CASE REPORTS

Acute Tumor Lysis Syndrome in a Cat With Lymphoma Cathryn M. Calia, Ann E. Hohenhaus, Philip R. Fox, and Karri A. Meleo

young adult, female, feline leukemia virus-positive, A Domestic Short Hair cat was treated for advanced (stage Vb) lymphoma. Response to induction chemotherapy (L-asparaginase IP, prednisone PO) was poor, and adjunctive radiation therapy was provided. Approximately 7 hours after radiation therapy and 55 hours after chemotherapy, acute tumor lysis syndrome was detected. Associated clinicopatho- logic changes included hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, azotemia, and acidosis. Diag- nostic and therapeutic considerations of acute tumor lysis syndrome (TLS) are discussed.

Case Report A 2-kg, 2-year-old female Domestic Short Hair cat who had tested

positive for feline leukemia virus 1 year prior to presentation was referred for a 6-week history of progressive anorexia and lethargy. The referring veterinarian had diagnosed pleural effusion and a cra- nial mediastinal mass from survey thoracic radiographs, and was treating the cat with amoxicillin (37.5 mg PO bid), prednisolone (2.5 mg PO bid), furosemide (6.25 mg PO bid), and a vitamin- mineral supplement (1.0 mL PO bid) (Lixotinic; SmithKline Beecham, West Chester PA).

Salient physical examination findings included cachexia, de- creased cranial thoracic compressibility, and axillary lymphadenopa- thy. Hydration was judged to be normal on the basis of normal skin turgor and moist mucous membranes. Clinicopathologic abnormali- ties included severe leukocytosis with a left shift and circulating lymphoblasts; azotemia; and mild hyperphosphatemia, hypona- tremia, and hyperchloremia (Tables 1 and 2, day 1). A pretreatment urinalysis could not be obtained. Diagnosis of stage Vb' lymphoma was made based on cytological evaluation of bone marrow aspiration and fine needle aspiration of the cranial mediastinal mass. Mainte- nance volume of lactated Ringer's solution with 2.5% dextrose was administered over 24 hours before and for 48 hours after initial antineoplastic therapy.

Induction chemotherapy was begun with an IP injection of L-

asparaginase (400 mgikg) and prednisone (5 mg PO bid). Serum sodium concentration had normalized by day 4 (Table 3), but the cat had become progressively weaker, more depressed, and tachypneic. Because of the poor response to chemotherapy by day 4 of hospital- ization, we decided to institute radiation therapy. The cat underwent general anesthesia for 15 minutes, using a mask delivering 2% isoflurane. No additional sedatives, tranquilizers, or preanesthetics were administered. Radiation was administered to the cranial medi- astinal mass using cobalt 60 teletherapy (Theratronics 780; Atomic Energy of Canada, Ltd Kanata, Canada); 2 equally weighted, parallel opposed fields were used to deliver a total dose of 800 cGy to the midplane of the cranial mediastinum.

Approximately 7 hours after radiation therapy (55 hours after L-

asparaginase administration), the cat became moribund with agonal respirations. Body temperature decreased to 35.5"C, severe bradycar- dia was detected (heart rate, 60 beats per minute), PCV decreased to 18%. and the blood glucose concentration (Chemstrip bG; Boeh- ringer Manneheim Corp, Indianapolis, IN) was 180 mg/dL. A lead I1 EKG revealed lack of P-waves and tall, peaked T-waves consistent with atrial standstill, at a rate of 60 beats per minute. Paroxysmal, wide QRS complex tachycardia also was recorded. Analysis of ve- nous blood gases and electrolytes revealed metabolic acidosis, severe hyponatremia and hyperkalemia, and hypocalcemia (Table 3; day 5,

12: 15 AM). To counter life-threatening hyperkalemia and related cardiac arrhythmia, 1U of regular insulin, lg of dextrose, and 3 mEq of sodium bicarbonate were administered IV. One hundred milliliters of 0.9% saline containing 2.5% dextrose and 3 mEq sodium bicar- bonate was infused IV over the next hour. The anemia was treated by transfusing 70 mL of feline type A whole blood through a second IV catheter. The normal saline plus 2.5% dextrose infusion was continued.

Shortly thereafter, the hyponatremia had resolved and the serum potassium concentration had decreased, but the acidemia had worsened slightly (Table 3; day 5, 1:15 AM). Although the PCV increased to 27%, the cat continued to be depressed and anorectic. Supportive care, including fluid therapy and antibiotics, was contin- ued. Subsequent analyses of venous blood gases and electrolytes over the next 8 hours showed that the hyperkalemia had resolved and the acidemia had improved (Table 3; day 5,4:00 and 9:30 AM). Urination was observed and volumes appeared empirically adequate, although urine output was not measured

On the 5th day of hospitalization, pertinent clinicopathologic changes included mature neutrophilia, resolution of lymphoblastosis, persistent azotemia, and persistent normokalemia (Tables 1 and 2, 9:OO AM); increased serum phosphorus, sodium, and total bilirubin concentrations; and decreased total COz concentration compared with day 1 (Table 2). Uric acid concentration was markedly increased to 1.5 mgldL (reference range, 0. I to 0.6 mgldL) (Calia CM, Hohen- haus AE, unpublished data, 1995).

By day 7 of hospitalization, the cat was eating voluntarily and was relatively active; the azotemia had improved and the hyperphos- phatemia was resolved (Table 2). Repeat survey thoracic radiographs showed that the cranial mediastinal mass was markedly smaller com- pared with the initial radiographic appearance. The cat was dis- charged on prednisone and amoxicillin (to avoid catheter-induced or other infection resulting from immunosuppression and procedures performed during the hospital stay). The cat was also placed on a PO potassium supplement (Tumil-K; Daniels Pharmaceuticals, Inc, St. Petersburg, FL) because the serum potassium concentration was low on day 7 (Table 2), despite supplementation of the IV fluids with potassium chloride.

During follow-up examinations, combination chemotherapy was administered at regular intervals. However, 32 days after initial pre- sentation, the cat developed weakness, anorexia, and dehydration, and the owner elected euthanasia.

Discussion This case illustrates clinical and clinicopathologic changes

consistent with acute TLS. After tumor lysis, neoplastic cells release large amounts of intracellular purines, phosphorus,

From the Department of Medicine at The Animal Medical Center,

Accepted February 19, 1996. All procedures were performed (it the Bobst Hospital of The Ani-

mal Medical Center, New York, NY. Reprint requests: Ann E. Hohenhaus, DVM, Department of Medi-

cine, The Animal Medical Center, 510 East 62nd St, New York, NY 10021.

Copyright 0 1996 by the American College of Veterinary Internal Medicine

0891-6640/96/1006-0011$3.00/0

New York, NY.

Journal of Veterinary Internal Medicine, Vol 10, No 6 (November-December), 1996: pp 40941 1 409

410 CALIA ET AL

Table 1. Results of CBCs Before and After the Development of Acute Tumor Lysis Syndrome in a Cat

Day 5 Normal Range Day 1 9:00 AM

WSCipL RBC (millions/pL) Hemoglobin (g/dL) Hematocrit (%) MCV (fL) MCH (pg) MCHC (g/dL) Monocytes/pL Lymph ocyteslp L Neut ro ph i Is/pL Band neutrophils/pl Metamyelocytes/pL Myelocytes/pL Eosinophils/pL Basophils/pL Atypical lymphocytes/pL

7,000-15,000 6.0-10.0 8.0-15.01

25.0-38.0 39.0-50.0 13.0-18.0 30.0-38.0

70-600 1,400-6,000 3,500-11,250

0-450 0 0

0-150 0

160-1,400

82,300 5.76 10.2 29.8 51.8 17.7 34.2

0 32,097 46,911

1,646 0 0

1,646 0

25,513*

43,900 6.12

9.1 28.1 45.9 14.9 32.4

1.756 2,634

39,510 0 0 0 0 0 0

* Lymphoblasts (included in total lymphocyte count).

uric acid, potassium, and lactate.2 Tumor lysis syndrome results from metabolic derangements associated with hyper- phosphatemia, hyperkalemia, hyperuricemia, and acidosis that occur after antineoplastic therapy. Although not reported in cats, TLS has been described in both humans and dogs with lymphoma.'-' In humans, TLS occurs most commonly in patients with aggressive hematopoietic malignancies, but can occur in association with solid tumor^.^ Associated risk factors include rapid cytoreduction of a large tumor burden, high tumor growth fraction, high serum lactate dehydroge- nase activity, and pretreatment renal insufficiency.'

The onset of signs after antineoplastic therapy is variable. In a report of 3 affected dogs, 1 developed TLS 8 days after chemotherapy, and 2 developed TLS 2 hours and 5 days after a second treatment of half body irradiation.5 Death ensued in all 3 dogs within 6 to 18 hours after the appearance of clinical signs. In this cat, clinical signs of TLS appeared 55 hours after induction of chemotherapy and 7 hours after radiation therapy.

Several factors may have predisposed this cat to TLS. Renal insufficiency was suggested by azotemia and hyper- phosphatemia in the presence of normal hydration, although a pretreatment urinalysis was unavailable. Pre-existing renal insufficiency and decreased glomerular filtration rate may reduce potassium and phosphorous excretion. The adminis- tration of general anesthesia during radiation therapy may have contributed to decreased renal function by hypotension and subsequent renal hypoxia. The large tumor burden and rapid cell kill after chemotherapy and radiation therapy may have overwhelmed hepatic capacity to metabolize tumor cell breakdown products and their associated renal excretion. Since hepatic transaminase activities were normal in this cat, no tests of hepatic function were performed. Undetected hepatic dysfunction could have been present from neoplastic infiltrate or subclinical hepatopathy, such as hepatic lipidosis secondary to prolonged anorexia.6

Hyperphosphatemia in TLS results from release of intra-

cellular adenosine triphosphate and nucleic acids on lysis of malignant tumor cells. These contain approximately 4 times the concentration of phosphorus present in normal cells. Pre- existing renal insufficiency and high intracellular concentra- tions of phosphorus predispose patients undergoing rapid cytolysis to hyperphosphatemia. Dogs with lymphoma and low tumor burden may effectively excrete a twofold to three- fold higher phosphorous load after ~hemotherapy.~ The cat in this report presented with mild hyperphosphatemia and azotemia, and had a large tumor burden. The hyperphospha- temia worsened markedly during the episode of TLS, despite improvement in serum creatinine and blood urea nitrogen concentrations.

Hypocalcemia has been reported in humans and dogs with TLS.'.' It results from hyperphosphatemia being affected by the law of mass action. Hypocalcemia was documented dur- ing the acute episode of TLS in this cat.

Hyperuricemia was also documented in this cat. In rapidly dividing tumor cells, high intracellular concentrations of pu- rine nucleotides can result in excessive uric acid production. Cats are thought to metabolize uric acid similarly to dogs.' In the latter, 2 mechanisms of uric acid metabolism are de- scribed. Most breeds oxidize uric acid to allantoin in the liver via the enzyme uricase; they also can excrete uric acid unchanged in the urine. Certain breeds (eg, Dalmatians) lack uricase, theoretically making them more susceptible to hy- peruricemia." Hyperuricemia with normal fractional excre- tion of uric acid has been reported before Chemotherapy in dogs with l y m p h ~ m a . ~ These values remain virtually un- changed after treatment, and never reach the concentrations reported to be associated with acute uric acid nephropathy in humans (>20 mg/dL). Renal excretion of uric acid was normal in affected dogs, even in the face of renal insuffi- ~ i e n c y . ~ Furthermore, hepatic dysfunction may decrease con-

Table 2. Results of Serum Biochemistries Before and After the Development of Acute Tumor Lysis

Syndrome in a Cat

Total protein Albumin Globulin Creatinine Urea nitrogen Calcium Phosphorus Sodium Potassium Chloride Total C02 Glucose Total bilirubin Alkaline phosphatase Alanine aminotransferase Aspartate aminotransferase Cholesterol Amylase Uric acid

Reference Day 5 Range Day 1 9:OOAM Day7

5.4-7.8 g/dL 6.7 5.4 4.1 2.3-3.9 g/dL 3.6 2.7 2.0 2.2-5.0 g/dL 3.1 2.7 2.1 0.5-1.8 mg/dL 4.2 2.2 1.9 8.0-35 mg/dL 77.7 74.5 56.6 8.2-11.2 mg/dL 9.6 10.1 8.1 2.5-6.5 mg/dL 8.3 13.7 5.7 140-158mEqiL 135 160 165 3.2-5.5 mEq/L 4.1 4.3 3.4 99-124 mEq/L 90 120 123 18-25 mEq/L 17.1 12.3 20.0 70-150mg/dL 104 242 144 0.1-0.6 mg/dL 0.3 0.9 1.0

18 39 81 1-40 IU/L 5-75 IU/L 57 75 99 5-60 IU/L 52 295 218

25-200 mg/dL 160 156 147 <300mg/dL 817 366 318

0.1-0.6 mg/dL - 1.5 -

TLS IN A CAT WITH LYMPHOMA 41 1

Table 3. Venous Blood Gas and Blood Electrolyte Values Before and After the Development of Acute Tumor Lysis Syndrome in a Cat

Day 4 2 3 0 PM Day 5 1215 AM Day 5 Day 5 Day 5 Normal Range (Pre-RT) (7h post RT) 1:15 AM 4:OO AM 9:30 AM

pH” 7.30 2 0.0870 7.44 7.16 6.97 7.18 7.28 PC02” 41.8 -t 9.12 mm Hg 34.7 16.6 44.1 37.8 32.0

Sodium 140-158 mEq/L 150 119 141 145.4 147 Potassium 3.2-5.5 mEq/L 3.2 9.1 7.0 4.1 3.8 Calcium (ionized)’* 4.69-5.5 meq/L 7.4 3.5 3.8 5.6 4.0

HCO,” 19.4 -t 4.0 mmol/L 23.5 7.5 9.0 14.0 15.5

Abbreviation: RT, radiation therapy.

version of uric acid to allantoin, also predisposing animals with lymphoma and neoplastic hepatic infiltration to TLS. In people, hyperuricemia may cause azotemia and subse- quent renal failure by precipitation of uric acid crystals in the distal renal tubules.

The clinical and clinicopathologic findings in acute renal failure may mimic those of TLS, making the differentiation difficult; however, quantitative and qualitative urinalysis would have been helpful. To better delineate pre-existing renal disease in this patient, it would have been ideal to obtain a pretreatment urinalysis.

Because potassium is the major intracellular cation, when large amounts are released into the circulation from tumor cytolysis, potentially dangerous hyperkalemia may result. Decreased potassium excretion due to pre-existing renal in- sufficiency, uric acid nephropathy, or nephrocalcinosis can exacerbate the hyperkalemia. In this cat, hyperkalemia after chemotherapy and radiation therapy was severe and life- threatening. Concurrent metabolic acidosis and hypocal- cemia probably predisposed this cat to atrial standstill and bradycardia.

Specific therapies have been proposed to alleviate the re- nal consequences of TLS. Allopurinol has been used prophy- lactically in humans to prevent hyperuricemia after chemo- therapy,“’ although its use has not been reported in dogs or cats with TLS. Allopurinol is a competitive inhibitor of xanthine oxidase. By inhibiting conversion of hypoxanthine to xanthine, it decreases the subsequent conversion of xan- thine to uric acid. The drug is eliminated by renal excretion, and dosing is influenced by renal dysf~nct ion .~ Urine alkalin- ization has been suggested to increase the solubility of uric acid. However, this increases phosphorous precipitation in the kidney and is not recommended.’

The optimal treatment of TLS in the cat is unknown. It would seem prudent to monitor electrolyte, acid-base, and renal status after cytolytic therapy in certain patients, for early detection of TLS. As suggested by this report, such candidates would include cats with large lymphoma tumor burden and renal or hepatic insufficiency. In this cat, correc- tion of acid-base and electrolyte abnormalities by standard therapies resolved the clinicopathologic changes and associ- ated clinical signs of TLS. If combination chemotherapy and radiation therapy are anticipated, a delay of 5 to 7 days between treatments may be desirable. However, as in this

case where tumor causes severe clinical signs, such a hiatus may be unavoidable. Drugs that promote renal excretion of potassium, phosphorus, and uric acid (eg, mannitol, furose- mide, or dopamine) may be desirable to increase glomerular filtration and excretion, although their utility in TLS awaits clinical documentation.

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