| By: Amy Chadburn, MD
A lymphoma is a cancer arising from cells known as lymphocytes, which are a type of white blood cell. For doctors and patients alike, the diagnosis and classification of lymphomas is complex and often confusing. These complexities arise because of advances in our understanding of how normal lymphocytes and lymphomas themselves develop. To understand lymphomas and lymphoma classification, one first must understand something about normal lymphocytes.
What are Normal Lymphocytes?
As a member of the white blood cell family, lymphocytes normally help fight infection. Lymphocytes are divided into two major groups: B lymphocytes (B cells) and T lymphocytes (T cells). When the body is challenged by an infection or other threat, B cells can change into different cells, called plasma cells. The role of transformed B cells (plasma cells) is to secrete antibodies. Antibodies are proteins which attach to infectious or other harmful particles (known as "antigens"). When other white blood cells recognize antibodies which are attached to antigens, these white cells will attack and destroy the particles.
T cells, on the other hand, are responsible for orchestrating the immune response and are also one of the cells which can attack foreign particles. They are helpful in eliminating viruses and tumor cells in the body by binding directly to antigens on these organisms and tumor cells. Unlike B cells, T cells do not secrete antibodies.
There are many, many T and B cells in the body. These cells circulate throughout the body, passing through lymph nodes and the spleen, as they look for "foreign" antigens to which they can react. Once they find an antigen, the lymphocytes become "stimulated" and divide rapidly to make other cells. If these stimulated cells are B cells, they also turn into plasma cells and begin secreting antibodies.
During an infection or other threat, many different B cells and T cells can recognize different pieces of an antigen, causing each of them to proliferate. This results in many large groups of T and B lymphocytes. The end result is a lot more lymphocytes, which can cause lymph nodes (the place where lymphocytes congregate) to enlarge. This is why swollen "glands" (which are lymph nodes), often mean an infection is present.
What are Lymphoma ("Malignant") Lymphocytes?
A lymphoma cell population is composed of identical lymphocytes - each cell is the same, arising from a single lymphocyte of either T or B cell origin. These cells may divide slowly and not die, or divide rapidly. Either way, the end result is an accumulation of a large number of identical lymphocytes which can cause lymph nodes to enlarge. Normal lymphocytes progress through stages as they mature, however, lymphoma cells do not mature normally. Malignant lymphocytes are actually "frozen" at one stage of development. In addition, some types of lymphomas are associated with specific genetic mutations.
Classifying Lymphoma
Lymphoma classification entails dividing lymphocyte tumors into different groups based on different characteristics of the tumor cells as well as the predicted clinical outcome for the patient. Over the last three decades, our knowledge concerning lymphocytes and lymphomas has greatly increased, resulting in the need to revise the classification scheme for lymphomas approximately every 10 years. The current classification system is known as the REAL classification. This classification uses the malignant cells' appearance, type and genetic make-up to determine the type of lymphoma.
The appearance (known as "morphology") of the malignant lymphocytes simply refers to how the cells and tissues look under a microscope. The type of malignant lymphocyte, known as the "phenotype," refers to different unique "markers" that can be found on cells. These markers can be determined in a laboratory with special tests. Lastly, the genetic make-up, known as the "genotype," refers to the DNA of the malignant lymphocytes, which often have specific genetic mutations. When the diagnosis of lymphoma is made, these special classification tests may take weeks to perform due to their complex nature. Therapy and prognosis are often closely related to the results of these tests.
In general, lymphomas are divided into two major groups:
Hodgkin's disease (HD): Composed of unique malignant cells known as Reed-Sternberg cells (thought to be B cells) and a mixture of other, inflammatory cells. This disease is much less common than Non-Hodgkin's Lymphoma (see below) and tends to affect young adults. Its behavior and treatment are different than other forms of lymphoma, and fortunately, it is considered curable in many cases.
Inflammatory cells
Reed-Sternberg Cell
Inflammatory cells
Non-Hodgkin's lymphomas (NHL): Cell proliferations composed of either B cells or T cells. The majority of the NHLs in the United States are of B cell origin. Its classification has many subdivisions and each sub-category of NHL can act very different from the others.
Non-Hodgkin's lymphomas are divided into four basic sub-groups based on the type of malignant cells:
- Precursor B-Cell Lymphomas - cell of origin is an"immature" B cell
- Peripheral B-Cell Lymphomas - cell of origin is a "mature" B cell
- Precursor T-Cell Lymphomas - cell of origin is a "immature" T cells
- Peripheral T-Cell Lymphomas - cell of origin is a "mature" T cell
The Peripheral B and T cell NHLs are further divided into separate categories based on their appearance, cell "markers" and genetic make-up. There are over 20 categories of NHL in all (confused yet?). To understand how detailed the sub-classification of NHLs can get, one need only look at examples of how cell appearance is used to determine the type of lymphoma. There are sub-categories for small vs. large lymphocytes, round vs. irregular lymphocytes, and whether or not the lymphocytes resemble (or are) plasma cells. In addition, when examining a piece of lymph node tissue under the microscope, the lymphoma may be put in a separate category based on whether the malignant cells are organized into round clusters (known as a nodular or follicular pattern) or are evenly spead out though the lymph node (known as a diffuse pattern). These can all be important prognostic factors.
Non-Hodgkin's Lymphomas are also divided into groups based on clinical behavior (i.e. how long the patient is predicted to live without treatment). The three clinical groups are:
- Indolent lymphomas--patients live years without treatment
- Aggressive lymphomas -- patients live months without treatment
- Highly aggressive lymphomas -- patients live weeks without treatment
Ironically, lymphomas which are "low" grade or indolent are difficult to cure. Thus, while the patients with indolent disease have a good prognosis and live many years with their disease, their lymphomas are very difficult to eradicate with currently used chemotherapy or radiation. These patients also usually present with extensive, wide-spread disease. In contrast, highly aggressive lymphomas ("high grade" lymphomas) can rapidly result in the death of the patient. However, if patients are aggressively treated and put in complete remission, many of them can be cured and not have a recurrence of their disease.
A diagnosis of lymphoma can be devastating to a person and his or her family. Unfortunately, the classification scheme is fairly complex and constantly changing, which can make things confusing. This complex classification, however, is a testament to the advancement in our knowledge about the disease and how it is most effectively treated.
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