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Overview of B-Cell Non-Hodgkin's Lymphomas

EIGHTY-five percent of non-Hodgkin's lymphomas originate from B-cells. This origin is inferrable in most cases from:
   1) surface immunoglobulin, which is found on no other cell type.
   2) other cell surface proteins such as CD19 that are both sensitive and specific for B-cells.
   3) rearranged immunoglobulin genes.
In almost all cases, both the surface immunoglobulin and the rearranged genes have features of clonality.
         The morphological and behavioral spectrum of B-cell lymphomas is astounding, partly because they derive from diverse normal lymphoid cells.

• Some lymphomas, such as small lymphocytic lymphoma, originate from small, demure lymphocytes that are quietly whistling in the dark of a lymph node. As expected, these lymphomas are indolent, mild, but inexorable diseases that string their victims along for up to a decade. Small lymphocytic lymphoma
Small lymphocytic lymphoma
• Other lymphomas (primarily pre-B cell lymphoblastic lymphoma/leukemia, large cell lymphoma and Burkitt lympohoma) derive from atypical-appearing, rapidly dividing cells. Lymphoid cells undergo 2 cycles of proliferation:
   1) An early cycle as they first emerge from the mists of their natal marrow milieu.
   2) A later, explosive cycle sparked by antigen exposure.
Thus proliferative lymphomas can correspond to either early or late stages of normal development. These lymphomas behave aggressively and untreated may kill their victims in less than a year.
Immunoblastic lymphoma
B-immunoblastic lymphoma
You can see some diagrams of normal lymphocyte maturation and the lymphoma equivalents to these stages.
         The following table
contrasts features of low and higher grade lymphomas, but first an important clarification: In the obsolete Working Formulation, high grade lymphomas referred specifically to lymphoblastic lymphoma and Burkitt lymphoma. Diffuse large cell lymphoma was considered intermediate grade. With the passage of this classification, the distinction is no longer strictly enforced, and diffuse large B-cell lymphomas are often referred to as high grade.
Low Grade Lymphomas
Higher Grade Lymphomas
• The cells are small with clumped chromatin and inconspicuous nucleoli. The growth pattern may be diffuse (as in small lymphocytic lymphoma) or follicular. The growth is relatively non-destructive. • The cells show large nuclei containing open (clear) or powdery chromatin. Nucleoli are usually prominent. Some higher grade lymphomas may have moderate amounts of cytoplasm. Almost always they grow diffusely and destructively.
• Patients mostly older, usually 50-60, rarely < 40 y/o. • The median patient age is 60. These lymphomas account for almost a half of adult lymphomas but are not uncommon in children.
• Patients present with multiple painless, enlarged lymph nodes, uncommonly with significant extranodal extension. Extranodal organs are only rarely involved except for the bone marrow, which is positive 75% of the time. • Patients often present with a single, quickly growing nodal or extranodal mass. Focal or extranodal disease is much more common.
• Pivileged sites (CNS, testis) are not invaded. • Lymphoma may involve privileged sites.
• Though not common, spleen and liver involvement takes the form of many tiny deposits. • Though not common, spleen and liver involvement takes the form of large, destructive masses.
• Although significant numbers of lymphoma cells spill into the peripheral blood only in small lymphocytic lymphoma, numbers of circulating low grade lymphoma cells can usually be detected by sensitive techniques. • Blood involvement with these relatively bulky cells is unusual.
In vitro lymphoma cells:
  1. respond to regulatory molecules
  2. cannot be transplanted
  3. will not grow in culture
In vitro lymphoma cells:
  1. grow autonomously
  2. can be transplanted to immunodeficient hosts
  3. subsist indefinitely in culture (immortalized)

         It is, however, a paradox of all lymphomas that the indolent, low grade lymphomas permit long survivals but are virtually uncurable and may not be treated initially. On the other hand, the higher grade lymphomas are often rapidly deadly, but all patients are treated and some respond even to the point of complete cure. Behind this paradox is the observation that both chemotherapy and radiotherapy target rapidly dividing cells.
         For some lymphomas, such as Burkitt's lymphoma, the cell of derivation has not been definitively identified. Other lymphomas start by resembling their cell of origin but subsequently dedifferentiate. For example, follicular center cell lymphomas may enter a diffuse growth phase, belying their origin from cells that grow in follicles. In such cases their follicular nature must be inferred from softer evidence, such as the presence of characteristic small-cleaved follicular center cells, certain antigens such as CD10, or the characteristic t(14;18) BCL-2 gene rearrangement.
         Also, many low-grade lymphomas tend to progress to higher grade disease. In Richter's transformation, for example, small lymphocytic lymphoma promotes itself to diffuse large cell lymphoma.

Immuno- and Genophenotype:

  • With few exceptions B-cell lymphomas express the pan-B cell antigens: CD19, CD20, CD22. As B-cells reach their final goal (the plasma cell stage), paradoxically they tend to lose these markers, and so do their malignant counterparts. Thus multiple myeloma cells are negative for these antigens.
  • CD5 and CD43, most frequently found on T-cells, are detected in small lymphocytic lymphoma and mantle cell lymphoma. Small lymphocytic lymphoma is also reactive for CD23.
  • CD10 is found in many cases of very different types of lymphomas: follicular center cell lymphomas, B-cell lymphoblastic lymphomas, and Burkitt's lymphomas.
  • Most follicular lymphomas, especially low grade ones, rearrange the BCL-2 gene, t(14;18).
  • Most Burkitt's lymphomas rearrange the MYC gene, t(8;14).
  • Most mantle cell lymphomas rearrange the BCL-1 gene, t(11;14).

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