Classifying Non-Hodgkin's Lymphomas
CLASSIFYING non-Hodgkin's lymphomas makes sense for several reasons:
- 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
- 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.
- By observing how the lymphomas group themselves, one can discover
important biological principles that underlie their appearance and behavior.
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.
- Immunophenotyping: 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:
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.
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:
Kiel and Lukes & Collins Classification
- 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
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.
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:
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
- 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.
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:
- diffuse proliferation
- follicular proliferation
- Nuclear outline
- cleaved (indented)
- Cell size
- mixed small and large
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.
I. Precursor B-cell neoplasm:
a. Precursor B-lymphoblastic leukemia/lymphoma
II. Mature (peripheral) B-cell neoplasms
Natural Killer Cell Neoplasms
- B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
- B-cell prolymphocytic leukemia
- Lymphoplasmacytic lymphoma
- Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes)
- Hairy cell leuekmia
- Plasma cell myeloma/plasmacytoma
- Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type
- Nodal marginal zone lymphoma (+/- monocytoid B-cells)
- Follicle center lymphoma, follicular,
- Mantle cell lymphoma
- Diffuse large cell B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma
- Burkitt's lymphoma/Burkitt's cell leukemia
I. Precursor T cell neoplasm:
a. Precursor T-lymphoblastic lymphoma/leukemia
II. Mature (peripheral) T cell and NK-cell neoplasms
Hodgkin's lymphoma (Hodgkin's Disease)
- T cell prolymphocytic leukemia
- T-cell granular lymphocytic leukemia
- Aggressive NK-Cell leukemia
- Adult T cell lymphoma/leukemia (HTLV1+)
- Extranodal NK/T-cell lymphoma, nasal type
- Enteropathy-type T-cell lymphoma
- Hepatosplenic gamma-delta T-cell lymphoma
- Subcutaneous panniculitis-like T-cell lymphoma
- Mycosis fungoides/Sézary's syndrome
- Anaplastic large cell lymphoma, T/null cell, primary cutaneous type
- Peripheral T cell lymphoma, not otherwise characterized
- Angioimmunoblastic T cell lymphoma
- Anaplastic large cell lymphoma, T/null cell, primary systemic type
In addition, multiple subcategories are offered for several of these diseases.
- Nodular lymphocyte predominance Hodgkin's lymphoma
- 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
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