Canine Lymphoma

Lymphoma in Dogs
Robyn Elmslie, DVM DACVIM (Oncology)
Kim Statham-Ringen, DVM DACVIM (Oncology)
Veterinary Cancer Specialists
Veterinary Referral Center of Colorado

Quick Facts at a Glance

Lymphoma is a cancer of the lymph nodes and lymphatic system
The most common presentation of lymphoma in dogs is peripheral lymph node enlargement, in an otherwise healthy dog
Most newly diagnosed patients are between 5-7 years of age
Hypercalcemia occurs in approximately 20% of dogs with lymphoma
Lymphoma stage, substage, immunotype and cell size all influence prognosis and treatment selection
Lymphoma progresses very rapidly in most dogs so survival time is very short, usually just a few weeks, without treatment.

What are the presenting signs of lymphoma in dogs?

Generalized peripheral lymph node enlargement in an otherwise healthy dog is the most common presentation of lymphoma. This lymphadenopathy is non-painful and the patient is typically asymptomatic at first. At this point, the clinical presentation is referred to as stage IIIa lymphoma. Clinical signs will vary depending on the stage of disease, volume of tumor and the anatomic location of the lymphoma. Clinical signs are typically non-specific and may include lethargy, weight loss and loss of appetite. If the patient has hypercalcemia, increased thirst and urination are often noted by the owner, in some cases even before lymph node enlargement is identified. Clinical signs will reflect the anatomic location of the lymphoma. Inflammation and bleeding into the eyes, known as hyphema, may result in sudden blindness. Lymphoma of the gastrointestinal system generally results in weight loss, vomiting, and/or diarrhea. When lymphoma originates in the mediastinal lymph nodes, dyspnea and decreased appetite are typical initial signs of illness..

What should the work-up include?

A thorough physical examination is the most important part of the diagnostic work-up. After completing the physical examination, the clinician can then determine what diagnostic tests will be required to confirm the diagnosis and accurately assess the patient's health status and prognosis. The diagnostic work-up should always include a complete blood count (CBC), platelet count, biochemical profile, urinalysis and fine needle aspiration of the tumor mass for lymph node cytology. The cytological examination in most cases is sufficient for confirming the diagnosis. The blood tests allow assessment of the blood calcium level, renal function, liver enzymes, red cell, neutrophil, monocyte, lymphocyte and platelet counts, all of which influence treatment decisions and prognosis.

Lymph node excision for histopathology and immunohistochemistry is still considered to be the preferred diagnostic test to histologically classify the lymphoma and determine the immunotype (for example, B cell vs. T cell lymphoma). This information provides important prognostic information and influences treatment decisions.

More recently, flow cytometry has become available to determine cell size, cell or origin (B cell versus T cell) and the cell surface expression of the MHC class II molecule, all of which provide prognostic information. Flow cytometry also has the advantage of not requiring anesthesia for removal of a lymph node. The lymph nodes are gently aspirated to collect lymphoma cells that are then placed into a special transport media for shipment to the laboratory for analysis. Flow cytometry requires that the cells be healthy with intact cell membranes. If the specimen is damaged during collection or transportation to the laboratory, flow cytometry will not provide useful information.

Alternatively, genetic analysis of the lymph node can be performed by means of a PCR-based test. This test, which is also run on a lymph node aspirate, can be helpful to confirm a diagnosis of lymphoma in most animals. This test has the advantage of not requiring anesthesia for the patient or a special transport media for the specimen, since the aspirated lymphoma cells can simply be smeared on a microscope slide. This test allows for differentiation of T cell vs. B cell lymphoma when positive. However, up to 25% of the PCR tests are negative even in animals with confirmed lymphoma. Thus, a negative PCR test is not helpful.

Finally, immunocytochemistry (ICC) can be used to differentiate T cell vs. B cell lymphoma from a lymph node aspirate smeared onto a microscope slide. The specimen must be in good condition (ie lymphoma cells must be intact) for this test to provide accurate results.

When collecting a fine needle aspirate of the lymph node for cytological evaluation, it is optimal to stay as far away from the submandibular nodes as possible. Since submandibular lymph nodes tend to be more reactive even in normal animals, compared to lymph nodes further from the oral cavity, their state of reactivity can sometimes mask the presence of neoplastic lymphocyte infiltrates. Thus, samples from the mediastinal lymph nodes should be only used for diagnostics if other lymph nodes cannot be accurately sampled.

Additional diagnostic tests are required when complete staging of the lymphoma is desirable or if the patient is symptomatic. These diagnostic tests may include chest and abdominal radiographs, abdominal ultrasound and ultrasound guided aspirates of the liver and spleen for cytological evaluation and bone marrow aspirate and cytology.

Is supportive care required before starting chemotherapy?

Most dogs with lymphoma are in good condition at the time of the diagnosis and do not have any obvious hematological or biochemical abnormalities. These dogs do not require supportive care. Once the diagnosis has been confirmed, chemotherapy can be initiated.

However, some animals will have more advanced disease with hematologic or biochemical changes present. For these animals, hypercalcemia is the most common biochemical abnormality. If left untreated, hypercalcemia can result in severe and irreversible kidney failure. In such cases, the kidney injury, rather than the lymphoma itself, can become the life-limiting factor. For treating hypercalcemia, it is very important that diagnosis of lymphoma be confirmed first. When the diagnosis of lymphoma cannot be readily confirmed, the patient should be treated with fluid therapy to maintain renal blood flow and urine output. The fluid therapy of choice is 0.9% NaCl, without additives. Depending of the state of hydration, fluid therapy should be administered at 1.5-2x maintenance level (90 - 120 mls/kg/24hours). Once fluid therapy has been initiated, furosemide (Lasix) can be administered (2 mg/kg every 8-12 hours) to accelerate renal calcium losses (calciuresis). Although furosemide therapy can increase renal blood flow in the well-hydrated patient, it will initially decrease renal blood flow in a dehydrated animal and therefore should be avoided until the patient is rehydrated. Prednisone and other glucocorticoids are very effective at reducing the blood calcium level but should be avoided until the diagnosis of lymphoma has been confirmed, as steroids may alter the morphology of the tumor cells and make confirmation of a diagnosis of lymphoma quite challenging. Administration of prednisone alone will not affect the results of flow cytometry or PCR unless repeated doses of prednisone render the lymphoma so small that too few tumor cells are available for analysis.

Hematologic abnormalities can occur if the bone marrow is infiltrated with lymphoma cells. The malignant lymphocytes will crowd the normal precursor cells in the bone marrow, preventing them for releasing neutrophils and platelets. Consequently, neutropenia and thrombocytopenia develop. If severe, these hematologic abnormalities can lead to bleeding and development of infections. The presence of neutropenia and thrombocytopenia will also affect the choice of chemotherapy drugs.

What is the prognosis for a dog with lymphoma?

Most dogs with lymphoma have a medium to high-grade lymphoma that is very responsive to chemotherapy. More than 75% of dogs with lymphoma can be expected to achieve a complete remission with chemotherapy. The duration of the first remission is variable, depending on the chemotherapy protocol used. The stage and the immunotype of the lymphoma also affect remission duration. Median remission times have been reported from 6 months to 20 months, depending on lymphoma stage and treatment protocol. The second remission is more difficult to achieve, with approximately 40% of dogs with lymphoma achieving a complete remission with the second course of chemotherapy. Less than 20% of dogs with lymphoma will achieve a third complete remission. Approximately 40-45% of dogs with lymphoma live one year with treatment. Less than 20% of dogs with lymphoma live 2 years, with treatment. Without treatment, the average survival time of dogs is one month from the time of diagnosis. This is difficult for many pet owners to believe because their dog often appears to be quite healthy at the time of diagnosis.

How well do dogs tolerate chemotherapy?

Fortunately, most dogs tolerate chemotherapy extremely well. At our hospital, 80-85% of pet owners report that their pets' quality of life is acceptable to excellent while on treatment. However, approximately 5% of dogs will have life threatening side-effects. Of these, the most common are fever (due to drug-induced neutropenia) and vomiting and/or diarrhea. Animals with these side-effects often require hospitalization and aggressive supportive care. Because lymphoma is not a curable cancer for most dogs, our primary concern is the patient's quality of life. Thus, our goal is to ensure that quality of life is good to excellent for the majority of the time that the animal is being treated with chemotherapy.

Common side-effects that most pet owners consider to be acceptable may include short-term (1-2 days) loss of appetite, vomiting, diarrhea and/ or listlessness. However, most animals that develop these side-effects of chemotherapy quickly bounce back to normal in a day or two. Some animals that develop these side-effects will require a dose adjustment after their first chemotherapy treatment or require anti-nausea or anti-diarrhea medication to reduce the duration of side effects.

Certain breeds of dogs, including Collies and Australian Shepherds, carry a mutation in a gene known as the multi-drug resistance gene (MDR1) gene. This gene regulates the metabolism of several drugs, including several chemotherapy drugs because the gene encodes a protein, P-glycoprotein, that is responsible for pumping many drugs and toxins out of cells in the body. Dogs with the mutant gene are unable to pump certain drugs out of cells in the body, including brain cells. When these drugs are administered to dogs with the mutant MDR1 gene, the drugs accumulate to dangerous levels, especially in the brain. This in turn can produce severe illness, including seizures and even coma. . A simple blood test is available to determine if the patient is a possible carrier of the mutant gene. For animals that are carriers of the gene mutation, the chemotherapy protocol can be modified accordingly.

Are there other treatment options for lymphoma?

While chemotherapy is the standard of care for the treatment of canine lymphoma, several studies have investigated combining chemotherapy with half body radiation therapy, vaccine therapy and bone marrow transplantation. At present, these treatment options are not really good choices for most patients. The pros and cons of these additional treatments, as they pertain to the individual pet with lymphoma, should be discussed with your Oncologist.

Why do we treat dogs with lymphoma?

Pets are important part of our lives and our families. The decision to treat lymphoma is not always straightforward, and involves consideration of both the animal's and the owner's circumstances. These are highly emotional decisions, often with significant financial considerations as well. When making these decisions, it is important to remember that the objective of treatment is to extend the pet's life and with good quality time. If we are able to achieve complete remission of the lymphoma and the quality of the pet's life is good, the extra time enjoyed by the pet and the owner will likely be considered well-worthwhile.

What are the chemotherapy treatment options?

Multidrug protocol (CHOP): This is the most effective treatment approach for patients with B cell lymphoma. Treatment consists of a combination of several drugs including prednisone, L-asparaginase, vincristine, doxorubicin and vincristine. Multiple versions of this protocol have been published. Modifications of this protocol incorporating chemotherapy drugs such as methotrexate or mitoxantrone have also been reported. With some of these protocols, some patients may achieve long term survival (>3 years). In general, chemotherapy is given weekly for a total of 2 months, then spaced to every 2 weeks for an additional 4 months of treatment. Reported survival times for patients with B cell lymphoma, substage "a", is 12-15 months. Reported median survival times for patients with T cell lymphoma treated with this protocol is 6-9 months. Maintenance chemotherapy is recommended in some patients, and should be discussed with the Oncologist
Doxorubicin single agent: This is a reasonable protocol for patients with B cell lymphoma as greater than 80% of patients will achieve a partial or complete remission. A total of 5 treatments are given at 2-3 week intervals. Median survival times of 6 to 9 months have been reported. This particular protocol is not recommended for treating patients with T cell lymphoma, as fewer than 50% of these patients will achieve remission.
COP: This protocol has been used for treating canine lymphoma since the 1970s. It involves a combination of cyclophosphamide in tablet form, given together with injections of vincristine and prednisone. Four weekly intravenous treatments of vincristine are given, followed by injections at 3 - week intervals to complete the 6 months of treatment. Cyclophosphamide is given over 4 days, every 3 weeks (4 days on, 17 days off). Prednisone is given daily for 6 months if well-tolerated, then tapered. The average survival time with this protocol is reported to be 5 - 6 months. Many versions of this protocol are used and can be discussed with your Oncologist.
MOPP: This protocol is considered to be most effective for patients with T cell lymphoma, and can also be used to induce a second remission in the case of relapse. Treatment consists of a combination of the intravenous drugs mechlorethamine, vincristine, and the oral drugs prednisone and procarbazine. Multiple versions of this protocol are used and can be discussed with your Oncologist.
Other chemotherapy choices: Many chemotherapy drugs have been shown to have some benefit in the treatment of lymphoma. In some cases these drugs will be used as an alternative to a drug in the L-CHOP protocol if one of the normally scheduled drugs is not well tolerated. These alternative drugs may also be used alone or in combination in a rescue chemotherapy protocol
Prednisone alone: Prednisone, a steroid, can give given in pill form daily at home. Prednisone is used often in combination with chemotherapy but can be used alone for short-term control of the disease when the family decides against treatment with full-course chemotherapy. The median survival time for patients with lymphoma treated with prednisone alone is 60 days.

Table : Clinical Staging of Lymphoma

Stage I: Involvement of a solitary lymph node or lympoid tissue in a single organ (ie. nasal cavity)

Stage II: Regional involvement of multiple lymph nodes

Stage III: Generalized lymph node enlargement. Typically refers to enlargement of a lymph node on either side of the diaphragm

Stage IV: Involvement or liver and/ or spleen

Stage V: Involvement of bone marrow (some classifications consider cutaneous involvement in this stage)

Substage a: Without systemic signs of disease (patient generally feels well)

Substage b: With systemic signs of disease (patient generally does not feel well)

Additional Reading

Perry JA, Thamm DH, Eickhoff J, Avery AC, Dow SW. Increased monocyte chemotactic protein-1 concentration and monocyte count independently associate with a poor prognosis in dogs with lymphoma. Veterinary Comparative Oncology, in press, 2010.
Sorenmo K, Overley B, Krick E, et al. Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases. Veterinary and Comparative Oncology 2010 8;3:196-208.
Daters AT, Mauldin GE, Mauldin GN et al. Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma. Veterinary and Comparative Oncology 2010 8;1:11-22.
Lori JC, Stein TJ, Thamm DH. Doxorubicin and cyclophosphamide for the treatment of canine lymphoma: a randomized, placebo-controlled study. Veterinary and Comparative Oncology 2010 8;3:188-195.
Strottner, G., Beaver, L., Klein, M. Differences in Response Rates Between Dogs with B- and T-Cell Lymphoma to a Single Dose of Doxorubicin. Abstract presented at Veterinary Cancer Society Annual Meeting, Austin Texas, Oct 16-19m 2009.
Mealey KL, Fidel J, Gay JM, Impellizeri J, Clifford C, Bergman PJ. ABCB1-1D Polymorphism can predict hematologic toxicity in dogs treated with vincristine; J Vet Int Med 2008;996-1000.
Mealey KL, Meurs KM. Breed Distribution and Frequency of the ABCB1-1D (Multidrug Sensitivity) Polymorphism in Dogs; J Am Vet Med Assoc, 2008;233:921-924.
Lurie DM, Gordon IK, Theoon AP et al. Sequential Low-Dose Rate Half-Body Irradiation and Chemotheraapy for the Treatment of Canine Multicentric Lymphoma. J Vet Intern Med 2009: 23:1064-1070.

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