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Tumor Lysis Syndrome Tumor Lysis Syndrome Thomas B. Russell, MD,* David E. Kram, MD, MCR* *Section of Pediatric Hematology/Oncology, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC Practice Gaps Along with knowledge of how to evaluate a pediatric patient with a suspected malignancy, general pediatricians must maintain a high level of suspicion of tumor lysis syndrome for initial management and timely patient referral. This syndrome is largely preventable, and certainly manageable, with prompt diagnosis and appropriate intervention. Objectives After completing this article, readers should be able to: 1. Define and diagnose tumor lysis syndrome (TLS). 2. Recognize the risk factors for TLS. 3. Stratify pediatric patients with cancer according to risk of developing TLS. 4. Identify interventions to prevent TLS. 5. Discuss management strategies for patients with TLS. INTRODUCTION Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency that occurs when cancer cells break down, either spontaneously or after initiation of cytotoxic chemo- therapy, and release their intracellular contents into the bloodstream. This massive release of uric acid, potassium, and phosphorous, which under normal physiologic conditions are excreted in the urine, can lead to hyperuricemia, hyperkalemia, hyper- phosphatemia, and hypocalcemia. These metabolic derangements increase the risk of severe complications, including acute kidney injury (AKI), cardiac arrhythmias, sei- zures, and even death. TLS is the most common oncologic emergency, and it occurs AUTHOR DISCLOSURE Drs Russell and Kram fi most frequently in children with acute leukemia and non-Hodgkin lymphoma. TLS is have disclosed no nancial relationships relevant to this article. This commentary does often preventable; clinicians must maintain a high index of suspicion and rely on not contain a discussion of an unapproved/ effective prevention and treatment strategies. This review will serve to update the investigative use of a commercial product/ readership on TLS in pediatric oncology patients, including the definition, common risk device. factors, epidemiology, pathophysiology, and clinical consequences, as well as preventive ABBREVIATIONS and management measures for children with suspected or newly diagnosed cancers. AKI acute kidney injury ALL acute lymphoblastic leukemia DEFINITION OF TLS HRD high-risk disease IRD intermediate-risk disease TLS consists of a constellation of laboratory findings, including hyperuricemia, LRD low-risk disease hyperkalemia, hyperphosphatemia, and hypocalcemia and the consequential TLS tumor lysis syndrome 20 Pediatrics in Review Downloaded from http://pedsinreview.aappublications.org/ at Bibliotheque Univ Paris V on January 1, 2020 clinical toxicities from these metabolic abnormalities. The hypocalcemia, which can include an array of symptoms widely accepted classification system for TLS in pediatrics, such as tetany, seizures, and dysrhythmia (particularly in initially proposed by Hande and Garrow in 1993, (1) modified the context of hyperkalemia, or as a consequence of calcium by Cairo and Bishop in 2004, (2) and remodified by Howard phosphate precipitation in the cardiac conduction system). et al in 2011, (3) includes definitions for both laboratory and Hyperuricemia is the consequence of massive purine clinical TLS (Table 1). Laboratory TLS is defined as a level above breakdown (Fig 1). Renal clearance of uric acid, a relatively or below the limits of normal for age for 2 or more of the insoluble metabolite, is highly dependent on glomerular following serum values: elevated uric acid, potassium, or filtration rate and urine pH (exacerbated by urine acidifica- phosphorus and decreased calcium. These abnormalities must tion). An elevated uric acid burden, beyond the body’s also be present during the same 24-hour period and within 3 normal coping mechanisms, can lead to uric acid crystalli- days before or up to 7 days after the initiation of chemotherapy. zation in the renal collecting system, resulting in AKI. Clinical TLS requires the presence of laboratory TLS plus 1 of Xanthine can also precipitate in the renal collecting system, the following clinical sequelae: increased creatinine level, and thus crystal-induced AKI can be caused by calcium seizures, cardiac dysrhythmia, or death. The definition of phosphate, uric acid, and xanthine precipitation and clinical TLS presumes that the symptom of TLS exhibited is obstruction. definitely or at least probably a direct consequence of at least 1 of the laboratory TLS metabolic abnormalities. RISK ASSESSMENT OF TLS PATHOPHYSIOLOGY OF TLS TLS most commonly occurs in patients with tumors that have both a high proliferation rate and a great tumor mass. When malignant cells lyse spontaneously or as a conse- In children, these tumors are predominantly hematologic quence of cytotoxic chemotherapy, they release their intra- malignancies, such as acute lymphoblastic leukemia (ALL), cellular contents, most problematic of which are potassium, Burkitt leukemia/lymphoma, and diffuse large B-cell lym- phosphorus, and nucleic acids. Nucleic acids are metabo- phoma. (4)(5) The lack of a historically unified definition of lized into uric acid. Hyperkalemia can cause life-threatening TLS has made estimating the incidence in children chal- arrhythmias and even sudden death. Hyperphosphatemia lenging. However, 2 multicenter studies in Europe reported can result in intravascular calcium phosphate salt formation a TLS incidence of 4.4% in non-Hodgkin’s lymphoma and and can crystallize in various organs, including the kidney, 8.4% in Burkitt leukemia and ALL. (6) Generally, the leading to AKI. The net loss of serum calcium as a conse- incidence of TLS depends on the type of tumor and tumor quence of precipitation also can lead to symptomatic TABLE 1. Definitions of Laboratory and Clinical TLS Laboratory TLS (‡2) Uric acid > the ULN range for age Potassium ‡6.0 mEq/L (‡6.0 mmol/L) Phosphorus ‡6.5 mg/dL (‡2.1 mmol/L) Calcium (corrected) £7.0 mg/dL (£1.75 mmol/L) Clinical TLS (‡1) ‡ Â Figure 1. Nucleic acid breakdown and mechanisms of action of Serum creatinine 1.5 the ULN for age allopurinol and rasburicase. On cell lysis, DNA is released from the Cardiac arrhythmia or sudden death nucleus and enzymatically degraded eventually into xanthine and uric acid, which is insoluble. Xanthine oxidase converts hypoxanthine to Seizure xanthine, and xanthine to uric acid. Allopurinol is a purine analogue and an inhibitor of xanthine oxidase. This medication prevents new uric acid Neuromuscular instability from being formed; excesses of hypoxanthine and guanine do not contribute to renal calculi. Rasburicase enzymatically converts insoluble TLS¼tumor lysis syndrome, ULN¼upper limit of normal. uric acid into an inactive and water-soluble metabolite, allantoin, which is readily excreted in the urine. This medication reduces serum uric acid levels. Vol. 41 No. 1 JANUARY 2020 21 Downloaded from http://pedsinreview.aappublications.org/ at Bibliotheque Univ Paris V on January 1, 2020 cellular burden and on other risk factors, such as premorbid be considered intermediate. As for lymphomas, aside from patient characteristics such as renal insufficiency and hydra- Hodgkin lymphoma, which is always considered an LRD, tion status. Burkitt lymphoma/leukemia typically has such a the risk for TLS tends to depend on the tumor stage and the high tumor proliferation rate that it can outgrow its own lactate dehydrogenase level, which is a marker of cell pro- metabolic needs, resulting in spontaneous and severe tumor liferation and turnover. lysis at presentation. On the other hand, TLS can occur in children with slow-growing tumors if the tumor is causing MANAGEMENT OF TLS urinary tract obstruction. Finally, the risk of TLS should be considered in parallel with the effectiveness of therapies to TLS management centers on maintaining a high index of cause cell lysis. Historically untreatable cancers are being suspicion, identifying patients at higher risk for TLS, and targeted more effectively, which could lead to TLS in cancer using an aggressive prophylactic strategy to prevent the types previously deemed lower risk. laboratory and clinical manifestations of TLS. This effort In 2008, an international panel of experts in pediatric requires aggressive volume repletion and/or expansion and and adult oncology, as well as experts in TLS pathophysiol- prevention of and treatment of hyperuricemia, hyperkale- ogy, prophylaxis, and treatment, met in an effort to develop a mia, hyperphosphatemia, and hypocalcemia. Any pediatric comprehensive TLS risk stratification system. This panel patient that presents with concerns for a new malignancy developed a final model of low-, intermediate-, and high-risk should undergo up-front measurement of serum uric acid, TLS classification (Figs 2 and 3). (7) Burkitt leukemia/ potassium, phosphorus, and calcium levels, as well as lymphoma and ALL are the highest-risk cancers, and Burkitt serum creatinine levels, along with consideration of empir- leukemia is always a high-risk disease (HRD) for TLS. ical intravenous fluid administration. A quick risk strati- Burkitt lymphoma risk and ALL risk depend on the tumor fication should be considered then, which includes a stage and presenting white blood cell count, respectively. differential diagnosis of the malignancy at hand, as well Solid tumors, on the other hand, are almost always consid- as specific disease features, such as disease stage and initial ered low-risk diseases (LRD); however, in
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