a large subset of sporadic HSs may inherit the B-lymphocyte genotype. These findings provide new insights into the pathogenesis of HS, although the etiology of HS is still unknown. HS is a diagnosis of exclusion. It is necessary to rule out other diseases that could be misdiagnosed as HS with extensive immunophenotypical analysis before diagnosing HS. J Clin Exp Hematop 53(1): 1-8, 2013
Marginal zone B-cell lymphomas (MZLs) are a group of clinically indolent B-cell lymphomas postulated to derive from memory B lymphocytes in the ‘marginal zone’ of secondary lymphoid tissue. Today, ...MZL is recognised as a nosological umbrella term encompassing distinct entities with some shared phenotypic and genotypic features, including extranodal marginal zone B-cell lymphoma (EMZL) or mucosa-associated lymphoid tissue (MALT) lymphoma, splenic MZL, and nodal MZL, accounting for approximately 70%, 20%, and 10% of MZLs, respectively. These lymphomas share some phenotypic and genotypic features and have some variants and related provisional diseases, but are different in regards to their clinical and molecular characteristics. In addition, they are frequently associated with chronic antigenic stimulation represented either by infectious agents, particularly bacteria and viruses, or autoimmune diseases as exemplified by Sjögren syndrome, Hashimoto thyroiditis, and newly recognised IgG4-related disease. Furthermore, several chromosomal translocations have been identified in EMZL. In this review, we will focus on the updated histopathological criteria and the main problems with differential diagnoses in order to aid the diagnostic approach in our routine practice.
Background
Epstein‐Barr virus (EBV) is detected in a variety of B‐cell lymphomas (BCLs) and B‐cell lymphoproliferative disorders (B‐LPDs). Immunodeficiency has been considered to play a key role in ...the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV+ BCLs and B‐LPDs. The PD‐1/PD‐L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T‐cell function. We now consider PD‐L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism.
Methods
We reviewed articles of EBV+ BCLs and B‐LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD‐L1 IHC.
Results
Based on PD‐L1 IHC, we consider that EBV+ BCL and B‐LPD can be classified into three types: “immunodeficiency”, “immune escape”, and “immunodeficiency + immune escape” type. The immunodeficiency type includes EBV+ diffuse large BCL (DLBCL) of the elderly, EBV+ sporadic Burkitt lymphoma, EBV+ mucocutaneous ulcer, and methotrexate (MTX)‐associated B‐LPD. The immune escape type includes EBV+ classic Hodgkin lymphoma (CHL) and EBV+ DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX‐associated LPD and a minor subset of EBV+ DLBCL of the elderly.
Conclusions
Recently, good results have been reported for immune check‐point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD‐L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency.
We now consider PD‐L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism. Based on PD‐L1 IHC, we consider that EBV + BCL and B‐LPD can be classified into three types: “immunodeficiency,” “immune escape,” and “immunodeficiency + immune escape” type.
Recently, a unique clinicopathologic variant of multicentric Castleman's disease (MCD) has been identified in Japan. This disease is characterized by a constellation of symptoms, as listed in the ...title, and multiple lymphadenopathy of mild degree with a pathologic diagnosis of atypical CD, often posing diagnostic and therapeutic problems for pathologists and hematologists, respectively. These findings suggest that this disease represents a novel clinical entity belonging to systemic inflammatory disorders with a background of immunological abnormality beyond the ordinal spectrum of MCD. To define this disorder more clearly, Japanese participants presented clinicopathologic data at the Fukushima and Nagoya meetings. Many of the patients presented by the participants were significantly accompanied by a combination of thrombocytopenia, ascites (anasarca), pleural effusions, microcytic anemia, fever, myelofibrosis, renal dysfunction, and organomegaly (TAFRO). Multiple lymphadenopathies were generally of mild degree, less than 1.5 cm in diameter, and consistently featured the histopathology of mixed- or less hyaline vascular-type CD. Autoantibodies were often detected. However, this disease did not fulfill the diagnostic criteria for well-known autoimmune diseases including systemic lupus erythematosus. Castleman-Kojima disease and TAFRO syndrome (the favored clinical term) were proposed for this disease. The patients were sensitive to steroid and anti-interleukin-6 receptor antibody (tocilizumab), but some exhibited a deteriorated clinical course despite the treatment. The participants proposed a future nationwide survey and a Japanese consortium to facilitate further clinical and therapeutic studies of this novel disease. J Clin Exp Hematop 53(1): 57-61, 2013
Cancer‐associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that ...CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor‐cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse‐Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells.
Figure 2 shows that CAF and conditioned media support survival of primary lymphoma cells. We show CAF support survival of various disease types and lineages of primary lymphoma cells in Figure 2.
The Immunology of DLBCL Takahara, Taishi; Nakamura, Shigeo; Tsuzuki, Toyonori ...
Cancers,
01/2023, Volume:
15, Issue:
3
Journal Article
Peer reviewed
Open access
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and is the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival and ...proliferation activity, others depend on interactions with non-malignant cells for their survival and proliferation. Recent next-generation sequencing studies have linked these interactions with the molecular classification of DLBCL. For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex. Single-cell technologies have also provided detailed information about cell-cell interactions and the cell composition of the microenvironment of DLBCL. Aging-related immunological deterioration, i.e., immunosenescence, also plays an important role in DLBCL pathogenesis, especially in Epstein-Barr virus-positive DLBCL. Moreover, DLBCL in "immune-privileged sites"-where multiple immune-modulating mechanisms exist-shows unique biological features, including frequent down-regulation of immune recognition molecules and an immune-tolerogenic tumor microenvironment. These advances in understanding the immunology of DLBCL may contribute to the development of novel therapies targeting immune systems.
Nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL) is a primary nodal peripheral T-cell lymphoma (PTCL) characterized by a cytotoxic phenotype and EBV on the tumor cells. This ...disease reportedly accounts for 21% of PTCL not otherwise specified (NOS). However, few nodal EBV+ lymphomas have been documented in detail. Nodal EBV+ CTL and nasal-type NK/T-cell lymphoma (NKTL) both exhibit cytotoxic molecule expression and EBV positivity on the tumor cells; however, nodal EBV+ CTL is characterized as a systemic disease without nasopharyngeal involvement, and exhibits a CD8+/CD56− phenotype distinct from NKTL. The clinicopathological uniqueness of nodal EBV+ CTL is further supported by its T-cell origin in most reported cases. In the 2008 WHO classification, it was unclear whether nodal EBV+ CTL should be classified as PTCL or NKTL. However, based on additional data, the 2017 revision classifies nodal EBV+ CTL as PTCL. In the present review, we focus on the clinicopathological characteristics of nodal EBV+ CTL, discuss the relationship between chronic active EBV infection and nodal EBV+ lymphoma, and highlight future perspectives regarding the treatment of this disease.
Background
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the most common gastrointestinal lymphoma. The prognostic/predictive indicators among patients with gastric and ...intestinal DLBCL (giDLBCL) are controversial beyond their anatomical sites. We compared giDLBCL cases and investigated the clinical utility of newly emerging indicators with an emphasis on programmed cell death ligand 1 (PD-L1) expression.
Methods
This retrospective study included 174 patients with primary gastric (
n
= 129) or intestinal (
n
= 45) DLBCL treated with rituximab-containing chemotherapy between 1995 and 2018.
Results
Compared with gastric DLBCL (gDLBCL) cases, patients with intestinal DLBCL (iDLBCL) had a significantly higher rate of advanced Lugano stage (71% vs 37%,
P
< 0.001), perforation (13% vs. 0.8%,
P
= 0.001), PD-L1 expression on microenvironment immune cells (miPD-L1, 70% vs 46%,
P
= 0.008), CD10 positivity (47% vs 28%,
P
= 0.027), and CD5 positivity (9% vs 1.6%,
P
= 0.040). The iDLBCL patients showed significantly worse progression-free survival (PFS) and overall survival (OS) than gDLBCL cases (
P
= 0.0338 and
P
= 0.0077, respectively). PD-L1 expression on tumor cells was detected in only 3 (2%) of 174 cases with early relapse and/or an aggressive clinical course; whereas, miPD-L1-positive cases had significantly better OS than the miPD-L1-negative gDLBCL and iDLBCL cases (
P
= 0.0281 and
P
= 0.0061, respectively). Multivariate analysis revealed that miPD-L1 negativity (
P
= 0.030) was an independent adverse prognostic factor for OS in giDLBCL.
Conclusions
The anatomical site of disease did not influence outcome in giDLBCL cases treated with rituximab-containing chemotherapy; while, miPD-L1 expression had a favorable impact on the outcome.
The constitutive activation of nuclear factor-κB (NF-κB) has been implicated in tumorigenesis of lymphoid malignancies. We have previously shown that chromosome 6q was frequently deleted in ocular ...marginal zone B-cell lymphoma and identified TNFAIP3/A20, a negative regulator of NF-κB pathways, as the primary target for 6q deletion. In the study reported here, we extended the analysis to other subsets of non-Hodgkin lymphomas and found that A20 is frequently deleted in mantle cell lymphoma and diffuse large B-cell lymphoma. Importantly, A20 promoter methylation or gene mutation is also frequently detected in these lymphomas, raising the possibility that inactivation of A20 may be involved in lymphomagenesis. To address this question, we conducted overexpression experiments in lymphoma cell lines with A20 deletion and down-regulated expression of A20 with an siRNA technique in Epstein-Barr virus–infected lymphoblastoid cell lines. These experiments found that overexpression of A20 induced apoptosis and silencing of A20 was associated with resistance to apoptosis and enhanced clonogenicity. The cells with down-regulated A20 exhibited enhanced NF-κB activities, which may account for the observed effects. These results indicate that our study provides a novel insight into molecular mechanisms leading to lymphoma and that specific targeting of NF-κB pathways may be advantageous for treatment.
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