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Principles of treatment for feline lymphoma
Principles of Treatment for Feline Lymphoma Susan N. Ettinger, DVM
Lymphoma is the most commonly diagnosed neoplasm in cats. As feline leukemia virus antigenemia has decreased over the past 15 years, there has been a profound shift in the presence, signalment, and frequency of sites of feline lymphoma in North America. There is variation in anatomic classification systems, but most studies have divided lymphoma into four groups: alimentary, mediastinal, multicentric, or extranodal. Clinical signs and common differential diagnoses for each of the forms are described. Staging allows for evaluation of the extent of disease. As in the dog, lymphoma is a systemic disease in the cat, and chemotherapy is the treatment of choice for most forms. Exceptions are described, in contrast to canine lymphoma, feline lymphoma is generally more challenging and frustrating to treat than canine lymphoma. Response rates are lower, and remission duration is shorter. Fortunately, cats treated with chemotherapy tend to have less toxicity than dogs. Positive prognostic factors are feline leukemia virus-negative, clinically well at time of diagnosis, and response to therapy. Achieving a complete remission is prognostic for survival. Unfortunately, response cannot be predicted before treatment. © 2003 Elsevier Inc. All rights reserved.
Ymphoma is the most commonly diagnosed neoplasm in
L cats and accounts for 30% of all feline tumors. In general,
there is no gender predilection. Over the past 15 years, there has been a profound shift in the presence, signalment, and frequency of sites of feline lymphoma in North America. 1 In older studies, feline leukemia virus (FeLV)-positive lymphoma was the most common cause of hematopoietic tumors; 60% to 70% had FeLV antigenemia. The median age was 4 to 6 years, and the common forms were mediastinal and multicentric. Eighty to 95% of cats with the spinal cord form were FeLVpositive. However, as FeLV serologic testing and vaccinations have increased, the overall incidence of FeLV-positive lymphomas has decreased. Antigenemia is as low as 25%. Today alimentary lymphoma is more common, and generally affects older cats (10-12 years old). Still, cats with a negative serumantigen test can be found to be positive with more sensitive testing, such as polymerase chain reaction. Thus, it is plausible that FeLV is still involved in the tumorgenesis of lymphoma today. FeLV is a retrovirus, which consists of single-stranded RNA, core and envelope proteins, and reverse transcriptase. The virus is very fragile and easily killed. Transmission occurs via prolonged intimate contact, such as biting, licking, grooming, and
From the Animal Medical Center, New York, NY. Address reprint requests to Susan N. Ettinger, 510 East 62rid Street, New York, NY 10021. © 2003 Elsevier Inc. All rights reserved. 1096-2867/03/1802-0007530.00/0 doi:l 0.1053/svms.2003.36623 98
shared pans and bowls. FeLV infects lymphoid tissue, intestines, and bone marrow. The provirus integrates into the hostcell DNA. As an insertional mutagen, the virus alters cellular growth and may lead to neoplastic transformation. Approximately 25% of persistently infected cats develop lymphoma. 2,3 Latency is affected by age, viral subgroup, strain, and anatomic location. FeLV-positive cats are 60 times more likely to develop lymphoma. 4 Most cats will develop disease within 5 to 17 months of persistent viremia, and the lymphoma often has a T-cell phenotype. Feline immunodeficiency virus (FIV) is also a singlestranded RNA retrovirus. Despite homology between strains, there is significant difference in pathogenicity and infectivity. Transmission is predominantly through biting and cat fights, due to the high saliva concentration and low viral concentration in blood. FIV can increase the incidence but plays an indirect role in tumorgenesis of lymphoma. One study demonstrated a 5-fold increase of lymphoma in FIV-infected cats. 4 The virus is not oncogenic but is immunosuppressive. This impairs the ability of the immune system to remove cancer ceils. FIVpositive lymphoma is typically extranodal and in middle-aged cats. The immunophenotype of FIV-associated lymphoma varies. Coinfection with FeLV further potentiates the development of lymphoma. Siamese and Oriental breeds appear to be at higher risk for lymphoma, but this may reflect the higher risk of FeLV infection in catteries. Prevalence in catteries and multiple-cat households can be as high as 30%, in contrast to less than 1% in single-cat households.
Anatomic Forms There is variation in anatomic classification systems, but most studies have divided lymphoma into four groups. 5 • Alimentary: The alimentary form typically involves the gastrointestinal tract, lymph nodes, and sometimes liver. FeLV antigenemia is low. The neoplastic population is often derived from B-lymphocytes in gut-associated lymphoid tissue. However, one study reported the majority of 21 alimentary cases were T-cell. 6 Lesions can be solitary or diffuse. Annular thickening may cause a partial or complete obstruction. In descending order, the most common sites are small intestine, stomach, and the ileocecal junction and colon. One study has demonstrated that colonic adenocarcinoma was slightly more common than colonic lymphoma, r • Mediastinal or thoracic: The mediastinal form includes thymus and mediastinal and sternal lymph nodes, which can extend out of the thoracic inlet. Mediastinal lymphomas are more commonly T-cell in origin, s but unlike the dog, hypercalcemia is rare. Affected cats are usually young and FeLVpositive .9
Clinical Techniques in Small Animal Practice, Vol 18, No 2 (May), 2003: pp 98-102
• Multicentric: In contrast to dogs, peripheral lymph-node (PLN) involvement alone is rare in cats. More commonly, there is also splenic and/or hepatic involvement, and the disease may progress to the bone marrow. In general, only one third of lymphomas are T-cell and carry FeLV-positivity. An important differential for peripheral lymphadenomegaly is distinctive peripheral lymph-node hyperplasia. Distinctive peripheral lymph-node hyperplasia is a non-neoplastic disorder of young cats and is associated with episodes of fever, previous viral infections, and a polyclonal gammopathy. A rare distinct form of lymphoma has been reported that involves only solitary or regional head and neck lymph nodes.l° This form may be comparable to human Hodgkin's lymphoma. • E x t r a n o d a l or Unclassified
Renal: Renal lymphoma can be primary or associated with gastrointestinal or multicentric involvement. Twenty to 50% of these animals will be FekV-positive. At time of relapse, extension into the central nervous system (CNS) is commonly observed.11 Some authors classify renal lymphoma in the alimentary group; some consider it a separate form, and some group abdominal lymphoma as one group, s Primary CNS lymphoma: CNS lymphoma may be primary or secondary to multicentric disease, especially if there is renal or bone-marrow disease. Meningioma is the most common brain neoplasm in catsand is therefore a differential for intracranial disease. Spinal cord lymphoma lesions are typically extradural, and cats present for hindlimb paresis. Affected cats are young (mean age 3-4 years) and FekV-positive (85-90%).9,17 Nasal: Nasal lymphoma is usually localized in FeLV-negarive, older cats (8-9 years). Histologically, the cells are interme-
diate to high grade. Immunophenotype is consistent with Bcell. FeLV-positive cats tend to have systemic involvement. Cutaneous: Similar to dogs, cutaneous lymphoma can be solitary or generalized and occurs in FeLV-negative, older cats. Two forms have been described. Epitheliotrophic consists of T-cells in intraepidermal nests of 5 to 10 cells. The second form consists of nonepitheliotrophic B-cells that are seen deeper in the epidermis.
Histologic Classifications Similar to dogs, the majority of feline lymphomas are intermediate to high grade (88.5-90%). 8,12 High-grade lymphoma is generally seen in younger cats (less than 6 years). In contrast, low grade, well-differentiated lymphoma occurs in older cats in the gastrointestinal tract. Commonly diagnosed diffusely in the small-intestinal tract, the neoplastic population arises in the superficial layers and invades into underlying layers. There is some discussion that this represents malignant transformation of the lymphocytic-plasmacytic cells of inflammatory bowel disease. 13 Immunophenotype is not predictive for outcome in cats.14 In one study of 145 cats, B-cell lymphoma was the predominant immunophenotype, especially in the gastrointestinal tract. An Australian study confirms that gastrointestinal lymphoma was the most common form, and the majority of gastrointestinal cases were B-cell of intermediate or high grade. 8
History and Clinical Signs Clinical signs and common differential diagnoses are described in Table 1.
TABLE 1. History and Clinical Signs Anatomic Form
History and Clinical signs (CS)
Notes
Differential Diagnoses
GI
Weight loss, anorexia, vomiting, diarrhea; -+abdominal distension, 1"spleen, $ platelets, pica; 70-85% have abdominal mass or thickened GI loops Dyspnea, tachypnea, dysphagia, noncompressible cranial thorax, dull heart and/or lung sounds; pleural effusion is common, may see lymphoblasts on cytology, can be chylous 1"PLN and organomegaly; 50% only one solitary node; clinical signs vary with disease extent; commonly depressed and lethargic Consistently bilateral disease, renomegaly, kidneys may be lumpy and irregular, PU/PD, 50% have renal insufficiency CS vary with spinal location, can include gradual or sudden posterior paresis/ paralysis, UMN bladder, progressive ataxia, flaccid tail
Only small percentage present as acute abdomen with GI perforation and peritonitis
IBD, adenocarcinoma, mast-cell tumor, hyperthyroidism, foreign body, FIP Thymoma, chylothorax, cardiomyopathy, pyothorax, FIP, mesothelioma, diaphragmatic hernia
PCNSL: intracranial Nasal
Seizures, circling, blindness, cranial nerve deficits, ataxia Nasal discharge, dyspnea, epistaxis, stertor, facial deformity, anorexia, epiphora, exophthalmus, sneezing
Typically multicentric
Cutaneous
Solitary or diffuse; alopecia, erythema, crusted papules; _+mild I" PLN Acute: severe anemia, episodes of fever, 1"spleen; Chronic: longer duration of CS with mild anemia, _+ 1"spleen
Usually have clinical signs for months
Mediastinal
Multicentric
Renal
PCNSL (primary CNS lymphoma): spinal cord
Leukemia
Less common: Homer's syndrome, head edema (cranial caval syndrome)
Reactive LN, FIV, infection Often part of multicentric disease, but subclinical Most lesions extradural and solitary; commonly bone marrow + & FeLV+
Often localized disease
PCKD, FIP, ARF, other renal tumors (ie, carcinoma, metastatic disease) Other spinal tumors, FIP, discospondylitis, IVDD, aortic emboli, trauma, non-neoplastic FeLV myelopathy Meningioma is primary neoplastic differential Rhinitis, polyps, cryptococcus, other tumors (sarcoma, SCC, ACA) Advanced lymphoma
Abbreviations: GI, gastrointestinal; IBD, inflammatory bowel disease; FIP, feline infectious peritonitis; PU, polyuria; PD, polydipsia; PCKD, polycystic kidney disease; ARF, acute renal failure; UMN, upper motor neuron; IVDD, intervertebral disc disease; SCC, squamous cell carcinoma; ACA, adenocarcinoma. PRINCIPLES OF TREATMENT FOR FELINE LYMPHOMA
99
Diagnostics and Staging
TABLE 3. Anatomic Staging System
Staging allows evaluation for extent of disease. It is based on physical examination, laboratory tests, imaging studies, and cytology of tissues and bone marrow. A minimum database should be performed, including a complete blood count with a platelet count, a chemistry panel, and a urinalysis. • Complete blood count: Anemia is common with alimentary lymphoma. Base-line neutropenias may affect chemotherapy , induction decisions. • Biochemical profile: Approximately one fourth of cats with the gastrointestinal form are hypoproteinemic. Monoclocal gammapathy is rare in cats. Azotemia was not prognostically significant in one study of cats with renal lymphoma. ~ Because lymphoma is an infiltrative process, functional recovery of the kidneys will occur if the disease is treated promptly. • Urinalysis: A urinalysis is especially important to determine specific gravity and evaluate renal function • FeLV and FIV Status • To make a diagnosis, lymph-node or organ biopsy is necessary. Unlike in the dog, lymph-node fine-needle aspirate in the cat alone is insufficient. Benign hyperplastic lymph nodes can be difficult to distinguish from lymphoma on cytology. Lymph-node excision should be performed to determine histologic grade. • Bone-marrow aspiration or biopsy should be included in the workup, especially if there is anemia, lymphocytosis, peripheral lymphocyte atypia, neutropenia, or thrombocytopenia. A normal complete blood count does not rule out bonemarrow involvement, although bone-marrow involvement is uncommon at initial presentation. However, more than 50% of spinal cord and CNS lymphomas have bone-marrow involvement. Advanced stages of lymphoma that involve the bone marrow can be indistinguishable from leukemia. • Thoracic radiographs are performed to evaluate for an anterior mediastinal mass, which can indicate thymic or mediastinal lymph-node involvement. Pleural effusion, pulmonary infiltrates, or other lymph nodal involvement can also be seen. • Abdominal radiographs confirm a mass in one third of cats with gastrointestinal lymphoma. Seventy to 90% have abnormal abdominal ultrasound studies, including mesenteric lymph-node
TABLE 2. The Clinical Staging System for Feline Lymphoma Stage 1. Single tumor (extranodal) or single anatomic site (nodal) Includes primary intrathoracic tumors 2. Single tumor (extranodal) with regional lymph nodes (LN) -> 2 nodes on same side of diaphragm 2 extranodal tumors _+ regional LN on same side of diaphragm resectable primary GI tumor _+ mesenteric LN 3.2 extranodal tumors +_ regional LN on opposite sides of diaphragm -> 2 nodes opposite sides of diaphragm extensive primary unresectable intrabdominal disease all paraspinal and epidural) tumors, regardless of other sites 4. Stage 1, 2, or 3 with spleen and/or liver 5. Stage 1, 2, 3, or 4 with initial CNS, bone marrow, or both Substage a No signs of systemic illness b Signs of systemic illness
100
Site Alimentary AMM CNS Multicentric Nasal Renal Substage a b
•
•
•
•
•
•
Gastrointestinal tract _+ lymph nodes Thymus or mediastinal lymph nodes Neural (brain or spinal) Multiple organs Nasal only Main lesion is kidneys No signs of systemic illness Signs of systemic illness
involvement, a distinct intestinal mass, diffusely thickened intestines, organomegaly (liver, spleen), or ascites. 6,x5 Ancillary tests include cytologic evaluation of anterior mediastinal mass aspirates and thoracic fluid. Thoracic ultrasound is an excellent imaging modality to confirm a mediastinal mass and for guided aspirates or biopsy. Fine-needle aspirate of thymoma, the primary differential for mediastinal lymphoma, contains small lymphocytes, often with mast cells. The use of endoscopic biopsies to confirm gastrointestinal lymphoma must be performed with caution. It is often difficult to distinguish lymphoma from inflammatory bowel disease, especially with partial thickness biopsies. Small sample size may inhibit the evaluation of the lymphoma cell in deeper intestinal layers. Complete thickness biopsies obtained at surgical exploratory are preferred. For spinal lymphoma, survey radiographs are rarely diagnostic. Extradural compression is observed in 75% of cases with a myelogram. Fluoroscopy-guided biopsy can confirm the diagnosis. Cerebrospinal fluid cytology is positive in less than one third of spinal cord cases and half of intracranial cases. Cerebrospinal fluid may contain lymphoblasts and hyperproteinemia. Computer tomography (CT) scan is helpful for nasal lymphoma to determine the extent of disease, especially for radiation therapy planning. Nasal biopsy or nasal bulb flush can confirm the diagnosis. These cats should be completely staged. For cutaneous lymphoma, the punch biopsy should be taken at the most representative and infiltrative area that is not infected. Cats with cutaneous lymphoma should be completely staged. No prognostic significance has been demonstrated with immunophenotype, AgNOR, Kc67, or histologic grade in cats.S,~4,t6
The clinical staging system was first described by Mooney et at. (Table 2). t7 In contrast to canine staging, the numerical system is confusing, and prognostic significance has not been consistently demonstrated. Alternatively, the anatomic staging system is easier to apply and use clinically (Table 3).
Treatment Chemotherapy Similar to the dog, lymphoma in the cat is a systemic disease, and chemotherapy is the treatment of choice for most forms. Exceptions are described below. In contrast to canine lymphoma, feline lymphoma is generally less rewarding to treat than canine lymphoma. Response rate is lower, and remission SUSAN N. ETTINGER
TABLE 4. Chemotherapy Protocols for Feline Lymphoma Author
Protocol
CR Rate (%)
Notes
Moore et a118and Moore and Ogilvie~
Doxorubicin-containing protocols (COP + doxorubicin +_ Elspar)
47%-54%
Kristal et al 2°
Single-agent doxorubicin
26-32%
Mooney et aF 1 and Jeglum et a126 Moore et al, 18 Cotter, 22 and Teske et a123 Rassnick et a124
COP + Elspar & MTX
52-62%
COP: (cyclophosphamide, vincristine, prednisone)
47-79%
Addition of doxorubicin is beneficial; 47% for COP induction; MRD for COP = 83 d vs MRD w/COP induction then doxorubicin = 281 d + Elspar: 54% CR Not effective in cats; cats less tolerant (high toxicity, including renal) to high dose (30 rag/M2); recommended dose: 1 mg/kg IV; cardiotoxicity not seen clinically MST = 7 mos21; MST = 7 weeks, median duration = 5 mos. 26 Well tolerated; 75% CR, MRD = 251 days
CCNU
Fondacaro et a113
MOPP
40-50% as rescue protocol
Prednisone only
50%
Prednisone and chlorambucil
69%
duration is shorter. Fortunately, cats treated with chemotherapy tend to have less gastrointestinal toxicity than dogs. The addition of doxorubicin to multiagent chemotherapy protocols has been demonstrated to significantly increase survival time. 14,18 In Moore's study, 38 cats were treated with cyclophosphamide, vincristine, and prednisolone (COP) induction, and the complete remission (CR) rate was 47%. Median remission duration (MRD) for cats treated with COP maintenance was 83 days, whereas the MRD with COP induction followed by single-agent doxorubicin was 281 days. is Length of chemotherapy protocol varies. The Madison-Wisconsin protocol is a 25-week protocol, is well-tolerated, and is a short, nonmaintenance protocol. 1 Other protocols include treatment for 1 to 2 years, typically at slightly lower doses. Unlike dogs, single-agent doxorubicin has not been shown to be efficacious and is not recommended. CR rates of 26% to 32% have been reported. 19,2° The COP protocol consists of cyclophosphamide, vincristine (Oncovin®), and oral prednisone. This protocol was originally described by Cotter. 22 The CR rate was 79%. In contrast, the COP induction described by Moore in 1996 only achieved a 47% CR. Recently, Teske et al. described a 75% CR with a MRD of 251 days. 23 Response was once again a significant positive
Recommended dose: 50-60 mg/m 2 every 6 weeks; neutropenia is dose-limiting toxicity; time of neutrophil nadir was variable (7-28 d) Use as induction protocol with doxorubicin being investigated Not generally effective alone; MDR not demonstrated in cat Oral protocol; for low-grade, welldifferentiated lymphoma; 69% CR, median ST = 17 mos.
prognostic factor; CR is necessary for long-term survival. In general, this protocol is well tolerated with minimal toxicity. Many feline protocols also include cytosine arabinoside (Cytosar®), an antimetabolite that can cross the blood-brain barrier. CCNU (Lomustine ®) has recently been shown to be effective. 2~ However, cats should be treated at a lower dose and less frequently than dogs. See Table 4 for protocol options. Radiation T h e r a p y Lymphoma cells are quite radiation sensitive, so radiation can be an effective treatment modality for localized forms of lymphoma, such as nasal, spinal, and intracranial, and refractory mediastinal lymphoma. Radiation therapy has not been critically evaluated as an adjunctive treatment to chemotherapy. Often, a smaller total dose is needed for tumor control compared with other tumors. 25 Radiation is most effective for nasal lymphoma. Response rates are high; 75% to 100% achieved CR. MRD is greater than 1.5 years for FeLV-negative cats. 1 Coarsely fractionated protocols (ie, weekly for 3 to 6 treatments) may be as effective as definitive protocols (daily for 16 treatments). Because FeLVpositive cats are at increased risk for developing systemic dis-
TABLE 5. Prognostic Factors for Feline Lymphoma Author
Prognostic Factor
Vail et aH4
Response
Mahony et aHs Vail et aP4
Clinical substage FeLV status
b FeLV-positive: significantly shorter ST
Shetton et al4
FIV
Moore et a 1 1 8
Doxorubicin-containing protocol Anatomic location Stage
5 times more likely to develop lymphoma, but no effect on ST Increased ST and remission durations
Mooney et alm
Positive CR
Negative
Notes
PR, no response
Prolonged remission duration and ST CR MST = 253 d; PR MST = 48 d; PD MST = 46 d Prognostic for response and ST No effect on ability to attain remission FELV - MST = 170 d vs. FELV + MST 37 d
Nasal
PRINCIPLES OF TREATMENT FOR FELINE LYMPHOMA
Advanced stages
Prolonged ST Numerical staging is difficult to apply clinically
101
ease, chemotherapy with or with adjunct radiation therapy is recommended, although there are few studies published. For FeLV-negative cats, we currently recommend multiagent chemotherapy in combination with radiation therapy, weekly for the first 6 weeks.
Surgery In general, feline lymphoma is systemic and thus best addressed with a systemic approach. Obviously, surgery is often used to obtain a diagnosis. Surgery is appropriate to relieve intestinal obstruction, but the effect of resection on survival time is not clear. Involvement of mesenteric lymph nodes and adhesions often makes resection difficult or impossible. However, without surgical resection, there is the risk that a solitary lesion can rupture after treated with chemotherapy.
6.
7.
8.
9. 10. 11. 12.
Supportive Care Supportive care is an essential part of the management of the feline patient with lymphoma. In particular, nutritional support must be addressed in inappetant cats. To meet the cat's nutritional requirements, feeding tubes, such as esophagostomy tubes or percutaneous endoscopic gastrostomy (PEG) tubes, should be placed. Alternatively, total parenteral nutrition can be used when the enteral route cannot be used. Although gastrointestinal toxicity is uncommon in cats, antinausea medications are helpful for inappetant cats.
Prognostic Factors Prognostic factors are summarized in Table 5. In conclusion, feline lymphoma is more challenging and frustrating than canine lymphoma to treat for the clinician. Positive prognostic factors are FeLV-negative, clinically well at time of diagnosis (substage a), and response to therapy. Achieving a complete remission is prognostic for survival. Unfortunately, response cannot be predicted before treatment.
13.
14.
15.
16.
17.
18.
19. 20.
21.
References 1. Vail DM, MacEwen EG: Feline lymphoma and leukemia, in Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology (ed 3). New York, Saunders, 2001, pp 590-611 2. Reinacher M: Diseases associated with spontaneous feline leukemia virus (FeLV) infection in cats. Vet Immunol Immunopathol 21:85-95, 1989 3. Reinacher M, Theilen G: Frequency and significance of feline leukemia virus infection in necropsied cats. Am J Vet Res 48:939-945, 1987 4. Shelton GH, Grant CK, Cotter SM, et al: Feline immunodeficiency virus and feline leukemia virus infections and their relationships to lymphoid malignancies in cats: A retrospective study (1968-1988). J Acquir Immune Defic Syndr 3:623-630, 1990 5. Moore AS, Ogilvie GK: Lymphoma, in Ogilvie GK, Moore AS (eds): Feline Oncology: A Comprehensive Guide to Compassionate Care.
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22.
23.
24.
25.
26.
Trenton, New Jersey, Veterinary Learning Systems, 2001, pp 191215 Zwahlen CH, Lucroy MD, Kraegel SA, et al: Results of chemotherapy for cats with alimentary malignant lymphoma: 21 cases (1993-1997). J Am Vet Med Assoc 213:1144-1149, 1998 Slawienski MJ, Mauldin GE, Mauldin GN, et al: Malignant colonic neoplasia in cats: 46 cases (1990-1996). J Am Vet Med Assoc 211:878-881, 1997 Gabor LJ, Canfield PJ, Malik R: Immunophenotypic and histological characterisation of 109 cases of feline lymphosarcoma. Aust Vet J 77:436-441, 1999 Court EA, Watson AD, Peaston AE: Retrospective study of 60 cases of feline lymphosarcoma. Aust Vet J Jun 75:424-427, 1997 Gabor LJ, Malik R, Canfield PJ: Clinical and anatomical features of lymphosarcoma in 118 cats. Aust Vet J 76:725-732, 1998 Mooney SC, Hayes AA, Matus RE, et al: Renal lymphoma in cats: 28 cases (1977-1984). J Am Vet Med Assoc 191:1473-1477, 1987 Valli VE, Jacobs RM, Norris A, et al: The histologic classification of 602 cases of feline lymphoproliferative disease using the National Cancer Institute working formulation. J Vet Diagn Invest 12:295-306, 2000 Fondacaro JV, Richter KP, Carpenter JL, et al: Feline gastrointestinal lymphoma: 67 cases (1988-1996). Eur J Comparative Gastroenterol 4:5-11, 1999 Vail DM, Moore AS, Ogilvie GK, et al: Feline lymphoma (145 cases): proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats. J Vet Intern Med 12:349-354, 1998 Mahony OM, Moore AS, Cotter SM, et al: Alimentary lymphoma in cats: 28 cases (1988-1993). J Am Vet Med Assoc 207:1593-1598, 1995 Rassnick KM, Mauldin GN, Moroff SD, et al: Prognostic value of argyrophilic nucleolar organizer region (AgNOR) staining in feline intestinal lymphoma. J Vet Intern Med 13:187-190, 1999 Mooney SC, Hayes AA: Lymphoma in the cat: An approach to diagnosis and management. Semin Vet Med Surg Small Anim 1:5157, 1986 Moore AS, Cotter SM, Frimberger AE, et al: A comparison of doxorubicin and COP for maintenance of remission in cats with lymphoma. J Vet Intern Med 10:372-375, 1996 Peaston AE, Maddison JE: Efficacy of doxorubicin as an induction agent for cats with lymphosarcoma. Aust Vet J 77:442-444, 1999 Kristal O, Lana SE, Ogilvie GK, et al: Single agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (1994-1997). J Vet Intern Med 15:125-130, 2001 Mooney SC, Hayes AA, MacEwen EG, et al: Treatment and prognostic factors in lymphoma in cats: 103 cases (1977-1981 ). J Am Vet Med Assoc 194:696-702, 1989 Cotter SM: Treatment of lymphoma and leukemia with cyclophosphamide, vincristine, and prednisone: II. Treatment of cats. J Am Anita Hosp 19:166-172, 1983 Teske E, van Straten G, van Noort R, et al: Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: New results with an old protocol. J Vet Intern Med 16:179-186, 2002 Rassnick KM, Gieger TL, Williams LE, et al: Phase I evaluation of CCNU (Iomustine) in tumor-bearing cats. J Vet Intern Med 15:196199, 2001 Turrel JM: Radiation therapy and hyperthermia, in Holzworth J (ed): Disease of the Cat. Medicine and Surgery. Philadelphia, PA, Saunders, 1987, p 606 Jeglum KA, Whereat A, Young K: Chemotherapy of lymphoma in 75 cats. J Am Vet Med Assoc 190:174-178, 1987
SUSAN N. ETTINGER
Lymphoma is the most commonly diagnosed neoplasm in cats. As feline leukemia virus antigenemia has decreased over the past 15 years, there has been a profound shift in the presence, signalment, and frequency of sites of feline lymphoma in North America. There is variation in anatomic classification systems, but most studies have divided lymphoma into four groups: alimentary, mediastinal, multicentric, or extranodal. Clinical signs and common differential diagnoses for each of the forms are described. Staging allows for evaluation of the extent of disease. As in the dog, lymphoma is a systemic disease in the cat, and chemotherapy is the treatment of choice for most forms. Exceptions are described, in contrast to canine lymphoma, feline lymphoma is generally more challenging and frustrating to treat than canine lymphoma. Response rates are lower, and remission duration is shorter. Fortunately, cats treated with chemotherapy tend to have less toxicity than dogs. Positive prognostic factors are feline leukemia virus-negative, clinically well at time of diagnosis, and response to therapy. Achieving a complete remission is prognostic for survival. Unfortunately, response cannot be predicted before treatment. © 2003 Elsevier Inc. All rights reserved.
Ymphoma is the most commonly diagnosed neoplasm in
L cats and accounts for 30% of all feline tumors. In general,
there is no gender predilection. Over the past 15 years, there has been a profound shift in the presence, signalment, and frequency of sites of feline lymphoma in North America. 1 In older studies, feline leukemia virus (FeLV)-positive lymphoma was the most common cause of hematopoietic tumors; 60% to 70% had FeLV antigenemia. The median age was 4 to 6 years, and the common forms were mediastinal and multicentric. Eighty to 95% of cats with the spinal cord form were FeLVpositive. However, as FeLV serologic testing and vaccinations have increased, the overall incidence of FeLV-positive lymphomas has decreased. Antigenemia is as low as 25%. Today alimentary lymphoma is more common, and generally affects older cats (10-12 years old). Still, cats with a negative serumantigen test can be found to be positive with more sensitive testing, such as polymerase chain reaction. Thus, it is plausible that FeLV is still involved in the tumorgenesis of lymphoma today. FeLV is a retrovirus, which consists of single-stranded RNA, core and envelope proteins, and reverse transcriptase. The virus is very fragile and easily killed. Transmission occurs via prolonged intimate contact, such as biting, licking, grooming, and
From the Animal Medical Center, New York, NY. Address reprint requests to Susan N. Ettinger, 510 East 62rid Street, New York, NY 10021. © 2003 Elsevier Inc. All rights reserved. 1096-2867/03/1802-0007530.00/0 doi:l 0.1053/svms.2003.36623 98
shared pans and bowls. FeLV infects lymphoid tissue, intestines, and bone marrow. The provirus integrates into the hostcell DNA. As an insertional mutagen, the virus alters cellular growth and may lead to neoplastic transformation. Approximately 25% of persistently infected cats develop lymphoma. 2,3 Latency is affected by age, viral subgroup, strain, and anatomic location. FeLV-positive cats are 60 times more likely to develop lymphoma. 4 Most cats will develop disease within 5 to 17 months of persistent viremia, and the lymphoma often has a T-cell phenotype. Feline immunodeficiency virus (FIV) is also a singlestranded RNA retrovirus. Despite homology between strains, there is significant difference in pathogenicity and infectivity. Transmission is predominantly through biting and cat fights, due to the high saliva concentration and low viral concentration in blood. FIV can increase the incidence but plays an indirect role in tumorgenesis of lymphoma. One study demonstrated a 5-fold increase of lymphoma in FIV-infected cats. 4 The virus is not oncogenic but is immunosuppressive. This impairs the ability of the immune system to remove cancer ceils. FIVpositive lymphoma is typically extranodal and in middle-aged cats. The immunophenotype of FIV-associated lymphoma varies. Coinfection with FeLV further potentiates the development of lymphoma. Siamese and Oriental breeds appear to be at higher risk for lymphoma, but this may reflect the higher risk of FeLV infection in catteries. Prevalence in catteries and multiple-cat households can be as high as 30%, in contrast to less than 1% in single-cat households.
Anatomic Forms There is variation in anatomic classification systems, but most studies have divided lymphoma into four groups. 5 • Alimentary: The alimentary form typically involves the gastrointestinal tract, lymph nodes, and sometimes liver. FeLV antigenemia is low. The neoplastic population is often derived from B-lymphocytes in gut-associated lymphoid tissue. However, one study reported the majority of 21 alimentary cases were T-cell. 6 Lesions can be solitary or diffuse. Annular thickening may cause a partial or complete obstruction. In descending order, the most common sites are small intestine, stomach, and the ileocecal junction and colon. One study has demonstrated that colonic adenocarcinoma was slightly more common than colonic lymphoma, r • Mediastinal or thoracic: The mediastinal form includes thymus and mediastinal and sternal lymph nodes, which can extend out of the thoracic inlet. Mediastinal lymphomas are more commonly T-cell in origin, s but unlike the dog, hypercalcemia is rare. Affected cats are usually young and FeLVpositive .9
Clinical Techniques in Small Animal Practice, Vol 18, No 2 (May), 2003: pp 98-102
• Multicentric: In contrast to dogs, peripheral lymph-node (PLN) involvement alone is rare in cats. More commonly, there is also splenic and/or hepatic involvement, and the disease may progress to the bone marrow. In general, only one third of lymphomas are T-cell and carry FeLV-positivity. An important differential for peripheral lymphadenomegaly is distinctive peripheral lymph-node hyperplasia. Distinctive peripheral lymph-node hyperplasia is a non-neoplastic disorder of young cats and is associated with episodes of fever, previous viral infections, and a polyclonal gammopathy. A rare distinct form of lymphoma has been reported that involves only solitary or regional head and neck lymph nodes.l° This form may be comparable to human Hodgkin's lymphoma. • E x t r a n o d a l or Unclassified
Renal: Renal lymphoma can be primary or associated with gastrointestinal or multicentric involvement. Twenty to 50% of these animals will be FekV-positive. At time of relapse, extension into the central nervous system (CNS) is commonly observed.11 Some authors classify renal lymphoma in the alimentary group; some consider it a separate form, and some group abdominal lymphoma as one group, s Primary CNS lymphoma: CNS lymphoma may be primary or secondary to multicentric disease, especially if there is renal or bone-marrow disease. Meningioma is the most common brain neoplasm in catsand is therefore a differential for intracranial disease. Spinal cord lymphoma lesions are typically extradural, and cats present for hindlimb paresis. Affected cats are young (mean age 3-4 years) and FekV-positive (85-90%).9,17 Nasal: Nasal lymphoma is usually localized in FeLV-negarive, older cats (8-9 years). Histologically, the cells are interme-
diate to high grade. Immunophenotype is consistent with Bcell. FeLV-positive cats tend to have systemic involvement. Cutaneous: Similar to dogs, cutaneous lymphoma can be solitary or generalized and occurs in FeLV-negative, older cats. Two forms have been described. Epitheliotrophic consists of T-cells in intraepidermal nests of 5 to 10 cells. The second form consists of nonepitheliotrophic B-cells that are seen deeper in the epidermis.
Histologic Classifications Similar to dogs, the majority of feline lymphomas are intermediate to high grade (88.5-90%). 8,12 High-grade lymphoma is generally seen in younger cats (less than 6 years). In contrast, low grade, well-differentiated lymphoma occurs in older cats in the gastrointestinal tract. Commonly diagnosed diffusely in the small-intestinal tract, the neoplastic population arises in the superficial layers and invades into underlying layers. There is some discussion that this represents malignant transformation of the lymphocytic-plasmacytic cells of inflammatory bowel disease. 13 Immunophenotype is not predictive for outcome in cats.14 In one study of 145 cats, B-cell lymphoma was the predominant immunophenotype, especially in the gastrointestinal tract. An Australian study confirms that gastrointestinal lymphoma was the most common form, and the majority of gastrointestinal cases were B-cell of intermediate or high grade. 8
History and Clinical Signs Clinical signs and common differential diagnoses are described in Table 1.
TABLE 1. History and Clinical Signs Anatomic Form
History and Clinical signs (CS)
Notes
Differential Diagnoses
GI
Weight loss, anorexia, vomiting, diarrhea; -+abdominal distension, 1"spleen, $ platelets, pica; 70-85% have abdominal mass or thickened GI loops Dyspnea, tachypnea, dysphagia, noncompressible cranial thorax, dull heart and/or lung sounds; pleural effusion is common, may see lymphoblasts on cytology, can be chylous 1"PLN and organomegaly; 50% only one solitary node; clinical signs vary with disease extent; commonly depressed and lethargic Consistently bilateral disease, renomegaly, kidneys may be lumpy and irregular, PU/PD, 50% have renal insufficiency CS vary with spinal location, can include gradual or sudden posterior paresis/ paralysis, UMN bladder, progressive ataxia, flaccid tail
Only small percentage present as acute abdomen with GI perforation and peritonitis
IBD, adenocarcinoma, mast-cell tumor, hyperthyroidism, foreign body, FIP Thymoma, chylothorax, cardiomyopathy, pyothorax, FIP, mesothelioma, diaphragmatic hernia
PCNSL: intracranial Nasal
Seizures, circling, blindness, cranial nerve deficits, ataxia Nasal discharge, dyspnea, epistaxis, stertor, facial deformity, anorexia, epiphora, exophthalmus, sneezing
Typically multicentric
Cutaneous
Solitary or diffuse; alopecia, erythema, crusted papules; _+mild I" PLN Acute: severe anemia, episodes of fever, 1"spleen; Chronic: longer duration of CS with mild anemia, _+ 1"spleen
Usually have clinical signs for months
Mediastinal
Multicentric
Renal
PCNSL (primary CNS lymphoma): spinal cord
Leukemia
Less common: Homer's syndrome, head edema (cranial caval syndrome)
Reactive LN, FIV, infection Often part of multicentric disease, but subclinical Most lesions extradural and solitary; commonly bone marrow + & FeLV+
Often localized disease
PCKD, FIP, ARF, other renal tumors (ie, carcinoma, metastatic disease) Other spinal tumors, FIP, discospondylitis, IVDD, aortic emboli, trauma, non-neoplastic FeLV myelopathy Meningioma is primary neoplastic differential Rhinitis, polyps, cryptococcus, other tumors (sarcoma, SCC, ACA) Advanced lymphoma
Abbreviations: GI, gastrointestinal; IBD, inflammatory bowel disease; FIP, feline infectious peritonitis; PU, polyuria; PD, polydipsia; PCKD, polycystic kidney disease; ARF, acute renal failure; UMN, upper motor neuron; IVDD, intervertebral disc disease; SCC, squamous cell carcinoma; ACA, adenocarcinoma. PRINCIPLES OF TREATMENT FOR FELINE LYMPHOMA
99
Diagnostics and Staging
TABLE 3. Anatomic Staging System
Staging allows evaluation for extent of disease. It is based on physical examination, laboratory tests, imaging studies, and cytology of tissues and bone marrow. A minimum database should be performed, including a complete blood count with a platelet count, a chemistry panel, and a urinalysis. • Complete blood count: Anemia is common with alimentary lymphoma. Base-line neutropenias may affect chemotherapy , induction decisions. • Biochemical profile: Approximately one fourth of cats with the gastrointestinal form are hypoproteinemic. Monoclocal gammapathy is rare in cats. Azotemia was not prognostically significant in one study of cats with renal lymphoma. ~ Because lymphoma is an infiltrative process, functional recovery of the kidneys will occur if the disease is treated promptly. • Urinalysis: A urinalysis is especially important to determine specific gravity and evaluate renal function • FeLV and FIV Status • To make a diagnosis, lymph-node or organ biopsy is necessary. Unlike in the dog, lymph-node fine-needle aspirate in the cat alone is insufficient. Benign hyperplastic lymph nodes can be difficult to distinguish from lymphoma on cytology. Lymph-node excision should be performed to determine histologic grade. • Bone-marrow aspiration or biopsy should be included in the workup, especially if there is anemia, lymphocytosis, peripheral lymphocyte atypia, neutropenia, or thrombocytopenia. A normal complete blood count does not rule out bonemarrow involvement, although bone-marrow involvement is uncommon at initial presentation. However, more than 50% of spinal cord and CNS lymphomas have bone-marrow involvement. Advanced stages of lymphoma that involve the bone marrow can be indistinguishable from leukemia. • Thoracic radiographs are performed to evaluate for an anterior mediastinal mass, which can indicate thymic or mediastinal lymph-node involvement. Pleural effusion, pulmonary infiltrates, or other lymph nodal involvement can also be seen. • Abdominal radiographs confirm a mass in one third of cats with gastrointestinal lymphoma. Seventy to 90% have abnormal abdominal ultrasound studies, including mesenteric lymph-node
TABLE 2. The Clinical Staging System for Feline Lymphoma Stage 1. Single tumor (extranodal) or single anatomic site (nodal) Includes primary intrathoracic tumors 2. Single tumor (extranodal) with regional lymph nodes (LN) -> 2 nodes on same side of diaphragm 2 extranodal tumors _+ regional LN on same side of diaphragm resectable primary GI tumor _+ mesenteric LN 3.2 extranodal tumors +_ regional LN on opposite sides of diaphragm -> 2 nodes opposite sides of diaphragm extensive primary unresectable intrabdominal disease all paraspinal and epidural) tumors, regardless of other sites 4. Stage 1, 2, or 3 with spleen and/or liver 5. Stage 1, 2, 3, or 4 with initial CNS, bone marrow, or both Substage a No signs of systemic illness b Signs of systemic illness
100
Site Alimentary AMM CNS Multicentric Nasal Renal Substage a b
•
•
•
•
•
•
Gastrointestinal tract _+ lymph nodes Thymus or mediastinal lymph nodes Neural (brain or spinal) Multiple organs Nasal only Main lesion is kidneys No signs of systemic illness Signs of systemic illness
involvement, a distinct intestinal mass, diffusely thickened intestines, organomegaly (liver, spleen), or ascites. 6,x5 Ancillary tests include cytologic evaluation of anterior mediastinal mass aspirates and thoracic fluid. Thoracic ultrasound is an excellent imaging modality to confirm a mediastinal mass and for guided aspirates or biopsy. Fine-needle aspirate of thymoma, the primary differential for mediastinal lymphoma, contains small lymphocytes, often with mast cells. The use of endoscopic biopsies to confirm gastrointestinal lymphoma must be performed with caution. It is often difficult to distinguish lymphoma from inflammatory bowel disease, especially with partial thickness biopsies. Small sample size may inhibit the evaluation of the lymphoma cell in deeper intestinal layers. Complete thickness biopsies obtained at surgical exploratory are preferred. For spinal lymphoma, survey radiographs are rarely diagnostic. Extradural compression is observed in 75% of cases with a myelogram. Fluoroscopy-guided biopsy can confirm the diagnosis. Cerebrospinal fluid cytology is positive in less than one third of spinal cord cases and half of intracranial cases. Cerebrospinal fluid may contain lymphoblasts and hyperproteinemia. Computer tomography (CT) scan is helpful for nasal lymphoma to determine the extent of disease, especially for radiation therapy planning. Nasal biopsy or nasal bulb flush can confirm the diagnosis. These cats should be completely staged. For cutaneous lymphoma, the punch biopsy should be taken at the most representative and infiltrative area that is not infected. Cats with cutaneous lymphoma should be completely staged. No prognostic significance has been demonstrated with immunophenotype, AgNOR, Kc67, or histologic grade in cats.S,~4,t6
The clinical staging system was first described by Mooney et at. (Table 2). t7 In contrast to canine staging, the numerical system is confusing, and prognostic significance has not been consistently demonstrated. Alternatively, the anatomic staging system is easier to apply and use clinically (Table 3).
Treatment Chemotherapy Similar to the dog, lymphoma in the cat is a systemic disease, and chemotherapy is the treatment of choice for most forms. Exceptions are described below. In contrast to canine lymphoma, feline lymphoma is generally less rewarding to treat than canine lymphoma. Response rate is lower, and remission SUSAN N. ETTINGER
TABLE 4. Chemotherapy Protocols for Feline Lymphoma Author
Protocol
CR Rate (%)
Notes
Moore et a118and Moore and Ogilvie~
Doxorubicin-containing protocols (COP + doxorubicin +_ Elspar)
47%-54%
Kristal et al 2°
Single-agent doxorubicin
26-32%
Mooney et aF 1 and Jeglum et a126 Moore et al, 18 Cotter, 22 and Teske et a123 Rassnick et a124
COP + Elspar & MTX
52-62%
COP: (cyclophosphamide, vincristine, prednisone)
47-79%
Addition of doxorubicin is beneficial; 47% for COP induction; MRD for COP = 83 d vs MRD w/COP induction then doxorubicin = 281 d + Elspar: 54% CR Not effective in cats; cats less tolerant (high toxicity, including renal) to high dose (30 rag/M2); recommended dose: 1 mg/kg IV; cardiotoxicity not seen clinically MST = 7 mos21; MST = 7 weeks, median duration = 5 mos. 26 Well tolerated; 75% CR, MRD = 251 days
CCNU
Fondacaro et a113
MOPP
40-50% as rescue protocol
Prednisone only
50%
Prednisone and chlorambucil
69%
duration is shorter. Fortunately, cats treated with chemotherapy tend to have less gastrointestinal toxicity than dogs. The addition of doxorubicin to multiagent chemotherapy protocols has been demonstrated to significantly increase survival time. 14,18 In Moore's study, 38 cats were treated with cyclophosphamide, vincristine, and prednisolone (COP) induction, and the complete remission (CR) rate was 47%. Median remission duration (MRD) for cats treated with COP maintenance was 83 days, whereas the MRD with COP induction followed by single-agent doxorubicin was 281 days. is Length of chemotherapy protocol varies. The Madison-Wisconsin protocol is a 25-week protocol, is well-tolerated, and is a short, nonmaintenance protocol. 1 Other protocols include treatment for 1 to 2 years, typically at slightly lower doses. Unlike dogs, single-agent doxorubicin has not been shown to be efficacious and is not recommended. CR rates of 26% to 32% have been reported. 19,2° The COP protocol consists of cyclophosphamide, vincristine (Oncovin®), and oral prednisone. This protocol was originally described by Cotter. 22 The CR rate was 79%. In contrast, the COP induction described by Moore in 1996 only achieved a 47% CR. Recently, Teske et al. described a 75% CR with a MRD of 251 days. 23 Response was once again a significant positive
Recommended dose: 50-60 mg/m 2 every 6 weeks; neutropenia is dose-limiting toxicity; time of neutrophil nadir was variable (7-28 d) Use as induction protocol with doxorubicin being investigated Not generally effective alone; MDR not demonstrated in cat Oral protocol; for low-grade, welldifferentiated lymphoma; 69% CR, median ST = 17 mos.
prognostic factor; CR is necessary for long-term survival. In general, this protocol is well tolerated with minimal toxicity. Many feline protocols also include cytosine arabinoside (Cytosar®), an antimetabolite that can cross the blood-brain barrier. CCNU (Lomustine ®) has recently been shown to be effective. 2~ However, cats should be treated at a lower dose and less frequently than dogs. See Table 4 for protocol options. Radiation T h e r a p y Lymphoma cells are quite radiation sensitive, so radiation can be an effective treatment modality for localized forms of lymphoma, such as nasal, spinal, and intracranial, and refractory mediastinal lymphoma. Radiation therapy has not been critically evaluated as an adjunctive treatment to chemotherapy. Often, a smaller total dose is needed for tumor control compared with other tumors. 25 Radiation is most effective for nasal lymphoma. Response rates are high; 75% to 100% achieved CR. MRD is greater than 1.5 years for FeLV-negative cats. 1 Coarsely fractionated protocols (ie, weekly for 3 to 6 treatments) may be as effective as definitive protocols (daily for 16 treatments). Because FeLVpositive cats are at increased risk for developing systemic dis-
TABLE 5. Prognostic Factors for Feline Lymphoma Author
Prognostic Factor
Vail et aH4
Response
Mahony et aHs Vail et aP4
Clinical substage FeLV status
b FeLV-positive: significantly shorter ST
Shetton et al4
FIV
Moore et a 1 1 8
Doxorubicin-containing protocol Anatomic location Stage
5 times more likely to develop lymphoma, but no effect on ST Increased ST and remission durations
Mooney et alm
Positive CR
Negative
Notes
PR, no response
Prolonged remission duration and ST CR MST = 253 d; PR MST = 48 d; PD MST = 46 d Prognostic for response and ST No effect on ability to attain remission FELV - MST = 170 d vs. FELV + MST 37 d
Nasal
PRINCIPLES OF TREATMENT FOR FELINE LYMPHOMA
Advanced stages
Prolonged ST Numerical staging is difficult to apply clinically
101
ease, chemotherapy with or with adjunct radiation therapy is recommended, although there are few studies published. For FeLV-negative cats, we currently recommend multiagent chemotherapy in combination with radiation therapy, weekly for the first 6 weeks.
Surgery In general, feline lymphoma is systemic and thus best addressed with a systemic approach. Obviously, surgery is often used to obtain a diagnosis. Surgery is appropriate to relieve intestinal obstruction, but the effect of resection on survival time is not clear. Involvement of mesenteric lymph nodes and adhesions often makes resection difficult or impossible. However, without surgical resection, there is the risk that a solitary lesion can rupture after treated with chemotherapy.
6.
7.
8.
9. 10. 11. 12.
Supportive Care Supportive care is an essential part of the management of the feline patient with lymphoma. In particular, nutritional support must be addressed in inappetant cats. To meet the cat's nutritional requirements, feeding tubes, such as esophagostomy tubes or percutaneous endoscopic gastrostomy (PEG) tubes, should be placed. Alternatively, total parenteral nutrition can be used when the enteral route cannot be used. Although gastrointestinal toxicity is uncommon in cats, antinausea medications are helpful for inappetant cats.
Prognostic Factors Prognostic factors are summarized in Table 5. In conclusion, feline lymphoma is more challenging and frustrating than canine lymphoma to treat for the clinician. Positive prognostic factors are FeLV-negative, clinically well at time of diagnosis (substage a), and response to therapy. Achieving a complete remission is prognostic for survival. Unfortunately, response cannot be predicted before treatment.
13.
14.
15.
16.
17.
18.
19. 20.
21.
References 1. Vail DM, MacEwen EG: Feline lymphoma and leukemia, in Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology (ed 3). New York, Saunders, 2001, pp 590-611 2. Reinacher M: Diseases associated with spontaneous feline leukemia virus (FeLV) infection in cats. Vet Immunol Immunopathol 21:85-95, 1989 3. Reinacher M, Theilen G: Frequency and significance of feline leukemia virus infection in necropsied cats. Am J Vet Res 48:939-945, 1987 4. Shelton GH, Grant CK, Cotter SM, et al: Feline immunodeficiency virus and feline leukemia virus infections and their relationships to lymphoid malignancies in cats: A retrospective study (1968-1988). J Acquir Immune Defic Syndr 3:623-630, 1990 5. Moore AS, Ogilvie GK: Lymphoma, in Ogilvie GK, Moore AS (eds): Feline Oncology: A Comprehensive Guide to Compassionate Care.
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23.
24.
25.
26.
Trenton, New Jersey, Veterinary Learning Systems, 2001, pp 191215 Zwahlen CH, Lucroy MD, Kraegel SA, et al: Results of chemotherapy for cats with alimentary malignant lymphoma: 21 cases (1993-1997). J Am Vet Med Assoc 213:1144-1149, 1998 Slawienski MJ, Mauldin GE, Mauldin GN, et al: Malignant colonic neoplasia in cats: 46 cases (1990-1996). J Am Vet Med Assoc 211:878-881, 1997 Gabor LJ, Canfield PJ, Malik R: Immunophenotypic and histological characterisation of 109 cases of feline lymphosarcoma. Aust Vet J 77:436-441, 1999 Court EA, Watson AD, Peaston AE: Retrospective study of 60 cases of feline lymphosarcoma. Aust Vet J Jun 75:424-427, 1997 Gabor LJ, Malik R, Canfield PJ: Clinical and anatomical features of lymphosarcoma in 118 cats. Aust Vet J 76:725-732, 1998 Mooney SC, Hayes AA, Matus RE, et al: Renal lymphoma in cats: 28 cases (1977-1984). J Am Vet Med Assoc 191:1473-1477, 1987 Valli VE, Jacobs RM, Norris A, et al: The histologic classification of 602 cases of feline lymphoproliferative disease using the National Cancer Institute working formulation. J Vet Diagn Invest 12:295-306, 2000 Fondacaro JV, Richter KP, Carpenter JL, et al: Feline gastrointestinal lymphoma: 67 cases (1988-1996). Eur J Comparative Gastroenterol 4:5-11, 1999 Vail DM, Moore AS, Ogilvie GK, et al: Feline lymphoma (145 cases): proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats. J Vet Intern Med 12:349-354, 1998 Mahony OM, Moore AS, Cotter SM, et al: Alimentary lymphoma in cats: 28 cases (1988-1993). J Am Vet Med Assoc 207:1593-1598, 1995 Rassnick KM, Mauldin GN, Moroff SD, et al: Prognostic value of argyrophilic nucleolar organizer region (AgNOR) staining in feline intestinal lymphoma. J Vet Intern Med 13:187-190, 1999 Mooney SC, Hayes AA: Lymphoma in the cat: An approach to diagnosis and management. Semin Vet Med Surg Small Anim 1:5157, 1986 Moore AS, Cotter SM, Frimberger AE, et al: A comparison of doxorubicin and COP for maintenance of remission in cats with lymphoma. J Vet Intern Med 10:372-375, 1996 Peaston AE, Maddison JE: Efficacy of doxorubicin as an induction agent for cats with lymphosarcoma. Aust Vet J 77:442-444, 1999 Kristal O, Lana SE, Ogilvie GK, et al: Single agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19 cases (1994-1997). J Vet Intern Med 15:125-130, 2001 Mooney SC, Hayes AA, MacEwen EG, et al: Treatment and prognostic factors in lymphoma in cats: 103 cases (1977-1981 ). J Am Vet Med Assoc 194:696-702, 1989 Cotter SM: Treatment of lymphoma and leukemia with cyclophosphamide, vincristine, and prednisone: II. Treatment of cats. J Am Anita Hosp 19:166-172, 1983 Teske E, van Straten G, van Noort R, et al: Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: New results with an old protocol. J Vet Intern Med 16:179-186, 2002 Rassnick KM, Gieger TL, Williams LE, et al: Phase I evaluation of CCNU (Iomustine) in tumor-bearing cats. J Vet Intern Med 15:196199, 2001 Turrel JM: Radiation therapy and hyperthermia, in Holzworth J (ed): Disease of the Cat. Medicine and Surgery. Philadelphia, PA, Saunders, 1987, p 606 Jeglum KA, Whereat A, Young K: Chemotherapy of lymphoma in 75 cats. J Am Vet Med Assoc 190:174-178, 1987
SUSAN N. ETTINGER