Pediatric Tumor Lysis Syndrome 

Tumor lysis syndrome (TLS) is a very serious and potentially life-threatening complication of cancer therapy. It can be defined as a constellation of metabolic abnormalities that results from spontaneous or treatment-related tumor necrosis. The metabolic abnormalities observed in patients with tumor lysis syndrome include hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These can lead to acute renal failure (ARF). The main principles of tumor lysis syndrome are the identification of high-risk patients, initiation of preventive therapy, and early recognition and intervention of its complications.

Tumor lysis syndrome can be precipitated as a spontaneous event prior to the initiation of therapy and usually lasts as long as 3 days after the start of chemotherapy, especially with tumors that have a high growth fraction and high sensitivity to chemotherapy. Burkitt lymphoma and T-cell acute lymphoblastic leukemia are most frequently associated with this complication.

Tumor lysis syndrome has also been observed in association with solid tumors, such as hepatoblastoma and stage IV neuroblastoma. From a non-oncologic perspective, intraoperative cardiac arrest secondary to tumor lysis syndrome has been reported after a preoperative splenic artery embolization.^[1] Although no tumor was present, the patient was noted to have a clinical presentation similar to tumor lysis syndrome, which included hyperkalemia and hyperphosphatemia with ARF and cardiac arrhythmia. No source for the hyperkalemia was identified other than tissue lysis.

In 1980, Cohen et al identified risk factors that predispose patients to metabolic derangements, such as bulky abdominal disease, elevated pretreatment uric acid level, elevated lactate dehydrogenase level, and poor urine output.^[2] Lysis of tumor cells results in rapid release of potassium, purine nucleic acids, and phosphorus, which leads to hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These metabolic abnormalities can subsequently lead to ARF. These complications may result in multiple organ failure and death.

The kidney is the primary organ involved in the clearance of uric acid, phosphorus, and potassium. Uric acid (pKa = 5.4) is soluble at physiologic pH, but can precipitate in the acidic environment of renal tubules. Hemoconcentration and decreased tubular flow rate within the renal system also contributes to the precipitation of uric acid. Precipitation of uric acid crystals within the collecting ducts and ureters can cause an obstructive uropathy.

The phosphorus content of the lymphoblasts is 3-4 times the content of normal lymphocytes. When these cells lyse as a result of therapy or spontaneous apoptosis, the serum phosphorous rises. The elevated phosphorous can spurn nephrocalcinosis from calcium phosphate crystal precipitation. This occurs in the renal tubules and microvasculature as the in vivo calcium-phosphorus solubility product exceeds 60-70 because of hyperphosphatemia and may be worsened with iatrogenic alkalinization. Symptomatic hypocalcemia may result from hyperphosphatemia.

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%).^[3] 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%. As advances are made in cancer treatment and more aggressive regimens become in favor, the incidence of tumor lysis syndrome may increase and the syndrome may emerge in a broader spectrum of malignancies.

Mortality/Morbidity

• ARF: Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes ARF. This often is oliguric (< 400 mL/d) in nature, leading to volume overload and complications of hypertension and pulmonary edema. High 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 usually is 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: ARF 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 rapidly treated. Proper fluid management, correction of acidosis, and attention to infections are the mainstays of therapy.

Race

No race predilection is noted.

Sex

No sex predilection is noted.

Age

Although tumor lysis syndrome occurs in all age groups, advanced age is associated with more frequent underlying impaired renal function, which may in turn, predispose patients to clinically significant tumor lysis syndrome secondary to decreased ability to dispose of tumor lysis byproducts.