What is tumor lysis syndrome and how is it diagnosed?

Tumor Lysis Syndrome: Diagnosis and Management

Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic complication characterized by massive and abrupt release of cellular components into the blood after rapid lysis of malignant cells, resulting in hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and potentially life-threatening clinical consequences. 1

Definition and Classification

• TLS is classified into laboratory TLS (LTLS) and clinical TLS (CTLS) 1

• Laboratory TLS is defined by the presence of two or more of the following abnormal serum values within three days before or seven days after initiation of anticancer therapy: 2

  • Hyperuricemia: ≥8 mg/dL (476 μmol/L) or 25% increase from baseline 2
  • Hyperkalemia: ≥6.0 mmol/L (6 mEq/L) or 25% increase from baseline 2
  • Hyperphosphatemia: ≥4.5 mg/dL (1.45 mmol/L) in adults or ≥6.5 mg/dL (2.1 mmol/L) in children or 25% increase from baseline 2
  • Hypocalcemia: ≤7 mg/dL (1.75 mmol/L) or 25% decrease from baseline 2

• Clinical TLS requires the presence of laboratory TLS plus one or more of the following clinical complications: 2, 1

  • Renal insufficiency (creatinine ≥1.5 times upper limit of normal)
  • Cardiac arrhythmias/sudden death
  • Seizures

Clinical Manifestations

• Common symptoms include nausea, vomiting, diarrhea, anorexia, lethargy, edema, fluid overload, and hematuria 1
• Severe manifestations may include congestive heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possible sudden death 1
• Symptoms typically occur within 12-72 hours after initiation of cytoreductive therapy but can sometimes occur spontaneously before treatment 1, 3

Risk Factors

Tumor-Related Factors:

• High-grade hematologic malignancies with rapid proliferation rates (Burkitt's lymphoma, ALL, AML) 2, 1
• Large tumor burden or bulky disease 3
• High sensitivity to cytotoxic therapy 1

Patient-Related Factors:

• Pre-existing elevated uric acid levels 2
• Pre-existing renal dysfunction 2
• Advanced age 2
• Tumor infiltration in the kidney 2

Treatment-Related Factors:

• Highly active, cycle-specific chemotherapeutic agents 2
• Corticosteroid therapy in lymphoid malignancies 2

Incidence

• TLS occurs most frequently in patients with non-Hodgkin lymphoma (NHL) and other hematologic malignancies 1
• In high-grade NHL, laboratory TLS was found in 42% of patients, with clinically significant symptoms in 6% 1
• In pediatric NHL patients, 4.4% developed TLS, with higher rates in Burkitt's lymphoma or B-ALL (8.4%) 1
• In B-ALL specifically, TLS rates reached 26.4% 1
• In AML patients, hyperuricemia and TLS rates were 14.7% and 3.4%, respectively 1

Diagnosis

The diagnosis of TLS is based on laboratory findings and clinical manifestations:

• Laboratory monitoring should include serum levels of uric acid, potassium, phosphorus, calcium, and creatinine 1, 2
• Patients should be monitored before treatment initiation and at least daily for 3-7 days after starting anticancer therapy 2
• Renal function should be assessed using eGFR calculated by MDRD formula or Cockroft-Gault equation 2
• Clinical TLS is graded based on the severity of clinical manifestations (renal insufficiency, cardiac arrhythmias, seizures) 1

Prevention and Management

Risk Stratification:

• High-risk patients: Hydration and rasburicase should be administered 1
• Intermediate-risk patients: Hydration plus either allopurinol or rasburicase 1
• Low-risk patients: Hydration and oral allopurinol 1

Prevention Strategies:

1. Aggressive hydration:

   • Fundamental to prevention and management of TLS 1
   • Promotes excretion of uric acid and phosphate by improving intravascular volume, renal blood flow, and glomerular filtration 1
   • Diuretics may be necessary to maintain adequate urine output but are contraindicated in hypovolemia or obstructive uropathy 1

2. Hypouricemic agents:

   • Allopurinol: Blocks xanthine oxidase activity, preventing conversion of hypoxanthine and xanthine to uric acid 1
   • Rasburicase: Recombinant urate-oxidase enzyme that converts existing uric acid to allantoin, which is 5-10 times more soluble in urine than uric acid 1, 4
   • In clinical trials, rasburicase demonstrated superior uric acid control compared to allopurinol, with 87% response rate for rasburicase vs. 66% for allopurinol 4

3. Alkalinization:

   • Not recommended, especially when using rasburicase 1

Management of Established TLS:

• Laboratory TLS: Hydration and rasburicase should be administered to adults and high-risk children 1
• Clinical TLS: Requires immediate hydration and rasburicase administration 1
• Severe cases: May require dialysis for management of refractory hyperkalemia, hyperphosphatemia, or acute kidney injury 5

Monitoring

• Patients at risk should be monitored for at least 24-72 hours after initiation of therapy 1
• Laboratory parameters (uric acid, potassium, phosphorus, calcium, creatinine) should be checked frequently based on risk level 2
• Urine output should be monitored closely to ensure adequate hydration 1

Common Pitfalls and Caveats

• Failure to identify high-risk patients before initiating cytotoxic therapy 1
• Inadequate hydration, which is crucial for prevention 1
• Delayed recognition of laboratory abnormalities that precede clinical manifestations 1
• Using alkalinization with rasburicase, which is not recommended 1
• Underestimating the risk in patients with solid tumors, as TLS can occur in these patients as well, albeit less frequently 1

By promptly identifying patients at risk, implementing appropriate preventive measures, and aggressively managing established TLS, the morbidity and mortality associated with this oncologic emergency can be significantly reduced.