WITH this section we step gingerly into the territory of lymphomas
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:
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: