What is tumor lysis syndrome (TLS) in patients with cancer, particularly those with hematological malignancies such as leukemia or lymphoma?

What is Tumor Lysis Syndrome?

Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency that occurs when rapid destruction of cancer cells releases massive amounts of intracellular contents—including nucleic acids, proteins, phosphorus, and potassium—into the bloodstream, causing hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, which can lead to acute kidney injury, cardiac arrhythmias, seizures, and death. 1

Pathophysiology

The syndrome develops through a specific metabolic cascade:

• Released nucleic acids from lysed tumor cells are catabolized to hypoxanthine, then xanthine, and finally to uric acid by xanthine oxidase 1
• Uric acid precipitates in renal tubules along with calcium phosphate deposits, causing acute kidney injury or renal failure 1, 2
• Potassium release causes life-threatening cardiac arrhythmias and potential sudden cardiac death 2
• Phosphate release leads to hyperphosphatemia with reciprocal hypocalcemia, triggering seizures and tetany 1

Classification Systems

TLS is categorized into two distinct entities:

Laboratory TLS (LTLS)

• Defined by presence of two or more abnormal serum values (hyperuricemia >8 mg/dL in adults, hyperkalemia, hyperphosphatemia, hypocalcemia) within 3 days before or 7 days after initiation of anticancer therapy 1, 2

Clinical TLS (CTLS)

• Requires laboratory TLS plus one or more clinical complications: renal insufficiency (creatinine ≥1.5 times upper normal limit or creatinine clearance <60 mL/min), cardiac arrhythmias, or seizures 1, 2
• Clinical TLS is graded from I to IV based on the highest grade of observed complications 3
• Mortality rate for clinical TLS reaches 83% in acute myeloid leukemia patients versus 24% in those without TLS 1

High-Risk Malignancies

The risk varies dramatically by cancer type:

Hematologic Malignancies (Highest Risk)

• Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (B-ALL) represent the absolute highest-risk malignancies, with TLS developing in approximately 26.4% of B-ALL patients 1
• Acute myeloid leukemia (AML) with white blood cell count >100 × 10⁹/L carries extremely high risk 1
• Diffuse large B-cell lymphoma (DLBCL) with bulky disease shows approximately 6.1% TLS rate 1
• Chronic lymphocytic leukemia (CLL) carries the lowest risk among hematologic malignancies, with TLS suspected in only 0.42% of patients 1, 4

Solid Tumors (Lower but Significant Risk)

• TLS is uncommon in solid tumors but carries a surprisingly high mortality rate of approximately 35%, higher than hematologic malignancies, due to delayed recognition and less aggressive prophylaxis 3, 5
• High-risk solid tumors include bulky small cell lung cancer and metastatic germ cell carcinoma (gonadal or extragonadal) 3
• Bulky disease with massive liver metastases significantly increases risk 1, 5

Risk Factors

Tumor-Related Factors

• High tumor burden reflected by serum lactate dehydrogenase (LDH) >2 times upper normal limit 3, 1
• White blood cell count >50,000-100,000/mm³ in acute leukemias 3, 1
• Extensive bone marrow involvement and large tumor size 3
• High proliferative rate and high tumor sensitivity to chemotherapy 3

Patient-Related Factors

• Elevated pre-treatment serum uric acid level (>8 mg/dL in children, >10 mg/dL in adults) 3, 1
• Pre-existing renal damage or impairment 3, 1
• Tumor infiltration in the kidney or obstructive uropathy 3
• Advanced age 3
• Dehydration and hyponatremia 3

Treatment-Related Factors

• Highly active, cycle-specific cytotoxic drugs (cytosine arabinoside, etoposide, cisplatin) 3
• Corticosteroids used as primary therapy for highly proliferating lymphoid disorders 3
• Novel targeted agents including monoclonal antibodies (rituximab, gemtuzumab ozogamicin), kinase inhibitors (idelalisib, ibrutinib), and venetoclax 3, 4

Clinical Timing

• TLS typically develops within 12-72 hours after initiation of cytotoxic therapy, though it can occur spontaneously before treatment or up to 7 days after therapy begins 2
• Rarely, TLS occurs as a spontaneous event without any treatment intervention 3

Clinical Manifestations

Renal Complications

• Acute kidney injury with oliguria or anuria 1, 2
• Serum creatinine ≥1.5 times upper normal limit 1, 2

Cardiac Complications

• Arrhythmias ranging from brief interventions not indicated to life-threatening arrhythmias with congestive heart failure, hypotension, syncope, or shock 1, 2
• Sudden cardiac death from severe hyperkalemia 2
• Palpitations and muscle cramps 5

Neurologic Complications

• Seizures ranging from brief generalized seizures to status epilepticus 1, 2

Critical Pitfalls

• In solid tumors, TLS is often recognized late because clinicians have lower suspicion, leading to the paradoxically higher 35% mortality rate compared to hematologic malignancies 3, 5
• Children with malignancies have a 70% chance of developing TLS, requiring heightened vigilance 3
• Novel targeted therapies capable of eliciting rapid response pose increasing TLS risk, particularly in combination regimens 4