Canine lymphoma is a disease arising from the uncontrolled and pathologic clonal expansion of lymphoid cells of either B- or T-cell immunophenotype. Canine lymphoma most commonly involves organized primary and secondary lymphoid tissues, including the bone marrow, thymus, lymph nodes, and spleen. In addition to these lymphoid-rich organs, extranodal sites affected by lymphoma include the skin, intestinal tract, liver, eye, CNS, and bone. Lymphoma is reported to be the most common hematopoietic neoplasm in dogs, with an incidence reported to approach 0.1% in susceptible dogs.
Despite the prevalence of malignant lymphoma, the underlying causes for its development remain poorly characterized; however, advanced genetic studies have revealed that canine lymphoma can be molecularly distinguished and categorized into discrete groups that correlate with biologic aggressiveness. Hypothesized causes include retroviral infection with Epstein-Barr virus–like viruses, environmental contamination with phenoxyacetic acid herbicides, magnetic field exposure, chromosomal abnormalities, and immune dysfunction.
Clinical Findings of Canine Lymphoma
Canine lymphoma is a heterogeneous cancer, with variable clinical signs, responses to therapy, and survival times. The heterogeneity associated with canine lymphoma is influenced in part by several tumor and host factors, including anatomic involvement, extent of disease, morphologic subtype, host constitution, and immune competence. In dogs, the most common clinical forms of lymphoma are high-grade T- or B-cell variants, which manifest as generalized, nonpainful, peripheral lymphadenopathy in the majority (80%–85%) of all diagnosed cases. Less commonly, lymphoma primarily affects other organ systems, including the alimentary tract, skin, mediastinum, and other extranodal sites. In dogs with significant tumor burden, systemic constitutional signs, including profound lethargy, weakness, fever, anorexia, and dehydration, may become evident.
Alimentary lymphoma accounts for < 10% of all canine lymphomas. Dogs with focal intestinal lesions may exhibit clinical signs consistent with partial or complete luminal obstruction (eg, vomiting, constipation, abdominal pain). With diffuse involvement of the intestinal tract, dogs with alimentary lymphoma may show significant and debilitating GI signs, including anorexia, vomiting, diarrhea, hypoproteinemia, and weight loss secondary to malabsorption and maldigestion.
Exclusive involvement of the cranial mediastinum with lymphoma comprises only a small fraction of diagnosed cases and is typically characterized by enlargement of the cranial mediastinal lymph nodes, thymus, or both. Mediastinal lymphoma arising from the thymus is predominantly comprised of high-grade malignant T lymphocytes, and with advanced disease, clinical signs may include respiratory distress associated with pleural fluid accumulation, direct compression of adjacent lung lobes, or caval syndrome. In addition to respiratory signs, some dogs with mediastinal lymphoma may have primary polyuria with secondary polydipsia resulting from humoral hypercalcemia of malignancy, a paraneoplastic syndrome seen in 10%–40% of dogs with lymphoma. Confirmation of humoral hypercalcemia of malignancy can be documented through the measurement of ionized calcium, parathyroid hormone, and parathyroid hormone–related peptide within circulating blood.
The most common extranodal form of lymphoma involves the skin, referred to as cutaneous lymphoma. Cutaneous lymphoma (epitheliotropic and non-epitheliotropic) may appear as solitary, raised, ulcerative nodules or generalized, diffuse, scaly lesions. Involvement of peripheral lymph nodes and mucocutaneous junctions is frequent. Clinical signs associated with lymphoma involving other extranodal sites may include respiratory distress (lungs), renal failure (kidneys), blindness (eyes), seizures (CNS), and skeletal pain or pathologic fracture (bone).
Although high-grade lymphoma of either B- or T-cell origin is most commonly diagnosed in dogs, low-grade or indolent lymphoma is a molecular variant of canine lymphoma. Indolent lymphoma consists of several histopathologic subtypes, including marginal zone, follicular, mantle cell, and T-zone lymphoma. Collectively, indolent lymphomas are slowly progressive, and dogs often remain asymptomatic for a prolonged time regardless of therapy.
Lesions of Canine Lymphoma
Commonly, peripheral and various internal lymph nodes are 3–10 times normal size (multicentric form) and nonpainful on digital palpation. Affected nodes are initially freely movable, but firm. However, with disease progression, lymph nodes can become fixed and compress surrounding normal structures, leading to discomfort or functional compromise. Histologically, effaced lymph nodes are gray-tan in coloration, and when transected will bulge and have loss of cortical-medullary demarcation. Frequently, there is hepatosplenomegaly, with either diffuse enlargement or multiple, pale nodules of variable size disseminated in the parenchyma. In the alimentary form, any part of the GI tract or mesenteric lymph nodes may be affected. Involvement of the bone marrow, CNS, kidney, heart, tonsils, pancreas, and eyes can be seen but is less common.
Diagnosis of Canine Lymphoma
Clinical evaluation: thorough physical examination with the identification of generalized, nonpainful, lymphadenopathy should raise suspicion for multicentric lymphoma. However, other infectious and inflammatory diseases should be ruled out through appropriate diagnostic tests, including fine-needle aspirate cytology of affected lymph nodes.
The definitive diagnosis of canine lymphoma is often uncomplicated and can be obtained by either cytologic or histopathologic evaluation of the affected organ system. Cytologically, lymph node or tissue aspirates may identify a monomorphic population of lymphoid cells, either of large (lymphoblastic), intermediate, or small (lymphocytic) size. Despite the ease of diagnosis, conventional cytology cannot readily differentiate the heterogeneous spectrum of lymphomas with regard to morphologic subtype (diffuse versus follicular, cleaved versus non-cleaved) and histologic grade (high versus low). Specialized cytology utilizing lineage-specific antibodies can differentiate between B- and T-cell lymphomas and can provide some information regarding prognosis based on immunophenotype. Histopathologic tissue evaluation can provide additional morphologic information required for definitive classification, as well as guide therapeutic recommendations.
In rare situations when cytology or histopathology fails to confirm the diagnosis of lymphoma, more advanced molecular techniques are available for definitive diagnosis, including flow cytometry for specific cell surface markers called cluster of differentiation (CD) antigens and PCR for antigen receptor rearrangement (PARR). The use of PARR allows for the amplification of DNA sequences that confirms or denies the presence of lymphocytes of either clonal, oligoclonal, or polyclonal origin. Because most neoplastic outgrowths result from the clonal expansion of one malignantly transformed cell, PCR techniques can differentiate lymphocyte expansion as a consequence of cancer (lymphoma) versus inflammation (reactive or hyperplastic lymphocytosis). Although PCR techniques are highly sensitive, the methodology should be reserved for cases in which conventional cytology and histopathology prove non-diagnostic, or when results are discordant with clinical signs and disease progression.
Treatment of Canine Lymphoma
Supportive care: Canine lymphoma is generally responsive to conventional systemic therapies, with the majority of dogs achieving complete clinical responses to treatment, with correlative improved quality of life and overall survival times. Although initial response rates to systemic chemotherapies are exceptionally high (90% or greater), the vast majority of dogs will ultimately relapse, with disease that progressively becomes refractory to continued therapies. Given that only a small fraction of dogs achieve a cure with conventional treatment options, the primary goal for current therapies are palliative.
Treatment of high-grade, multicentric canine lymphoma with aggressive, multi-agent chemotherapy protocols is often rewarding, with >90% of all dogs achieving complete reduction of tumor burden, termed complete remission. The most common chemotherapeutic agents used in combination protocols are vincristine, doxorubicin, cyclophosphamide, l-asparaginase, and prednisone. Individual treatment protocols vary with respect to dosage, frequency, and duration of treatment; advantages and disadvantages of each treatment protocol can be found in medical oncology textbooks.
With combination chemotherapy, the expected survival time for dogs with B-cell lymphoma is ~12 months, whereas for dogs with T-cell lymphoma, expected survival times are often in the range of 6 months. Although immunophenotype (B- versus T-cell) provides a general guideline for treatment prognosis, multiple factors (tumor and host) contribute to the overall response duration and survival time of dogs diagnosed with lymphoma. Dogs that do not respond to traditional combination chemotherapy or that relapse may achieve disease remission, added survival times, or both with the use of various rescue agents and protocols (eg, lomustine, mitoxantrone, rabacfosadine, MOPP, ADIC, DMAC).
Although systemic chemotherapy remains the cornerstone to treat high-grade lymphoma, the inclusion of half-body radiation in conjunction with chemotherapy has been demonstrated to be safe and clinically efficacious, providing another option to achieve durable remission times through the rational combination of divergent therapies (radiation and chemotherapy). For select cases, autologous canine bone marrow transplant after systemic chemotherapy and whole-body radiation can afford some dogs extended, progression-free intervals and survival times. More recently, the potential for stimulating the immune system through the infusion of antibodies or vaccine strategies has received considerable attention for improving the treatment of dogs when instituted in conjunction with or following the completion of systemic chemotherapies.
Despite the favorable outcomes expected in treating high-grade multicentric lymphoma, the successful management of other anatomic forms of lymphoma is often more difficult and less rewarding. Alimentary lymphoma, if focal, can be treated effectively with surgical resection and combination chemotherapy. However, with diffuse involvement of the intestinal tract, low constitutional reserve, severe malabsorption of nutrients, and loss of proteins often result in poor clinical responses and short survival times (ie, < 3 months). The use of combination chemotherapy with or without palliative radiation therapy can afford dogs with mediastinal lymphoma considerable improvement in survival times and quality-of-life scores. Lymphoma involving other extranodal sites (such as the skin) can be managed with either single-agent oral lomustine or combination systemic chemotherapies (eg, CHOP); however, the development of refractory and progressive disease is common and ultimately life limiting.
Clinical prognosis for dogs diagnosed with low-grade, indolent lymphoma tends to be good. The institution of low-intensity oral chemotherapy protocols (chlorambucil and prednisone) often provides prolonged survival times (>2 years), and in specific dogs with localized and low-grade disease (eg, splenic involvement), splenectomy can be an effective and durable treatment option without the necessity of adjuvant chemotherapy administration. ( See also Targeted Antineoplastic Agents in Animals Targeted Antineoplastic Agents in Animals Alternative modes of cancer treatment have become increasingly available in veterinary medicine. Rather than indiscriminately inhibiting cells engaged in the cell cycle, many newer drugs target... read more .)
Canine lymphoma is the most common hematopoietic tumor affecting pet dogs, and it frequently can be readily diagnosed collectively through physical examination and fine-needle aspirate cytology of enlarged lymph nodes.
Treatment of canine lymphoma with systemic chemotherapies is typically highly rewarding, with the majority of dogs responding positively, with correlative improvements in quality of life and overall survival times.
Although most canine lymphomas will be multicentric, large B-cell tumors, lymphoma is a heterogenous disease, and thorough diagnostics and categorization of canine lymphoma can impact treatment recommendations and prognosis.