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Lymphoma in Dogs & Cats

Every veterinary student knows that lymphoma is the most common hematopoietic neoplasm in dogs and cats.  However, we are now recognizing that lymphoma isn’t a single clinical entity.  Rather, it is a collection of neoplastic disorders triggered by a myriad of genetic mutations and epigenetic factors that culminate in uncontrolled proliferation of lymphocytes.  Multi-institutional collaborative efforts are underway to illuminate the molecular fingerprints of canine and feline lymphomas that will allow for better understanding of the biology of lymphoma as well as improving treatment strategies and outcomes.  These benefits are likely to extend across species – even to humans as the field of comparative oncology grows.

Figure 1. Lymphoma in dogs typically presents as generalized peripheral lymphadenopathy. Mandibular swelling due to lymph node enlargement, as shown here, often is a sign that leads clients to seek evaluation.

Diagnosis and Staging

The most common presentation of canine lymphoma is the seemingly well, middle aged dog that is brought to the veterinarian for evaluation of a lump.  The establishment of the lump as an enlarged lymph node typically is accompanied by the discovery of generalized peripheral lymphadenopathy.  Nevertheless, lymphoma can arise in any lymphoid tissue, such as the spleen, liver or thymic remnant.  Alimentary, cutaneous, central nervous system or other extranodal forms are less common in the dog.

In contrast, alimentary lymphoma predominates in older cats.  The cranial mediastinal form associated with feline leukemia virus infection in young cats has declined in frequency as prevalence of this retroviral infection has diminished.  Extranodal forms, such as those arising in the nasal cavity and retrobulbar space, appear to occur more frequently in cats compared with dogs, whereas peripheral lymph node involvement is less common.

Figure 2: CT scan of cat with nasal lymphoma. The left nasal cavity is replaced by neoplastic tissue extending into and around the orbit. Extranodal lymphoma is more commonly seen in cats.

The diagnosis of lymphoma is often straightforward, particularly in forms involving medium-to-large, immature cells.  In these cases, fine needle aspirate cytology is often sufficient.  When cytology is inconclusive biopsy may be necessary.  Alternatively, PCR for antigen receptor rearrangement (PARR) testing may be helpful in establishing clonality of lymphocyte populations in cytologic specimens.  In small-cell lymphomas, biopsy is often required for histopathologic examination of tissue architecture.

Once a diagnosis is established, staging is often performed to assess the extent of disease and to identify intercurrent disorders that may impact treatment.  Testing routinely performed includes complete blood count, chemistry profile, urinalysis, thoracic radiographs, abdominal ultrasound and bone marrow aspirate.  Some oncologists reserve bone marrow evaluation for cases in which thrombocytopenia, neutropenia or significant anemia is present.

In addition to clinical staging, a clinical substage is often assigned according to whether significant clinical signs associated with lymphoma are absent (substage a) or present (substage b).  Clinical substage is an important and consistent prognostic indicator in both dogs and cats, as substage b animals are less likely to respond to treatment and have shorter survival times than asympomatic animals.  Other prognostic indicators include anatomic location, immunophenotype and histopathologic grade.

Treatment Options for Lymphoma

Chemotherapy continues to be the mainstay of treatment for most dogs and cats with lymphoma.  Five drugs have been the foundation of effective protocols for intermediate- to high-grade lymphoma:  cyclophosphamide, doxorubicin, vincristine, L-asparaginase and prednisone.  There are many variations in these protocols, although none has been found to be clearly superior.

Traditionally, chemotherapy protocols have consisted of an intensive induction phase of about 8-16 weeks, followed by a long maintenance phase in which chemotherapy drugs  are given at greater intervals for a total of 18-24 months.  In the past decade, discontinuous short protocols – often ranging from 12-20 weeks without maintenance – have gained popularity in treating canine lymphoma.  After the short protocol is completed, the animals are given a break from treatment while they are monitored for relapse.  Once disease recurrence is detected, the same protocol is restarted.  Studies in dogs have indicated that overall survival is similar with both short and long protocols.  The suitability of short protocols for cats is still a matter of debate among oncologists, although most published protocols for cats are a minimum of 6 months duration.

Eventually lymphoma will become resistant to standard initial drugs and alternative chemotherapy agents will need to be employed.  Ultimately, most dogs and cats succumb to chemotherapy-refractory disease.  Without treatment, most dogs with multicentric lymphoma die within 1-2 months of diagnosis.  Multi-agent chemotherapy that includes doxorubicin extends average survival to approximately one year.  Two-year survival rates have been reported to be 20-25%.  An exception to this is canine gastrointestinal lymphoma, which is rapidly progressive and poorly responsive to therapy.  Reported survival times with treatment average 2-3 months.  In contrast, cats with alimentary lymphoma treated with combination chemotherapy protocols have reported median survival times of 6-9 months.

Figure 3. The same cat undergoing radiation therapy: A) First treatment

Figure 3. The same cat undergoing radiation therapy: B) At fourth treatment. Lymphoma is exquisitely sensitive to radiation therapy and can be the treatment of choice in localized forms of the disease or for palliation.

For clients who elect not to pursue conventional combination chemotherapy, single-agent protocols can provide some benefit.  Doxorubicin used alone extends median survival to about 6 months.  Lomustine or cyclophosphamide, both of which can be administered orally, have lower overall response rates and may prolong average survival to about 3-4 months, although long-term responses have been observed.  Prednisone given as a sole treatment may help alleviate clinical signs of lymphoma but generally is not considered to significantly improve survival in high-grade lymphomas.  In addition, there is strong evidence that prednisone may induce resistance to other chemotherapy drugs, so clients should be advised of this potential pitfall before electing a course of prednisone.

The addition of whole- or half-body radiation therapy to chemotherapy protocols once complete remission has been achieved has shown some promise in extending remission duration in both dogs and cats.  However, some investigators have questioned whether this benefit is outweighed by toxicity and cost.  It is likely that further study will determine whether refinement of radiation protocols can optimize the benefits of radiation for patients with lymphoma.  Radiation therapy can also be useful as a local therapy for lymphoma confined to extranodal sites, such as nasal lymphoma in cats.

Small-cell and other indolent lymphomas are rare in dogs but appear to develop with greater frequency in cats.  In some cases, indolent lymphoma may not require treatment until dogs become uncomfortable due to the space-occupying effects of the disease.  Since most small-cell lymphomas occur in the gastrointestinal tract in cats, the diagnosis often is not made until clinical signs develop.  Consequently, therapy is usually indicated in cats.  Generally, indolent lymphomas are considered to respond well to oral alkylating agents such as chlorambucil, cyclophosphamide and possibly lomustine.  These low-grade lymphomas may not have a robust response to chemotherapy, and treatment success may be defined as control of clinical signs in the context of a chronic disease.

The treatment of lymphoma in dogs and cats can be very rewarding.  Most of our veterinary patients enjoy an excellent quality of life during treatment.  Ongoing efforts to better classify subtypes of lymphoma will help to advance our understanding of this common neoplasia and to refine our treatment strategies.