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The name non-Hodgkin lymphoma (NHL) implies a diagnosis ancillary to Hodgkin lymphoma, which is also known as Hodgkin disease. However, the incidence of NHL is several times that of Hodgkin disease and has doubled since the early 1970s. Risk factors are primarily associated with an immune system deficiency or a history of immunosuppressive therapy. Although the higher incidence can be attributed to improved diagnostic techniques and increased access to medical care, environmental factors and the increasing median age of the population are contributors. Toxins related to chemicals used in the farming industry also occasionally increase incidence of NHL.1

Non-Hodgkin lymphoma represents approximately 5% of all malignancies. NHL is the fifth most common cancer among both men and women, with a slight predominance in men. The only patient population to experience a decrease in incidence of NHL is young males, primarily because of improved treatment for HIV infections and subsequent lower incidence of associated lymphoma with HIV progression.

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Patients with NHL may present with fever, weight loss of 10% or more, and night sweats; these symptoms are also known as B symptoms. Many indolent types of lymphoma manifest with only painless swelling of the lymph nodes. After NHL is diagnosed, patients often undergo a litany of procedures such as extensive evaluation for peripheral lymphadenopathy, hepatospleno­megaly, various imaging studies (most often positron emission tomography [PET] and CT, but other imaging studies may be needed), and bone marrow aspiration and biopsy.

The primary diagnosis is made via molecular testing of a resected lymph node specimen, the most informative of which is flow cytometry. Another diagnostic tool, especially for cases of the more rarely occurring T-cell lymphomas, is PCR (polymerase chain reaction) for antigen receptor rearrangements (PARR). These tests determine whether the specimen cells are derived from a single cell line or from what is typically referred to as clonality.1-3 Clonality is the hallmark of malignancy and manifests as all cells having the same sequence of nucleic acid or DNA (monoclonal expressions). Nonmalignant tissue has polyclonal expressions. PARR studies evaluate the T-cell receptor gene variable region in T-cell lymphomas, whereas the variable regions of the immunoglobulin receptor gene is evaluated in B-cell lymphomas. As implied by the name, the variable region by nature should vary in order to mount unique responses to unique antigens, and the loss of this variability implies a malignancy exists. PARR studies amplify the abnormal variable region of the clonal population in B-cell lymphomas.

Flow cytometry is more commonly used because the technique is the most important study for analyzing lymphoma-involved tissue, usually lymph node or bone marrow. A solution with the malignant tissue is treated with various fluorochromes and antibodies and passed through a laser beam. The laser recognizes and sorts out the cells based on size, DNA content, and antibody reactions. A pattern that identifies the lymphoma develops as the receptors are labeled. Each type of lymphoma produces a distinct “fingerprint” based on the cluster differentiation (CD) positivity that occurs within the panel. The various CD types are designated by numbers; for example, CD20 is very often expressed on individual B-cell lymphoma cells.2,3


The most important factor in diagnosing NHL is identifying the type of non-Hodgkin lymphoma. Although most normal circulating lymphocytes are T lymphocytes, 85% of NHL clonality involves B lymphocytes versus 15% for T-cell lymphomas.

In the 1970s, the National Cancer Institute (NCI) designed a working classification for the NHLs. Previous attempts at organizing the various NHL types were very difficult because many institutions had their own preferred classification system. The NCI classification designated lymphomas based on the clinical aspects of the disease and subcategorized NHLs as indolent, intermediate, and aggressive types, often designated as low-, intermediate-, and high-grade, respectively. Much of this work was accomplished prior to the widespread use of flow cytometry and PARR. When these molecular techniques became available, they were incorporated into the working classification. Thus, the Revised European American Lymphoma (REAL) classification system was developed, which more precisely identified the various types of NHL.1-3

Although there are literally dozens of NHL types, most disease are within a select number of types (Table 1).1-3 Follicular lymphoma is the most common low-grade type. Diffuse large B-cell lymphoma, an intermediate-grade type, is the most common of all lymphoma types. High-grade lymphomas are usually either Burkitt lymphoma or lymphoblastic B-cell type lymphoma; the latter has a morphology similar to acute lymphoblastic B-cell leukemia. Human herpesvirus 8 (HHV-8)-associated primary effusion lymphoma, a virally associated lymphoma type, was most prevalent in HIV-infected persons prior to the advent of highly active antiretroviral therapy (HAART) for HIV infection.1-3

Most T-cell lymphomas also are designated as low-, intermediate-, and high-grade types.1-3 The most common cutaneous T-cell lymphoma is mycosis fungoides, a low-grade type. T-cell lymphoblastic lymphoma, which is a high-grade disease, is akin to a T-cell type of lymphoblastic leukemia. Human T-cell lymphoma virus (HTLV)-associated aggressive leukemia/lymphoma, a virally associated lymphoma, often affects Caribbean or Asian populations.1-3

In addition, some types of lymphoma have no designation, including a prelymphomatous condition known as lymphomatoid papulosis, some cutaneous and subcutaneous T-cell types of lymphomas, large B-cell lymphoma of the skin, and large B-cell lymphoma of the leg. These unique lymphoma types are rarely seen and have profound cutaneous presentations. They are mentioned here for the sake of completeness.


Similar to most cancers, lymphomas are staged as I, II, III, or IV disease. Unlike solid tumors, however, staging is less significant in NHLs as most cases involve more advanced disease. The treatment, primarily chemotherapy, is universally distributed and effective in managing the disease process. Staging of non-Hodgkin disease is a by-product of evaluating Hodgkin disease; however, unlike Hodgkin disease, NHL seldom progresses from one lymph node to the next nearest one in a contiguous spreading fashion. Therefore, staging has less applicability to NHL. Nevertheless, the Ann Arbor staging technique devised for Hodgkin disease has been applied to NHL.