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Classifying Non-Hodgkin's Lymphomas

CLASSIFYING non-Hodgkin's lymphomas makes sense for several reasons:

  1. The categories appear to correspond to biological entities that behave distinctly. Thus the pathologist gives the clinician important guidance for treating the lymphoma and assessing its prognosis.
  2. A knowledge of the features of each category helps the pathologist to recognize a lymphoma. Since lymphomas can assume a bewildering variety of appearances, it's helpful to know what the coherent patterns are.
  3. By observing how the lymphomas group themselves, one can discover important biological principles that underlie their appearance and behavior.
H&E stained tissue
       Pathologists have traditionally depended heavily on the morphologic appearances of lymphomas to categorize them. Thirty years ago, morphology was the only tool available. Suspicious lymphoid tissue was (and still is) fixed in formalin or a mercury-containing fixative, embedded in paraffin, sliced very thinly (5 microns or less), placed on a glass slide, and stained with the all-purpose tissue stain, hematoxylin and eosin. The earliest attempts to categorize lymphomas relied solely on this method.
       Starting in the 1970's additional techniques have been developed to study the nature of both benign and malignant lymphoid cells.
  • ImmunophenotypingMembrane antigens: Different types of lymphoid cells express different molecules on their surface cell membrane. Clever scientists enhance their careers by making antibodies that will adhere specifically to these molecules, in this context called antigens. If the antibodies are altered in special ways so their presence can be detected (for example, they may be rendered fluorescent), this technique can be used to assess what kinds of antigens decorate the cell membrane. These antibodies are eventually given so-called "cluster designation" or "CD" numbers. Immunophenotyping has become important in evaluating 1) the malignancy of a lymphoid proliferation and 2) the lymphoma category to which it belongs. Three methods of immunophenotyping that yield the similar information are:
      1) immunohistochemistry
      2) immunofluorescence
      3) flow cytometry.
  • Cytogenetics: Like all cells, malignant lymphoid cells can be made to proliferate in vitro, and their metaphase chromosomes can be examined for characteristic translocations (call "karyotyping"). It is encouraging to the morphologically oriented hematopathologist that his or her careful microscopic observations very frequently correspond to genetic distinctions uncovered by "scientific" techniques. As Oscar Wilde said, only very superficial people are uninterested in surface appearances.
  • FISH: Besides the technique of karyotyping, which displays whole chromosomes from metaphase spreads of dividing cells, fluorescent in-situ hybridization (FISH) can be used to look for specific chromosomal abnormalities in the DNA of interphase cells. The advantages of this technique are its ability to utilize non-dividing cells, to examine 200 or so cells at a time rather than the 20 of conventional karyotyping, and to find subtle defects invisible to the coarser technique of karyotyping. Its major drawback is that it uses probes for specific anomalies and so can find only the defect for which the probes were designed.
  • Molecular analysis: This technique is usually geared toward finding clonal (neoplastic) rearrangements of the immunoglobulin gene in B-cell malignancies or of the T-cell receptor gene in T-cell malignancies. These rearrangements are too subtle to be detected by conventional cytogenetics.
           The last several years have seen an explosion of interest in cDNA or oligonucleotide microarray techniques, in which the expression levels of thousands of messenger RNAs are simultaneously measured. This creates a genome-wide portrait of the cell's gene activity, a global perspective that has yielded many fresh fresh insights. It is not yet a clinical technique.

       Most classifications are based on the assumption that lymphoma cells are the malignant counterparts of benign lymph node cells. The various lymphomas are often named after the benign cell from which they are assumed to derive. The following classifications are the most important ones from the previous half-century. Anyone lacking historical curiousity or otherwise without a need to understand superannuated terminology should probably skip to the currently accepted WHO classification.

Rappaport Classification
The oldest classification that still crops up is the Rappaport classification, which was developed before lymphoid cells were divided into B-cells and T-cells. Occasionally the following terms may be heard:

  • Well-differentiated lymphocytic lymphoma = small lymphocytic lymphoma.
  • Poorly differentiated lymphocytic lymphoma = follicular center cell lymphoma with a large component of small-cleaved cells.
  • Histiocytic lymphoma = large cell lymphoma
Kiel and Lukes & Collins Classification
A gala year for classifications, 1974 saw the introduction of 2 new ones. The Kiel Classification is popular in Europe. The Lukes and Collins Classification, which was the first to separate B-cell and T-cell lymphomas using immunologic techniques, has been popular in the United States. Some of the terminology from both classifications has made its way into the lingua franca of hematopathology.

Working Formulation
By the early nineteen-eighties, so many classifications and systems had proliferated that a large study was initiated to separate the sheep from the goats (i.e., tell which systems were valid). Investigators at the National Cancer Institute looked at 1175 cases of non-Hodgkin's lymphoma and concluded that each of the classifications had clinical value but none was clearly superior. True hematopathologists, they therefore invented yet another classification, a meta-classification called the Working Formulation. It is important (or at least interesting) to remember that this grouping:

  • was originally intended to translate among the previous classifications, not to replace them.
  • was based solely on the morphology of H&E stained sections.
  • groups the lymphomas into morphologic categories that may encompass several individual diseases, and biologically unique diseases may appear in multiple categories.
      Despite these significant drawbacks, the Working Formulation Formulation's categories do have clinical validity (therapeutic and prognostic)and are based on relatively simple, reproducible morphologic features. The criteria are both architectural (low magnification) and cytological (high magnification):
  1. Architectural
    • diffuse proliferation
    • follicular proliferation
  2. Cytological
    • Nuclear outline
      • cleaved (indented)
      • non-cleaved
    • Cell size
      • small
      • large
      • mixed small and large
      Note that there is no consideration of B or T-lineage. Using data from the study of the original 1175 cases, the Working Formulation entities are divided into low, intermediate, and high grade lesions:

Low Grade

Intermediate Grade

High Grade

Small lymphocytic

Follicular large cell

Large cell immunoblastic

Follicular small-cleaved cell

Diffuse small cleaved cell


Follicular mixed small-cleaved and large cell

Diffuse mixed small and large cell

Small non-cleaved cell (Burkitt's and non-Burkitt's type)


Diffuse large cell



REAL/WHO Classification
As the years have rolled by, many lymphomas have been distinguished as individual entities with the help of immunologic, cytogenetic and molecular techniques. These lymphomas appear to be unique diseases, as opposed to lymphoid malignancies that morphologically fall into one of the Working Formulation's categories. In the mid-90's an informal group of hematopathologists, the International Lymphoma Study Group, proposed a consensus list of lymphomas, the Revised European-American Lymphoma classification. This list sets forth the diagnostic features of lymphomas that the group members consider currently widely recognized and diagnosable by contemporary techniques.
        This classification is the basis of the WHO classification, which is currently accepted as the authoritative standard. Unlike the Working Formulation, this classification does not group the lymphomas into prognostic categories. In part this is because each lymphoma is seen as a separate disease process that may be more or less aggressive in individual patients. Just as breast cancers are graded, for example, follicular lymphomas may be graded from 1 to 3.

B-Cell Neoplasms

I. Precursor B-cell neoplasm:
    a. Precursor B-lymphoblastic leukemia/lymphoma

II. Mature (peripheral) B-cell neoplasms

  1. B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
  2. B-cell prolymphocytic leukemia
  3. Lymphoplasmacytic lymphoma
  4. Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes)
  5. Hairy cell leuekmia
  6. Plasma cell myeloma/plasmacytoma
  7. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type
  8. Nodal marginal zone lymphoma (+/- monocytoid B-cells)
  9. Follicle center lymphoma, follicular,
  10. Mantle cell lymphoma
  11. Diffuse large cell B-cell lymphoma
    • Mediastinal large B-cell lymphoma
    • Primary effusion lymphoma
  12. Burkitt's lymphoma/Burkitt's cell leukemia
T-Cell and Natural Killer Cell Neoplasms

I. Precursor T cell neoplasm:
    a. Precursor T-lymphoblastic lymphoma/leukemia

II. Mature (peripheral) T cell and NK-cell neoplasms

  1. T cell prolymphocytic leukemia
  2. T-cell granular lymphocytic leukemia
  3. Aggressive NK-Cell leukemia
  4. Adult T cell lymphoma/leukemia (HTLV1+)
  5. Extranodal NK/T-cell lymphoma, nasal type
  6. Enteropathy-type T-cell lymphoma
  7. Hepatosplenic gamma-delta T-cell lymphoma
  8. Subcutaneous panniculitis-like T-cell lymphoma
  9. Mycosis fungoides/Sézary's syndrome
  10. Anaplastic large cell lymphoma, T/null cell, primary cutaneous type
  11. Peripheral T cell lymphoma, not otherwise characterized
  12. Angioimmunoblastic T cell lymphoma
  13. Anaplastic large cell lymphoma, T/null cell, primary systemic type
Hodgkin's lymphoma (Hodgkin's Disease)

  1. Nodular lymphocyte predominance Hodgkin's lymphoma
  2. Classical Hodgkin's lymphoma
    •Nodular sclerosis Hodgkin's lymphoma
    •Lymphocyte-rich classical Hodgkin's lymphoma
    •Mixed cellularity Hodgkin's lymphoma
    •Lymphocyte depletion Hodgkin's lymphoma
In addition, multiple subcategories are offered for several of these diseases.

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