Abstract
Most mature B cell lymphomas arise as clonal expansions corresponding to differentiation pathway stages with few exceptions. Many immunologic, toxic, and genetic factors predispose to lymphoma development. B-cell lymphomas are the most frequent types, often widely disseminated, involving the bone marrow and hemopoietic system. Many reactive conditions simulate lymphomatous infiltrates and need special diagnostic consideration, including viral and immunological reactions. The diagnosis should integrate clinicopathologic features, imaging, comprehensive hematologic examination, immunophenotyping, cytogenetics, molecular profile, and risk stratification. This comprehensive assessment also helps with treatment selection and potential targeted therapy.
TopIntroduction
Mature B-cell lymphomas, arising from neoplastic clonal expansions along the B-cell differentiation pathway, are intricately linked to the immune system. While most follow well-defined stages, exceptions like hairy cell leukemia (HCL) challenge this norm. These lymphomas exhibit lineage heterogeneity, aberrant phenotypes, and even lineage plasticity.
In the realm of lymphoma, mature B-cell variants dominate, with distinct diagnostic entities. Among adults, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and multiple myeloma (MM) prevail. In pediatric cases, Burkitt-like lymphoma (BL), lymphoblastic lymphoma (LBL/L), and large B-cell lymphoma (LBCL) are common, while FL and marginal zone lymphoma (MZL) remain less frequent.
At diagnosis, most mature B-cell lymphomas have already disseminated widely. Unlike T-cell lymphomas, extra-nodal presentation is more frequent, and B symptoms or mediastinal involvement are less common (except for lymphoblastic lymphoma and mediastinal LBCL).
Diagnostic challenges arise due to reactive conditions mimicking lymphomatous infiltrates, including viral infections and autoimmune lymphoproliferative disorders (LPDS). To navigate this complexity, an integrated approach is essential:
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Pathogenic Mechanisms: Understanding the underlying processes driving lymphomagenesis.
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Clinicopathologic Features: Detailed assessment of clinical presentation, physical findings, and medical history.
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Diagnostic Criteria: Incorporating morphologic, immunophenotypic, and genetic information.
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Staging and Risk Stratification: Evaluating disease extent and prognosis.
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Treatment Strategies: Tailoring therapeutic approaches based on subtype and patient factors.
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Therapeutic Response Criteria: Monitoring treatment effectiveness.
The main mature B-cell lymphoma subtypes, guided by the International Consensus Conference (ICC, 2022) and the 5th WHO classification (2022):
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Small Lymphocyte Lymphomas/Leukemias: Characterized by small, mature lymphocytes.
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Splenic B-cell lymphomas and Leukemias: Involving the spleen and related tissues.
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Lymphoplasmacytic and Plasma Cell Neoplasms: Including paraprotein-related disorders.
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Follicular Lymphoma (FL): Indolent lymphoma with nodal and extra-nodal involvement.
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Mantle Cell Lymphoma (MCL): Aggressive lymphoma arising from mantle zone B-cells.
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Large Cell and High-Grade Mature B-cell lymphoid Neoplasms: Encompassing diverse aggressive variants
Key Terms in this Chapter
IG Loci Promiscuity: The IG loci show promiscuity in their translocation partners. Many new translocations have been identified using defined breaks within the IG loci to clone the translocation breakpoints. Specific recurrent disease-specific clonal translocations involving the immunoglobulin genes characterize certain types of B-cell lymphoma such as Burkitt’s Lymphoma with t(8;14) involving MYC and IG loci, Follicular Lymphom a with t(14;18) involving BCL2 and IG loci, and Mantle Cell Lymphoma with t(11;14) involving Cyclin D1 and IG loci.
Osteoclasts-Myeloma Interaction: Osteoclasts are recruited around MM cells in the bone marrow. They enhance MM cell growth and survival through direct cell-to-cell contact. They also produce cytokines like interleukin-6 (IL-6) and osteopontin (OPN), promoting MM cell survival. The interaction between MM cells and OCs forms a vicious cycle, exacerbating bone destruction and MM expansion. This interplay is crucial for developing targeted therapies to mitigate bone damage in multiple myeloma patients.
Cancer Stem Cells (CSCs): A subpopulation of cancer cells found within tumors or hematological cancers. They possess characteristics associated with normal stem cells, specifically the ability to self-renew. They are tumorigenic (tumor-forming) and persist in tumors as a distinct population that can cause relapse and metastasis.
Immunoglobulin Gene Hypermutation: A cellular mechanism for immunoglobulin diversity involving a programmed process of mutation affecting the hypervariable regions, affecting antigen recognition sites on the immunoglobulin. It plays a crucial role in affinity maturation, diversifying B cell receptors used for antigen recognition. Somatic hypermutation has been implicated in the development of B-cell lymphomas and many other cancers.
IG Locus-Associated Translocations: Chromosomal rearrangements involving the immunoglobulin (IG) loci, which encode the variable regions of B-cell receptors (BCRs). They juxtapose fragments of DNA that are usually located on different chromosomes, leading to altered gene expression and potential oncogenic effects. These translocations play a pivotal role in B-cell malignancies by altering gene expression and contributing to tumor development. Understanding their mechanisms can also guide targeted therapies and improve patient outcomes. They are a hallmark of many B-cell malignancies.
Castleman Disease: is a non-neoplastic B-cell predominant lymphoid proliferation with three clinicopathologic entities: unicentric, idiopathic multicentric, and KSHV/HHV8- associated multicentric Castleman disease. Diagnosing Castleman disease is particularly critical due to its resemblance to lymphoma.
Cancer-associated Fibroblasts (CAFs): A complex and abundant cell type within the tumor microenvironment. They promote tumorigenic features by initiating the remodeling of the extracellular matrix or by secreting cytokines. CAFs support tumor growth by secreting growth factors, stimulating angiogenesis, and contributing to drug resistance, and play a role in cancer progression and metastasis.