CE Article #1

Lymphoid Leukemia in Dogs

Robert H. Presley, DVM
Auburn University

Andrew Mackin, BSc, BVMS, MVS, DVSc, FACVSc, DSAM, DACVIM

Mississippi State University

William Vernau, BSc, BVMS, DVSc, PhD

University of California, Davis

ABSTRACT: Lymphoid leukemias are malignant neoplasms of lymphocytes originating primarily

in the bone marrow. Lymphoid leukemias include both acute lymphoblastic leukemia and chronic
lymphocytic leukemia. Both forms are considered uncommon and may mimic more common
diseases, such as lymphoma or chronic ehrlichiosis.Therefore, lymphoid leukemias can sometimes be
difficult to diagnose. Newer techniques, such as immunophenotyping and assessment of clonality
by polymerase chain reaction testing, have been developed to aid in the diagnosis of lymphoid
leukemia. Once lymphoid leukemia is diagnosed, management may require aggressive chemotherapy.
This article reviews the cause, classification, diagnosis, and treatment of lymphoid leukemias.

L
ymphoid leukemias are defined as malig- Of these, lymphoma is the most common, com-
nant neoplasms of lymphocytes, originat- prising approximately 83% of canine hematopoi-
ing most often from the bone marrow. etic neoplasia.1,2 Primary lymphoid leukemias are
Lymphoid leukemias can be divided into acute less common, comprising approximately 10% of
lymphoblastic leukemia (ALL) and chronic lym- hematopoietic neoplasia in dogs.3,4
phocytic leukemia (CLL), depending on the
stage of maturation of the neoplastic cells. Lym- CAUSE
phoid leukemias are a form of neoplastic lym- The cause of lymphoid leukemia in dogs is
phoproliferative disease (neoplasia resulting from currently unknown. In humans, acute leukemias
overproduction of T or B lymphocytes or natural are known to be caused by exposure to various
killer [NK] cells). Malignant lymphoproliferative carcinogens, such as benzene and phenylbuta-
diseases are some of the most common types of zone, as well as radiation.5,6 A recent study7 has
neoplasia in dogs, accounting for approximately also suggested that genetic alteration of multiple
40% of all canine neoplasia.1–3 tumor-suppressor gene 1 is a possible cause of
Send comments/questions via email to Neoplastic lymphoproliferative certain types of human lymphoid leukemia. In
[email protected] disease can be divided into dogs, however, similar associations have not
or fax 800-556-3288.
three major subtypes: been documented. Retroviruses have been
Visit CompendiumVet.com for • Lymphoma shown to cause lymphoid leukemia in a large
full-text articles, CE testing, and CE • Plasma cell tumors variety of other veterinary species, including
test answers. • Primary lymphoid leukemias cats, cattle, and birds.8–12 In contrast, retroviruses

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832 CE Lymphoid Leukemia in Dogs

have not been proven to be leukemogenic in dogs, stage of disease. There are two major classes of lymphoid
although several single case reports13,14 have implicated leukemia: ALL and CLL. This classification system is
retroviruses as a potential cause of canine lymphoid based on the severity of disease and the characteristics of
leukemia. One report13 on large granular lymphocytic the neoplastic lymphocytes. Although both leukemias
leukemia in a dog described virus particles budding from produce cells that cannot terminally differentiate, the
the plasma membrane of leukemic cells. The virus maturation arrest occurs at different stages. CLL pro-
resembled a mammalian type C oncovirus, a virotype duces cells that are morphologically similar to normal
that is from the same subfamily of retroviruses that cause small, mature lymphocytes. ALL, on the other hand,
feline leukemia, enzootic bovine leukosis, and avian originates from more immature cells and results in cells
leukosis.8–13 In a separate study,14,15 retroviral particles re- that morphologically resemble large blast cells.

Lymphocyte counts exceeding 20,000/µl are almost pathognomonic

for primary lymphocytic leukemia. In advanced stages, lymphocyte
numbers may exceed levels greater than 100,000/µl.

sembling a lentivirus were isolated from mononuclear Both types of lymphoid leukemia may arise from B-,
cells of a dog with lymphoblastic leukemia. However, T-, or NK-cell clones. In humans, B-cell neoplasia pre-
detection of retroviral particles in leukemic dogs does not dominates and represents 95% of CLL cases; in con-
necessarily confirm that the virus is the direct cause of trast, B-cell neoplasia is less common than T-cell
disease. Therefore, the true cause(s) of canine lymphoid neoplasia in canine CLL.19–21 In studies19,21 of 73 and 12
leukemia remains unknown. dogs with CLL, a B-cell phenotype was found in only
26% and 30% of cases, respectively, with most (approxi-
CLASSIFICATION mately 70%) involving T-cell CLL. In contrast, recent
Leukemias are classified according to the cell lineage studies19 have shown the incidence of B-cell neoplasia to
from which the neoplasm originates. Myeloid or myelo- be higher than that of T-cell neoplasia in cases of canine
proliferative diseases refer to neoplasia originating from ALL. Although one study22 reported only a 20% B-cell
cells that normally give rise to erythrocytes, granulocytes, incidence, in another study of 38 canine cases of acute
monocytes, and megakaryocytes. Lymphoid leukemia leukemias (myeloid and lymphoid), B-cell neoplasia
refers to neoplasms originating from cells that normally represented 16% of cases, whereas T-cell neoplasia
give rise to T, B, or NK cells. Although the true incidence accounted for only 8%.19,22 This finding is supported by
of lymphoid leukemia in dogs is unknown, it is considered recent unpublished research conducted by one of the
to be more common than myeloproliferative diseases.16,17 authors (W. V.), which also found B-cell ALL to be
ALL is generally believed to be the most common form of more common than T-cell ALL in dogs.
leukemia in dogs, although this assertion is disputed by Normal T-cell populations in dogs are made up of two
some sources that suggest that up to 50% of acute unique lineages, αβ and γδ, based on T-cell receptor
leukemias initially diagnosed as lymphoid based on mor- (TCR) expression. T lymphocytes expressing the TCR
phology are reclassified as myeloid following cytochemical αβ are the most common T cells in circulation and can
staining or immunophenotyping.3,17,18 Acute myeloid be subdivided into cluster of differentiation (CD) sub-
leukemia (AML) was reported to be more common than sets (i.e., CD4+ and CD8+).20,23–25 CD4+ expression is
ALL in a recent study19 of 38 cases of acute leukemia in most commonly found on T helper cells, which are
dogs. Because many early studies19 relied on morphology responsible for activation of cellular or humoral immu-
alone to determine the cell type involved in canine nity via interaction with antigen-presenting cells and
leukemias, the true incidence rates of the different recognition of antigens in the context of major histo-
leukemias in dogs has not been well established. compatibility complex (MHC) class II molecules.24,25
Lymphoid leukemias may be further subcategorized CD8+, on the other hand, is a surface antigen found on
based on cell type, number of cells in circulation, and cytotoxic T cells. CD8+ cytotoxic T cells are important

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in the elimination of intracellular pathogens, such as common form of lymphoid leukemia in dogs and is typ-
viruses, and recognize antigens in the context of MHC ically a fulminant and devastating disorder.17,18
class I molecules.24,25 T lymphocytes expressing the TCR ALL generally affects young to middle-aged dogs. In
γδ are found most commonly in mucosal surfaces and a study31 of 30 canine cases of ALL, the average age of
the splenic red pulp and are very uncommon in the cir- affected dogs was 6.2 years, with a range of 1 to 12
culation of normal dogs, comprising less than 2% of years; eight dogs (27%) were younger than 4 years of
peripheral blood lymphocytes.20,26,27 Interestingly, in one age. ALL has even been reported in a dog as young as 5
study19 of canine CLL, 23% of T-cell CLL involved T months.32 Males tend to be affected slightly more often
cells that expressed the TCR γδ. These TCR γδ–positive than females, with a 3:2 male:female ratio reported. 31
CLLs were characterized exclusively by proliferation of Although German shepherds seem to be overrepre-
large granular lymphocytes (LGLs). LGLs in dogs are sented in one study of ALL, no confirmed associations
made up of two distinct populations of cells: cytotoxic with breed, weight, or sexual intactness have been docu-
(CD8+) T cells and NK cells.19,26,28 In the largest study19 mented.31
of canine CLL, 54% of cases were a result of LGL T- During the early stages of ALL, immature lympho-
cell leukemia. Routine morphologic assessment of blasts rapidly proliferate in the marrow. As the tumor
splenic and bone marrow aspirates from dogs with LGL burden increases, neoplastic cells affect other normal cell
leukemia, along with the high incidence of expression of lineages in the marrow and may also enter the circula-
TCR γδ and other specific membrane receptors by these tion. Once neoplastic cells enter the circulation, infiltra-
cells, has led researchers to believe that LGL leukemia tion into other organ systems is common: The spleen
in dogs is of splenic, rather than marrow, origin.19,20,26 and liver are most frequently affected, but infiltration of
Leukemias may also be classified according to the the nervous system, gastrointestinal tract, and lungs has
number of cells reaching the general circulation.3,29,30 also been reported.31,33,34 Systemic infiltration with neo-
Early in the disease process, neoplastic cells may be plastic cells causes many of the acute but generally non-
present only in the bone marrow, which is a stage called specific clinical signs in patients with ALL. Clinical
aleukemic or preleukemic leukemia, because no neoplastic signs vary in type and intensity, depending on the
cells have entered the circulation. As the disease pro- amount of neoplastic infiltration within the target
gresses, leukemic cells may begin circulating in low organs (Figures 1 and 2). The most commonly observed

Immunophenotyping can be used to distinguish acute and chronic leukemias as

well as acute leukemias and the leukemic phase of lymphoma in instances in which
more routine methodologies cannot.

numbers, which is a stage called subleukemic leukemia. clinical signs include lethargy, anorexia, weight loss,
Finally, with a larger tumor burden, larger numbers of vomiting, and diarrhea.3,17,31 Less common signs that
cells leave the bone marrow, enter the circulation, and may be noted at presentation include fever, respiratory
begin infiltration of other organs, which is a stage called distress, neurologic deficits, polyuria, and polydip-
leukemic leukemia. This classification may not necessarily sia.3,31,33–35 Physical examination reveals splenomegaly in
apply to LGL leukemias because infiltration of the bone more than 70% of dogs affected with ALL. 3,31,35
marrow may occur later in the disease process as a result Hepatomegaly is also a common finding observed in
of the primary splenic origin.16,19 approximately 50% of dogs with ALL. 31,35 Approxi-
mately 40% to 50% of dogs with ALL present with mild
Acute Lymphoblastic Leukemia generalized lymphadenopathy.31,36 Lymphadenopathy
ALL is defined as the neoplastic proliferation of mor- associated with ALL is usually milder than that in
phologically immature lymphocytes primarily in the patients with canine lymphoma, in which the lymph
marrow of affected dogs. Although it is considered an nodes are often massively enlarged.3,36 Mucous mem-
uncommon or rare disease, ALL is reportedly the most branes often appear pale at examination, and in more

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Figure 1. Thoracic radiographs of a dog diagnosed with Figure 2. Repeat thoracic radiographs of the patient in
ALL showing a diffuse bronchointerstitial lung pattern Figure 1 taken 1 week after induction therapy using
compatible with leukemic infiltration. vincristine, cyclophosphamide, L-asparaginase, and
prednisone. The bronchointerstitial markings have cleared
considerably.

Right lateral view. Right lateral view.

Ventrodorsal view. Ventrodorsal view.

severe cases of canine ALL, the membranes may also may range from low (i.e., <4,000/µl) to very high (i.e.,
contain petechiae or appear icteric.31,35 >100,000/µl). 31,35–37 Leukocytosis in ALL patients is
Hematologic abnormalities are very common in dogs usually due to the presence of neoplastic lymphocytes in
with ALL. The most common and striking abnormality the circulation, and in extreme cases, lymphocyte counts
is an altered total leukocyte count. Leukocyte counts can exceed 500,000/µl.35–37 On occasion, patients with

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 Lymphoid Leukemia in Dogs CE 837

ALL may be lymphopenic during the aleukemic or sub-

leukemic stages of disease.31,37 Despite the frequent pres-
ence of greatly increased lymphocyte counts, cytopenias,
bicytopenias, and pancytopenias of normal lineages are
also common in dogs with ALL. Anemia is the most
common abnormality, occurring in more than 50% of
canine ALL cases.31,35 In general, this anemia is classi-
fied as normocytic, normochromic as well as nonregen-
erative.31,38 Thrombocytopenia also occurs in one-third
to one-half of canine ALL cases: Thrombocytopenia
may be mild to severe, with platelet counts under
50,000/µl reported in some cases.22,31 Neutropenia is also Figure 3. Right lateral abdominal radiograph showing
common in canine ALL: One study19 reported that 65% moderate hepatosplenomegaly in a dog diagnosed with
of dogs with non-LGL acute leukemia were neu- CCL.
tropenic (<3,000/µl), with two-thirds of these neu-
tropenic dogs having counts below 1,000/µl. Cytopenias
in dogs with ALL are typically caused by bone marrow Physical examination of dogs with CLL may reveal
dysfunction associated with the presence of large num- splenomegaly, hepatomegaly, mild generalized lym-
bers of neoplastic cells within the marrow cavity—a phadenopathy, or fever.19,26,39 Splenomegaly is the most
phenomenon known as myelophthisis. common finding, occurring in approximately 70% of
affected dogs, whereas hepatomegaly occurs in 40% to
Chronic Lymphocytic Leukemia 50% of cases19,39,40 (Figure 3). Mucous membranes often
CLL is defined as the abnormal proliferation of mor- appear pale and may rarely contain petechiae.3,16,39 Hema-
phologically mature lymphoid cells in the bone marrow tologic abnormalities are common in dogs with CLL.
or peripheral circulation of affected dogs. Although the The most common abnormality is leukocytosis due to
incidence of CLL in dogs is reportedly lower than that mild to marked lymphocytosis. Lymphocyte counts can
of ALL, CLL is more common than its myeloid coun- range from 6,000 to over 100,000/µl, with rare, advanced
terpart.17 Compared with ALL, CLL is a much less cases associated with lymphocyte counts of over
aggressive form of leukemia, and the clinical course of 1,000,000/µl.3,19,23,26,29,39
CLL can often last months or even years.3,16,17,19,38 Anemia is quite common, affecting approximately 80%
Dogs with CLL are typically older than those with of dogs with CLL.3,37,39 Anemia is usually normocytic,
ALL: The average age of dogs with CLL is approxi- normochromic as well as nonregenerative, although
mately 10 to 12 years, with a range of 1 to 15 nearly 20% of dogs with CLL in one study39 had macro-
years.19,26,36,39,40 Unlike in humans, there does not appear cytic, hypochromic, regenerative anemias. The anemia in
to be a consistent sex predilection for the development dogs with CLL is usually mild to moderate. 19,39 Mild
of canine CLL, with various studies 19,39 reporting a thrombocytopenia is also common, with up to 50% of
slight preponderance of either males or females. There is CLL-affected dogs presenting with platelet counts as
also no confirmed predilection for sexual intactness or low as 100,000/µl.39 In contrast to patients with ALL,
breed, although German shepherds and golden retriev- neutropenia is rare in dogs with CLL.19,26
ers appeared to be overrepresented in one study.26 Some dogs with CLL present with hyperglobuline-
Clinical signs of canine CLL vary dramatically, mia as a result of increased immunoglobulin production
depending on the stage of disease. Up to 50% of affected by neoplastic B cells.39 In one study39 of 22 dogs with
dogs are asymptomatic during presentation, and inciden- CLL, 32% presented with hyperglobulinemia. Sixty-
tal lymphocytosis is often noted during routine blood eight percent of dogs also presented with monoclonal
work or senior health profiling.3,16 Dogs with CLL may gammopathy.39 This is an intriguing finding, consider-
also present with a long history of recurrent, nonspecific ing that, in canine CLL (unlike human CLL), B-cell
signs. The most frequent owner complaint at presentation neoplasia is reportedly much less common than T-cell
is lethargy; other common abnormalities include reduced neoplasia.19,21 Unfortunately, immunophenotyping was
appetite, polyuria, polydipsia, and sporadic vomiting.16,39 not conducted in the canine CLL study that reported a

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high incidence of monoclonal gammopathies. 39 Most DIFFERENTIAL DIAGNOSIS

commonly, dogs with CLL and monoclonal gam- The diagnosis of ALL or CLL in dogs is straightfor-
mopathies had increased IgM levels, although patients ward in advanced cases with extremely high lymphocyte
with increased IgA and IgG levels were also reported.39 counts. However, in less severe cases with solely marrow
In humans, the monoclonal production of IgM is also involvement or mild to moderate lymphocytosis, the
known as Waldenström’s macroglobulinemia.17,38,41 Exces- diagnosis can be quite challenging, and associated non-
sive amounts of IgM may result in the development of specific clinical signs and mild hematologic abnormali-
hyperviscosity syndrome, which can cause hemostatic ties may be difficult to interpret. Lymphoid leukemias
disorders, ocular changes, neurologic signs, renal fail- must be differentiated from other diseases, such as lym-
ure, or congestive heart failure. In dogs with hypervis- phoma, AML, and chronic ehrlichiosis. Lymphoma and

Chemotherapy may not be initially indicated in patients with chronic lymphocytic leukemia and
no clinical signs. It is recommended if the patient presents with or develops significant
abnormalities, such as hyperproteinemia, cytopenia, or lymphocyte counts over 60,000 µl.

cosity syndrome, hemostatic disorders are common and AML are the two most common rule-outs for ALL,
may partly result from the coating of platelets with whereas chronic ehrlichiosis more closely resembles
immunoglobulins.41 Petechiae, epistaxis, and mucosal CLL. Because therapeutic protocols and prognoses vary
hemorrhage are common sequelae to hyperviscosity tremendously not only between the differential diseases
syndrome. 23,41 In dogs with CLL presenting with that mimic lymphoid leukemia but also between sub-
hyperglobulinemia, approximately 40% also have pro- types of the disorder itself, an accurate diagnosis must be
teinuria, possibly due to the presence of Bence-Jones made when possible.
proteins in the urine.39 Bence-Jones proteins are the
result of failure to assemble normal combinations of DIAGNOSTIC TESTING
light- and heavy-chain immunoglobulin molecules. A diagnosis of canine lymphoid leukemia can be
Most common with multiple myelomas, these proteins attained using a combination of clinical signs, routine
are small enough to undergo glomerular filtration and hematology, blood smears, bone marrow aspirations and
collect in the urine. In general, and in contrast to the biopsies, immunophenotyping, and clonality assessment
condition in humans, Bence-Jones proteins cause no by polymerase chain reaction (PCR) testing. In chal-
adverse effects, other than mild polyuria, in dogs.29,41 lenging cases, all of these tools may be required to
Despite remaining clinically stable for long periods, obtain an accurate diagnosis.
dogs with CLL eventually decompensate. The termi-
nal event in canine CLL may be the development of Physical Examination
large cell lymphoma, called Richter’s syndrome, 3,17,39 Clinical signs and physical examination can often
which is characterized by the development of rapidly provide useful diagnostic clues in dogs with suspected
progressive, generalized lymphadenopathy. This lym- lymphoid leukemia. Dogs with advanced (i.e., stage V)
phadenopathy may become so severe that it resembles lymphoma may have a large number of circulating neo-
that of multicentric lymphoma, with lymph nodes five plastic lymphoid cells (secondary leukemia) and can
to 15 times their normal size.42 Other dogs with CLL therefore be difficult to differentiate from patients with
may develop acute blast crisis, a syndrome character- true primary lymphoid leukemia. Because the prognoses
ized by progression to and rapid proliferation of for these two forms of lymphoproliferative disease can
immature blast cells both in the bone marrow and cir- vary greatly, it is important to differentiate the two con-
culation. Terminal CLL syndromes such as large-cell ditions. One simple clinical feature that often allows
lymphoma and acute blast crises, like ALL, typically differentiation between these two lymphoproliferative
become very difficult to treat, and remission rates are diseases is the degree of lymphadenopathy. Only 50% of
very low.3,17 dogs with ALL present with lymphadenopathy, and, if

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840 CE Lymphoid Leukemia in Dogs

the patient has it, it is typically only mild.38 In contrast, usually mild, with lymphocyte counts ranging from
dogs with stage V lymphoma tend to have massive lym- 10,000 to 20,000/µl.3 Patients with lymphoid leukemia
phadenopathy.3,17,36,43 Furthermore, if a dog appears sys- commonly present with lymphocytosis that is much
temically ill, the diagnosis is more likely to be ALL more extreme than that associated with other condi-
rather than lymphoma or CLL, although it should be tions, with lymphocyte counts ranging from 6,000 to
remembered that stage B lymphoma patients are also well over 100,000/µl.3,17,31,39 Lymphocyte counts exceed-
systemically ill at presentation.3,36 ing 20,000/µl are almost pathognomonic for primary
lymphocytic leukemia.3
Routine Blood Work Serum calcium levels may aid in the diagnosis of lym-
A complete blood count and serum biochemical pro- phoid leukemia. Dogs with hypoadrenocorticism may
file often help exclude or confirm a diagnosis of present with hypercalcemia. Although the mechanism
leukemia. In patients with lymphoid leukemia, lympho- of hypercalcemia in patients with hypoadrenocorticism
cytosis is the most consistent abnormality found on rou- is poorly understood, it is believed that increased
tine blood work. Although there are numerous causes of absorption of calcium occurs in the small intestine and
lymphocytosis, the degree and duration of lymphocyto- decreased excretion occurs in the kidneys because of the
sis can often provide diagnostic clues. Transient or phys- lack of glucocorticoids.46 In addition, approximately
iologic lymphocytosis due to catecholamine release 20% to 40% of dogs with lymphoma are hypercal-
associated with stress or excitement may lead to lym- cemic.42,43 Production of parathyroid hormone–related
phocyte counts as high as 10,000 to 15,000/µl.36,44 How- protein by neoplastic cells is believed to be the major
ever, lymphocyte counts typically return to normal levels cause of hypercalcemia in dogs with lymphoma.43,47
rapidly and are often within reference limits if the Although hypercalcemia has been documented, it is rare
patient is retested at a later date. Hypoadrenocorticism in dogs with primary lymphoid leukemia.32,48
(Addison’s disease) can also cause lymphocytosis, Hyperproteinemia due to hyperglobulinemia associ-
although lymphocyte counts in affected dogs are gener- ated with monoclonal gammopathy can occur in dogs
ally less than 8,000 to 10,000/µl.44 Hypoadrenocorticism with B-cell CLL, although monoclonal gammopathy is
should be considered in patients with mild lymphocyto- more commonly associated with plasma cell neoplasia
sis when consistent electrolyte abnormalities (hyper- and chronic ehrlichiosis.41,49 Protein electrophoresis is
kalemia and/or hyponatremia) are detected or when, indicated in patients with hyperglobulinemia and typi-
based on history and clinical signs, a stress leukogram cally confirms the presence of monoclonal gammopathy

A complete blood count and serum biochemical profile

often help exclude or confirm a diagnosis of leukemia.

(which typically causes lymphopenia) was the expected in hyperglobulinemic patients with CLL. Immunoelec-
leukocyte response. Chronic antigenic stimulation, such trophoresis may then be used to determine the exact
as that associated with rickettsial or fungal infection, immunoglobulin type elevated in dogs with monoclonal
may also result in lymphocytosis, with lymphocyte hyperglobulinemia and can thereby help predict the
counts reaching 6,000 to 10,000/µl. 36,44 However, probability of hyperviscosity syndrome, which is most
patients with severe fungal disease or (especially) commonly found with IgM or IgA clonality.41 Immuno-
chronic ehrlichiosis may sometimes have lymphocyte electrophoresis may also help indicate whether mono-
counts that are even higher.44 Patients with lymphoma clonal gammopathy is a result of ehrlichiosis or CLL.
may also occasionally present with lymphocytosis. At CLL monoclonal gammopathies are most commonly
most, only 20% of dogs with lymphoma develop lym- associated with excessive IgM production (although IgA
phocytosis.17 In one study45 of 75 dogs with lymphoma, and IgG have also been documented), whereas chronic
only eight had lymphocytosis, and 30 dogs actually had ehrlichiosis is almost exclusively an IgG gammopathy.39,41
lymphopenia. Lymphocytosis in lymphoma patients is Although immunoelectrophoresis may be diagnostically

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 Lymphoid Leukemia in Dogs CE 841

Figure 4. Photomicrograph of a blood smear containing

LGLs. The LGLs contain pink granules in the cytoplasm. (Original Figure 5. Photomicrograph of a blood smear containing
magnification ×100; courtesy of Dr. Roger Easley, Mississippi State blast cells. Subsequent immunophenotyping confirmed acute B-
University) cell leukemia. (Original magnification ×100)

beneficial in dogs with monoclonal gammopathy, run- of special stains that demonstrate the presence of specific
ning serum titers for Ehrlichia spp is a necessary and (lineage-related) enzymes in the blast cell cytoplasm.
often preferred adjunctive test. Many dogs diagnosed with ALL based on morphology
alone are reclassified as having myeloid leukemoid fol-
Cytologic Evaluation of Blood Smears lowing application of cytochemical stains.3,51 However,
Cytologic evaluation of blood smears by an experi- the diagnostic use of cytochemical staining may some-
enced clinical pathologist is often the simplest and least times be limited because a relatively small number of
invasive way to definitively diagnose lymphocytic stains are available and because malignant cells can have
leukemia. Patients with ALL have circulating immature a loss of cellular enzyme activity and variable staining
or blast neoplastic cells that are often very large— characteristics.22,30 Cytochemical diagnosis of lymphoid
approximately two to three times larger than normal leukemias can be particularly challenging because stains
mature lymphocytes. Blast cells typically have a round specific for lymphoid cells are unavailable.22,52 Therefore,
to slightly indented nucleus; immature, finely stippled lymphocytes are generally negative using standard cyto-
chromatin; one to multiple prominent nucleoli; and a chemical stains, although alkaline phosphatase may
thin rim of basophilic cytoplasm.29,36,50 In contrast, circu- sometimes appear positive.3 Therefore, the cytochemical
lating neoplastic cells in patients with CLL are often diagnosis of lymphocytic leukemia is usually one of
morphologically indistinguishable from normal mature exclusion (i.e., excluding a myeloid origin).
lymphocytes.29,38,50 However, approximately 50% of dogs
with CLL have increased numbers of mature-appearing Immunophenotyping
lymphocytes in the blood that contain fine, pink, cyto- Immunophenotyping is a relatively recent technique
plasmic granules.16,19,29 Dogs with LGL CLL may also that has been developed to determine cell lineage (Fig-
have chunky, pink granules, often clustered near the ure 5). As the technique has become more available in
nuclear indentation26,28,29 (Figure 4). veterinary medicine over the past decade, immunophe-
A challenging problem that can be associated with the notyping has increased in popularity as a valuable tool
cytologic evaluation of blood smears in leukemic patients in classifying the various types of lymphoid leukemia.
is the difficulty in differentiating ALL from AML. Both The basic premise of immunophenotyping is that neo-
leukemias involve neoplastic proliferation of blast cells plastic leukemic cells generally maintain an antigenic
that can have very similar morphology.51 Cytochemical expression pattern similar to that of their normal
stains may allow differentiation of the two conditions. counterparts. 19 Immunophenotyping can detect the
Cytochemical staining involves application of a number expression of specific leukocyte antigens using a panel

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Clonality Assessment by Polymerase

1 2 3 4 5 6
Chain Reaction Testing
A PCR test developed in dogs can deter-
mine the clonality status of potentially neo-
plastic lymphocytes. 19,53,54 Clonality, or the
production of identical cells or clones from a
single neoplastic precursor, is the hallmark of
malignancy. Tests for clonality can be used to
determine whether lymphocytosis is due to
▲

100 neoplasia or to benign reactive proliferation.

Base Although the distinction between the two
pairs conditions may be obvious in cases of extreme
lymphocytosis, PCR testing is proving to be
Figure 6. Clonality PCR products run on a GelStar-stained 10% extremely useful in cases in which lymphocyte
polyacrylamide gel. Lanes 1 through 6 are amplified with canine- counts are below 20,000/µl16 (Figure 6). The
specific T-cell “clonality” primers that produce a product rationale behind this test is that both T and B
approximately 111 base pairs in size. Lanes 1 through 4 represent lymphocytes have specific surface antigen-
duplicate PCR amplifications of genomic DNA extracted from purified blood
binding receptors that are unique for each
mononuclear cells (1 and 2) and whole blood (3 and 4) from a 5-year-old
rottweiler with mature granular lymphocytosis (i.e., approximately 10,000/µl) cell. This specificity is produced through the
that was mostly TCR γδ–positive T cells. Lane 5 is from a normal dog, and recombination of V, D, and J gene seg-
lane 6 is a positive control (cell line). Lanes 1, 2, 3, 4 (patient), and 6 represent ments. 16,19,53,54 These rearranged DNA seg-
clonal bands, whereas lane 5 represents a polyclonal smear.The results in ments provide a unique “fingerprint” for any
lanes 1 through 4 confirmed incipient CLL. (Reprinted with permission from Vernau given lymphocyte. 16 DNA is extracted from
W: Chronic lymphocytic leukemia in dogs and cats: The veterinary perspective. Vet Clin
North Am, Small Anim Pract, Hematol 33[6]:1393, 2003.)
the lymphocyte proliferation in question, and
PCR testing is used to determine the nature
of the antigen-receptor gene rearrangements
in the extracted DNA. The presence of a sin-
of monoclonal antibodies to accurately determine the gle or clonal rearrangement is indicative of neoplasia,
phenotype, and hence the lineage, of leukemic cells.19 whereas the presence of numerous different rearrange-
Immunophenotyping may be conducted on a range of ments is indicative of benign reactive proliferation. In
samples, including snap-frozen tissues, formalin-fixed one study 53 of 77 dogs with confirmed lymphoid
paraffin sections, unfixed blood or cytologic smears, malignancy, 91% demonstrated clonality (i.e., clonally
and via flow cytometry (i.e., fluids such as blood or rearranged antigen-receptor genes). In the same study,
bone marrow aspirate).20 24 dogs without lymphoid malignancy were also
Immunophenotyping can also be used to distinguish tested, and only a single dog with elevated Ehrlichia
acute and chronic leukemias as well as acute leukemias canis titers was found to have a clonal antigen-recep-
and the leukemic phase of lymphoma when more routine tor gene rearrangement.53 Clonality was also demon-
methodologies cannot. CD34 is a surface glycoprotein strated in a separate canine case of E. canis infection.19
that, although expressed on immature hematopoietic Therefore, it should be noted that although most neo-
progenitor cells, is not present on more mature and dif- plastic lymphocyte proliferations are clonal, not all
ferentiated cells. Therefore, acute leukemia (CD34+) can clonal lymphocyte proliferations are neoplastic. Con-
often be differentiated from chronic leukemia (CD34–) sequently, the interpretation of PCR clonality assays
or the leukemic phase of lymphoma (also CD34–) by the should always be made in the context of patient his-
presence of CD34 on neoplastic cells because only the tory, clinical signs, and routine laboratory testing. In
immature blast cells in acute leukemia express addition, it is impossible to accurately interpret the
CD34.16,19,29 Other proteins are used to determine the results of PCR c lonalit y assays without prior
actual cell lineage of the neoplasia: For example, CD3 immunophenotyping to determine the lineage of the
antigen is used to classify cells as T cell in origin, lymphocyte proliferation in question (see box on page
whereas B cells are classified using CD79 and CD21.19,20 843).

COMPENDIUM December 2006

 Lymphoid Leukemia in Dogs CE 843

BONE MARROW EVALUATION Clinical Vignette

Bone marrow aspiration and core biopsies are com-
Routine blood work in an asymptomatic 5-year-old
monly implemented during the diagnostic evaluation of
spayed rottweiler revealed the following: hematocrit:
lymphocytic leukemia. Bone marrow evaluation is most 31% (reference range: 40% to 55%); reticulocytes:
valuable in cases of aleukemic or subleukemic leukemia. 52,700/µl (reference range: 7,000 to 65,000/µl);
However, it is also generally recommended that bone leukocytes: 17,180/µl (reference range: 6,000 to
marrow evaluation be conducted on dogs with either 13,000/µl); and platelets: 241,000/µl (reference range:
cytopenia or a lymphocyte count above approximately 150,000 to 400,000/µl). The leukocytes consisted of
14,000/µl.52,55 However, bone marrow evaluation may 7,645 neutrophils/µl (reference range: 3,000 to
not be necessary if an unequivocal diagnosis can already 10,500/µl) and 8,659 lymphocytes/µl (reference range:
be made based on hematology and examination of a 1,000 to 4,000/µl). The great majority of lymphocytes
blood smear, particularly in dogs with markedly elevated were mature-appearing granular lymphocytes. Several
lymphocyte counts. complete blood counts over the course of the next
month indicated relatively stable hematologic findings
Blast cells normally account for a very small percent-
and persistent mature granular lymphocytosis that
age of the cells within the bone marrow because the
increased slightly to approximately 10,000 cells/µl.
division of one blast cell eventually produces 16 to 32 Testing for Ehrlichia sp infection produced negative
mature cells of a specific lineage. Approximately 80% to results. Flow cytometric immunophenotyping was
90% of the marrow should, therefore, be made up of conducted on peripheral blood, and more than 95% of
more mature cell types.56 Greater than 30% blast cells in peripheral lymphocytes were CD3+ T cells (as expected,
the marrow is, therefore, usually indicative of acute given the granular morphology). Thirty-five percent of
leukemia.30,52,57 The specific lineage of cells infiltrating the T cells expressed TCR αβ, and 65% expressed
the marrow in patients with acute leukemia often can- TCR γδ, representing a markedly expanded population
not be determined because of the similar morphologic of TCR γδ granular lymphocytes in the periphery, which
appearance of neoplastic lymphoid and myeloid blast typically constitutes less than 2% of lymphocytes. This
cells, and further evaluation of marrow samples via finding was most suggestive of an incipient T-cell LGL
CLL that was confirmed with PCR clonality assessment
immunophenotyping may, therefore, be required to
(Figure 6). A subsequent slow progressive increase in
accurately determine the lineage of the blast cells. In
peripheral granular lymphocyte numbers was further
some patients, it may not be possible to differentiate confirmation of CLL in this patient, but clonality
stage V lymphoma from ALL based on bone marrow assessment had facilitated the diagnosis significantly
evaluation alone.52 Immunophenotypic assessment of earlier in the course of disease.
CD34 expression is useful in these instances.19
Small, mature lymphocytes may also be found in the
bone marrow of normal dogs but should account for less immune stimulation (e.g., fungal disease or chronic ehrlich-
than 10% of nucleated cells. In most dogs, less than 5% iosis) rather than lymphocytic leukemia.52
of marrow nucleated cells are mature lymphocytes.52 Early in the course of ALL, the marrow may be only
Markedly increased proportions of small lymphocytes focally infiltrated with neoplastic cells.3,36,38 However,
(>30% of total nucleated cells) in the bone marrow are typically normal marrow architecture is then rapidly
considered to be diagnostic of CLL.16,19,39,52,57 replaced by neoplastic blast cells. Marked infiltration of
Bone marrow in normal dogs is usually 25% to 75% the marrow with malignant lymphocytes (myelophthi-
cellular. As the animal ages, the marrow becomes less cel- sis) results in a decreased number of normal erythroid
lular and adipose tissue more extensive.52,57 The bone and myeloid precursors, often leading to the develop-
marrow of dogs with lymphoid leukemia is often hyper- ment of pancytopenia on routine hematolog y. 3,17
cellular due to severe infiltration with neoplastic cells.57 Cytopenias in dogs with ALL are believed to be due to
Dogs with acute ehrlichiosis may similarly present with a combination of neoplastic exhaustion of nutrients,
hypercellular bone marrow.58,59 In contrast, chronic ehrlich- physical crowding of the marrow, and possible alteration
iosis tends to cause hypocellular marrow with an of normal bone marrow blood supply.38
increased proportion of plasma cells.56,58,59 Bone marrow In dogs with CLL, the rate of effacement of the bone
plasmacytosis (i.e., more than 5% plasma cells within the marrow with neoplastic cells is much slower, if it occurs
marrow) is indicative of plasma cell neoplasia or chronic at all.52 This is especially true in patients with LGL

December 2006 COMPENDIUM

844 CE Lymphoid Leukemia in Dogs

Table 1. Rai Classification for nutritional support, and whole blood or blood products
Lymphoid Leukemia in Humans60,61 may be necessary.
To return hematopoiesis to normal in patients with
Stage Risk Level
ALL, a 1.5 to 2 logarithmic reduction in neoplastic cells
0 Low risk: lymphocytosis only; absolute is required. 17 Aggressive chemotherapy is typically
lymphocyte count is ≥15,000/µl needed to adequately reduce the marrow tumor burden.
I Intermediate risk: lymphocytosis plus Chemotherapy induction agents used in treating ALL
lymphadenopathy include vincristine, prednisone, cytosine arabinoside,
II Intermediate risk: lymphocytosis plus cyclophosphamide, and L-asparaginase.3,17,30 Doxoru-
hepatomegaly and/or splenomegaly bicin is also commonly used to treat ALL but is gener-
ally reserved for use in intensification protocols or as a
III High risk: lymphocytosis plus anemia
(hemoglobin ≤11 g/dl) with or without rescue agent.
hepatomegaly, splenomegaly, or A combination of vincristine and prednisone is the
lymphadenopathy foundation of induction therapy for ALL and was the
most successful protocol in a study of 30 dogs with
IV High risk: lymphocytosis plus
thrombocytopenia (<100,000 platelets/µl) ALL.3,17,31 This combination uses vincristine administered
with or without hepatomegaly, at 0.5 to 0.7 mg/m2 IV once weekly with prednisone given
splenomegaly, or lymphadenopathy concurrently at 40 to 50 mg/m2 PO once daily for 1 week
and then slowly tapered until remission occurs.3,17 L-
Asparaginase may be added (400 IU/kg IM) to increase
CLL, in which, due to the probable splenic (rather than initial response rates.17 However, L-asparaginase should
marrow) origin of the neoplastic process, significant not be used routinely in maintenance therapies because of
bone marrow infiltration does not occur until later in the rapid development of drug resistance.62 In nonrespon-
the disease process.16,19 However, during the terminal sive cases, other chemotherapeutics such as cyclophos-
stages of CLL, infiltrating small lymphocytes may com- phamide or cytosine arabinoside may be added for
prise 80% to 90% of the nucleated cells within the mar- intensification. Cyclophosphamide may be given at a pulse
row, with subsequent myelophthisis.37 rate of 250 mg/m2 IV once weekly or at a continuous rate
of 50 mg/m2 PO every other day.3,17 Cytosine arabinoside
CLINICAL STAGING (100 mg/m2) may also be effective and should be given
A true clinical staging system for lymphoid leukemia divided into two to four daily doses for up to 5 days sub-
in dogs has not been well developed. According to the cutaneously or as a continuous intravenous infusion3,62
current World Health Organization classification for (Figures 7 and 8).
lymphoma, all cases of lymphoid leukemia are consid- During chemotherapy, a complete blood count should
ered stage V disease.17,52 A more useful staging system be conducted before each weekly treatment. Chemo-
specific to lymphoid leukemia has been developed to therapy should be delayed if the platelet count falls
provide prognostic information in humans (Table 160,61). below approximately 50,000/µl or the neutrophil count
However, no research has been published describing drops below 2,500/µl.62–65 Life-threatening sepsis is a
application of this staging system to dogs with lym- potential complication of severe neutropenia. Therefore,
phoid leukemia.16,17 broad-spectrum antibiotics should be implemented if
severe neutropenia is detected (i.e., neutrophil count
THERAPY below 1,000 to 2,000/µl), and hospitalization of the
Acute Lymphoblastic Leukemia patient and administration of intravenous antibiotics
Treatment of ALL is often unrewarding, and remis- should be considered if neutrophil counts drop below
sion can be difficult to achieve. Aggressive chemother- 500/µl.62,64
apy and supportive care are required if owners choose to Destruction of a large number of neoplastic cells dur-
treat the condition. Depending on the patient’s clinical ing treatment of ALL may result in tumor lysis syn-
status and hematologic values, supportive therapy such drome. 64,65 This syndrome is believed to result from
as administration of broad-spectrum antibiotics to pre- massive release of intracellular products, which can
vent sepsis, intravenous fluids to correct dehydration, occur during initial treatment of a tumor that is highly

COMPENDIUM December 2006

 Lymphoid Leukemia in Dogs CE 845

Figure 7. Photomicrograph of a blood smear from a Figure 8. Photomicrograph of a blood smear from the
dog diagnosed with ALL. Numerous blast cells with large dog in Figure 7 following induction therapy using a
round nuclei and thin rims of basophilic cytoplasm are apparent combination of cyclophosphamide, vincristine,
in the smear. Although AML can be similar in appearance, ALL prednisone, and L-asparaginase. Note that only one blast cell
was diagnosed via immunophenotyping. (Original magnification ×40; can now be seen. (Original magnification ×40; courtesy of Dr. Roger
courtesy of Dr. Roger Easley, Mississippi State University) Easley, Mississippi State University)

responsive to chemotherapy. Lymphocytes contain ness is probably due to the low rate of proliferation of
increased amounts of phosphorus compared with other the neoplastic cells involved.3 Currently recommended
cells in the body, and release of intracellular phosphorus treatments of CLL usually involve a combination of
and other products during chemotherapy can cause chlorambucil and prednisone administered via either a
hyperphosphatemia, hyperkalemia, hypocalcemia, and pulse or a continuous therapy protocol.16,17,23 Pulse ther-
hyperuricemia.64,65 Clinical signs associated with tumor apy protocols involve high-dose chlorambucil given at
lysis syndrome can include vomiting, diarrhea, and 20 mg/m2 PO once every other week, with concurrent
lethargy. Death can occur within hours of initiation of prednisone given in refractory cases at a dose of 50
chemotherapy. Treatment with aggressive intravenous mg/m2 PO once daily for 1 week, then every other day
fluids is indicated to correct metabolic disturbances in beginning in the second week.3,23 Continuous therapy
patients with tumor lysis syndrome.64 protocols involve lower doses of chlorambucil given
more frequently (6 mg/m2 PO once daily for 7 to 14
Chronic Lymphocytic Leukemia days initially, with a subsequent dose reduction to 3
In contrast to ALL, aggressive chemotherapy is gen- mg/m2 daily), with concurrent prednisone given at an
erally not required to manage patients with CLL. Initial initial dose of 30 mg/m2 PO daily (first week), with sub-
chemotherapy may not even be indicated in some sequent doses tapering to 20 mg/m2 PO daily (second
patients with CLL. Chemotherapy is recommended if week) and then 10 mg/m2 PO every other day.17 In
the patient presents with or develops clinical signs such refractory cases of CLL, cyclophosphamide, instead of
as hepatosplenomegaly or lymphadenopathy.17 Patients chlorambucil, may be administered at a dose of either
with CLL and hematologic abnormalities such as ane- 200 mg/m2 IV once weekly or 50 mg/m2 PO 4 days per
mia, thrombocytopenia, or leukocyte counts over week.3,17,23 Protocols used to treat ALL may be instituted
60,000/µl should also undergo chemotherapy, as should if remission of CLL is not attained using either
hyperproteinemic patients at risk of developing hyper- cyclophosphamide or chlorambucil.
viscosity syndrome.17
The response to chemotherapy in patients with CLL PROGNOSIS
can be slow, and complete remission may not occur for Lymphoid leukemias vary tremendously in their
weeks or even months. Sluggish treatment responsive- prognoses, depending on their classification, with ALL

December 2006 COMPENDIUM

846 CE Lymphoid Leukemia in Dogs

have a poorer prognosis than those with B-cell tumors,

and T-cell tumors are often more resistant to
chemotherapy.43,66 In contrast, in dogs with lymphoid
leukemia, no prognostic differences among B or T lym-
phocyte or LGL leukemia have been documented.

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 Lymphoid Leukemia in Dogs CE 849

57. Hahn KA: Getting a diagnosis, in Veterinary Oncology. Boston, Butterworth 4. Retroviruses have been confirmed to cause lym-
Heinemann, 2002, pp 36–49. phoid leukemia in a wide range of veterinary
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leukemia: A review of 745 cases and assessment of clinical staging. Cancer 5. Which statement regarding ALL is incorrect?
50(12):2951–2955, 1982. a. ALL is caused by neoplastic proliferation of morpho-
62. Barton CL: Chemotherapeutics, in Boothe D (ed): Small Animal Clinical logically immature lymphocytes.
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b. ALL generally affects young to middle-aged dogs.
c. Common hematologic abnormalities in patients
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Animal Internal Medicine. St. Louis, Mosby, 2003, pp 1108–1121. d. The course of disease in patients with ALL tends to
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in Withrow ME (ed): Small Animal Clinical Oncology. Philadelphia, WB
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6. What percentage of small, mature lymphocytes
66. Dobson JM, Blackwood LB, McInnes EF, et al: Prognostic variables in
canine multicentric lymphosarcoma. J Small Anim Pract 42(8):377–384, 2001.
in the bone marrow is consistent with CLL?
a. <5% c. 20%
b. 10% d. >30%

ARTICLE #1 CE TEST
This article qualifies for 2 contact hours of continuing CE 7. Hyperviscosity syndrome associated with CLL is
most commonly related to
education credit from the Auburn University College of a. IgG and IgA.
Veterinary Medicine. Paid subscribers may purchase b. IgM and IgA.
individual CE tests or sign up for our annual CE c. IgM and IgE.
program. Those who wish to apply this credit to fulfill state d. IgG and IgE.
relicensure requirements should consult their respective
state authorities regarding the applicability of this program. 8. Which statement regarding CLL is incorrect?
To participate, fill out the test form inserted in this a. CLL most commonly affects dogs 10 to 12 years of
issue or take CE tests online and get real-time scores age.
at CompendiumVet.com.Test answers are available b. Many patients with CLL are asymptomatic at the time
online free to paid subscribers as well. of diagnosis.
c. Aggressive chemotherapy is warranted for long-term
1. With which type of monoclonal gammopathy is survival of patients with CLL.
chronic ehrlichiosis primarily associated? d. Terminal events in patients with CLL are usually
a. IgM c. IgG related to the development of large cell lymphoma or
b. IgA d. IgE acute blast crisis.

2. An acute or “blast type” leukemia may be diag- 9. According to the current World Health Organi-
nosed via immunophenotyping by the presence zation classification for lymphoma, all cases of
of lymphoid leukemia are considered stage
a. CD79–. c. CD34–. a. I. c. IV.
b. CD79+. d. CD34+. b. II. d. V.

3. T lymphocytes expressing TCR γδ are most com- 10. With appropriate therapy, what is the median
monly found in the survival time of dogs with ALL?
a. bone marrow. a. 1 to 2 weeks
b. spleen and mucosal surfaces. b. 1 to 6 months
c. liver. c. 6 to 12 months
d. lymph nodes. d. 1 to 2 years

December 2006 COMPENDIUM