Max's House

     Feline Lymphoma and Leukemias

E. Gregory MacEwen

 

INCIDENCE AND RISK FACTORS

Lymphoma is a proliferative disease arising from lymphoid tissues involving any organ or tissue and accounts for 50 to 90% of all hematopoietic tumors in the cat. Since hematopoietic tumors (lymphoid and myeloid) account for approximately one-third of all feline tumors, it is estimated lymphoid neoplasia accounts for an incidence of 200 per 100,000 cats at risk. In one series of 400 cats with hematopoietic tumors, 61% had lymphoma, 39% had leukemias and myeloproliferative disorders, of which 21% were categorized as undifferential leukemias, which were most likely myeloid in origin.

The mean age neoplastic development is reported to range from 2 to 6 years. In one study, males were at greater risk, and in another study females were reported to have a greater risk.

The feline leukemia virus (FeLV) is the most common cause of hematopoietic tumors in the cat. The incidence of FeLV (positive), based on indirect immunofluorescent antibody (IFA), will range from 30 to 80%, depending on the location of the tumor and the age of the cat. Younger cats tend to be FeLV positive and have leukemia or mediastinal lymphoma. Older cats tend to be FeLV negative and alimentary lymphoma are usually FeLV negative.

There is mounting evidence that feline immunodeficiency virus (FIV) infection will increase the incidence of lymphoma in cats. Shelton et al. determined that FIV infection alone in cats was associated with a fivefold increased risk for development of lymphomas. Coinfection with FeLV will further potentiate the development of lymphoproliferative disorders. Experimentally, cats infected with FIV have developed lymphoma in the kidney and liver of B-lymphocyte origin. It has been suggested that FIV infection may be associated with alimentary lymphoma of ▀-cell origin, and this may be related to chronic dysregulation of the immune system or the activation of oncogenic pathways.

PATHOLOGY AND NATURAL BEHAVIOR

The classification of lymphoma and leukemias can be correlated with anatomic location and histologic criteria. Anatomic classification for lymphoma has been categorized as mediastinal, alimentary, multicentric, leukemic, and extranodal form. The frequency of anatomic form will vary with geographic distribution and may be related to FeLV strain as well as prevalence of FeLV vaccine use.

Mediastinal Form

This form involves the thymus, mediastinal, and sternal lymph nodes. More commonly the disease involves the anterior and posterior lymph nodes in the mediastinum. Pleural effusion is common. Occasionally the tumor will extend out of the thoracic inlet and can be palpated in the ventral neck region. Hypercalcemia occurs frequently with mediastinal lymphoma in dogs and is very rare in cats. The majority of cats with mediastinal lymphoma are young and FeLV positive.

Alimentary Form

Alimentary lymphoma usually consists of gastrointestinal, mesenteric lymph nodes and liver involvement. Some reports will limit the alimentary form to gastrointestinal involvement with or without extension to the liver. The low prevalence of FeLV infection in cats with gastrointestinal involvement is because most of these tumors are from ▀-lymphocytes in gut-associated lymphoid tissue. Although recent evidence suggests some FeLV negative tumors may be derived from transformation of multipotent lymphoid or monocyte precursors or FIV transformed ▀-lymphocytes.  The most common site of involvement is the small intestines (50%), then the stomach (25%), followed by ileocecocolic junction and colon. The tumor can be solitary or diffuse throughout the intestines, muscle layers, and intestinal submucosa, resulting in annular thickening, leading to partial or completed intestinal obstruction. There is a report describing chronic lymphocytec-plasmacytic enteritis in cats progressing to overt lymphoma, following 6 to 1S months of conservative therapy

Multicentric Form

The multicentric form will usually involve peripheral lymph nodes with or without simultaneous abdominal (spleen/liver) involvement.
Peripheral lymphadenopathy alone is very unusual. Cats with generalized peripheral lymphadenopathy due to lymphoma may have minimal signs of illness. As the lymphoma progresses, bone marrow infiltration with malignant cells and hepatosplenomegaly may
develop.

There have been reports of nonneoplastic peripheral lymphadenopathy in cats, which clinically resembles lymphoma and histologically has features that may also resemble lymphoma. These lymph nodes may be two to three times normal size. In one report, this syndrome was termed distinctive peripheral lymph node hyperplasia (DPLH) of young cats. These cats tend to be young (2-4 years), many have had   episodes of fever, previous viral infections, may have hypergammaglobulinemia (polyclonal gammopathy) and most are negative forFeLV.  Histopathologically the nodal architecture is severely distorted with loss of subcapsular and medullary sinuses. The cell population   shows  an admixture of histiocytes, lymphocytes, plasma cells, and immunoblasts, and occasionally effaced lymphoid follicles. The lymph nodes will regress spontaneously in most of these cats. The histologic changes noted in these lymph nodes resemble the histologic features of    AIDS-related lymphadenopathy in humans.

Anatomic Forms of Feline Lymphomas

Form

Frequency(%)

Age Average

FeLV +

Mediastinal 

20-50%

2-3 years

80%

Alimentary

15-45%   8 years   30%

Multicentric

20-40%   4 years 80%

Leukemia

25-30%   3 years  80% 

Extra-nodal
     CNS
               Cutaneous

5-10%
< 5
3-4 years
8-10 years
80%
< 10%


Extranodal Lymphoma

The most common extranodal sites for lymphoma include the kidneys, eyes, retrobulbar, central nervous system (CNS), nasal cavity, and skin. Renal lymphoma can be primary or associated with alimentary lymphoma. In a study of 28 cases of renal lymphoma the mean age was 7 years and 50% were FeLV positive. Metastasis to the CNS is a frequent sequela to renal lymphoma and occurs in 40 to 50% of treated cats.

Primary CNS lymphoma (PCNSL) is most commonly seen extradural in the spinal canal and most cats are FeLV (positive) (80%). Following meningioma, lymphoma is reported to be the second most common tumor involving the CNS in cats. The mean age is 3 to 4 years with some suggestion of a male predilection. Most cats present with paresis of the hindlegs and thoracolumbar spine and epidural space are most commonly involved. The predilection for thoracolumbar spine in cats is unknown. Feline PCNSL may be primary or secondary to multicentric involvement (especially renal or bone marrow). Bone involvement is rarely seen radiographically. In necropsy findings, renal involvement and bone marrow are the common sites in cats presenting with spinal lymphoma.

Cutaneous lymphoma is usually primary but can rarely be seen secondary to multicentric involvement. It is commonly seen in older cats (5-14 years) with an average age of 10 to 12 years. No sex or breed predominance has been found. Uniformly, cats with cutaneous lymphoma test FeLV negative. However, one recent case report using polymerase chain reaction (PCR) technology found evidence of FeLV provirus in tumor DNA. Cutaneous lymphoma can be solitary or generalized. Two, forms of cutaneous lymphoma have been distinguished histologically and immunohistochemically. The epitheliotrophic form, also called mycosis fungoides, is associated with Tlymphocytes. Nonepitheliotrophic form is usually composed of Blymphocytes. Neoplastic T-lymphocytes are characterized as large with abundant cytoplasm and convoluted nuclei (mycosis cells). These cells usually form iritraepidermal nests of 5 to 10 cells, separated from surrounding keratinocytes by a clear space (Pautrier's microabscesses). The B-cell lymphomas show lymphocytes deep in the epidermis, with sparing of the papillary dermis and epidermis. Confirmation, using immunohistophenotyping of B-cell lymphoma in cats with cutaneous lymphoma is lacking.

Recently, a cat with cutaneous T-cell lymphoma with circulating atypical lymphocytes was diagnosed. The circulating cells were lymphocytes with large, hyperchromatic, grooved nuclei. In humans, cutaneous T -cell lymphoma with circulating malignant cells is called Sezary syndrome. This syndrome has also been reported in dogs.

Histologic Classification of Lymphomas

A number of histopathologic staging systems have been developed and used to classify human non-Hodgkin's lymphoma. Recently, the morphologic criteria of the NIH Working Formulation  was used to classify more than 600 cases of feline lymphoma. Low-grade lymphoma was found in 8.6%, intermediategrade in 35.1%, and high-grade in 55.2% of the cases. The remaining 1.1% were plasmacytomas. More than one-third of the tumors were of the immunoblastic type. Lymphoblastic lymphoma, a subtype of the high-grade tumor, constituted less than 3%. There was considerable variation in age of the animals with various subtypes, but in general, low-grade tumors tended to develop in older cats (>10 years) and high-grade tumors developed in younger cats (<6 years). The majority of lymphomas in the cats are composed of T-cells transformed by FeLV. Lymphomas arising from the gastrointestinal tract are usually B-lymphocytes and most of these test FeLV negative.

A rare reported form of alimentary lymphoma is classified as large granular lymphoma. Large granular lymphocytes are characterized by abundant cytoplasm with prominent azurophilic granules. This population of cells includes natural killer cells and cytotoxic Tcells. These tumors commonly originate in the small intestine, especially the jejunum or mesenteric lymph nodes. All cats reported with this type of tumor have been FeLV negative. Large granular lymphocytes must be differentiated from several other granular cell types that may be found in the small intestine, including globule leukocytes, enterochromaffin cells, mast cells, and eosinophils.

Leukemias

The classification of leukemias in cats is difficult because of the similarity of clinical and pathological features and the transition, overlap, or mixture of cell types involved.

Leukemia is defined as a neoplastic proliferation of hematopoietic cells originating within the bone marrow. Cell lineage includes myeloid, neutrophils, basophils, eosinophils, monocytes, lymphoid, megakaryocytes, and erythrocytes. . Well-differentiated leukemias are usually called "chronic" leukemia. The poorly differentiated leukemias are usually referred to as "acute." This distinction has been very important in the therapeutic management and prognosis of human and canine leukemias.

Granulocytic Leukemia (Myeloid, Neutrophilie)

The total leukocyte count is variable, and may range from leukopenia to marked leukocytosis. Chronic granulocytic leukemia (GL) must be distinguished from leukemoid reactions associated with infections. Acute GL is characterized by a large percentage of myeloblasts or progranulocytes, or both, in blood and bone marrow. The myeloblast can be difficult to distinguish from the lymphoblast but has a finer chromatin pattern, a smaller nucleus -to-cytoplasmic ratio, more prominent or multiple nucleoli, and sometimes cytoplasmic granules. It is not uncommon in cats with GL to have no recognizable neoplastic cells in the peripheral blood. The bone marrow is hypercellular because of granulocytic leukemia cells.

Myelomonocytic Leukemia     Myelomonocytic leukemia (MML) results from malignant transformation of both neutrophils and monocytes. This form of leukemia is one of the most common forms of leukemia reported.

Monocytic Leukemia   Monocytic leukemia (ML) is a rarely reported leukemia. ML is generally considered to be an acute leukemia, regardless of the morphologic appearance of the cells.

Eosinophilic Leukemia (EL)    Eosinophilic Leukemia (EL) is rarely diagnosed in cats and is considered a variant of chronic granulocytic or myeloid leukemia. EL has been induced experimentally by FeLV. Mature eosinophils will outnumber immature stages and anemia is uncommon in cats associated with EL. Cats will usually have an eosinophil count of 15,000 cells/Ál or greater with or without immature cells in the peripheral blood. The bone marrow will show hyperplasia of eosinophilic precursors and the M:E ratio will be significantly increased. Organ infiltration, such as lymph nodes, spleen, and liver can be seen. It is important to rule out eosinophilic enteritis, parasitism, eosinophilic granuloma complex, and allergic disorders in establishing a diagnosis of EL. The diagnosis of EL can be very difficult because of the hypereosinophilic syndrome (HES) seen with other disease conditions in cats. HES is characterized by marked increase in eosinophilic count, bone marrow hyperplasia of eosinophilic precursors, and multiple organ infiltration by mature eosinophlis. Most cats have signs related to gastrointestinal involvement.

Basophilic Leukemia  Basophilic leukemia (BL) is considered a variant of chronic granulocytic leukemia. Only one confirmed case of BL has been reported in the cat. It is important to differentiate BL from systemic mastocytosis with mast cell leukemia. Mast cells have numerous cytoplasmic granules and round nuclei. Basophils have segmented nuclei and cytoplasmic granules that superimpose on the nucleus, giving it a "moth-eaten" appearance.

Erythremic Myelosis Erythemic myelosis (EM) is a myeloproliferative disorder characterized by excessive proliferation of erythroid elements, resulting in an increase in nucleated erythrocytes (rubriblasts to metarubricytes), and is common in cats. Severe anemia is common and within the peripheral blood numerous nucleated erythrocytes, moderate to marked anisocytosis, and increased erythrocyte mean cell volume will be seen. The bone marrow contains a preponderance of normal-appearing erythrocytec precursors. Some cats will undergo blast transformation to myeloblastic, granulocytic, or a poorly differentiated leukemia (previously referred to as reticuloendotheliosis). The transition from EM to erythroleukemia to acute granulocytic leukemia is well recognized in humans.

Erythroleukemia (Reticuloendotheliosis) Erythroleukemia or acute erythremic myelosis can develop from blast transformation of erythremic myelosis. Primitive erythroid precursors in blood and bone marrow predominate. Primitive cells resembling myeloblasts are often present in low numbers.

Primary Erythrocytosis  Primary erythrocytosis is rarely reported in cats and the diagnosis is based on increased packed cell volume (65-80%) with low to normal serum erythropoietin activity. Most clinical signs are associated with increased RBC volume, which increases blood volume and viscosity, causing impaired blood flow, stasis, and tissue hypoxia. Neurologic signs such as seizures, blindness, and mental depression are common. The oral mucous membrances may appear brick red. It is important to differentiate this from secondary polycythemia, caused by renal tumors, chronic hypoxia, and right-to-left cardiac shunts.

Megakaryocytic Leukemia Megakaryocytic leukemia is characterized by abnormal megakaryocytic hyperplasia in the bone marrow. The megakaryocytes are morphologically abnormal and some are small (dwarf megakaryocytes) and have few or no nuclear lobulations. Thrombocytopenia or thrombocytosis may be present. In people, this form of leukemia is often associated with extensive marrow fibrosis, with an increase in reticulum or collagen.

Primary Thrombocythemia  Primary throbocythemia is a very rare chronic myeloproliferative disease characterized by proliferation of megakaryocytes and elevated platelet counts of >1 million. Giant platelets and platelets with abnormal morphology may be seen in the peripheral blood. One case has been reported in the cat.

Malignant Histiocytosis Malignant histiocytosis is a rare condition in cats and is characterized by systemic proliferation of malignant macrophages (histiocytes) and their precursors. A distinguishing characteristic of this disease is erythrophagocytosis. Hepatosplenomegaly with progressive anemia, sometimes Coomb's (+), and thrombocytopenia are characteristic. The erythrophagocytosis may be confused with a possible immune-mediated anemia. Bone marrow biopsy, as opposed to aspiration, as well as splenic biopsy, may be necessary to establish a diagnosis. Special stains using acid phosphatase and nonspecific esterase with fluoride inhibition (naphtol butyrate substrate) may be necessary to indicate macrophage origin.

Myelofibrosis and Myeloid Metaplasia  Myelofibrosis and myeloid hyperplasia are characterized by abnormal growth and differentiation of erythroid, myeloid, and megakaryocytic cell types with varying proliferation of fibroblasts in the marrow. Anemia, leukopenia, or thrombocytopenia or varying combinations are common. Myelofibrosis has been diagnosed in FeLV positive cats and is directly associated with the virus rather than a consequence of myeloproliferative disorders. Myeloid metaplasia may terminate in acute leukemia and thus may be considered a preleukemic event.

Lymphoid Leukemia Lymphoid leukemia is the most common leukemia in cats. Approximately 25% of the cats with lymphoma will also have a leukemic blood picture. Acute lymphoblastic leukemia (ALL) is the most common of the lymphoid leukemias. ALL is characterized by poorly differentiated lymphoblasts and prolymphocytes in blood and bone marrow. The majority of cats with ALL have normal to low white blood cell counts. A few cats will have leucocytosis with circulating blasts. A moderate to marked anemia is common. A bone marrow usually reveals extensive infiltration with lymphoblasts. Approximately 60 to 80% of cats with ALL are FeLV positive and most malignant cells have T -cell phenotypes.

Chronic lymphocytec leukemia (CLL) is rarely reported in cats and is characterized by well-differentiated small, mature lymphocytes in peripheral blood and bone marrow.  Most cats have elevated white blood cell counts greater than 50,000/ul. Most cats will be FeLV negative.

 

HISTORY AND CLINICAL SIGNS

The clinical signs associated with feline lymphoma and leukemia are variable and depend on location as well as extent of disease. The clinical signs of the mediastinal form include dyspnea, tachypnea, noncompressible anterior mediastinum with dull heart and lung sounds. Rarely a Horner's syndrome will be seen due to pressure on the sympathetic nerve as it ascends around the first rib, and edema of the head from pressure on the cranial vena cava. Pleural effusion is common and the pleural fluid is characterized by serohemorrhagic to chylous effusion.

The alimentary form is most commonly associated with an abdominal mass originating from the gastrointestinal tract and may commonly be associated with enlarged mesenteric lymph nodes, or other organ involvement. In a minority of cats, diffuse thickening of the small bowel or localized gastric involvement will be present. Clinical signs consist of vomiting, diarrhea, anorexia, and weight loss.

Cats with the multicentric form present with variable clinical signs, depending on the location and extent of disease. Peripheral lymphadenopathy, as the only physical finding, is a very uncommon presentation for cats with the multicentric form. Peripheral lymphadenopathy, without organomegaly, seen in cats is mostly hyperplastic or reactive.

The extranodal sites include the kidneys, skin, eye, and CNS. Renal lymphoma is most consistently bilateral, even in cats that appear to have unilateral disease. In general, the kidneys are uniformly enlarged; however, they may also palpate lumpy. More than 50% cats will present with evidence of renal insufficiency

Cutaneous lymphoma may be solitary or diffuse, with alopecia, erythema, and crusted papules. Minimal peripheral lymphadenopathy may also be present. In most cats the duration of signs will be prolonged, lasting months.

Cats with primary CNS lymphoma (PCNSL) most commonly present with signs associated with thoracolumbar involvement. The most common sites are between the second thoracic and fourth lumbar vertebrae and most are extradura1. Signs include gradual or sudden onset of weakness, upper motor neuron paralysis to bladder, tail flaccidity, hyperpathia in the region of the lesion, and progressing ataxia. The neurologic dysfunction may be insidious or progress rapidly. Cats with cervical spinal cord or nerve root involvement generally show peracute tetraparesis, and diminished sensation in the thoracic limbs. Cervical root involvement may show root lesions (root signature), such as lameness and hyperesthesia upon shoulder extension. Bone marrow involvement is common in cats with PCNSL and most are FeLV positive.

All cats with lymphoma, regardless of site, may have secondary bone marrow infiltration leading to anemia and a leukemic blood profile. Cats with acute leukemia will usually show signs of severe anemia (pale mucous membranes), splenomegaly, and febrile episodes. Anemia is a common condition in cats with lymphoma, with at least 50% of them having moderate to severe anemia, most nonregenerative. Cats with chronic leukemia may have a longer duration of signs and mild anemia, with or without splenomegaly.

A number of disease conditions can be confused with lymphoma in cats.

DIAGNOSTICS AND CLINICAL STAGING

For most cats with suspect lymphoma or leukemia, the diagnostic evaluation should include a complete blood count (CBC with differential cell count), platelet count, and a serum chemistry profile and test for FeLV and feline immunodeficiency virus (FIV). A bone marrow aspiration or biopsy is indicated to evaluate for possible involvement and complete staging of the extent of disease. Bone marrow evaluation is particularly indicated if anemia, cellular atypia, and leukopenia are present. Lymph node or involved organ biopsy, via surgical incision or needle-core, to obtain tissue for histopathologic evaluation is essential for a definitive diagnosis. Lymph node aspiration, especially peripheral lymph nodes may not provide a definitive diagnosis. A misdiagnosis may occur in cats with hyperplasia or distinctive lymph node hyperplasia.

Serum chemistry profiles can help establish the overall health and clinical staging of cats. Elevated liver enzymes may indicate hepatic infiltration with lymphoma. An elevated BUN and creatinine may indicate renal lymphoma. Hypercalcemia is rarely seen in cats but has been reported in cats with mediastinal lymphoma. Elevated globulin levels may indicate the presence of a monoclonal gammopathy, with or without serum hyperviscosity. This is a rarely reported paraneoplastic syndrome in cats with lymphoma.

For cats with mediastinal lymphoma, fine-needle aspiration of suspected mass(es) or cytologic evaluation of pleural fluid may be sufficient to establish a diagnosis. In most cats the finding of lymphoblasts will establish a diagnosis. However, definitive diagnosis of lymphoma in cats with a mediastinal mass and concurrent chylothorax can be challenging. If lymphoblasts are not identified in the pleural chylous effusion, then cholesterol and triglyceride concentrations should be measured. In chylous effusions, the pleural fluid triglyceride concentration will be greater than in the serum; however, anorectic cats will have lower triglyceride levels in the pleural fluid. A major differential for mediastinal lymphoma is thymoma. The cytologic features of thymoma were recently described and found to be distinct from lymphoma. Cytology of thymoma can be difficult because of the preponderance of small lymphocytes as opposed to lymphoblasts, seen with lymphoma. Mast cells can also be seen in up to 50% of the aspirations from thymomas.

For the alimentary form, especially if primary gastrointestinal lymphoma is suspected, a wedgebiopsy through serosa and muscularis, avoiding the mucosa, may be necessary to establish a diagnosis. Caution must be used when using endoscopically obtained tissue because of the difficulty in differentiating lymphoplasmacytic gastroenteritis from primary, diffuse, intestinal lymphoma. Most gastrointestinal lymphomas have secondary mesenteric lymph node involvement and ultrasound guarded biopsy may be adequate to obtain enough tissue for a diagnosis.

In cats with suspected spinal lymphoma, survey radiographs of the spine will rarely reveal osseous lesions. Myelograms are indicated and in approximately 75% of the cases an extradural pattern of compression will be detected. Fluoroscopic-guided fine-needle aspiration of the epidermal lesion may yield enough tissue for a cytologic diagnosis. In one study, cerebrospinal fluid (CSF) analysis revealed a clear and colorless fluid with a mixed pleocytosis (mean 140 cells/UL: range 0 to 1,625 cells/ul) with elevated protein content (mean of 140.7 mg/dl range of 12-405 mg/dl) was identified in most cats evaluated. Malignant lymphocytes were identified in 6 of 17 cats evaluated with CSF analysis. Because of the high percentage of bone marrow involvement, a bone marrow aspiration is recommended for complete clinical staging.

For cutaneous lymphoma, punch biopsies (3-4 mm) should be taken from the most representative and infiltrative, but not infected, skin lesions. No clinical staging system for cutaneous lymphoma has been established; however, a staging system is presented in the chapter on canine lymphoma as well as recommended staging procedures.

A WHO staging system routinely used to stage feline lymphoma is presented in Table. This staging system is similar to the one used for dogs; however, because of the high incidence of visceral involvement, clinical staging is difficult and another staging system has been evaluated. For cats with suspected leukemia a bone marrow aspiration or biopsy is usually diagnostic. The preferred sites for bone marrow aspirates are the proximal humerus or iliac crest. Cats with acute leukemia are likely to have malignant cellular infiltrates in organs other than bone marrow. A bone marrow aspirate with greater than 30% abnormal blast cells is necessary to make a diagnosis of an acute leukemia. In cats with suspected CLL, infiltration of the bone marrow with more than 20% mature lymphocytes helps confirm the diagnosis. All cats with leukemia should be tested for FeLV.

TREATMENT OF MALIGNANT LYMPHOMA

Significant advances have been made in the treatment of canine lymphoma; however, the response rate and duration of response using chemotherapy to treat feline lymphoma have not been as impressive.

The chemotherapeutic agents used most commonly to treat feline lymphoma include vincristine, cyclophosphamide, methotrexate, Lasparaginase and prednisone. Current protocols for treating feline lymphoma are detailed in below tablesA current protocol in use at the University of Wisconsin-Madison is presented in table below. This protocol has been used in more than 25 cats with various forms of lymphoma and is tolerated well.

Doxorubicin is a very effective agent and is commonly used for treating canine lymphoma; however, in cats significant toxicity results when it isused at a dose of 30 mg/m2 IV q 3 weeks. However, at lower doses, 20 mg/m2 IV or 1 mg/kg IV doxorubicin can be used without significant toxicity. The major toxicity noted with doxorubicin is profound anorexia; myelosuppression; and if perivascular leaking, severe tissue damage. Doxorubicin-induced cardiac toxicity has not been documented in cats, but there is no information indicating cats are resistant to myocardial damage. Renal toxicity has been produced experimentally in rats and rabbits, and has been reported in cats. In our experience, the incidence is low in cats at total accumulative doses of less than 50 mg doxorubicin total dose per cat.

Response and duration of response will vary depending on the stage of disease, FeLV status, and anatomic location. Most combination chemotherapy protocols will induce 60 to 70% complete response rate (CR) and median survival times of 5 to 7 months with an approximate 30% survival at 1 year. In general, cats tolerate chemotherapy very well. Gastrointestinal toxicity is less common when compared to the dog.

Radiation therapy has been effectively used to treat localized lymphoma, such as epidural, mediastinal masses, and nasal lymphoma. Total doses of 10 to 15 Gy usually result in a CR. Recently, 10 cats with localized lymphoma were treated with radiation alone or with chemotherapy, using doses of 8 to 40 Gy. Eight of 10 cats achieved a CR with a median response of 114 weeks. Radiation therapy has also been used to treat nasal lymphoma, and in one study the disease-free survival was greater than 500 days in a small number of cats.

Very little has been published regarding the treatment of cutaneous lymphoma or mycosis fungoides in cats. Cats with a solitary mass should be treated with surgical excision, although clinical staging may be necessary to rule out possible internal involvement. For cutaneous lymphoma (nonmycosis fungoides) combination chemotherapy can be considered. If the disease is localized to a small region, radiation therapy is usually effective. Mycosis fungoides may be effectively treated with retinoids, such as isotretinoin (Accutane) at 3 to 4 mg/kg PO daily or etretinate (Tegison) at 1.25 mg/kg PO daily. However, no clinical studies have been published demonstrating efficacy in cats.

World Health Organization's Classification for Lymphoma

Stage Grouping (To Include Anatomic Type)

I. Involvement limited to a single node or extra-nodal site, or lymphoid tissue in a single organ, including cranial mediastinum.,

II. Involvement of many lymph nodes in a regional area, a resectable GI tract tumor, extra-nodal site with regional lymph node involvement.

         III. Generalized lymph node involvement, non- resectable-intra-abdominal disease or epidural tumor. IV. Liver               and/orspleen involvement associated with stages I-III.

         V. Manifestation in the blood and involvement of bone marrow involvement with stages I-IV Each stage is             subclassified into:
                    a. without systemic signs, or
                    b. with systemic signs.

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TREATMENT OF LEUKEMIAS

Lymphoid Leukemia

The use of chemotherapy to treat acute lymphoblastic leukemia (ALL) has been disappointing. Using a combination of Cyclophosphamide, vincristine, and prednisone (COP), a 27% complete response rate was reported. One report described a short-term remission in a cat with lymphoid leukemia, using a low dose (10 mg/m2) of cytosine arabinoside SQ twice daily.

Chronic lymphoid leukemia (CLL) can be treated with chlorambucil at a dose of 0.2 mg/kg PO or 2 mg/cat QOD, and prednisone at a dose of 1 mg/kg PO daily.

Nonlymphoid Leukemia

A combination of cytosine arabinoside combined with cyclophosphamide, combined with multiple blood transfusions was effective in inducing a response for 3 months in a cat with acute megakaryocytic leukemia. Hydroxyurea (Hydrea) can be used to treat chronic myeloid leukemia and primary erythrocytosis. Hydroxyrea is available in 500 mg capsules and the dose is 25 to 50 mg/kg PO daily. Some cats have been given 500 mg every 5 to 7 days; however, methemoglobulinemia and hemolytic anemia with Heinz bodies has been seen. A better recommendation is to have the drug recapsuled into 125 mg capsules, which is a more appropriate dosage. However, care must be used in making these capsules because hydroxyurea is potentially carcinogenic. A recommended treatment schedule for hydroxyurea is 125 mg daily to every other day depending on the type of leukemia under treatment. At this dose level the drug is tolerated very well.

GENERAL RECOMMENDATIONS

It is difficult to provide precise treatment recommendation for the wide variety of clinical settings of cats with lymphoma. Our current recommendation is to treat cats with lymphoma using the protocol as outlined in Table.. If the treatment veterinarian is unfamiliar with doxorubicin, then an alternative protocol to consider the COP protocol as published by Cotter, and outlined in Table.

All cats undergoing chemotherapy need to be monitored for toxicity. A CBC needs to be performed prior to each chemotherapy treatment. It is advised that at least a 2,500 to 3,000 granulocyte/u be maintained. If the WBC count drops below the above recommended level, withhold chemotherapy for 5 to 7 days and repeat the CBC.

Hair loss is not a problem in cats on chemotherapy, although they may lose whiskers as well as guard hairs. One of the most common side effects of chemotherapy is anorexia. Diazepam has been used to stimulate appetite but has minimal benefit. Cryoheptadine at a dose of 1 to 2 mg BID to TID or megestrol acetate 2 mg BID PO may be helpful to stimulate appetite.

Nutritional support, especially for cats with alimentary lymphomas, is especially important. It may be necessary to place a feeding tube into cats undergoing chemotherapy for alimentary lymphoma, particularly if anorexia is present.

Relapse of tumor is common following or during chemotherapy. Few studies have been performed to evaluate chemotherapy agents to be used as rescue agents in cats. Agents such as mitoxantrone, actinomycin-D, and L-asparaginase can be considered.

PROGNOSIS

Cotter reported on the results of treating 38 cats with lymphoma and 15 with lymphoblastic leukemia. All cats were treated with COP (cyclophosphamide, vincristine and prednisone) as presented in Table 1. Overall 79% of the cats with lymphoma had a complete response (CR) compared to 27% with ALL. The median duration of remission was 5 months, with 9 cats (26%) remaining in remission at 1 year. Cats with primarily peripheral nodal disease had a median remission time of 28 months (n=5).

In another study of 75 cats with lymphoma, treated with combination chemotherapy, (vincristine, cyclophosphamide, methotrexate with or without prednisone, and L-asparaginase of the 62 cats that had follow-up, 32 (52%) attained a CR for a median of 4 months, and the overall median survival time was 2 months for all cats treated. Response and duration of response varied with tumor location. Mediastinal lymphoma (n=31) had a 45% response rate with a median survival time of 1.5 months. Multicentric lymphoma (n=16) had a 68% response rate with a median survival of 18 months; renal lymphoma (n=6) showed only a 16% response rate and a median survival of 5 months, and alimentary form (n=9) showed a 50% response rate and a median survival time of 9.6 months.

Mooney et al. presented the results of 103 cats treated with combination chemotherapy (vincristine, L-asparaginase, cyclophosphamide, methotrexate, and prednisone.  Sixty-four (62%) of 103 cats had a CR with a median survival time of 7 months, with a 30% survival at 1 year. Cats with stage I and II disease (median survival time of 7.6 months) had a statistically better prognosis than stages III, IV, and V (median of 2.5-3 months). Another important factor related to prognosis was FeLV status. FeLV negative cats had a median survival time of 7.0 months, compared to 3.5 months for FeLV positive cats. For cats that had a complete response, those FeLV negative had a median survival of 9 months, compared to 4.2 months for FeLVpositive cats. The cats with the best prognosis are FeLV negativestage I and II disease. The expected median survival time is 17 months.

In another study by Mooney et al., 28 cats with primary renal lymphoma were treated with combination chemotherapy.  A complete response was noted in 17 cats (61%) and 9 (33%) had a partial response (PR). The median survival time for the CR cats was 5.7 months, and 1 month for cats showing a PR. Duration of response to chemotherapy did not correlate to the degree of renal insufficiency except in those cats with a BUN> 150 mg/dl. Metastasis to the CNS developed in 40% of these treated cats. The investigators revised their chemotherapy protocol to include cytosine arabinoside, which can penetrate the blood barrier, to prevent or reduce CNS metastasis.

In a recent study, 36 cats with lymphoma were treated with COP chemotherapy, and 19 (50%) who achieved a CR were randomized at week 7 to receive maintenance COP or doxorubicin (25 mg/m2 IV q 3 weeks) for another 6 months. The median remission for the 7 cats given doxorubicin was 259 days (range 123-547 days), and those on COP had a median survival of 83 days (range 45-208 days).

In a study of cats with alimentary lymphoma, 28 received COP  chemotherapy. Some cats also were given other drugs, including doxorubicin, L-asparaginase, chlorambucil, idarubicin, and mitoxantrone. Nine cats (32%) had a CR for a median of 213 days and four cats survived 1 year or longer. For all cats treated, the overall median survival was 50 days.

Few studies have been reported on the results of treating cats with spinal lymphoma. In one study of four cats treated with chemotherapy (Lasparaginase, vincristine, prednisone) combined with spinal radiation (n=3) or surgical cytoreduction (n=1), most cats were euthanatized by 5 months, although one cat survived 13 months. In another study of nine cats treated with chemotherapy (vincristine, cyclophosphamide, and prednisone), three cats achieved a complete response with a duration of 14 weeks, and three cats achieved a partial response with a duration of 6 weeks. One cat treated with dorsal decompression laminectomy and chemotherapy survived 13 months. Although the numbers are small overall, the prognosis for spinal lymphoma is poor.

In 15 cats with ALL treated with COP, four achieved a CR and six cats had a PR The median remission was 7 months (range 1-24 months).

The prognosis for other acute nonlymphoblastic leukemias is very poor. However, cats with CLL have a good prognosis and survive 1 to 2 years when treated with chlorambucil. Cats with primary erythrocytosis, without treatment, are reported to survive 6 to 20+ weeks. Phlebotomy alone every 2 to 3 months was used to treat one cat and the survival was greater than 20 months. Hydroxyurea treatment for primary erythrocytosis was used in eight cats and all survived longer than 1 year.

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