Tumor Lysis Syndrome – Diagnosis and Treatment

Authors: Chris Belcher, MD (EM Resident Physician, University of Kentucky) and Rob Rogers, MD (Professor of EM, University of Kentucky) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

 Background/Diagnosis

Tumor lysis syndrome (TLS) is an oncologic emergency with a constellation of laboratory findings that result from the lysis of cancer cells.  This is typically seen in hematologic cancers, but can be seen more rarely in solid tumor diseases.  TLS can occur spontaneously in cancers with high proliferative rates or more commonly following chemotherapy initiation of large burden cancers as tumor cells are lysed.  This is most likely to occur in acute leukemia and in high-grade lymphomas.  As mentioned above, it can be seen rarely in solid tumors such as breast cancer and small cell cancers that respond rapidly to chemotherapy.

TLS is characterized by the following laboratory findings (1,2):

• Hyperkalemia
• Hyperphosphatemia
• Hyperuricemia (from the release/breakdown of intracellular nucleic acids)
• Hypocalcemia (secondary to calcium-phosphate creation)

The precipitation of uric acid crystals and calcium phosphate crystals in the renal tubules can result in acute kidney injury.

TLS should be on the list of differential diagnoses for any patient who recently started chemotherapy.  It should also be considered in a new diagnosis of malignancy, particularly in a newly diagnosed leukemia/lymphoma patient with a large burden of disease as it can occur prior to initiation of chemotherapy.  As clinical symptoms are typically vague, TLS may be difficult to diagnose. Symptoms can include nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, arrhythmias, cramps, seizures, and other nonspecific symptoms. As these symptoms can also be seen with the initiation of most chemotherapy regimens, TLS is difficult to diagnose clinically and relies on the laboratory findings as outlined above.

Pearl: Obtain extended electrolyte panels in patients at risk for TLS, including those who recently started chemotherapy with vague symptoms. Always consider this diagnosis in patients with vague symptoms.

Treatment

Initial management involves recognition of the syndrome, high volume intravenous fluid administration as tolerated, decreasing uric acid production through allopurinol, decreasing uric acid levels through rasburicase if indicated, and determining the need for renal replacement therapy (RRT).

Hyperkalemia is the most immediate life-threatening issue and should be initially medically managed per usual protocols. All patients at risk should receive an EKG early in their workup and given calcium if changes are present. If indicated or hyperkalemia doesn’t respond to medical therapy, RRT should be initiated in consultation with nephrology.  High volume intravenous fluids should be started to decrease the risk of crystal precipitation. The goal is a urine output of 100 ml/m2/hour in adults (3).  A good starting point for those able to tolerate is 1.5 times maintenance fluid.  Symptomatic hypocalcemia should be treated with calcium as indicated or RRT as needed.

Alkalinization of the urine has been previously advocated to increase the solubility of uric acid.  There has been no data to support the efficacy of this approach (3).  Due to the widespread use of hypouricemic agents, uric acid crystallization has become less of an issue than in the past. Furthermore, alkalinization promotes calcium phosphate deposition which increases risk for organ injury.

Allopurinol should be used in those who are at risk of TLS. It competitively inhibits xanthine oxidase, thus decreasing the formation of uric acid.  For those who have markedly elevated levels of uric acid already, it will not decrease those levels and they should be considered for rasburicase based on your local pharmacy protocols.

Rasburicase is a recombinant form of the enzyme urate oxidase and catalyzes the conversion of uric acid to allantoin which is water soluble (4).  This rapidly breaks down already existing uric acid and uric acid byproducts into water soluble forms. Rasburicase is contraindicated in those with G6PD deficiency, as it will promote hemolysis and exacerbate TLS.  Its use has dramatically decreased the risk of kidney injury from uric acid crystals in TLS and the need for RRT in these patients.

Indications for RRT are similar to any patient with AKI, although the provider should be consulting with nephrology early in their stay to determine the need. Patients with TLS who are oliguric or with a history of chronic kidney disease are more likely to need RRT. Also a condition that precludes high volume fluids such as congestive heart failure makes the need for RRT more likely.  Rasburicase has decreased the risk of nephropathy from uric acid crystallization but patients are still at high risk for acute tubular necrosis due to phosphate crystals (5).  Thus there is a lower threshold to initiate RRT in a patient with TLS.  This decision should be made in conjunction with nephrology and oncology.  Similarly, indications for and usage of phosphate binders should be discussed with nephrology.

Pearl: Begin IV fluid resuscitation, and beware of hyperkalemia. A low threshold for RRT is advised. 

Summary

TLS is an oncological emergency and requires recognition by the emergency provider. A history or new diagnosis of hematological malignancy or recent initiation of chemotherapy should raise suspicion.  Laboratory abnormalities from lysis of cells include hyperkalemia, hyperphosphatemia, elevated uric acid levels, and hypocalcemia.  Treatment goals involve managing hyperkalemia and symptomatic hypocalcemia, high volume intravenous fluids, decreasing uric acid levels and production through use of rasburicase and allopurinol, and determining the need for RRT.   All patients with TLS should be admitted to a highly monitored telemetry or ICU unit as indicated and consultation with nephrology and oncology should be made early in their stay.

References / Further Reading

1. McCurdy MT, Shanholtz CB.  Oncologic Emergencies. Crit Care Med. 2012 Jul;40(7):2212-22.  PMID: 22584756
2. Krimsky WS, et al.  Oncologic emergencies for the internist.  Cleve Clin J Med. 2002 Mar;69(3):209-10, 213-4.  PMID 11890211
3. Jones GL, Will A, Jackson GH, Webb NJ, Rule S; British Committee for Standards in Haematology.  Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology.  Br J Haematol. 2015 Jun;169(5):661-71.  PMID: 25876990
4. Cammalleri L, Malaguarnera M.  Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout.  Int J Med Sci. 2007 Mar 2;4(2):83-93.  PMID: 17396159
5. El-Husseini A, Sabucedo A, Lamarche J, Courville C, Peguero A.  Acute kidney injury associated with tumor lysis syndrome: a paradigm shift.  Am J Emerg Med. 2012 Feb;30(2):390.e3-6.  PMID: 21296524