Canine Malignant Lymphoma: Introduction - The Merck Veterinary Manual

Canine Malignant Lymphoma: Introduction

Canine malignant lymphoma is a progressive, fatal disease caused by the malignant clonal expansion of lymphoid cells. Although lymphoid cell neoplastic transformation is not restricted to specific anatomic compartments, lymphoma most commonly arises from organized lymphoid tissues including the bone marrow, thymus, lymph nodes, and spleen. In addition to these primary and secondary lymphoid organs, common extranodal sites include the skin, eye, CNS, testis, and bone. Lymphoma is reported to be the most common hematopoietic neoplasm in dogs, with an incidence reported to approach 0.1% in susceptible, older dogs. Despite the prevalence of malignant lymphoma, its etiology remains poorly characterized. Hypothesized etiologies include retroviral infection, environmental contamination with phenoxyacetic acid herbicides, magnetic field exposure, chromosomal abnormalities, and immune dysfunction.

Clinical Findings:

Canine lymphoma is a heterogeneous cancer, with variable clinical signs depending in part on the anatomic region involved and extent of disease. In dogs, 4 well recognized anatomic forms of lymphoma have been described: multicentric, alimentary, mediastinal, and extranodal (renal, CNS, and cutaneous). Multicentric lymphoma is by far the most common form, accounting for ~80% of all diagnosed cases. An early clinical sign of multicentric lymphoma is the rapid and nonpainful development of generalized lymphadenopathy. In addition to dramatic peripheral lymphadenopathy, malignant lymphocytes may infiltrate internal organs including the spleen, liver, bone marrow, and other extranodal sites. Late in the course of disease, when a significant tumor burden exists, patients may show constitutional signs of illness, including lethargy, weakness, fever, anorexia, and depression.

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, abdominal pain). With diffuse involvement of the intestinal tract, dogs with alimentary lymphoma may show significant GI signs, including anorexia, vomiting, diarrhea, and profound weight loss secondary to severe malabsorption and maldigestion.

Mediastinal lymphoma, similar to the alimentary form, comprises only a small fraction of diagnosed cases. It is typically characterized by enlargement of the cranial mediastinal lymph nodes, thymus, or both. Mediastinal lymphoma arising from the thymus is predominantly comprised of malignant T lymphocytes; with advanced disease, clinical signs may include respiratory distress associated with pleural fluid accumulation, direct compression of adjacent lung lobes, or superior vena cava syndrome. In addition to respiratory signs, some dogs with mediastinal lymphoma may exhibit polyuria and polydipsia secondary to the development of hypercalcemia of malignancy, a paraneoplastic syndrome seen in 10-40% of dogs with lymphoma.

The clinical findings associated with extranodal lymphoma (which may involve the skin, lungs, kidneys, eyes, and CNS) can be quite variable and are dictated by the organ infiltrated. Cutaneous lymphoma may appear as solitary, raised, ulcerative nodules or generalized, diffuse, scaly lesions. Clinical signs of lymphoma at other extranodal sites include respiratory distress (lungs), renal failure (kidneys), blindness (eyes), and seizures (CNS).

Lesions:

Commonly, all superficial and various internal lymph nodes are 3-10 times normal size (multicentric form). 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.

Diagnosis:

The definitive diagnosis of lymphoma is often uncomplicated and can be obtained by either cytologic or histopathologic evaluation of the affected organ system. In dogs with multicentric lymphoma, fine-needle aspiration of enlarged peripheral lymph nodes usually provides specimens of adequate cellular content and detail to make a definitive diagnosis. Cytologically, lymph node aspirates may identify a monomorphic population of lymphoid cells, either of large (lymphoblastic), intermediate, or small size. Despite the ease of diagnosis, cytology is unable to differentiate or categorize the wide spectrum of lymphomas with regard to morphologic pattern (diffuse versus follicular) and histologic grade (high versus low). Due to these constraints, histopathologic tissue evaluation remains the gold standard for the diagnosis of lymphoma, providing additional morphologic information required for definitive classification.

In rare situations where cytology or histology fails to confirm the diagnosis, new molecular techniques may allow for its identification. The use of PCR allows for the amplification of DNA sequences that confirms the presence of malignant lymphocytes. Although PCR methods are highly sensitive, the methodology should be reserved for cases where conventional cytologic and histologic diagnostic techniques have failed.

Treatment:

Treatment of multicentric canine lymphoma with aggressive, multi-agent chemotherapy protocols is often rewarding, with >90% of all dogs achieving some clinical response. The most common chemotherapeutic agents used in combination protocols are vincristine, adriamycin, 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 ~9-12 mo. For dogs with T-cell lymphoma, expected survival times are shorter (6 mo). Dogs that fail to 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, half-body radiation).

Although systemic chemotherapy remains the cornerstone for treating lymphoma, the idea that both induction and maintenance phases of chemotherapy are necessary for achieving durable remission times has recently changed. Short but 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 demonstrated clinical efficacy and provides another option for maintaining durable remission times without the need for chronic chemotherapy.

Despite the favorable outcomes expected in treating 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 and severe malabsorption of nutrients and loss of proteins often results 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, but the expected median duration of remission is ~6 mo for T-cell lymphoma. Dogs with hypercalcemia of malignancy, often associated with mediastinal lymphoma, are also less likely to achieve prolonged survival times, due to the multi-organ damage associated with chronic elevations in ionized calcium. Lymphoma involving other extranodal sites such as the skin, can be managed with combination therapies including surgery, radiation, and systemic chemotherapy; however, the development of refractory and progressive disease is common.