Most of us have heard of leukemia and know it is a kind of cancer that people commonly get. We know it is generally a serious and often fatal disease. This article explains what leukemia is in dogs, and why it is bad; it also reviews the most common forms of leukemia for dogs, called the lymphocytic forms.
The large purple cells are circulating malignant lymphocytes. Photo courtesy of the University of Georgia
Leukemia is a word describing exactly what it is: “Leuk” means white (in this case white blood cells) and “emia” means blood. Leukemia means “white blood” or more specifically an over-abundance of white blood cells in the bloodstream. Now, white blood cell counts go up in response to infection, inflammation, allergy, and even stress. We are not talking about elevations in these ranges. The patient with leukemia has an over-abundance of a particular white blood cell but in magnitudes so great that it is amazing that the change cannot be seen with the naked eye. The bloodstream is swarmed with cancerous white blood cells, and the bone marrow from whence they came is consumed with making cancer cells and making very few of the other blood cells needed to survive. In the case of lymphocytic leukemia, the cancer cells are of lymphocyte origin, though there are many other types of leukemia, potentially one for every type of blood cell made by the bone marrow. In this article, we stick to the lymphocytic leukemias.
What Causes Lymphocytic Leukemia?
In dogs, we do not have much of a list of possibilities though in other species some culprits have been identified. It may be that these same factors are causes in dogs as well. In humans, radiation exposure had been linked to lymphocytic leukemia development as has exposure to benzene. In cats, birds, and cattle there is a “leukemia virus” (though not the same virus for these different animals). Not surprisingly, given the name, leukemia viruses cause leukemia as well as other lymphocytic cancers such as lymphoma.
Chronic Versus Acute Lymphocytic Leukemia
In most of these patients, the diagnosis of lymphocytic leukemia is clear when an impossibly high lymphocyte count is seen. A normal lymphocyte count is generally less than 3,500 cells per microliter. In lymphocytic leukemias, lymphocyte counts over 100,000 are common.
Numbers of this magnitude generally flag the sample at the reference laboratory for reading by a clinical pathologist (or if the initial testing is done in the veterinarian’s office, the lymphocyte reading will cause the sample to be submitted for further analysis). The pathologist will then review the slide visually for signs of malignancy within the cells. The diagnosis of lymphocytic leukemia is usually fairly obvious (for exceptions see below) but the key is to determine whether the lymphocytic leukemia is chronic or acute.
Normally the term chronic means a process or disease has been going on for a long time and acute means that the process started suddenly. For lymphocytic leukemia, these terms have a different meaning: they refer to how mature the cancer cells look. Lymphocytes develop from precursor cells in the bone marrow or lymph nodes and undergo several stages of development before they are released into the bloodstream. When a leukemia involves earlier stages of lymphocytes, it is said to be an acute leukemia. When cells are more developed, the patient is said to have a chronic leukemia. As a general rule, the acute leukemias act more malignantly than the chronic ones. There is some controversy over whether acute or chronic lymphocytic leukemia is more common.
Acute Lymphocytic Leukemia (ALL)
Lymphoblasts Under Microscope
Patient with Acute Lymphocytic Leukemia. Photocredit: Public Domain Image from the Armed Forces Institute of Pathology
ALL (acute lymphocytic leukemia) involves the obliteration of the bone marrow by immature lymphocytes called lymphoblasts, or simply blasts. When 30 percent of the bone marrow cell population consists of blast lymphocytes, ALL is confirmed. In 90% of patients, the blast cells spill out into the circulating blood where they can be detected in a blood sample. The lymphoblast cell is the hallmark cell of ALL.
The most common symptoms include: listlessness, poor appetite, nausea, diarrhea, and weight loss. The average age at diagnosis is only 6.2 years with 27 percent of patients being under age 4 years. Over 70 percent of patients have enlarged spleens due to cancer infiltration, over 50 percent have enlarged livers, and 40-50 percent have lymph node enlargement (though this last is not dramatic). On lab tests, over 50 percent will have anemia (red blood cell deficiency), 30-50 percent will have a platelet deficiency (platelets are blood clotting cells so deficiency can lead to spontaneous bleeding), and 65 percent have what is called neutropenia. Neutrophils are white blood cells that serve as the immune system’s first line of defense. Neutropenia is a neutrophil deficiency that leaves the patient vulnerable to infection.
Pets with ALL are generally very sick and require aggressive chemotherapy. Often they need blood transfusions because of the severe anemia or antibiotics to make up for the neutropenia. Typical chemotherapy protocols include: prednisone, vincristine, cyclophosphamide, L-asparaginase, and doxorubicin. Still, even with aggressive chemotherapy only 30 percent of patients achieve remission, and with no therapy most patients die within a few weeks. Prognosis is poor when ALL is diagnosed so it is important to distinguish ALL from lymphoma or from more treatable forms of leukemia.
Chronic Lymphocytic Leukemia (CLL)
s rapid and aggressive as acute lymphocytic leukemia is, chronic lymphocytic leukemia is the opposite with most patients having few symptoms and long survival times. The clinical course of CLL is long, lasting months to years, with the average age at diagnosis being 10 to 12 years. In up to 50 percent of cases there are no symptoms of any kind at the time of diagnosis, and the leukemia is discovered by chance on a routine blood evaluation. In CLL, it is the sheer number of circulating cells rather than what they look like is what makes the diagnosis.
There are three forms of CLL: T cell (called T-CLL), B cell (called B-CLL), and a form involving both B and T cells ( called atypical CLL). The T-cell form is the most common and has the best prognosis as median survival times are at least three times longer than for the other CLL forms. The type of CLL that a given patient has can be determined by blood testing (immunophenotyping or PARR testing, which stands for PCR testing for antigen receptor rearrangements), thus revealing the most information regarding prognosis and what to expect.
Because CLL progresses slowly, treatment is often forgone unless one of several conditions exist. Conditions for which treatment of CLL is recommended include: lymphocyte counts are greater than 60,000; if there are symptoms or organ enlargement; hyperviscosity syndrome (more common with B-CLL, see below); or if other white blood cell lines are suppressed by the tumor. If treatment is deemed necessary, common protocols involve prednisone, chlorambucil, vincristine, and/or cyclophosphamide. Survival times of one to three years with good life quality are common.
Golden Retrievers and German Shepherd dogs are predisposed to CLL.
What else Could it Be?
In most cases, the diagnosis is fairly obvious but not always. In early cases, the lymphocyte count may not have climbed to its ultimate level so the diagnosis may be unclear. Similarly, in late stages the bone marrow may be so damaged that it can no longer turn out many cells at all. In these cases, tests may be needed because when lymphocytic leukemia is ambiguous, there are other diseases that must be ruled out:
- Lymphoma in its most advanced stages involves the bone marrow and circulating cancerous lymphocytes spill into the bloodstream. Dramatically enlarged lymph nodes, if present, are a good indicator of lymphoma; lymphocytic leukemia patients usually have mild or no lymph node enlargement.
- Infection with the blood parasite Ehrlichia canis can lead to high lymphocyte counts and can be hard to distinguish from CLL. Special blood tests for Ehrlichia may be in order.
- Some other types of leukemia can be so poorly differentiated that special stains, PCR testing or a type of analysis called immunophenotyping might be necessary to characterize the type of cancerous white blood cells involved.
- Acute stress can cause lymphocyte counts as high as 15,000 cells per microliter but this is a temporary phenomenon.
- Hypoadrenocorticism (Addison’s disease) can lead to a lymphocyte count up to 10,000 cells per microliter.
- Chronic infection with fungus (if severe) or blood parasites can elevate lymphocyte counts dramatically.
- Lymphocyte counts over 20,000 are almost always from a lymphocytic leukemia.
What is a Monoclonal Gammopathy? What is Hyperviscosity Syndrome?
Antibodies are members of a group of blood proteins called gamma globulins. When an infection occurs, B-cell lymphocytes begin to produce antibodies. Not all B-cell lymphocytes produce antibodies, only the ones that recognize the infectious organism. Each activated lymphocyte will divide over and over with all the daughter cells ultimately producing antibodies against a specific portion of the infectious agent. Each member of a line of daughter cells is called a clone and, when all is said and done, there are many clonal lines each producing their own unique antibody. The gamma globulin levels in the bloodstream are high because of all the antibodies there but because many clonal lines are involved, there are many antibody shapes.This type of gamma globulin elevation is called a polyclonal gammopathy and generally indicates immune stimulation or infection.
Lymphocyte cancer is not like an infection. Infection stimulates many lymphocyte clones to divide, but cancer stems from one single cell gone wrong. There is only clonal line involved. If that clonal line is an antibody-producing lymphocyte line, then only one antibody is produced. The gamma globulin levels still rise but there is only one antibody shape. This is called a monoclonal gammopathy because only one single line of daughter cells participates. This is an unusual way for antibodies to be produced and the list of conditions that can stimulate only one clonal line like this is short:
- Ehrlichia infection (the only non-tumorous cause)
- Plasma cell cancer (multiple myeloma)
- B cell chronic lymphocytic leukemia.
The reason why monoclonal gammopathy is bad is because it can cause hyperviscosity syndrome. Antibodies are blood proteins, and if enough blood protein is circulated, the blood thickens. Smaller blood vessels are too delicate to circulate thickened blood. They break and bleeding results. What symptoms occur depend on where these small vessels bleed. There could be nose bleeds, seizures, blurred vision or even blindness.
In one study, monoclonal gammopathy was common in dogs with CLL. Antibodies, also called immunoglobulins, are classified as different types: IgG, IgA, IgE, IgM, and IgD. Monoclonal gammopathy from CLL is almost always of the IgM type, while monoclonal gammopathy from Ehrlichia infection produces IgG antibodies.
Lymphocytic leukemia is a cancer that not all veterinarians are comfortable treating. Discuss with your veterinarian whether referral to a specialist would be best for you and your pet.