What causes NHL?
Many people try to determine what gave cancer a foothold, sometimes from intellectual curiosity and sometimes from a determination not to suffer a relapse.
Only two causes of NHL have been proven, but there are several circumstances and substances which are suspected to play a part in the development of at least some NHLs. It's probable that you'll never know the exact cause of your illness, but the following sections offer possible explanations.
Before a clear discussion of the causes of NHL can ensue, you need to know a bit about what causes cancers in general.
How cancer develops
Human DNA is stored on forty-six paired chromosomes. With a couple of exceptions, each cell in our body has one copy of all forty-six chromosomes, coiled tightly in a ball, stored in the cell nucleus. Each chromosome is composed of two long strings of genes held together like a ladder, with rungs consisting of electrochemical bonds.
Many if not all instances of cancer are accompanied by changes in the tumor cell's DNA. At times, a gene is entirely missing, or has been half-spliced with another gene after DNA strands from two entirely different chromosomes accidentally overlap, break apart, and rejoin. Such chromosomal inversions and transpositions are well known among the NHLs and other cancers. Translocations between chromosomes 14 and 18, for example, are common among the follicular lymphomas. In some cases, an entire chromosome may be missing, as with some acute leukemias.
All of the body's work is accomplished using proteins. Our bodies build proteins from genes by reading the base pairs of DNA in groups of three, until special repeating sequences recognized as terminators are encountered. Each triplet encodes for one amino acid, and the complete string of amino acids comprises a protein. The string of amino acids that accumulates--that is, the protein built as the DNA is transcribed--is unique to that gene.
If the gene is damaged by the crossing-over of two chromosomes, a protein built from it will be based half on one gene and half on another, and most likely will be completely nonfunctional or even toxic.
If one base pair is deleted from DNA, the transcription of the three base pairs into one amino acid is shifted off by one, almost exactly like placing one's fingers on a piano or computer keyboard in the wrong starting position: every subsequent movement up and down the keyboard will produce wrong notes or wrong letters when the starting point is wrong. Thus, when one or more base pairs are missing, the resulting protein will be entirely different from that which the body is expecting to accomplish some metabolic task.
When these aberrant changes occur in, or very near, genes that regulate cell growth, trigger orderly cell death (apoptosis), or regulate maturation or cell division and reproduction, cancer may result.
Two known viral causes of NHL
Two viruses have been linked to some cases of NHL:
- Epstein-Barr virus (EBV).
- Human T-cell lymphoma/leukemia virus (HTLV-I).
It is known with certainty that 1-2 percent of those who are immunosuppressed shortly after solid organ transplantation, or owing to HIV/AIDS, develop NHL that is linked to the presence of Epstein-Barr virus, a human herpes virus present in more than 90 percent of humans by adulthood. These virally induced NHLs can regress if immunosuppression is reduced, and clearly are linked to the suppression of functioning white blood T-cells. Unlike other cancers, which are monoclonal, indicating growth from only one precursor cell, these NHLs can be polyclonal, more closely resembling a process of white blood cell growth similar to that following infection.
Moreover, virtually all cases of Burkitt's lymphoma found among children in Africa test positive for the Epstein-Barr virus, although this is not always the case among Burkitt's lymphoma found elsewhere in the world.
For those with transplanted organs, reducing immunosuppression involves lowering doses of immunosuppressive medications. For those with AIDS, reducing immunosuppression currently involves raising the count of white blood T-cells by using AZT and the protease inhibitors.
It is also known that those who are infected early in life with the human T-cell lymphoma/leukemia virus I (HTLV-I) have about a 3 percent chance of developing aggressive T-cell lymphomas or leukemias, as well as other health problems such as illnesses of the central nervous system. Although present worldwide in small pockets, HTLV-I is found in highest concentrations in parts of the Caribbean, parts of Japan, and in lower concentrations in the southeastern U.S. Very intimate exposure is required for transmission, such as sexual contact or the ingestion of breast milk from an infected woman.
Unproven, possible causes of NHL
As mentioned earlier, there are a number of possible causes of NHL that have yet to be proven scientifically. Some have stronger evidence than others, and some have produced conflicting results in studies, but all have at least some validity.
Nitrates in drinking water
One very strong candidate for at least those cases of NHL that arise in the American Midwest that are not explained by other risk factors is the ingestion of high levels of nitrates from drinking water. Nitrates are thought to find their way into drinking water from runoff following the use of nitrogen fertilizer by the farming industry. One study has shown a dose effect among those who were exposed to nitrates in drinking water; that is, as levels of nitrates in drinking water sources rose, more cases of NHL were found among those using that source. Demonstration of a dose effect between exposure to a substance and the development of cancer, while not a guarantee of causality, is nevertheless a compelling piece of evidence.
Pesticides, including Agent Orange
Pesticides, consisting of insecticides and herbicides, have been examined as a possible cause of NHL.
The higher incidence of NHL among Midwestern farmers may support the theory of increased risk associated with pesticide exposure, as may the lower incidence of NHL among those in the same or similar professions who wear protective clothing and masks. Particularly interesting is the demonstration of higher rates of NHL among those exposed to pesticides, even when rates of other cancers in these groups remain level or decrease. Some studies have shown a fifty to two-hundred-fold increase in risk among those exposed to the herbicide 2,4-D.
As home use of pesticides contributes five to ten times more contaminant to the environment than does farming, we are wise to continue to study this possibility, to protect ourselves if we must use pesticides, and to use only the safest products available. Some or most pesticides can be absorbed directly through the skin and often are inadvertently inhaled, thus making questionable the safety studies performed by the industry which rely on oral dosing to prove that some pesticides do not cause cancer in laboratory animals.
The herbicide dioxin, also known as Agent Orange, has received a great deal of scrutiny. Some studies have shown no clear connection between exposure to dioxin in Southeast Asia and the development of lymphomas, but other studies have. The U.S. Veterans Administration acknowledges a link between dioxin and certain cancers, however, and will pay disability benefits to those who have developed certain lymphomas (including NHL) if they can document exposure to dioxin based on the geography of their military assignments in Southeast Asia.
Hair dye use
Some studies have shown that those who use dark hair dye are more likely than the general population to develop NHL, but other studies have not supported this.
Some studies have shown that those who drink a great deal of milk are more likely than the general population to develop NHL, but not all studies examining the connection between NHL and milk consumption have supported this conclusion.
High consumption of meat has been linked in some studies to an increased risk of NHL, but other studies show no connection.
On the other hand, studies have shown that those eating a diet rich in carotenes, vitamin C, carrots, dark green vegetables, citrus fruits, whole-grain breads, and pasta have a lower incidence of NHL.
Drug, alcohol, and tobacco use
Amphetamines, Quaaludes, lysergic acid diethylamide (LSD), and especially cocaine use have been linked to the development of NHL in men by one recent study, as was prescription amphetamine use in a second recent study that did not specify gender. Other studies suggest that the long-term illegal use of narcotic drugs may also increase NHL incidence. More research is needed to confirm these associations.
Phenytoin, or Dilantin, used for control of seizures, has been shown to increase the rate of a lymphoproliferative syndrome that resembles NHL.
Alcohol and tobacco use have been shown by several studies to have no effect on the rate of NHL.
Other infectious suspects
Two known viral causes of NHL, Epstein-Barr virus and HTLV-I, are implicated in some cases of NHL. Other infectious agents are suspected as well.
The higher incidence of NHL among slaughterhouse workers and farmer-breeders also hints at possibly a third, as yet unknown, viral association.
Those who have chronic liver disease caused by infection with the hepatitis C viruses early in life are more likely to develop primary splenic and liver (hepatic) NHL.
AIDS-associated NHL, usually an aggressive NHL with a diffuse appearance, has in some cases been linked to human herpes virus 8 (HHV-8) based on traces of viral protein found within the tumor, but less research on this link has been done than on that between Epstein-Barr virus and NHL in the immune-suppressed. Nonetheless, HHV-8 is a reasonable suspect, as it's known to cause Kaposi's sarcoma, a skin tumor, among those with AIDS, and also has been linked to aggressive body-cavity or primary-effusion NHL.
In recent years, it has become clear that some cases of gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) is linked to infections of Helicobacter pylori, a bacterium capable of surviving in the acidic stomach environment. When H. pyloriis treated with antibiotics, in many cases the lymphoma recedes. Not all grades of gastric MALT lymphoma recede when H. pylori is treated with antibiotics, however. The effect of antibiotic treatment on other MALT lymphomas has not been closely studied to date, but a few studies have shown a possible link between H. pylori and MALT lymphoma in the lungs.
Many people diagnosed with NHL become concerned that their siblings or children also may face a risk of developing NHL. Unfortunately, the familial aspect of NHL remains unclear. For example, a family history of leukemia or lymphoma increases the risk for NHL to two to three times the risk of the general population, but cases occurring within the same family account for less than 5 percent of all cases.
It is most important to bear in mind that, as the cause of NHL is still the subject of research, "familial" may imply an inherited genetic error, a shared exposure to an infectious cause, or a shared lifestyle. That is, the risk might come from inherited genes that predispose someone to develop NHL, just as there are genes that affect other aspects of our body's appearance and function. The risk might be that family members tend to be exposed to the same viruses or bacteria. Or the risk might turn out to be that families that live together are drinking the same water or living next to the same toxic dump.
Attempts to understand any increased risk among family members may be made even more difficult if the way that many research studies use the word "genetic" is not understood. We who are not involved in research tend to use the word "genetic" interchangeably with "heritable" or "inherited," but the study of genetics encompasses a broader meaning, and researchers usually are not referring to genetics in the heritable sense when they use the word "genetics." Many genetic changes occur within cancerous cells, but only genetic changes or errors that arise and persist in sperm or ova can be inherited.
Predisposition to a certain illness can arise when there are natural variations in genes. Such multiple versions of genes are called alleles, and many such exist. For example, it is highly likely that you have two alleles for every gene in your body, having inherited one allele for each from your father and one from your mother.
Genes are translated into proteins to accomplish their metabolic goals; proteins always fold into a specific shape dictated by their chemical makeup. Even a small difference in only one location of a gene can cause a protein string to fold differently, and this final shape dictates how or if the protein will function. Proteins that are created from the differing alleles, then, may have different structures and shapes, and may behave differently in metabolic reactions. Thus, researchers have begun to note that those who have specific versions of the HLA-DR gene on chromosome 6, for example-a gene controlling some of the behavior of white blood cells--appear in some cases to be more likely to develop certain diseases.
In fact, throughout this discussion of potentially causative factors, you can see that most of these factors could be explained using predisposition, heritability, or infection as the scientific model.
Familial immunodeficiency appears to predispose certain families to more than the expected incidence of NHL. The following list of inherited immune deficiencies has been adapted from Chapters 19, 21, 45, and 47 of Magrath's 1997 text, The Non-Hodgkin's Lymphomas:
- X-linked severe combined immunodeficiency (SCID).
- Omenn's syndrome.
- Purine nucleoside phosphorylase deficiency.
- X-linked agammaglobulinemia.
- Ig-A deficiency.
- Common variable immune deficiency.
- X-linked hyper-IgM syndrome.
- IgG subclass deficiency.
- Wiskott-Aldrich syndrome.
- Ataxia telangiectasia.
- DiGeorge anomalad.
- Hyper-IgE syndrome.
- X-linked lymphoproliferative syndrome.
- Chediak-Higashi syndrome.
- Bloom's syndrome.
- Enteropathy-associated T-cell lymphoma among northern Europeans.
- Hashimoto's thyroiditis (for MALT lymphomas).
There is a low but present risk of developing NHL following blood transfusions, especially among the elderly. This might indicate an infectious process or a derangement of the regulatory efforts of the immune system when coping with alien blood products.
An increased incidence of NHL has been noted among those in the following professions: farming, livestock breeding, rubber workers, chemists, chemical workers, dry cleaners, metal workers, funeral directors and embalmers, petroleum refinery workers, printing workers, those exposed to ethylene oxide, beauticians/cosmetologists, woodworkers (including those in sawmills and pulp mills), and those exposed to certain chemicals such as ammonia or to organic solvents such as benzene.
Risk associated with other illness
A small increased risk is seen among those with asthma, allergies, arthritis, rheumatic fever, nontropical celiac sprue, tuberculosis, and infectious mononucleosis. Epstein-Barr virus is considered to be the cause of infectious mononucleosis. Asthma, allergies, nontropical celiac disease, and some forms of arthritis are illnesses caused by the inappropriate or misdirected activity of white blood cells. As NHL also is a disorder of white blood cell production and maturation, and can in some cases be triggered by over-activity of white blood cells, some researchers speculate that there may be a connection between these disorders and NHL.
Continuous antigenic stimulation
Many of the possible causes of NHL that we have discussed in the preceding paragraphs may act by soliciting an ongoing reaction from our immune system. Some researchers believe that chemicals, infections, or allergic or auto-immune reactions are all capable of producing an ongoing immune system reaction that triggers NHL and other related illnesses. This is sometimes called continuous antigenic stimulation.
The substance or infectious agent itself may not be causing the cancer, but the immune system reacting to the substance is. For example, some B-cell lymphomas such as gastric MALT lymphomas appear unable to grow unless white blood cells specific for killing Helicobacter pylori bacteria are also present. This growth of cancer only following action by part of the immune system also is seen in the failure of growth of grafted B-cell tumors in severe combined immunodeficiency (SCID) mice, which are bred without immune systems for research purposes. But when missing T-cells are injected, the tumors begin to grow.
Currently, the best place for this theory remains within the laboratory. It is of little practical import whether a substance, or the immune system's reaction to it, is to blame for cancer if simply avoiding a substance can reduce your risk.
The possibility for dangerous continuous antigenic stimulation is also the basis for the FDA ruling requiring warning labels on some nutritional supplements, such as melatonin, sold as immune boosters.
The aging immune system
In opposition to continuous antigenic stimulation discussed above, some researchers feel that the greatly increased rate not only of NHL, but of most other cancers among those over age 65, hints at a general weakening of the immune system with age. Others feel that this more likely may be a product of the modern world we live in: that genetic damage from substances in an industrialized environment accumulates over time and first becomes apparent among the oldest.
Grading and staging NHL
It is most important that your disease be correctly identified, graded, and staged so that the best treatment can be planned. All biopsies of tumor tissue should be reviewed by an experienced hematopathologist to be certain that subtype and grade are correctly identified.
Brief definitions of stage and grade are:
- Staging describes how far disease has spread from its original site. Staging for many, but not all, cancers consists of stages I through IV.
- Grading describes how aggressive the tumor is. Grades for the NHLs are low-, intermediate-, or high-grade, although many researchers combine intermediate- and high-grade diseases in discussion of treatment.
There are important deviations in what these characteristics mean to success of treatment. It is not always true, for instance, that a stage IV, high-grade patient has fewer hopes for cure than a stage IV, low-grade patient.
For years, the Rappaport and Ann Arbor systems used for Hodgkin's lymphoma, and the Working Group and Kiel systems, were adapted to describe NHL in a way that attempted to reflect tumor characteristics, and thus to some degree prognosis, but none was entirely satisfactory. Most recently, the Revised European American Lymphoma (REAL) classification system was proposed by an international cooperative group of researchers to more correctly identify lymphomas based on immunologic characteristics.
The lack of fully acceptable staging and grading systems for NHL has resulted in many universities and cancer treatment centers devising their own systems. Each system attempts to correlate cellular or disease characteristics to treatment outcome.
One consequence of this variety of descriptive systems is that you may become confused when talking to other survivors who state that they have the same subtype, grade, and stage as you do, but who are receiving different treatment with perhaps different results.
Some cases of NHL have characteristics of two or more known entities. In these cases, identity or staging decisions can be difficult to make. The following sections describe efforts to grade and stage NHLs for choosing the best treatment.
A tumor can be graded as indolent, intermediate, or highly aggressive by several measures. All NHL tumors are graded on their appearance under the microscope, known as histologic grade; some are graded on behaviors that leave traces of tumor activity in the bloodstream or other body tissues.
The grade of a tumor often can be correlated to the cell's appearance under the microscope. The description of this appearance is known as histology. While some characteristics of cell appearance for some subtypes of NHL do indeed correlate to the stage of disease, such as increasing tumor cell size in low-grade disease converting to a higher grade, for other subtypes this is not so. Nevertheless, at one time, histological staging of NHL was the best that could be done.
Other factors affecting grade
Recent progress in research has shown that there are additional characteristics, not related to cell appearance, that bear on grade. For example, proteins called immunoglobulins created by damaged genes within cancerous white cells and circulating in the bloodstream may be meaningful to the aggressiveness of disease by virtue of their unusual quantity or shape.
Staging is a measure of how much of the body is affected by NHL.
Often, the Ann Arbor staging system is used for staging NHL patients, but it was developed to describe Hodgkin's lymphoma, not non-Hodgkin's lymphoma. As a result, it is not an entirely satisfactory measure of the effect of NHL on the patient's body. Many oncologists and institutions incorporate other clinical measures-age, ability to do normal everyday things, tumor size, lactate dehydrogenase (LDH) blood levels-to discuss more accurately the effect of disease. Ask your oncologist what standard was used to assess the spread and effects of your disease.
The divisions of the Ann Arbor staging system are:
Stage I designates disease in a single lymph node or lymph node region, or localized involvement of just one extranodal site, such as the spleen, which is designated as stage IE.
Stage II designates disease in two or more lymph node regions on the same side of the diaphragm.
Stage IIE is local disease in a single extranodal site, such as the lung, including its regional lymph nodes, with or without affecting other lymph node regions on the same side of the diaphragm. The number of nearby lymph node regions affected may be indicated by an appended number, such as II3.
Stage III means that lymph node regions on both sides of the diaphragm are affected. Disease also may be accompanied by local involvement of an extranodal organ or site, such as the liver, or by involvement of the spleen (IIIS), or both (IIIS+E).
Stage IV means widely spread, multiple involvement at one or more extralymphatic sites such as the bone marrow, with or without associated lymph node involvement, or involvement of an isolated extranodal organ with distant nodal involvement.
Extranodal sites are identified by the following notation:
- N = lymph nodes
- H = liver (hepatic)
- L = lung
- M = bone marrow
- S = spleen
- P = pleura (lung)
- O = bone
- D = skin (dermis)
Staging may be clinical staging (CS), based only on a physical examination, or pathologic staging (PS), based on the later findings of node biopsy and other diagnostic procedures such as bone marrow aspiration or abdominal surgery.
This means that you might initially be staged at level II, based on your oncologist's first physical exam detecting just a few swollen lymph nodes in your neck, armpit, or groin, but after bone marrow biopsy and a bronchoscopy, you might be restaged at level IIE, III, or IV.
Often you'll find in the medical literature that patients who have relapsed are no longer discussed by stage, but are instead described as having recurrent disease. In some cases, recurrent disease may be the equivalent of stage I, such as is seen in the relapse of certain patients with limited low-grade disease. For intermediate- and high-grade disease, though, recurrent disease often is considered to be the equivalent of stage III or IV.
One of the most important strides that has been made in understanding not only NHL, but the behavior of all cells, was the discovery that all cells have on their surface bits of protein that extend outward and interact with other cells and proteins, somewhat like business people trading business cards. These tags, or cell surface antigens, have been analyzed, and it has been found that tumors have antigens that differ from those on healthy cells. It has been found that different types of cancer and--most important for our purposes--different subtypes of NHL have differences in types and quantities of cell surface antigens.
Immunophenotyping is the categorization of cells based on these cell surface antigens. Moreover, it is known that these antigens, which dictate cellular immunity, change in tandem with corresponding changes in the cell's DNA.
But what is phenotype? By definition, one's phenotype is the outward, visible, or demonstrable expression of one's genes or genotype. For example, blue eyes are the phenotypic expression of the genotype for blue eyes. Thus, any outward or visible cellular characteristic related to immune function that changes with genetic change is an immunophenotypic characteristic.
An example of immunophenotyping that you are probably familiar with is the red blood cell antigen system, ABO. Most of us learn eventually whether we have blood type A, B, AB, or O, where type O indicates the absence of any such marker. This information is critical to those needing whole blood transfusions, because receiving the wrong blood type can cause a fatal immunologic war within, as incoming alien blood cells are targeted for destruction by our own white blood cells and vice versa. (The ABO system, while meaningful to NHL survivors who must have transfusions, is used in this paragraph only as an example of phenotype; that is, the ABO system has no bearing on the type or outcome of NHL treatment.)
Cell surface antigens have become very important in the categorization and treatment of NHL. Cancerous cells produce different cell surface antigens, or a great deal more of them, than do healthy cells. Tumors may express in turn different cell surface antigens at different levels of disease progression. They may express more than one abnormal cell surface antigen or may express the abnormal antigens along with normal antigens.
The REAL lymphoma classification system relies heavily on these immunophenotypic markers exhibited by lymphoma and leukemia cells (as well as on unusual proteins secreted by cancerous white blood cells), rather than on cell appearance, to separate the various subtypes of NHL. Because categorization by immune marker is a completely new way to identify lymphomas, the REAL system includes not only NHL, but also other hematologic cancers that share these markers, such as the Hodgkin's lymphomas, plasma cell myeloma, and chronic lymphocytic leukemia (CLL). As you can see, the REAL classifications system has breached significant traditional boundaries in the thinking about differences among lymphomas and leukemias.
In its initial form, REAL has not met with complete acceptance by all researchers and clinicians, some of whom would prefer a classification system more meaningful to the everyday treatment of NHL. Proposed modifications to REAL are being evaluated.
New treatments have been designed that exploit the fact that tumors have different markers on their cell surface that our bodies seem to ignore, instead of sensing and attacking. Monoclonal antibodies (abbreviated as mabs or moabs) are perhaps the most widely known new treatment exploiting this characteristic. Monoclonal antibodies are molecules secreted by white blood cells that attach to foreign bodies such as viruses. Attachment is a signal to other classes of white blood cells to attack and kill the intruder. Because cancerous cells express more or different cell surface antigens than do normal cells, monoclonal antibodies can be designed and manufactured to recognize and attach to these tumor cells, thus tagging them for destruction. Monoclonal antibodies have been used for years in laboratory medicine to identify different cell types, but the first monoclonal antibody for cancer therapy was not approved by the FDA until 1997, when Rituxan for NHLs expressing the CD20 antigen was approved.
Another example of immunophenotyping is the broad categorization of white blood cells into B-cells and T-cells. B-cells are white blood cells that originate in bone marrow; T-cells, broadly speaking, are those that originate in marrow and travel to the thymus where they are trained (differentiation) to recognize specific enemies. B- and T-cell development, though, is far more complex than one would believe based on this brief description. Both B-cells and T-cells spend time within lymph nodes, either resting, maturing, or differentiating, and each fulfills different but complementary roles in immune surveillance. NHLs are divided somewhat successfully into T-cell or B-cell lymphomas; however, there are cases of NHL that are T-cell-rich B-cell lymphomas.
In the future, immunotyping may supplement or eclipse Ann Arbor staging and histologic grading as the means by which tumors are identified and assessed for their effect on the patient and the outcome of disease.