Multicentric canine lymphoma in a 12-year-old keeshond: chemotherapy options

Abstract

A 12-year-old, spayed female keeshond presenting with lethargy, anorexia, weight loss, and vomiting was diagnosed with multicentric lymphoma. Lymphoma usually responds well to multi-agent chemotherapy. Efficacy, cost, toxicity, and duration of treatment determine a treatment protocol. Outcomes are compared on the basis of remission, survival time, and treatment-related toxicity.

A 12-year-old, spayed female keeshond was presented with a history of lethargy, anorexia, weight loss, vomiting, and polyuria-polydipsia (day 1). The dog was depressed, pyrexic (39.2°C), tachypneic (40 breaths/ min), and thin. The pulse was normal (90 beats/min). Bilateral submandibular (2 cm), prescapular (3 cm), and inguinal (1.5 cm) lymph nodes, and the right popliteal lymph node (3 cm) were enlarged. Lymph nodes were firm, freely movable, and painless on palpation. The abdomen appeared distended and a large mass was palpated in the right cranial region of the abdomen.

Initial differential diagnoses included lymphoma, metastatic neoplasia, lymphoid hyperplasia, and lymphadenitis. A complete blood cell (CBC) count (VetTest, version 5.7; IDEXX Laboratories, Westbrook, Maine, USA) revealed nonregenerative anemia, with a hematocrit of 30.4 L/L (reference range, 37.0 to 55.0 L/L) and reticulocytes 0.8%; hemoglobinemia (hemoglobin 105 g/L; reference range, 120 to 180 g/L), leukocytosis (26.9 × 10⁹ cells/L; reference range, 6.0 to 16.9 × 10⁹ cells/L), and neutrophilia (21.3 × 10⁹ cells/L; reference range, 3.3 to 12.0 × 10⁹ cells/L). Abnormal serum biochemical results included elevated alanine transferase (416 U/L; reference range, 10 to 100 U/L) and alkaline phosphatase (1517 U/L; reference range, 23 to 212 U/L). Radiographs were unremarkable. A fine needle aspirate or biopsy of an affected lymph node (3) was recommended.

On day 3, the dog underwent lymph node biopsy under general anesthesia. A punch biopsy taken from the left prescapular lymph node appeared dark red and friable. The tissue was collected into 10% buffered formalin and submitted for histopathologic examination, which revealed complete destruction of lymph node architecture, with infiltration of the surrounding subcutaneous fat by neoplastic lymphocytes. Lymphocytes had scant basophilic cytoplasm and large nuclei with multiple prominent nucleoli, supporting a diagnosis of lymphoma.

Although lymphomas are rapidly progressive and fatal, most respond well to aggressive chemotherapy (3). The biopsy results, prognosis, and possible therapy were discussed with the client on day 8. Due to the age of the dog, chemotherapy was not an option. The dog was treated with meperidine (Demerol; Sanofi Canada, Markam, Ontario), 0.25 mg, PO, q24h, and prednisone (Apo-Prednisone; Apotex, Toronto, Ontario), 5 mg, PO, q24h. On day 16, the dog was euthanized for humane reasons.

Lymphoma (malignant lymphoma, lymphosarcoma) is a lymphoid malignancy originating from solid organs (lymph nodes, liver, spleen) and represents 8% to 10% of all canine tumors (1). In cats, lymphoma has been associated with the feline leukemia virus (FeLV); however, in dogs, the etiology is unknown. A genetic predisposition is suspected in certain breeds, such as the boxer, basset hound, rottweiler, cocker spaniel, Saint-Bernard, Scottish terrier, Airedale terrier, English bulldog, and golden retriever. Lymphoma is most often seen in dogs middle aged or older (6 to 12 y of age), as in this case, with no confirmed sex predilection (3).

The CBC count and serum biochemical profile abnormalities are nonspecific and rarely diagnostic for lymphoma. Hematologic findings result from the neoplastic infiltration of bone marrow; splenic malfunction; chronic disease; or paraneoplastic, immune-mediated abnormalities. Leukocytosis may result from the production of cytokines by the tumor cells. Biochemical abnormalities may be due to the release of cytokines from tumor cells or to organ damage caused by neoplastic infiltration.

The 4 anatomic forms of lymphoma seen in dogs are multicentric, mediastinal, alimentary, and extranodal. The multicentric form accounts for more than 80% of lymphomas and is characterized by generalized lymphadenopathy, with or without hepatomegaly, splenomegaly, and bone marrow involvement (1,3). The lymph nodes are markedly enlarged, painless, and freely movable under the skin. The most common clinical signs are nonspecific, including weight loss, anorexia, and lethargy. Coughing may occur if the airway is compressed by enlarged lymph nodes (3). In this case, presentation was typical of the multicentric form.

Several treatment options are available, including surgery, chemotherapy, immunotherapy, radiotherapy, and hyperthermia. Chemotherapy remains the treatment mainstay in the management of canine lymphoma (4). Most protocols are highly successful, with remission rates of 70% to 85% (2). Median survival times of 12 to 16 mo are reported in dogs treated with multiple-agent chemotherapy, compared with 4 to 8 wk in untreated dogs (3). Effective drugs include prednisone, vincristine, cyclophosphamide, L-asparaginase, and doxorubicin (5). Many protocols are based on these drugs, used either singly or in combination. Multiple-agent chemotherapy is associated with the longest remission and survival times, with the best results seen when doxorubicin is included in the protocol (5,6,7). Doxorubicin in combination with cyclophosphamide, vincristine, and prednisone (CVP) has a reported remission time of 210 d compared with 180 d for CVP without doxorubicin (5).

Chemotherapy protocols may be divided into several phases: induction of remission, maintenance, and reinduction of remission. The induction phase usually involves an aggressive multiple-agent chemotherapy protocol with close monitoring of the animal for signs of remission and toxicity. Complete remission occurs when lymph nodes have returned to their original size, and partial remission occurs when lymph nodes have been reduced to 50% of their pretreatment size. Once the dog is in remission, the maintenance phase is initiated, which consists of low-dose therapy with less intensive monitoring, continued until a relapse occurs. If relapse occurs, the reinduction or ‘rescue’ phase begins, with aggressive therapy comparable with that used in the induction phase (3).

The choice among different treatment protocols is influenced by efficacy, cost, toxicity, and duration of treatment (5). Most protocols reviewed in the literature have shown comparable efficacy and drug-related toxicity (2). Therefore, the decision to use a specific protocol is largely based on cost and expected duration of treatment. Consequently, the aim of several recent studies has been to find an alternative to long-term, low-dose, costly chemotherapy (2,7,8). Shorter, more intense, and cheaper therapies have been evaluated. Forty-nine dogs at the University of Wisconsin were treated with high doses of cyclophosphamide (250 mg/m², compared with 200 mg/m² in the control group) and doxorubicin (37.5 mg/m², compared with 30 mg/m² in the control group) for 25 wk, with no maintenance phase. There was no difference in survival between the high dose and control groups. However, the high dose protocol was associated with greater toxicity, and treatment-associated deaths were significantly higher in the high dose group (27%) compared with the control group (4%) (7). Another study compared an L-asparaginase-based, continuous chemotherapy (400 IU/kg bodyweight (BW)) protocol to a short-course, doxorubicin-based induction protocol (30 mg/m²). The differences in remission, survival, and toxicity between the 2 groups were not significant. Remission rates of 92% and 83% and survival times of 236 and 200 d were observed for the L-asparaginase-based and doxorubicin-based groups, respectively. In this study, only 5 dogs (4%) had to be hospitalized for drug-related toxicity (8).

Knowledge of favorable prognostic indicators for duration of remission and survival following chemotherapy aids in decision making for management of canine lymphoma. Prognostic factors that have been evaluated include age, weight, gender, clinical staging, histologic classification, and immunophenotype (2,9). Most researchers agree that T-cell phenotype and hypercalcemia, which have been shown to be related, are associated with shorter remission time, but not with survival (1,2,5,9,10). In this case, the dog's serum calcium levels were normal.

The roles of age, weight, gender, clinical staging, and histologic classification in the prognosis of lymphoma are controversial. Some studies found that younger dogs were more likely to achieve complete remission (10) and that smaller dogs had longer remission times (10) and survival times (5) than larger dogs. Other studies have not found age or weight to have any prognostic value (2,9). Gender had a negative correlation with survival in a retrospective study of 270 dogs: males had shorter survival times than females (1). In the same study, no difference in remission or survival was found between neutered and intact dogs. In contrast, in other studies, there was no relationship between gender and survival, but intact males and females had shorter survival times (2,9). The prognostic value of clinical staging and histologic classification in lymphoma is also still debatable (1,2). In a retrospective study, the World Health Organization's (WHO) clinical staging system (I-V) was not found to be significantly related to remission or survival when assessed by using multivariate analysis (1). Yet, in other studies, WHO substage b (presence of clinical signs) was associated with shorter remission and survival (2,10). Similarly, histologic classification according to the Kiel classification has been found to have prognostic value in some studies (9) and not in others (8,10).

Medical advances in cancer treatment have been ongoing for decades. Chemotherapy is now a common and accepted treatment in veterinary medicine. However, progress in the treatment of cancer in animals has been limited by financial and psychological constraints. Although treatment response rates are consistently high in dogs treated with chemotherapeutic protocols, few gains have been made in either survival or duration of remission (2). New treatment strategies need to be evaluated, such as higher induction dose protocols, different combinations of drugs, different schedules of treatment (pulse therapy and late intensification) (4), and new drugs need to be investigated. Alternatively, more studies evaluating prognostic indicators would be helpful to both the client and the veterinarian in the management decisions regarding canine lymphoma.