An Overview of Acute Lymphocytic Leukemia (ALL) in Dogs and Cats

Mary Ashley Waikart, DVM; Julie L. Webb, DVM; Holly A. Moore, DVM; Bruce E. LeRoy, DVM, PhD, Dipl. ACVP

Class of 2007 (Waikart) and Department of Pathology (Webb, Moore, LeRoy), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Leukemias are malignant neoplasms of hematopoietic stem cells arising in the bone marrow.¹ Acute lymphocytic leukemia (also known as ALL, acute lymphoblastic leukemia, or acute lymphoid leukemia) is a proliferation of undifferentiated lymphocytes and is the most common cancer in children. The disease affects 25-30% of all pediatric oncology patients. Even though the specific etiology is largely unknown, ALL is considered to be one of the most curable cancers in children.² Although there are many similarities between the human and animal forms of the disease, the clinical course and outcome are very different. The prognosis with chemotherapy treatment is poor in canine and feline patients, and the average survival time is only a few months. Untreated, the estimated survival time from diagnosis is less than two weeks.¹ ALL is more common in cats than in dogs, however neither is very common compared to lymphoma. ALL can occur at any age in animals, although it is more prevalent in young and middle-age populations.⁴

Pathogenesis

ALL begins with the malignant transformation of an undifferentiated lymphoblast in the bone marrow. The progeny of this single transformed cell are clones which proliferate rapidly. Varying numbers of these neoplastic cells can be found in the peripheral blood. As such, ALL is characterized by high numbers of lymphoblasts in the bone marrow and varying numbers of lymphoblasts in the blood. Leukemic profile stages include aleukemic (neoplastic blast cells in the bone marrow only – early stages), subleukemic (few blast cells in the blood) and leukemic (many blast cells in the blood). Therefore the peripheral white blood cell count (WBC) in these patients may be above, below, or within the reference range depending on the stage of the disease at diagnosis.

The cell of origin in ALL can be a B-cell, T-cell or NK-cell.^3,4 Leukemias from all three cell types have been reported in dogs and cats and most cases in dogs are T-cell or NK-cell.⁴ Despite the origin, once a cell begins to proliferate the progeny typically do not mature and remain in the blast form in the marrow as well as in peripheral circulation. These cells do not function as normal lymphocytes. Instead, they compromise the normal function of the remaining hematopoietic precursors in the animal’s bone marrow. This is called myelophthisis and may manifest as anemia, granulocytopenia, thrombocytopenia, or a combination thereof in the peripheral blood. The neoplastic lymphocytes can also involve the liver and spleen, as well as occasionally the lymph nodes, in the later stages of the disease.

Although no exact cause for ALL has been isolated, some toxins and specific diseases have been indicated as predisposing factors. Human risk factors include specific genetic diseases, such as Down’s Syndrome, as well as radiation exposure.² FeLV has been implicated as a potential cause for ALL in cats.¹ However, the correlation has become less common after the routine increase in FeLV testing and vaccination of cats.³

Clinical Signs

Most of the clinical signs associated with ALL are non-specific. Lethargy, anorexia, cachexia, vomiting, diarrhea, and persistent fever have all been commonly reported with the disease. On physical exam, splenomegaly, hepatomegaly, mild lymphadenopathy, pallor of the mucous membranes, and petechiae may be evident. Shifting leg lameness, epistaxis, dyspnea, tachycardia and recurrent infections have also been associated with ALL. Neurologic signs are less commonly reported, however they can be seen in ALL patients with meningeal metastasis of the lymphoblasts.⁵

Many clinical signs observed in ALL are the result of myelophthisis and the resulting cytopenias. Anemia leads to lethargy and pallor, thrombocytopenia leads to petechiae and epistaxis, and granulocytopenia leads to fever and infections. Other clinical signs are the result of tissue infiltration by leukemic cells and subsequent organ dysfunction.

Diagnosis

Lymphoblasts are large lymphocytes (larger than a neutrophil) with a round nucleus and a scant to small amount of basophilic cytoplasm. They have a fine granular chromatin pattern and a visible nucleolus (Figure 1). ALL is often suspected after discovering moderate to high numbers of lymphoblasts in the blood (Figure 2). Definitive diagnosis, however, requires bone marrow examination. Classically, greater than 30% of the nucleated bone marrow cells must be lymphoblasts to diagnose ALL. Fine needle aspirates of the liver and spleen can be helpful if these organs are enlarged and their involvement is suspected.

Figure 1. Lymphoblast in the blood of a dog.  Note the large size compared to the red blood cells, small amount of basophilic cytoplasm (arrowhead) and visible nucleolus (arrow).	Figure 2. Acute lymphoblastic leukemia in a dog.  Numerous lymphoblasts were found in this blood smear.

Dogs and cats can be afflicted with other forms of acute leukemia besides ALL. For instance, acute monocytic leukemia is a proliferation of undifferentiated monocytes/monoblasts and acute myeloid leukemia is a proliferation of undifferentiated granulocytes/myeloblasts. It may be difficult, if not impossible, to differentiate ALL from other forms of acute leukemia based on visual inspection alone (Figure 3). It is also unreliable to attempt to classify ALL as B- or T-cell based on morphology alone. All acute leukemias present with similar clinical signs and all undifferentiated hematopoietic cells have similar morphology. Immunophenotyping and/or immunohistochemistry is often necessary to correctly classify an acute leukemia (Table 1).

Figure 3. Acute myeloid leukemia in a cat.  Numerous large myeloblasts with a moderate amount of lightly basophilic cytoplasm (arrowhead) and a visible nucleolus (arrow).  Note the similarities to the lymphoblasts in Figures 1 and 2 that make it difficult to tell these cells apart based on visual clues alone.

Table 1: Immunophenotype and immunohistochemistry of certain acute leukemias

Other Lymphoid Neoplasms

Lymphoma and chronic lymphocytic leukemia (CLL) are two other lymphoid neoplasms that must be differentiated from ALL as their prognosis, clinical course and treatments vary. CLL arises in the bone marrow like ALL but, unlike ALL, CLL is a malignant proliferation of lymphocytes with a mature or very well-differentiated appearance. These lymphocytes are small in size (smaller than a neutrophil) and their nucleus contains dense, clumped chromatin (Figure 4) and a very small amount of cytoplasm. CLL is suspected by finding high numbers of mature lymphocytes in the peripheral blood. Definitive diagnosis requires a bone marrow exam with greater than 30% small lymphocytes. Unlike ALL, CLL has a slowly progressive clinical course lasting months to years. Affected animals may be asymptomatic until late in the disease.

Figure 4. Chronic lymphocytic leukemia.  Numerous small lymphocytes (arrows) with a mature, condensed chromatin pattern.

Lymphoma is a malignant proliferation of lymphocytes, usually lymphoblasts, that originates outside the bone marrow. The most common sites of origin are lymph nodes but alimentary, splenic, thymic, mediastinal, renal and cutaneous lymphoma also occur.³ As lymphoma progresses, the neoplastic lymphocytes may infiltrate the bone marrow and blood making it difficult to determine the site of origin. When lymphoma involves the bone marrow or peripheral blood, it is referred to as stage V lymphoma. Several factors may be used to differentiate ALL from stage V lymphoma. First, ALL is not associated with solid tissue masses (lymphadenopathy, splenomegaly, hepatomegaly), whereas lymphoma is.³ However, remember that some cases of ALL may involve the liver and spleen. In cases with significant peripheral lymphadenopathy or hypercalcemia, lymphoma is more likely. However, if pancytopenia or systemic illness is present, ALL should be considered the most likely diagnosis. Finally, the CD34 cell surface marker is usually positive in ALL and negative in stage V lymphoma.⁶

Treatment

Treatment of patients with ALL may be challenging. Consultation with a veterinary oncologist is highly recommended. Chemotherapy agents typically used in the treatment of ALL include prednisone, vincristine and l-asparaginase. Drug choice should be made on the basis of agents with the least amount of myelosuppressive side effects. Supportive care, including nutritional support and blood transfusions, will be needed for most patients as well. Prophylactic antibiotics are often used in cases with significant granulocytopenia or other risk factors for sepsis.⁶

References

1. Nelson RW, Couto CG: Small Animal Internal Medicine 2nd ed., St. Louis, Mosby, Inc. 1998, pp. 1134-1138.

2. Pui CH: Childhood Leukemia, 2nd ed., Cambridge, Cambridge  University Press, 2006, p. 52.

3. Latimer KS, Mahaffey EA, Prasse KW:  Duncan and Prasse’s Veterinary Laboratory Medicine: Clinical Pathology 4th ed., Ames, Blackwell Publishing,  2003, p. 86.

4. Meuten DJ: Tumors in Domestic Animals, 4th ed., Ames, Blackwell Publishing, 2002, pp. 173-177.

5. Vernau KM, Terio KA, LeCouterur RA, Berry WL, Vernau W, Moore PF, Samii VF:  “Acute B-Cell Lymphoblastic Leukemia with Meningeal Metastasis Causing Primary Neurologic Dysfunction in a Dog”   J. of Vet Internal Medicine  2000; 14: 110-115.

6. Lotter SM:  “Management of Leukemias” ACVIM, 2003, North Grafton, MA.

7. LeRoy BE:  “Cancers of the Blood Cells” Clinical Pathology (VPAT 5250) Notes, 2005, pp. 1-17.

8. Jones TC, Hunt RD, King NW:  Veterinary Pathology 6th ed., Baltimore, Williams and Wilkins, 1997, pp. 1029-1031.

Acknowledgement

"Dog and Cat Myth" by Michele Gauthier & Don Parker is from the Doggieart page of the 20th Century Glass Pottery Collectibles website. The piece illustrates the universal connection between dogs, cats, and humans and is used with permission.

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