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Tumor Lysis Syndrome
Updated: Mar 11, 2009
Introduction
Background
Tumor lysis syndrome (TLS) refers to the constellation of metabolic disturbances that may be seen after initiation of cancer treatment.1,2,3 Tumor lysis syndrome usually occurs in patients with bulky, rapidly proliferating, and treatment-responsive tumors.4 Tumor lysis syndrome is typically associated with acute leukemias and high-grade non-Hodgkin lymphomas,5 such as Burkitt lymphoma.6,7 Tumor lysis syndrome has also been reported with other hematologic malignancies and solid tumors.8,9
A potentially lethal complication of anticancer treatment,10 tumor lysis syndrome occurs when large numbers of neoplastic cells are killed rapidly, leading to release of intracellular ions and metabolic byproducts into the systemic circulation. Clinically, the syndrome is characterized by rapid development of hyperuricemia,11 hyperkalemia, hyperphosphatemia, hypocalcemia, and acute renal failure (ARF).12 The main principles of tumor lysis syndrome management are (1) identification of high-risk patients with initiation of preventive therapy and (2) early recognition of metabolic and renal complications with prompt supportive care, including hemodialysis.
Pathophysiology
Rapid tumor cell turnover results in release of intracellular contents into the circulation. This release can inundate renal elimination and cellular buffering mechanisms, which lead to numerous metabolic derangements. Clinically significant tumor lysis syndrome can occur spontaneously, but it is most often seen 48-72 hours after initiation of cancer treatment. Hyperkalemia is often the earliest laboratory manifestation. Hyperkalemia and hyperphosphatemia result directly from rapid cell lysis. Nucleic acid purines, which are also released by cell breakdown, are ultimately metabolized to uric acid by hepatic xanthine oxidase. This conversion leads to hyperuricemia. Hypocalcemia is a consequence of acute hyperphosphatemia with subsequent precipitation of calcium phosphate in soft tissues. In acute renal failure, decreased calcitriol levels also cause hypocalcemia.
Uric acid is the terminal catabolic product of purine metabolism in humans; it is a weak acid with pKa of approximately 5.4, is soluble in plasma, and is freely filtered at the renal glomeruli. However, uric acid is less soluble in renal tubular and collecting duct fluid due to normally acidic media, thus increasing the possibility of uric acid crystal formation in case of hyperuricemia.
The kidney is the primary organ involved in clearance of uric acid, potassium, and phosphate. Preexisting volume depletion or renal dysfunction predisposes patients to worsening metabolic derangements and acute renal failure. Acute renal failure is often oliguric and can be multifactorial in etiology; uric acid nephropathy is the major cause of acute renal failure. Its development is due to mechanical obstruction by uric acid crystals in the renal tubules. With a pKA of 5.6, uric acid precipitation is enhanced by high acidity and high concentration in the renal tubular fluid, becoming less soluble as renal tubule pH decreases. Renal medullary hemoconcentration and decreased tubular flow rate also contribute to crystallization.
Another cause of acute renal failure is acute nephrocalcinosis from calcium phosphate crystal precipitation, which may occur in other tissues. This occurs in the setting of hyperphosphatemia and is exacerbated by overzealous iatrogenic alkalinization, because calcium phosphate, unlike uric acid, becomes less soluble at an alkaline pH. Precipitation of xanthine, which is even less soluble in urine than uric acid, or other purine metabolites whose urinary excretion is increased by use of allopurinol are other causes of acute renal failure.
Frequency
International
Incidence is unknown. Prevalence varies among different malignancies; bulky, aggressive, and treatment-sensitive tumors are associated with higher frequencies of tumor lysis syndrome. In studies of frequency in patients with intermediate-grade or high-grade non-Hodgkin lymphomas, laboratory evidence of tumor lysis syndrome (42%) occurred much more frequently than the symptomatic clinical syndrome (6%). In children with acute leukemia receiving induction chemotherapy, silent laboratory evidence of tumor lysis syndrome occurred in 70% of cases, but clinically significant tumor lysis syndrome occurred in only 3% of cases. As advances are made in cancer treatment and as high-dose regimens become more commonplace, tumor lysis syndrome incidence may increase and the syndrome emerge in a broader spectrum of malignancies.
Mortality/Morbidity
- Acute renal failure: Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes acute renal failure. This is often oliguric (<400 mL/d) in nature, leading to volume overload and complications of hypertension and pulmonary edema. High blood urea nitrogen (BUN) levels due to increased protein catabolism and renal impairment can be severe enough to result in pericarditis, platelet dysfunction, and defective cellular immunity. Renal dysfunction can be severe enough to require dialysis, but with prompt supportive measures, it is usually reversible.
- Cardiac arrhythmia: Hyperkalemia can lead to ECG changes and life-threatening cardiac arrhythmia, including asystole. Severe potassium elevation can cause ECG alterations such as peaked T waves, flattened P waves, prolonged PR interval, widened QRS complexes, deep S wave, and sine waves. Hypocalcemia can lead to QT interval lengthening, which predisposes patients to ventricular arrhythmia.
- Metabolic acidosis: Acute renal failure and liberation of large amounts of endogenous intracellular acids from cellular catabolism result in acidemia. This acidemia causes a decrease in serum bicarbonate concentration and a high anion gap acidosis. Acidemic states can worsen the many electrolyte imbalances already present in tumor lysis syndrome; intracellular uptake of potassium is hindered, uric acid solubility is decreased, and extracellular shift of phosphate is promoted. Calcium phosphate solubility, however, improves in acidic conditions. The myriad of metabolic disorders must be assessed and treated rapidly. Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections are the mainstays of therapy.
Race
No racial predilection exists.
Sex
No sex predilection exists.
Age
Although tumor lysis syndrome occurs in all age groups, advanced age leading to impaired renal function may predispose patients to clinically significant tumor lysis syndrome owing to decreased ability to dispose of tumor lysis byproducts.
Clinical
History
A constellation of clinical symptoms, such as nausea, vomiting, lethargy, edema, fluid overload, congestive heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and sudden death may develop prior to initiation of chemotherapy or more commonly within 72 hours after administration of cytotoxic therapy.
Physical
- Symptoms reflect the severity of underlying metabolic abnormalities.
- Hyperkalemia can cause paresthesia and weakness. Severe hypocalcemia can also lead to paresthesia and tetany with positive Chvostek and Trousseau signs, anxiety, carpal and pedal spasms, and bronchospasm.
- Uremia can manifest as fatigue, weakness, malaise, nausea, vomiting, anorexia, metallic taste, hiccups, neuromuscular irritability, difficulty concentrating, pruritus, restless legs, and ecchymoses. As uremia progresses, paresthesia and evidence of pericarditis may develop, as well as signs of drug toxicity for administered medications eliminated by the kidney. Features of volume overload, such as dyspnea, pulmonary rales, edema, and hypertension, may develop.
- Rapidly increasing uric acid levels may lead to arthralgia and renal colic.
Causes
- Tumor lysis syndrome occurs most often in patients with acute leukemia with high WBC counts and in those with high-grade lymphomas in response to aggressive treatment. Tumor lysis syndrome may also occur in other hematologic malignancies and in a variety of solid tumors. It has occasionally occurred spontaneously, prior to any form of therapy.13
- Those at highest risk have bulky, rapidly proliferating tumors that are sensitive to treatment. An elevated pretreatment lactate dehydrogenase (LDH) level, which correlates with high tumor volume, is a strong prognostic indicator for developing clinically significant complications of therapy. Presence of renal insufficiency prior to therapy is also correlated with an increased likelihood of tumor lysis syndrome.
- Reports exist of tumor lysis syndrome associated with the administration of radiation therapy,14 corticosteroids, hormonal agents, biologic response modifiers, and monoclonal antibodies. Agents reported to cause tumor lysis syndrome include paclitaxel, fludarabine, etoposide, thalidomide,15 bortezomib,16 zoledronic acid,17 and hydroxyurea.
- Tumor lysis syndrome is not limited to systemic administration of agents; it can occur with intrathecal administration of chemotherapy and with chemo-embolization.
- Rare clinical situations in which tumor lysis syndrome has been observed include pregnancy and fever. Patients under general anesthesia have also experienced tumor lysis syndrome.
More on Tumor Lysis Syndrome |
 Overview: Tumor Lysis Syndrome |
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| Treatment & Medication: Tumor Lysis Syndrome |
| Follow-up: Tumor Lysis Syndrome |
| References |
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References
Bishop MR, Cairo MS, Coccia PF. Tumor lysis syndrome. In: Abeloff MD, ed. Clinical Oncology. 3rd ed. Orlando, Fl: Churchill Livingstone; 2004:50.
Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol. Jun 2000;27(3):322-34. [Medline].
King JE. What is tumor lysis syndrome?. Nursing. May 2008;38(5):18. [Medline].
Jagasia MH, Arrowsmith ER. Complications of hematopoietic neoplasms. In: Wintrobe MM, Greer JP, Foerster J, et al. Wintrobe's Clinical Hematology. Vol II. 11th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:1919-44.
Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med. Feb 1993;94(2):133-9. [Medline].
Cohen LF, Balow JE, Magrath IT, et al. Acute tumor lysis syndrome. A review of 37 patients with Burkitt's lymphoma. Am J Med. Apr 1980;68(4):486-91. [Medline].
Ezzone SA. Tumor lysis syndrome. Semin Oncol Nurs. Aug 1999;15(3):202-8. [Medline].
Fleming DR, Doukas MA. Acute tumor lysis syndrome in hematologic malignancies. Leuk Lymphoma. Nov 1992;8(4-5):315-8. [Medline].
Kalemkerian GP, Darwish B, Varterasian ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J Med. Nov 1997;103(5):363-7. [Medline].
Kelly KM, Lange B. Oncologic emergencies. Pediatr Clin North Am. Aug 1997;44(4):809-30. [Medline].
Klinenberg JR, Kippen I, Bluestone R. Hyperuricemic nephropathy: pathologic features and factors influencing urate deposition. Nephron. 1975;14(1):88-98. [Medline].
Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol. May 1993;13(3):273-80. [Medline].
Obrador GT, Price B, O'Meara Y, et al. Acute renal failure due to lymphomatous infiltration of the kidneys. J Am Soc Nephrol. Aug 1997;8(8):1348-54. [Medline].
Chen SW, Hwang WS, Tsao CJ, et al. Hydroxyurea and splenic irradiation-induced tumour lysis syndrome: a case report and review of the literature. J Clin Pharm Ther. Dec 2005;30(6):623-5. [Medline].
Lee CC, Wu YH, Chung SH, et al. Acute tumor lysis syndrome after thalidomide therapy in advanced hepatocellular carcinoma. Oncologist. Jan 2006;11(1):87-8; author reply 89. [Medline].
Jaskiewicz AD, Herrington JD, Wong L. Tumor lysis syndrome after bortezomib therapy for plasma cell leukemia. Pharmacotherapy. Dec 2005;25(12):1820-5. [Medline].
Kurt M, Onal IK, Elkiran T, et al. Acute tumor lysis syndrome triggered by zoledronic Acid in a patient with metastatic lung adenocarcinoma. Med Oncol. 2005;22(2):203-6. [Medline].
Lazarus JM, Brenner BM. Chronic renal failure. In: Fauci SA, ed. Harrison's Principles of Internal Medicine. Vol 2. 14th ed. New York, NY: McGraw Hill; 1998:1513-20.
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. Jun 1 2008;26(16):2767-78. [Medline].
Del Toro G, Morris E, Cairo MS. Tumor lysis syndrome: pathophysiology, definition, and alternative treatment approaches. Clin Adv Hematol Oncol. Jan 2005;3(1):54-61. [Medline].
Jones DP, Mahmoud H, Chesney RW. Tumor lysis syndrome: pathogenesis and management. Pediatr Nephrol. Apr 1995;9(2):206-12. [Medline].
Rohaly-Davis J, Johnston K. Hematologic emergencies in the intensive care unit. Crit Care Nurs Q. Feb 1996;18(4):35-43. [Medline].
Mahmoud HH, Leverger G, Patte C, et al. Advances in the management of malignancy-associated hyperuricaemia. Br J Cancer. Jun 1998;77 Suppl 4:18-20. [Medline].
Yim BT, Sims-McCallum RP, Chong PH. Rasburicase for the treatment and prevention of hyperuricemia. Ann Pharmacother. Jul-Aug 2003;37(7-8):1047-54. [Medline].
Browning LA, Kruse JA. Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann Pharmacother. Nov 2005;39(11):1932-5. [Medline].
Lorigan PC, Woodings PL, Morgenstern GR, et al. Tumour lysis syndrome, case report and review of the literature. Ann Oncol. Aug 1996;7(6):631-6. [Medline].
Further Reading
Keywords
tumor lysis syndrome, TLS, acute tumor lysis syndrome, ATLS, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, acute renal failure, ARF, malignancy-associated hyperuricemia, acute leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, Burkitt's lymphoma, malignancy, anticancer treatment, cancer treatment, acute hyperphosphatemia, cardiac arrhythmia, metabolic acidosis, rapid tumor cell turnover, metabolic derangements, rapid cell lysis
