Overview of Canine Lymphoma
Canine lymphoma is a disease term comprising a heterogeneous group of malignancies with varying biologic aggressiveness derived from the uncontrolled and pathologic clonal expansion of lymphoid cells of either B- or T-cell immunophenotype. Although neoplastic transformation of lymphocytes is not restricted to specific anatomic compartments, 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. With the completion of the dog genome, it is anticipated that genome-wide association studies will identify specific genetic and chromosomal signatures involved in the pathogenesis of 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 immunocompetence. In dogs, the most common clinical variants of lymphoma are high-grade T- or B-cell variants, and four conventionally recognized anatomic forms of lymphoma have been described: multicentric, alimentary, mediastinal, and extranodal (renal, CNS, cutaneous, ocular, bone, etc). Multicentric lymphoma is by far the most common anatomic form, accounting for ~80%–85% of all diagnosed cases. The most common and overt clinical manifestation of multicentric lymphoma is the rapid and nonpainful development of generalized lymphadenopathy. In addition to peripheral lymphadenopathy, most affected dogs will have malignant lymphocytes that are detectable by sensitive diagnostic tests, including flow cytometry or PCR for antigen receptor rearrangement (PARR) that involve internal organs, including the spleen, liver, bone marrow, 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; however, sternal lymph node enlargement is frequently observed in dogs with multicentric disease. Mediastinal lymphoma 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 measurment of ionized calcium, parathyroid hormone, and parathyroid hormone–related peptide within circulating blood.
The clinical signs associated with various high-grade extranodal lymphomas (which may involve the skin, lungs, kidneys, eyes, CNS, etc) are often variable and dictated by the organs infiltrated. The most common extranodal form of lymphoma involves the skin, referred to as cutaneous lymphoma. Cutaneous lymphoma (epitheliotropic and nonepitheliotropic) 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 recently described molecular variant of canine lymphoma and comprises up to 30% of all lymphoma diagnoses. Like high-grade 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.
Commonly, peripheral and various internal lymph nodes are 3–10 times normal size (multicentric form) and nonpainful on digital palpation. Affected nodes are freely movable, firm, and gray-tan; they bulge on cut surface and have no 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.
The definitive diagnosis of lymphoma is often uncomplicated and can be obtained by either cytologic or histopathologic evaluation of the affected organ system. Fine-needle aspiration of enlarged peripheral lymph nodes or affected visceral organs usually provides specimens of adequate cellular content and detail to make a definitive diagnosis. Cytologically, lymph node or tissue aspirates may identify a monomorphic population of lymphoid cells, either of large (lymphoblastic), intermediate, or small size. Despite the ease of diagnosis, conventional cytology is limited for differentiating or categorizing the heterogeneous spectrum of lymphomas with regard to morphologic subtype (diffuse versus follicular, cleaved versus noncleaved) 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. However, because of the inherent limitations associated with cytology, histopathologic tissue evaluation remains the gold standard for the diagnosis of lymphoma, providing additional morphologic information required for definitive classification, as well as guiding therapeutic decisions.
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 PARR. The use of PCR 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 nondiagnostic, or when results are discordant with clinical signs and disease progression.
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 mo, whereas for dogs with T-cell lymphoma, expected survival times are often in the range of 6 mo. 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 protocols (eg, lomustine, MOPP, ADIC, DMAC).
Although systemic chemotherapy remains the cornerstone to treat high-grade lymphoma, the idea that both induction and maintenance phases of chemotherapy are necessary to achieve durable remission times has changed. Shorter and more dose-intense chemotherapy protocols (eg, Madison Wisconsin protocol) without maintenance provide disease-free intervals and survival times equivalent to protocols that include chronic maintenance therapy. Additionally, the use of half-body radiation in replacement of maintenance chemotherapy has been demonstrated to be safe and clinically efficacious, providing another option to achieve durable remission times without the need for chronic 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.
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 mo). 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 yr), 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 Treatment of Canine Lymphoma.)