Definition

A progressive, malignant, cancer marked by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. The two types are lymphocytic leukemia and myelogenous leukemia.

Lymphocytic Leukemia

A cancerous transformation of lymphocytes (a type of white blood cell) produced in bone marrow, or spleen.

Myelogenous Leukemia

A cancerous transformation within the bone marrow, or spleen, of blood-forming cells (myeloid precursors) including granulocytic white blood cells that fight infection, erythrocytes (red blood cells which carry oxygen), and platelets (cells that aid in the clotting of blood).

*Note: The term “leukemia” was coined in 1848 by Dr. Rudolf Virchow, a German scientist known as the “father of pathology.” This can be a little confusing since it originates from the Greek words leukos “clear, white” + haima “blood” and “leukocyte” is the term used for all white blood cells. Yet, myelogenous leukemia affects red blood cells and platelets as well as white blood cells.

Most leukemias arise in the spleen in rats, whereas most leukemias in people arise in the bone marrow.

Clinical Signs

Non-specific signs may include:

• Lethargy/weakness/depressed state
• Pale mucus membranes and/or extremities
• Increased drinking (polydipsia)
• Increased urination (polyuria)
• Dark urine
• Labored breathing (dyspnea)
• Rapid breathing (tachypnea)
• Weight Loss
• Lack of appetite (inappetence)

Late stage signs may include:

• Wasting (cachexic)
• Jaundice
• Increasing weight loss
• Liver enlargement (hepatomegaly)
• Spleen enlargement (splenomegaly, which is nearly always pathognomonic)
• Kidney enlargement (renomegaly)
• Lymph node enlargement (lymphadenopathy)
• Increased heart rate
• Elevated or lowered body temperature
• Bleeding disorders
• Opportunistic bacterial or fungal infections

*Note: for information on recognizing various signs of pain or discomfort refer to: Signs of Pain In Rats.

Etiology

Bone marrow is a spongy-like substance found within longer bones where all blood cells begin as multipotential stem cells. These same types of cells are also found in the spleen of rats. As the cells differentiate, they branch off into two separate types of cells: myeloid and lymphoid.

The lymphoid cells branch off into lymphocytes. Lymphocytes are white blood cells that eventually mature in the thymus and the lymph organs. They are an integral part of the body’s natural immune system.

The myeloid cells branch out to become thrombocytes (platelets), erythrocytes (red blood cells), monocytes, mast cells, and granulocytic white blood cells (neutrophils, basophils, and eosinophils).

Leukemia starts when one or more of the myeloid or lymphoid cells experience chromosomal (DNA) damage or disruption. These damaged cells do not mature properly and are unable to perform their normal cellular functions. As they multiply, new generations of malignant cells are produced that live longer than normal cells of the same type and multiply at an accelerated rate. They accumulate in the bone marrow, circulate in the blood, accumulate in lymph nodes, and ultimately infiltrate the tissues throughout the body. The over production of malignant cells can limit the production of other blood cells.

The types of leukemia can be classified on the basis of:

• Cell type: Lymphoid or Myelogenous (including specific cells within these two groups)
  
• Duration: Chronic or Acute
  • In chronic leukemia the disease is of longer duration progressing slowly.
    
  • In acute leukemia the disease has an abrupt onset and spreads rapidly.

Lymphocytic Leukemia

In lymphocytic leukemia, only the lymphocytes are neoplastic. These malignant white blood cells tend to be long-lived and can cause problems by buildup (as opposed to simple overgrowth). The abundant malignant lymphocytes travel through the blood and lymphatic system and infiltrate the organs causing dysfunction and eventually organ failure. In rats’ lymphoid leukemia appears to originate in the spleen, or bone marrow.

The most common type of leukemia in rats is the large cell granular lymphocyte leukemia (LGL) which is also known as mononuclear cell leukemia (MNCL). The Natural Killer (NK) lymphocytes may be the cell of origin rather than lymphocytes with either T-cell or B-cell lineage. This type of leukemia is not commonly seen in humans.

Myelogenous Leukemia

Myelogenous leukemias are rare in rats and affect some/or multiple myeloid precursor cells in the bone marrow, or spleen. Myelogenous leukemia can cause abnormal and/or decreased numbers of erythrocytes and platelets as well as abnormal or increased white blood cells. This may produce severe anemia and/or a tendency toward bleeding. Lethargy and shortness of breath occur as the body tries to compensate for the shortage of oxygen being supplied to the cells of the body. The constriction of peripheral blood vessels can lower body temperature which may cause the rat to spend more time burrowing in its nest in order to maintain body warmth. In addition, the immune system can become severely depressed, resulting in a variety of opportunistic secondary infections.

Erythroblastic leukemia produces an excessive amount of abnormal red blood cells.

The cause of leukemia remains unknown. Research indicates that some factors that may pose a risk to development of leukemia are:

• Age (Leukemia is more common in aging rats)
• Genetic predisposition (i.e., certain strains, Most common in F344 rat)
• Toxin exposure (e.g., chemicals, certain pesticides, exposure to tobacco smoke)

*Note: Lymphoma, which is a white blood cell cancer, differs from leukemia in that can form outside bone marrow in lymph nodes and/or spleen and forms static tumors or can be seen in its leukemic phase with neoplastic cells being found in other organs.

Figures

• Fig. 1: Granulocytic leukemia (myelogenous) in male rat (Zissou).
  *Warning! Photos shown are very graphic.*
• Fig. 2: Mononuclear cell leukemia MNCL (lymphoid) in female rat (Lulu).
  *Warning! Photos shown are very graphic.*

Diagnostics

CBC (Complete Blood Cell Count) may show Leukocytosis (increased white blood cell count of up to 180,000/uL may be present), atypical mononuclear cells, large number of immature neutrophils.

RBC (Red Blood Cell count), Hgb (Hemoglobin) and Hct (hematocrit) may be decreased resulting in the diagnosis of anemia.

Late stage disease:

Direct Coombs’ test may reflect Hemolytic anemia (spherocytosis, reticulocytosis, anisocytosis, polychromasia,
neutrophilia, thrombocytopenia).

Analysis of the urine may reveal elevated liver enzymes reflecting hepatocellular injury (e.g. hemoglobinuria and bilirubinuria).

Gross findings may reflect: hepatomegaly and marked splenomegaly, organs can be discolored (due to infiltrates), particularly the liver, spleen, and the lungs.

Treatment

Palliative (supportive) care is the primary goal in rats.

Leukemia is a fatal disease of aged rats. There is no treatment that permanently controls or cures leukemia. Treating other underlying illnesses, opportunistic bacterial infections or fungal infections with antimicrobials, and inflammation and swelling with NSAIDs or corticosteroids will help to keep the rat comfortable. Care is based on providing comfort and controlling or preventing secondary infections until such time as death ensues or euthanasia is required.

For information regarding individual medications refer to the Rat Medication Guide.

Nursing Care

• Give medications as prescribed by veterinarian.
• Provide one level cage for rats with mobility issues, lethargy, or respiratory difficulty.
• Provide a safe and stress-free environment.
• Keep the food and water within easy reach.
• Provide nutritional supplements if appetite is poor.
• Provide additional warmth to maintain body temperature within normal limits. It is essential that the rat does not become overheated or dehydrated. The rat should also be able to move away from the heat source if it becomes uncomfortable. If the rat is unconscious or immobile extreme care must be taken to keep the heat low and stable.
  • You can use an isothermic product that is heated in the microwave such as SnuggleSafe®. Make sure to follow the product directions carefully and wrap in a towel before placing in the cage. SnuggleSafe® will provide heat for 12 hours before needing to be reheated. Other similar types of products may vary in re-heat time. Check directions for individual product.
  • If using a heating pad (good for long term use) use only the low heat setting, put a thick towel in between the pad and the cage bottom, and place beneath a corner of the cage.
  • If none of these options are available you can use a plastic bottle filled with hot water, and wrapped in a towel, in the corner of the cage.
• Contact veterinarian if any of the following are observed: changes from normal behavior, increased lethargy, weight loss, difficulty breathing, inflammation and/or swelling, pain, signs of bleeding.

Outcome

To minimize the clinical signs until the disease progresses and euthanasia is required.

• Secondary infections controlled
• Weight maintained
• Pain controlled
• Respiratory status not impaired
• Euthanasia may be indicated as disease progresses

Prevention

There is no known prevention at this time.

References

1. Thomas, J. , Haseman, J., Goodman J., Ward J., Loughran, Jr. T., and Spencer, P. “A review of large granular lymphocytic leukemia (LGLL) in Fischer 344 rats as an initial step toward evaluating the implication of the endpoint to human cancer risk assessment.” Toxicol Sci. 99, no. 1 (2007): 3-19. https://academic.oup.com/toxsci/redirect-unavailable?url=toxsci.oxfordjournals.org/cgi/reprint/kfm098v1.pdf (accessed January 12, 2010).
2. Boorman, G., Everitt, J. (2005). Neoplastic Disease. In M. Suckow, S. Weisbroth, & C. Franklin (Eds.), The Laboratory Rat, Second Edition (American College of Laboratory Animal Medicine) (pp. 479-512). Toronto: Academic Press.
3. Car, B., Eng, V., Everds, N., Bounous, D. (2005). Clinical Pathology of the Rat. In M. Suckow, S. Weisbroth, & C. Franklin (Eds.), The Laboratory Rat, Second Edition (American College of Laboratory Animal Medicine) (pp. 127-146). Toronto: Academic Press.