Tumor Lysis Syndrome

Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. This can lead to severe neurologic, cardiac, gastrointestinal, and urinary signs and symptoms. The diagnosis is made based on the metabolic derangements seen on laboratory evaluation in conjunction with the clinical history. In addressing tumor lysis syndrome, the goal is to initiate therapy early for those at high risk, including IV hydration, close electrolyte monitoring and correction, and hypouricemic agents.

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Overview

Epidemiology

National incidence reports are hampered by a lack of standard criteria for diagnosis.

Etiology

Tumor lysis syndrome results from massive tumor death and is primarily associated with the following hematologic malignancies:

  • ALL
  • AML
  • CLL
  • CML
  • Non-Hodgkin lymphoma
  • Hodgkin lymphoma

Risk factors

Malignancy characteristics:

  • Large tumor burden
  • Chemosensitivity
  • High tumor cell proliferation rate

Concurrent conditions:

  • Preexisting renal insufficiency
  • Oliguria
  • Dehydration
  • Hypotension
  • Acidic urine
  • Preexisting hyperuricemia

Pathophysiology

Tumor lysis syndrome occurs secondary to the chemotherapeutic treatment of malignancies, resulting in massive cell destruction.

  • Lysis of tumor cells → release of intracellular:
    • K and phosphate → hyperkalemia and hyperphosphatemia
    • Nucleic acids 
  • Calcium sequestration by phosphate to create calcium phosphate → hypocalcemia
  • Nucleic acid breakdown → hypoxanthine and xanthine → catalyzed to uric acid (via xanthine oxidase) → hyperuricemia
  • Consequences:
    • Uric acid and calcium phosphate crystals precipitate in the kidney → acute kidney injury
    • Hyperkalemia → impaired muscle function and cardiac conduction
    • Hypocalcemia → neuromuscular irritability
Tumor lysis syndrome in a patient with leukemia

Histological images taken from a patient with leukemia:
Left: The white areas represent extreme apoptosis of leukemic cells. Cell destruction leads to a release of potassium, phosphate, and nucleic acids, which contributes to tumor lysis syndrome.
Right: higher magnification of viable and proliferating leukemic cells

Image: “Hyperphosphatemia during spontaneous tumor lysis syndrome” by The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. License: CC BY 2.0, cropped by Lecturio.

Clinical Presentation

Symptoms typically occur within 72 hours of the initiation of cytotoxic therapy and are the consequence of hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia.

  • Neurological symptoms:
    • Altered mental status
    • Muscle weakness
    • Muscle spasms
    • Seizures
    • Tetany
    • Paralysis
  • Cardiac symptoms:
    • Palpitations (from cardiac dysrhythmias)
    • Syncope
    • Sudden death
  • GI symptoms:
    • Anorexia
    • Nausea and vomiting
    • Abdominal cramps
    • Diarrhea
  • Urinary symptoms:
    • Dysuria
    • Oliguria
    • Flank pain (from renal or ureteral stone formation)
    • Hematuria

Diagnosis

In addition to the clinical signs and symptoms, a laboratory diagnosis can be made with ≥ 2 of the following criteria (in the setting of recent cytotoxic therapy): 

  • ↑ Uric acid
  • ↑ Potassium
  • ↑ Phosphorus
  • ↓ Calcium

Patients should also be evaluated for evidence of renal failure:

  • ↑ Creatinine
  • ↑ BUN
  • ↓ HCO3 (metabolic acidosis)

Management

General measures

The following may be used to manage and prevent tumor lysis syndrome in high-risk patients:

  • Aggressive IV hydration
  • Monitoring of urine pH and urine output (to assess the adequacy of hydration).
  • Dietary restriction of foods high in potassium, phosphorus, and uric acid
  • Laboratory monitoring before and after cytotoxic therapy:
    • BUN
    • Creatinine
    • Phosphorus
    • Uric acid
    • Calcium  
    • Potassium 
    • Lactate dehydrogenase
  • Cardiac monitoring for arrhythmias
  • Electrolyte correction
  • Possible dialysis (indications are similar to those for patients with other causes of acute renal failure).

Hyperuricemia therapy

  • Xanthine oxidase inhibitors:
    • Options:
      • Allopurinol (preferred)
      • Febuxostat
    • Blocks the metabolism of hypoxanthine and xanthine
    • Often initiated before the start of chemotherapy
    • Note: This does not reduce preexisting serum uric acid levels.
  • Rasburicase:
    • Recombinant urate oxidase 
    • Rapidly catalyzes uric acid → allantoin
    • Effective for prevention and treatment of hyperuricemia

Differential Diagnosis

  • Hyperkalemia: an elevated level of potassium in the blood. Common causes include renal failure, rhabdomyolysis, hyperaldosteronism, and medications. Though mostly asymptomatic, hyperkalemia can be associated with palpitations, muscle pain, weakness, and fatal cardiac arrhythmias. The diagnosis is made with a serum potassium level. Emergency management of hyperkalemia includes administering calcium, IV insulin, albuterol, sodium bicarbonate, and cation exchange resins.  
  • Hyperphosphatemia: an electrolyte disorder in which there is an elevated level of phosphate in the blood. The disorder can occur as a result of impaired phosphate excretion or by high phosphate loads and is associated with impaired kidney function, hypoparathyroidism, crush injuries, rhabdomyolysis, fulminant hepatitis, and cytotoxic therapy. Management starts with a low-phosphate diet and phosphate binders in the diet of those at risk. In extreme cases, hemodialysis can be used.  
  • Hyperuricemia: a condition in which high uric acid levels exist in the blood. These increased levels can result from increased production, decreased excretion, or both. Hyperuricemia can lead to gout, nephrolithiasis, and chronic renal disease. There are no specific physical findings for hyperuricemia, and patients may be asymptomatic. Lab studies of patients with hyperuricemia will reveal elevated serum uric acid levels. Management consists of a low-purine diet as well as urate-lowering medications.
  • Rhabdomyolysis: a condition that results from direct or indirect injury to skeletal muscles, resulting in the release of electrolytes, myoglobin, creatinine kinase, and lactate dehydrogenase. Depending on the amount of intracellular contents released, patients can have no symptoms or life-threatening renal failure and cardiac arrhythmias. An elevated creatine kinase is the most sensitive test for evaluating rhabdomyolysis. Management is mostly supportive, including vigorous hydration.   
  • Diabetic ketoacidosis: a life-threatening complication of diabetes characterized by hyperglycemia and ketoacidosis. Symptoms include polyuria, polydipsia, abdominal pain, nausea, and vomiting. Laboratory studies will show elevated glucose and ketone levels, which are not seen in tumor lysis syndrome. Other abnormalities can include hyperkalemia, metabolic acidosis, and acute kidney injury. Management includes fluid resuscitation, insulin, and electrolyte correction.

References

  1. Howard, S., Jones, D., and Pui, C., (2011). The tumor lysis syndrome. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/21561350/
  2. Williams, S.M., Killeen, A.A. (2018). Tumor lysis syndrome. Arch Pathol Lab Med. https://reference.medscape.com/medline/abstract/30499695
  3. Mirrakhimov, A.E., Voore, P., Khan, M., Ali, A.M. (2015). Tumor lysis syndrome: A clinical review. World J Crit Care Med. https://reference.medscape.com/medline/abstract/25938028 
  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Retrieved December 21, 2020, from https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
  5. Mughal, T.I., Ejaz, A.A., Foringer, J.R., Coiffier, B. (2010). An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev. https://reference.medscape.com/medline/abstract/20031331
  6. Ikeda, A.K., and Jaishankar, D. (2020). Tumor lysis syndrome. In El-Deiry, W.S. (Ed.), Medscape. Retrieved April 8, 2021, from https://emedicine.medscape.com/article/282171-overview
  7. Larson, R.A., and Pui, C. (2021). Tumor lysis syndrome: Definition, pathogenesis, clinical manifestations, etiology, and risk factors. In Savarese, D.M.F. (Ed.), UpToDate. Retrieved April 8, 2021, from https://www.uptodate.com/contents/tumor-lysis-syndrome-definition-pathogenesis-clinical-manifestations-etiology-and-risk-factors
  8. Larson, R.A., and Pui, C. (2019). Tumor lysis syndrome: Prevention and treatment. In Savarese, D.M.F. (Ed.), UpToDate. Retrieved April 8, 2021, from https://www.uptodate.com/contents/tumor-lysis-syndrome-prevention-and-treatment
  9. Gale, R.P. (2020). Management of adverse effects of cancer therapy. MSD Manual Professional Version. Retrieved April 8, 2021, from https://www.msdmanuals.com/professional/hematology-and-oncology/principles-of-cancer-therapy/management-of-adverse-effects-of-cancer-therapy
  10. Adeyinka, A., and Bashir, K. (2020). Tumor lysis syndrome. [online] StatPearls. Retrieved April 8, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK518985/

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