Pathology > Basic Hematology > White Cell Disorders > Non-Hodgkin Lymphoma (Part 1)

Non-Hodgkin Lymphoma (Part 1)

The non-Hodgkin lymphomas are neoplasms of the immune system arising almost anywhere in the body, but most frequently (80%) developing in lymph nodes.

The pathology of a lymphoma depends on:

  1. the cell lineage
  2. on the degree of cell differentiation
  3. on the location of the cell of origin (humoral factors, i.e. growth factors).


The histologic appearance of the lymphoma and its clinical behavior are determined by the above three factors. The histologic appearance of the lymphoma can be used to predict behavior.

Survival can vary from 0.7 - 7.2 years and can be predicted by the histologic appearance. Thus classification (by histology and phenotype) of the non-Hodgkin lymphoma is important for determining proper treatment and predicting prognosis.

The diagnosis of non-Hodgkin lymphoma is based on 1) partial or complete obliteration of the lymph node by a usually monomorphous lymphoid cell type and 2) the pattern of growth.

The two most often encountered patterns of growth are 1) follicular (sometimes referred to as nodular) in which the lymphoma mimics follicular center structures and 2) diffuse in which the lymphoid cells proliferate in an apparently unorganized fashion. Occasionally lymphoma will be distributed within lymph node sinuses.



The histiologic classification schemes in use today reflect past and ongoing controversy over the nature of malignant lymphoma. The application of modern immunologic concepts to the classification of malignant lymphoma has led to modifications of old classifications and to the invention of new schemes.

Each system requires the identification of tumor cell types and patterns of growth.

The classification of a lymphoma should provide prognostic and therapeutic information for the clinician.

Non-Hodgkin Lymphoma: History

The "Rappaport Classification", proposed (1956) before the immunologic study of lymphoma, was at one time widely used.

The "Lukes-Collins Classification" (1975) was based on the origin of a tumor from either T lymphocytes or B lymphocytes. It attempted to relate morphology to immunologic function. However, cell morphology does not always reflect immunologic function. Although advancing our understanding of lymphoma immunology, it gave no prognostic improvement over Rappaport.

In Europe the "Kiel" classification (1975) has been widely used.


In 1982 the "New Working Formulation for Clinical Use" was introduced as a clinically relevant morphologic classification based on cell composition and pattern. It utilized three prognostic groups - low; intermediate, and high grade.

The "NWF" is accepted and used throughout the world.

Morphology (cytology and pattern) remains the "gold standard" by which malignant lymphomas are classified, although the morphologic diagnosis is supplemented by phenotypic and genotypic information.

The most recent classification scheme is the REAL classification (1994), but is not yet in widespread use as it is in large part a list and requires immunologic or phenotypic information.

We will study the "New Working Formulation for Clinical Use", the most widely used system in the US.


Non-Hodgkin Lymphoma: Cytology

The size; nuclear and cytoplasmic features of lymphoma cells allow for the morphologic identification of the lymphoma.

Generally speaking, non-Hodgkin ML is a proliferation of a uniform (monomorphous) type of cell.

One does not see reactive background cells as in Hodgkin lymphoma, nor does one usually see Reed-Sternberg cells (R-S like cells are occassionally found in non-HD, especially T-immunoblastic ML).

Cytology can predict biologic behavior, patterns of growth and prognosis.

For instance, the involvement of the bone marrow is uncommon (<10%) with large cell lymphoma, but common (60-70%) with ML, follicular, small cleaved cell.

In another example, lymphomas composed of lymphoblasts or small noncleaved lymphocytes have a rapid growth rate and a poor prognosis.

Non-Hodgkin Lymphoma: Pattern

The pattern by which a lymphoma infiltrates and replaces a previously normal lymph node is predictive of its biological behavior.

The architectural pattern of the proliferating process, that of either a diffuse or a follicular appearance, is of prognostic value - follicular MLs have a better prognosis than diffuse MLs and are rare below the age of 20.


The natural history of follicular lymphoma is to retain the follicular pattern for extended periods; progress to a diffuse aggressive form in 25 -30% of patients.

Follicular lymphomas frequently (50-60%) have bone marrow involvement at presentation.

The follicular structure implies B cell immunologic lineage.

Follicular lymphomas must be carefully distinguished from reactive follicular hyperplasia.

Follicular center lymphoma, follicular, Grade 1

Non-Hodgkin Lymphoma: Phenotype

Certain lymphomas, such as marginal zone B cell MLs, tend to grow filling lymph node sinuses. Still others home toward vessels causing a rare primary intravascular ML (intercellular adhesion molecules on the lymphoma and endothelial cells key to this pattern of growth and unique biologic behavior)

Most lymphomas are of B cell phenotype (75-85%), while about 20% are T cell lymphomas. There are prognostic and some treatment differences between T and B cell processes.

Immunochemistry allows for phenotypic determination of cell lineage. Surface or cytoplasmic Ig and/or surface B cell restricted molecules (CD19; CD20) identify cells as of B cell phenotype. Antigens (CD2; CD3; CD7) identify T cells, while (CD13;CD14; CD33) indicate myeloid or monocytic lineage.

Malignant lymphomas of B cell origin are monoclonal, that is they exclusively express one light chain (lambda or kappa). Reactive lymphoid populations are polyclonal.

Phenotyping assists in: 1) the distinction between non-hematopoietic and hematopoietic neoplasms, 2) the identification and subclassification of MLs, and 3) the distinction between reactive and malignant lymphoid populations.

Non-Hodgkin Lymphoma: Genotype

In T cell lymphomas and in some B cell lymphomas clonality cannot be determined by phenotyping. Molecular genetic studies, in particular analysis, can detect clonality by probes to immunoglobulin and T cell receptor genes. Thus, both lineage and clonality can be identified. In addition, oncogene probes can detect rearrangements of oncogenes associated with particular types of lymphomas, i.e. c-myc with small non-cleaved cell ML or bcl-2 with nodular B cell ML.

Another molecular genetic technique, PCR (Polymerase Chain Reaction), can detect minute quantities of abnormal DNA allowing for detection of residual disease following therapy.

Chromosomal translocations have been associated with specific types of lymphoma.

Follicular lymphomas are associated (>80%) with a t(14;18). Translocation of the bcl-2 gene from 18q21 to 14 at a site adjacent to the J-region of the Ig-heavy chain results in unregulated expression of the bcl-2 protein. Normally Bcl-2 prevents apoptosis of germinal center lymphocytes and in reactive germinal centers is "turned off" thus increasing cell turnover. In neoplastic cells bcl-2 is overexpressed thus promoting cell survival and allowing neoplastic lymphocytes to accumulate in the germinal center.

The translocation t(11;14) (q13;q32)causes a similar unregulated expression of the bcl-1 protein cyclin D1 controlling the cell cycle. Normal lymphoid cells do not express cyclin D1. The bcl-1 protein overexpression appears to be specific for mantle cell lymphoma (rare cases of large cell ML; myeloma reported).

Burkitt's lymphoma (small noncleaved lymphoma) is associated with the t(8;14) leading to unregulated production of the oncogene protein c-myc, a DNA transcription factor. The translocations t(8;2) and (8;22) produce similar deregulation of the c-myc oncogene.

Knowledge of these molecular markers is useful for understanding the pathogenesis of lymphoma; as an aid in the diagnosis and subclassification of lymphoma.

Non-Hodgkin Lymphoma

Morphology (cytology and pattern) remains the "gold standard" by which malignant lymphomas are classified, although the morphologic diagnosis is supplemented by phenotypic and genotypic information. We will study the "New Working Formulation for Clinical Use", the most widely used system in the US.

"New Working Formulation for Clinical Use"


A. Small lymphocytic (lymphocytic; plasmacytoid)
B. Follicular, predominantly small cleaved cell
C. Follicular, mixed, small cleaved and large cleaved cell


D. Follicular, predominantly large cell, cleaved and/or non-cleaved
E. Diffuse, small cleaved cell
F. Diffuse, mixed, large and small cell
G. Diffuse, large cell, cleaved or noncleaved


H. Large cell, immunoblastic -(B- or T-cell type)
I. Lymphoblastic
J. Small noncleaved cell (Burkitt's and non-Burkitt's)



The Low-Grade MLs have 5 year survival rates of 50-70%.

"New Working Formulation for Clinical Use"


A. Small lymphocytic (lymphocytic; plasmacytoid) - 4% *
B. Follicular, predominantly small cleaved cell - 25%
C. Follicular, mixed, small cleaved and large cleaved cell - 8%


* percent of all malignant lymphoma

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