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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 lucky ones can be cured.
        DLBCL is

Diffuse large cell lymphoma in spleen
one of the most common types of lymphoma (images), comprising about 20% of non-Hodgkin's lymphomas. The median age is 57, with a range of 10-88 years. Although most frequently seen in adults, large cell lymphomas 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. About one-third of B-cell diffuse large cell lymphomas fail to produce surface immunoglobulin. Fortunately for the diagnostician, these are overt malignancies, so proving clonality is usually an academic issue.
         As aggressive malignancies with a tendency to metastasize, the majority eventually demonstrate some 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.
        A majority of DLBCLs show expression of the bcl-6 protein, with some cases demonstrating a rearrangment of the BCL6 gene. About 20% of the cases have good evidence for a follicular center cell origin in the form of a t(14;18), Bcl-2 gene rearrangement. Another, soft indication of a follicular center cell origin (and perhaps transformation from a folliclar lymphoma) is the presence of small-cleaved cells interspersed among the large cells (images).
        Because patients with DLBCL have widely varying clinical outcomes, the discovery of prognostic markers is an important area of investigation. In the year 2000, researchers used cDNA microarrays to measure the levels of thousands of different mRNA species simultaneously in a series of DLBCLs. Using these measurements of gene expression levels, they applied an unsupervised data clustering technique to divide their lymphomas into cases with gene expression signatures resembling either germinal center cells or activated B cells, with the former signature predicting a substantially better prognosis. Subsequently a third group has been identified that lacks either of these distinctive signatures and has a poor prognosis.
        cDNA microarray technology is not yet suitable for wide-spread clinical use, so immunohistochemical markers for the germinal center and activated B cell groups have been sought. Although there is some controversey, DLBCLs that express germinal center markers CD10 and/or Bcl-6 tend to have a better prognosis than those that express activated B-cell markers MUM1/IRF4 and/or CD138. In the non-germinal center group, expression of Bcl-2 and cyclin D2 are adverse predictors.
        The WHO classification of DLBCLs takes note of several morphological variants:

  • Centroblastic
  • Immunoblastic
  • T-cell/histiocyte-rich
  • Lymphomatoid granulomatosis type
  • Anaplastic B-cell
  • Plasmablastic
        The immunoblastic type includes many cases with very atypical cells. The prototypical immunoblast (image) is a large cell with reddish-blue ("amphophilic") cytoplasm and a large, oval, vesicular nucleus with a single, prominent, cherry-colored, central nucleolus. The patients' median age is 52 with a range from 10-81 years of age. One-half have extranodal disease including marrow involvement in 12%. They account for only 8% of all non-Hodgkin's lymphomas but a much higher proportion of AIDS-related lymphomas. Another clinical association is auto-immune disease.
         Like diffuse large cell lymphomas, immunoblastic lymphomas are surface immunoglobulin negative one-third of the time. Their cytoplasm may, however, contain readily detectable amounts of immunoglobulin. Some studies, using the updated Kiel Classification's definition of immunoblastic lymphoma (>90% immunoblasts), show a worse prognosis for this type.
         In addition to these morphologic variants, the WHO Classification distinguishes several distinct subtypes:
  • 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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