Lymphoma

By | 2012-11-10

Lymphoma is the general term denoting malignant transformation of lymphoid cells, but it is often used in equine medicine in place of the term lymphosarcoma, which is specifically the malignant transformation of lymphoid cells into solid (or sarcomatous) tumors. Lymphoid leukemia (or “true” leukemia) denotes the malignant transformation of lymphoid cells within the bone marrow. Both forms of lymphoid neoplasia may be accompanied by circulating neoplastic cells.

Lymphoma is one of the most common internal neoplasms of the horse, but the prevalence of lymphoma in horse populations is relatively low — ranging from 0.002% to 0.05%, based on United States abattoir surveys and from 0.2% to 3.0%, based on necropsy surveys. No established risk factors for equine lymphoma exist, and the etiology is unknown. A breed or sex predilection does not appear to be a factor, and the majority of patients are between 4 and 10 years of age. However, individual cases of lymphoma in a fetus and in horses younger than 1 year or older than 20 years of age have been reported.

Clinical Signs of Lymphoma

A diverse spectrum of clinical signs has been associated with lymphoma. The signs and progression of disease relate to the sites of tumor involvement and are not specific to lymphoma. The most common clinical signs are decreased appetite, depression, weight loss, fever, lymphadenopathy, and dependent edema. In a study of 20 cases of lymphoma confirmed by histology, the clinical findings included — in descending order of frequency — weight loss, fever, peripheral lymphadenopathy, abdominal mass, upper or lower respiratory signs, ocular signs, colic, and diarrhea.

Numerous lymphoma tumor locations have been reported and include peripheral and internal lymph nodes, spleen, liver, kidney, intestine, heart, lung, nasopharynx, eye and adnexa, skeletal muscle, skin, reproductive organs, and central and peripheral nervous system. Four anatomic forms of lymphoma are well described: multi-centric — 50%; alimentary — 19%; mediastinal — 6%; and extranodal — 25%. Combinations of these four classic forms of lymphoma occur in approximately 50% of cases.

Multicentric, or generalized, lymphoma is the most commonly reported form and involves multiple peripheral and internal lymph nodes and other organs. The most commonly involved peripheral lymph nodes are the mandibular, caudal cervical, retropharyngeal, and superficial inguinal. The most commonly involved abdominal lymph nodes are the mesenteric, colonic, and deep iliac. Splenomegaly occurs in 25% of the cases, and hepatomegaly or perirenal masses are found infrequently. The multiple sites of involvement probably represent metastasis via the blood and lymphatic circulatory systems. Notably, this is the most common form to be associated with circulating neoplastic lymphocytes, referred to as the “leukemic phase” of lymphoma. Clinical signs reflect dysfunction of affected organs, and the course of the disease is typically rapid once signs become evident.

The alimentary type is the most acute form of lymphoma. It causes rapid deterioration and involves the small intestine and associated mesenteric lymph nodes. Distant metastasis appears slow to develop. Alimentary lymphoma is commonly detected in horses from 2 to 5 years of age. Signs are considered nonspecific and include weight loss, decreased appetite, fever, dependent edema, and diarrhea or abdominal pain of varying severity and duration. Affected horses may have a blunted oral glucose tolerance response and reduced serum albumin concentration, which suggests intestinal malabsorption. Immune-mediated hemolytic anemia and hyperglobulinemia have also been reported to accompany this condition.

Lymphoma of the mediastinal lymph nodes typically occurs in adult horses. The most common clinical signs are referable to compression of intrathoracic structures and include pleural effusion, tachypnea, dyspnea, and dependent edema. Less common findings include a persistent cough, tachycardia, jugular vein distention, and forelimb lameness. Neoplastic cells may be observed in the pleural fluid and the paraneoplastic syndrome of hypercalcemia has been associated with this form of lymphoma.

The most common extranodal sites of tumor development are — in descending order — the skin, upper respiratory tract, eyes or adnexa, and central nervous system. Lymphoma of the skin — the cutaneous form — is the least common form of lymphoma in horses, although it represented the most common form in one report. Tumors are readily identified as nonpainful, dermal, or subdermal masses that are firm and well circumscribed and may be haired, nonhaired, or ulcerated. Horses may have a solitary mass or multiple masses that range in size from a few millimeters up to several centimeters in diameter. The most commonly affected regions include the shoulder, perineum, axilla, and trunk. Clinical signs are referable to internal metastasis and may not be present during the initial examination. Tumors may develop rapidly or slowly and may spontaneously regress and reappear. However, cutaneous lymphoma generally manifests as a slowly progressive extension of an internal malignancy and involves multiple or single, nonulcerated dermal or subdermal masses of neoplastic lymphocytes (i.e., a sarcomatous form). The most rare form of cutaneous lymphoma is termed mycosis fungoides, which differs from the sarcomatous form in that it represents a diffuse infiltration with neoplastic lymphocytes of the dermis or subdermis. This rare form of cutaneous lymphoma is also chronic and progressive and, without appropriate histologic examination of the skin, may be easily mistaken for other diffuse non-neoplastic dermatoses.

Extranodal lymphoma of the eye or adnexa most commonly involves the palpebral conjunctiva and eyelids and may be associated with exophthalmus, exposure keratitis, uveitis, chemosis, and conjunctivitis. Lymphoma has been occasionally reported to involve the upper respiratory tract, thus causing signs of upper airway obstruction with and without nasal discharge. A single recent report involved tumor infiltration of the tongue. Reports of peripheral nerve sheath and epidural infiltration also exist and may be considered rare differentials for lameness and ataxia, respectively. Metastatic periarticular involvement that causes lameness has also recently been reported.

Diagnosis of Lymphoma

Diagnosis of lymphoma can be difficult, and ante mortem confirmation occurs in less than 60% of cases. The key to ante mortem diagnosis is a persistent diagnostician. Neoplasia must always be considered in an adult horse with recurrent inflammatory and febrile episodes that are unresponsive to antimicrobial therapy. The physical examination should include transrectal abdominal palpation and careful thoracic auscultation and percussion. However, the definitive diagnosis of lymphoma requires the observation of neoplastic cells in aspirates or biopsy specimens of lymph nodes and other masses or in centesis samples of body cavity fluids, bone marrow aspirates, or peripheral blood.

Cytologic observations consistent with neoplastic transformation of lymphoid cells include mitotic figures, prominent nucleoli, and binucleation, but evaluation of tissue architecture is equally important in the detection of neoplastic transformation and can only be obtained with biopsy. The observation of neoplastic lymphocytes in the peripheral blood is uncommon and may be a late manifestation of lymphoma in the horse, thus indicating dissemination and bone marrow involvement. When neoplastic cells are observed in the peripheral blood, the leukemia is characterized as subleukemic or leukemic if the total white blood cell count is normal or increased, respectively. Lymphoma is aleukemic when neoplastic cells are not present in peripheral blood. Furthermore, the leukemia may be characterized by the appearance of the transformed cells: acute or lymphoblastic leukemia if immature; chronic or lymphocytic leukemia if mature.

Since publication of the last edition of this text, significant strides have been made in classifying lymphomas using antibodies to cell surface antigens (). Probably the greatest anticipated utility of immunophenotyping equine lymphomas is in the prognostication and choice of anti-neoplastic agent(s), as has been realized in human and small animal veterinary medicine. In addition, immunophenotyping should aid in determining the cell lineage of more poorly differentiated equine tumors, in the correct classification as T cell versus B cell lymphomas, in recognizing phenotypic-specific distri-bution patterns, and in determining the apparent proliferation rates of lymphoid tumors. For example, immunophenotyping has lead to the discovery of a previously unrecognized form of equine lymphoma — the T cell-rich, B cell lymphoma, a form that appears to be prone to subcutaneous tumors. This phe-notype may be a major form of lymphoma in horses and represents 11 out of 24 (or 46%) B cell lymphoma cases and about 33% of all lymphomas.

Paraneoplastic syndromes are the indirect systemic effects of cancer and may have profound consequences on disease expression. The cause of these syndromes is often unknown but generally thought to be mediated by soluble substances released from the neoplastic cells. A few of the paraneoplastic syndromes that may be relevant to horse cancer patients include cachexia, hypercalcemia, hypoglycemia, hypertrophic osteopathy, anemia, disseminated intravascular coagulation, leukocytosis, hyperproteinemia, fever, and various neurologic abnormalities. Adjunct therapy aimed at diminishing paraneoplastic syndromes may have a profound effect on patient comfort and clinical course ().

Anemia is a common finding and occurs in 30% to 50% of horses with lymphoma. Typically, the anemia is mild, normochromic, and normocytic and reflects bone marrow suppression. Immune-mediated hemolytic anemia may be suspected based on a positive direct Coombs’ test. Thrombocytopenia can be profound and has resulted in bleeding diathesis. The number of leukocytes and lymphocytes in the peripheral blood is often within normal limits. With leukocytosis, mature neutrophilia and increased serum fibrinogen activity are most commonly observed and indicate the presence of inflammation. Leukopenia and pancytopenia are uncommon findings.

Common alterations of plasma proteins include increased fibrinogen, total protein, and globulin concentrations. Gammopathy may reflect chronic inflammation but may also reflect neoplastic clonal expansion of B cell lymphocytes (see later section on plasma cell myeloma). Hypoalbuminemia may occur in response to a profound gammopathy or from gastrointestinal loss and rarely from end-stage liver failure as a consequence of hepatic involvement. Both selective (immunoglobulin M [IgM]) and generalized immunoglobulin deficiencies have been occasionally associated with lymphoid neoplasia in horses. Biochemical alterations that may be seen include hypercalcemia, increased liver enzyme activity, and azotemia.

Prognosis and Treatment of Lymphoma

In the majority of patients, rapid deterioration follows the onset of clinical signs associated with internal disease. Horses with lymphoma limited to cutaneous involvement, however, have survived for several years with and without chemotherapeutic intervention. Immunosuppressive glucocorticoid therapy (0.02-0.2 mg/kg dexamethasone [Azium] IV, IM, or PO q24h) may be palliative for steroid-responsive malignancies and may also suppress immune-mediated sequelae, including hemolytic anemia and thrombocytopenia. Cutaneous lesions may regress in 2 to 6 weeks, at which time the dose may be gradually reduced. If glucocorticoid administration is tapered too quickly or is discontinued, more aggressive lymphoid tumors may reappear. Signs of acute laminitis have been observed during glucocorticoid therapy in equine cancer patients and were the grounds for discontinuing therapy.

Few reports discuss use of a specific antineoplastic agent in the treatment of equine lymphoma. The expense and possible toxicity of chemotherapy in the horse are the most common reasons cited for nontreatment. However, the use of a multiple-agent induction protocol in horses with lymphoma has been reported () and is summarized here. Cytosine arabinoside (Cytosar-U; 200-300 mg/m2 SQ or IM) is given once every 1 or 2 weeks. Chlorambucil (Leukeran; 20 mg/m2 PO) is given once every 2 weeks. Prednisone (Deltasone; 1.1-2.2 mg/kg PO) is given every other day throughout the treatment period. Alternatively, cyclophosphamide (Cytoxan; 200 mg/m2 IV given once every 2-3 weeks) is substituted for chlorambucil. Antineoplastic agents are given on alternating weeks but have been given on the same day without apparent consequence. Response to induction therapy should occur within 2 to 4 weeks, but if a response is not observed, adding vincristine (Oncovin; 0.5 mg/m2 IV once a week) to the induction protocol has been recommended.

With remission, the induction protocol is used for a total of 2 to 3 months and then is switched to a maintenance protocol. The first cycle of maintenance therapy increases the treatment interval for each antineoplastic agent by one week; prednisone, however, is given for the duration of therapy and is gradually reduced in dose. After 2 to 3 months on the first cycle, if the horse is still in remission, the second cycle is begun, adding one more week to the treatment intervals of each agent. Several cycles of maintenance therapy can be given; however, most horses in remission are treated for a total of 6 to 8 months.

Other reported protocols include single-agent use of l-asparaginase (Elspar; 10,000-40,000 IU/m2 IM once every 2-3 weeks) or cyclophosphamide (as described previously) and combinations of either cytosine arabinoside or cyclophosphamide with prednisone.

Unfortunately, the likelihood that remission rates and survival times for specific chemotherapeutic protocols and well characterized lymphoid neoplasms in horses (based on a suitably large number of cases) will soon be available is not high. Nevertheless, anecdotal reports suggest remission is possible in some cases of equine lymphoma.