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Diffuse Large B-Cell Lymphoma (DLBCL)

WITH this section we step gingerly into the territory of lymphomas
Aggressive histology
Aggressive histology
that are aggressive in histology and clinical behavior. Aggressive histology means that many of the lymphoma cells are highly atypical:  large and irregular, with vesicular nuclei and prominent nucleoli. Aggressive behavior means that, untreated, these lymphomas kill patients in 1-2 years. With contemporary chemotherapy, however, 50% of the patients have long-term, disease-free survival; and the fortunate ones can be cured.
        DLBCL is

Diffuse large cell lymphoma in spleen
the most common type of the non-Hodgkin lymphomas (images), comprising about 30% of them. The median age is 64 with a range of 10-88 years, though any age can be affected; they are not uncommon in children.
         The large cells may be cleaved or round to oval. The most characteristic cell, called a "centroblast", has a large, open nucleus with several moderately prominent nucleoli that apply themselves to the nuclear membrane.
         A less common cell type is the immunoblast, a large cell
with reddish-blue cytoplasm and a large, oval, vesicular nucleus with a single, prominent, cherry-colored, central nucleolus. DLBCLs composed mostly of immunoblasts are sometimes called immunoblastic lymphomas.
         As aggressive malignancies with a tendency to metastasize, 30% of cases present in extra-nodal sites, and 71% eventually demonstrate an extranodal component, including the gastrointestinal tract, testes, thyroid, skin, breast, central nervous system or bone. Although generally extra-nodal involvement is more common than in follicular lymphomas, the marrow is involved only about 10% of the time.
         Immunophenotypically DLBCLs express pan-B-cell markers such as CD20 and PAX-5 in addition to BCL6 (60%), BCL2 (50%), CD10 (40%), MYC (40% but widely variable) and other markers in smaller percentages. As mature B-cells they usually demonstrate surface immunoglobulin with clonal expression of either kappa or lambda light chains. About one-third fail to exhibit surface light chains, in itself an abnormal finding.
        DLBCLs include many variants and types:

  • DLBCL, Not Otherwise Specified
    • Morphologic variants
      • Centroblastic
      • Immunoblastic
      • Anaplastic
      • Other rare variants
    • Molecular subtypes
      • Germinal center B-cell-like (GCB)
      • Activated B-cell type
  • Other Lymphomas of Large B-Cells
    • T-cell/histiocyte-rich large B-cell lymphoma
    • Primary DLBCL of the central nervous system
    • Primary cutaneous DLBCL, leg type
    • Large B-cell lymphoma with IRF4 rearrangement (provisional entity)
    • Primary mediastinal (thymic) large B-cell lymphoma
    • Intravascular large B-cell lymphoma
    • DLBCL associated with chronic inflammation
    • Lymphomatoid granulomatosis
    • ALK+ large B-cell lymphoma
    • Plasmablastic lymphoma
    • HHV-8-positive diffuse large B-cell lymphoma
    • Primary effusion lymphoma
  • High-Grade B-Cell Lymphoma
    • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangement
    • High-grade B-cell lymphoma, NOS
  • B-cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Classical Hodgkin's Lymphoma
        Because patients DLBCLs are so heterogeneous with widely varying clinical outcomes, the discovery of prognostic markers is important. Gene expression level profiling (GEP) is a technique that divides DLBL into cases with gene expression signatures resembling either germinal center cells (50%) or activated B cells (30-40%), with the germinal center signature predicting a better outcome. A third group exists lacking either of these distinctive signatures (15-20%). Immunohistochemistry is a technique more clinically feasible than GEP that can distinguish DLBCLs that express germinal center markers CD10 or BCL6 without MUM1 from those that express activated B-cell marker MUM1 without CD10.
        Common genetic abnormalities include translocations of the BCL2 gene [t(14;18)], the MYC gene [most commonly t(8:14)], and the BCL6 gene [most commonly t(3;14)]. The immunoglobulin gene promoter, which is very powerful in B-cells, is located on chromosome 14; and the above translocations place a transforming gene under its control.
        In the venerable 2008 WHO lymphoma classification, a combination of morphology, immunophenotyping, and GEP defined a provisional category: B-cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Burkitt Lymphoma. Many cases had simultaneous rearrangements of MYC and BCL2 and/or BCL6. They were called "double hit" lymphomas and had a poor prognosis.
        In the 2016 WHO lymphoma classification, this provisional category has been replaced with the new category High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements (Double Hit) (HGBL-DH). Unlike Burkitt lymphoma, where MYC is juxtaposed to an immunoglobulin locus (heavy or light chain), in HGBCL-DH lymphomas the MYC gene has a non-immunoglobulin partner in 40% of cases. About half of the time there is a previous or concurrent follicular lymphoma, which should be noted in the diagnosis.
        An additional new category, High Grade B-Cell Lymphoma Not Otherwise Specified, has been created for cases that appear intermediate between DLBCL and Burkitt lymphoma but lack simultaneous MYC and BCL2/BCL6 rearrangements.
        Finally some DLBCL without simultaneous MYC and BCL2/BCL6 rearrangements may express MYC and BCL2/BCL6 on the protein level, as detected by immunohistochemistry. These case are called "double-expressors" and have a poor prognosis, though not as bad as true double hit lymphomas.
Just to demonstrate spectrum of distinct subtypes in the WHO classification, here are a few:
  • Mediastinal (thymic) large B-cell lymphoma most likely arises from thymic B-cells. Patients tend to be in their 20's to 40's with females predominating. The typical morpohology features large, irregular cells with ample, clear cytoplasm embedded as clusters in a network of delicate fibrosis. Although CD45 and pan-B-cell antigens are usually present, the cells often fail to express detectable immunoglobulin. Prognosis is strongly correlated with stage. The lymphoma has a reputation for spreading to unusual extra-nodal sites such as adrenal, skin, kidney, and brain (images).
  • Primary effusion lymphoma presents as large lymphoma cells floating in a serous effusion in the absence of a solid tumor mass. Seen most often in the context of immunodeficiency, it is always accompanied by human herpes virus 8 / Kaposi sarcoma herpes virus. Immunohistochemistry is tricky because the cells, while positive for CD45, are negative for pan-B-cell markers and often for surface and cytoplasmic immunoglobulin. They may be positive for plasma cell marker CD138. Proof of their B-cellishness is their rearranged and mutated immunogloblin genes.
  • Intravascular large B-cell lymphoma is rare. Characteristically it features small vessels, especially capillaries, stuffed with large lymphoma cells. It is seen most commonly in the skin and CNS but also in the lung, kidneys, adrenals and other organs. This lymphoma is very aggressive and unresponsive to chemotherapy.

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