CME REVIEW ARTICLE
Tumor Lysis Syndrome Risk Factors, Diagnosis, and Management Rebekah A. Burns, MD,* Irina Topoz, MD,† and Sally L. Reynolds, MD‡ Abstract: Tumor lysis syndrome (TLS) is a potentially fatal complication of induction therapy for several types of malignancies. Electrolyte derangements and even downstream complications may also occur prior to the initial presentation to a medical provider, before an oncologic diagnosis has been established. It is therefore imperative that emergency physicians be familiar with the risk factors for TLS in children as well as the criteria for diagnosis and the strategies for prevention and management. Careful evaluation of serum electrolytes, uric acid, and renal function must occur. Patients at risk for TLS and those who already exhibit laboratory or clinical evidence of TLS require close monitoring, aggressive hydration, and appropriate medical treatment. Key Words: tumor lysis syndrome, oncologic emergencies, hyperuricemia, allopurinol, rasburicase (Pediatr Emer Care 2014;30: 571–579)
TARGET AUDIENCE This CME activity is intended for pediatric emergency room physicians, nurses, hospitalists, and general pediatricians.
LEARNING OBJECTIVES After completion of this article, the reader should be able to: 1. Describe the pathophysiology and risk factors for tumor lysis syndrome. 2. Explain preventive and treatment strategies for tumor lysis syndrome including hydration, allopurinol, and rasburicase.
T
umor lysis syndrome (TLS) consists of a set of metabolic derangements resulting from the rapid release of intracellular contents from the lysis of malignant cells. It is most commonly seen in patients suffering from hematologic malignancies such as lymphoma and leukemia but may occur in patients with solid tumors as well. Although TLS is usually seen within 12 to 72 hours of initiating chemotherapy, it can occur prior to treatment and may be present at a child’s initial diagnosis. Complications can be life-threatening, so it is imperative that emergency medicine physicians understand the pathophysiology of this syndrome, as well as the evaluation and management necessary to prevent or mitigate the consequences. Assistant Professor (Burns), *Division of Emergency Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle Children’s Hospital, Seattle, WA; Assistant Professor of Pediatrics (Topoz), †Section of Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO; Medical Director, ‡Emergency Department and Associate Professor of Pediatrics (Reynolds), Division of Pediatric Emergency Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Chicago, IL. The authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interest in, any commercial organizations pertaining to this educational activity. Reprints: Irina Topoz, MD, Section of Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, 13123 E 16th Ave, Box 251, Aurora, CO 80045 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0749-5161
Pediatric Emergency Care • Volume 30, Number 8, August 2014
CASE PRESENTATION A 6 year-old boy is transferred to a children’s hospital emergency department complaining of 2 weeks of leg pain and 3 days of vomiting, abdominal pain, and decreased activity. He has not had a fever, respiratory symptoms, or weight loss. On physical examination, he has diffuse petechiae and tenderness in the left upper quadrant of his abdomen with splenomegaly. Laboratory values include sodium of 142 mEq/L, potassium 4.4 mEq/L, chloride 98 mEq/L, carbon dioxide 29 mEq/L, blood urea nitrogen 21 mg/dL, creatinine 0.56 mg/dL, calcium 10.5 mg/dL, phosphorus 5.3 mg/dL, lactate dehydrogenase (LDH) 438 IU/L, and uric acid 19.2 mg/dL. A complete blood cell count shows a white blood cell count of 79 103/μL with 50% blasts, hemoglobin of 12.6 g/dL, and platelets of 46 103/μL. He is admitted to the oncology service for further workup for malignancy. His physicians are concerned that he has TLS for which he will need further monitoring and management.
Pathophysiology of Tumor Lysis Syndrome Tumor lysis syndrome is caused by the rapid breakdown of tumor cells resulting in a sudden release of intracellular contents including anions, cations, and nucleic acids into the bloodstream. This may lead to electrolyte disturbances including hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Consequences of these abnormalities can be serious and include acute kidney injury, cardiac arrhythmias, seizures, and death. Hyperuricemia results from the release and breakdown of purine nucleic acids. These compounds are metabolized to uric acid by xanthine oxidase via the intermediate compounds of hypoxanthine and xanthine (Fig. 1). Uric acid is poorly soluble in water, and when normal limits of excretion are surpassed, precipitation of crystals occurs in the renal tubules leading to renal insufficiency and, potentially, failure.1 Malignant cells often have a higher phosphate concentration than normal cells.2 Rapid lysis can lead to hyperphosphatemia when the normal homeostatic mechanisms are overwhelmed. Excretion of phosphate may be further impaired because of acute kidney injury either from uric acid crystal deposition or from tumor involvement of the kidneys.3 In the setting of hyperphosphatemia, calcium phosphate precipitation may also occur in renal tubules, contributing further to acute kidney injury.1,4 Hyperphosphatemia may also cause nausea, vomiting, diarrhea, lethargy, or seizures. Hypocalcemia in TLS is a consequence of hyperphosphatemia causing calcium phosphate precipitation in tissues. It may be clinically asymptomatic, or patients may present with neurologic, cardiovascular, or muscular symptoms including seizures, arrhythmias, and tetany.5 Hyperkalemia is a potentially life-threatening consequence of TLS, occurring when large quantities of potassium are released from necrotic tumor cells. Acute kidney injury, if present, can worsen hyperkalemia. A rapid increase in serum potassium levels may result in cardiac arrhythmias and cardiac arrest.6,7
Incidence and Risk Factors Tumor lysis syndrome is associated with malignancies that have high cell turnover rates, large tumor burdens, and high sensitivity www.pec-online.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Pediatric Emergency Care • Volume 30, Number 8, August 2014
Burns
dysfunction have an increased risk of developing electrolyte abnormalities and acute kidney injury.5,20 Furthermore, if the kidneys have been infiltrated by a tumor, including hematologic malignancies, the child is at increased risk for developing TLS.21,22
Presentation Tumor lysis syndrome has been defined in the literature as occurring within 7 days of the initiation of treatment for malignancy, although it most often presents within 12 to 72 hours after starting chemotherapy.5,10,23 However, it has also been reported to occur after administration of steroids, radiation therapy for solid tumors, and total body irradiation.24–27 Electrolyte abnormalities and acute kidney injury may also be present before a malignant diagnosis has been established because of high tumor turnover. Spontaneous TLS and its consequences, including renal failure, have been reported in children with previously undiagnosed leukemia.20 Some children present with TLS in the setting of an infection, including urinary tract infection and pneumonia, suggesting that an inflammatory response can trigger the event.28–30 Spontaneous TLS has also been reported in a child with metastatic germinoma, and in adults, it has been seen in patients with undiagnosed lymphoma, AML, and nonhematologic solid tumors.31–37
Definition and Risk Stratification
FIGURE 1. Purine catabolism.
to treatment.8 It occurs most often in patients with non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Incidence rates of TLS in patients with high-grade non-Hodgkin lymphoma have been reported at up to 42%, although clinically significant derangements were present in only 4.4% to 6.1% of patients.6,9,10 In children with Burkitt lymphoma and preB ALL, the incidence of TLS was 8.4%.9 Tumor lysis syndrome was found in 17% of patients undergoing initial chemotherapy for AML, with 5% developing clinically significant consequences.11 The risk of TLS is also dependent on certain presenting features of the malignancy. In children with a new diagnosis of ALL, age 10 years or older, presence of a mediastinal mass, splenomegaly, or an initial white blood cell count of 20 103/μL or greater have all been shown to be independent risk factors for the development of TLS.12 In patients with AML, an initial white blood cell count of 25 103/μL or greater or an LDH level more than 2 times the upper limit of normal has been shown to be risk factors.11 Although TLS is most often associated with hematologic malignancies, it has been reported with solid tumors as well, especially in the presence of high tumor burden or metastases.13 Tumor lysis syndrome has been seen in children with several forms of solid malignancies including hepatoblastoma, neuroblastoma, thymoma, and neuroectodermal tumors.7,14–19 Although reported cases are rare, the risk is still present. In addition to a malignancy-specific risks, patient factors may also contribute to the development of TLS. Patients who present with dehydration, oliguria, or anuria or those with preexisting renal
572
www.pec-online.com
There have been several proposed definitions for TLS in the literature. Laboratory TLS (L-TLS) refers to specific electrolyte and metabolite abnormalities in the absences of clinical manifestations. Hande and Garrow10 defined L-TLS as a change in at least 2 of 5 measured values, including a 25% increase in serum phosphate, potassium, uric acid, or urea, or a 25% decrease in calcium within 4 days of initial treatment for a malignancy. The CairoBishop5 definition, on the other hand, requires 2 or more laboratory changes to occur between 3 days before and up to 7 days after initial cytotoxic therapy. Criteria for TLS diagnosis under this definition include uric acid of 8 mg/dL or greater, potassium 6.0 mmol/L or greater, phosphorus 2.1 mmol/L or greater, calcium 1.75 mmol/L or less, or a 25% change from baseline in any of these electrolytes. Clinical TLS is defined as presence of L-TLS and at least 1 clinical manifestation including a creatinine 1.5 times the upper limit of normal or greater, arrhythmia/sudden death, or seizure.5 Multiple risk stratification modules have been proposed.8,38,39 Cairo et al23 proposed a single stratification system inclusive of both pediatric and adult patients presenting with all types of malignancy. This system utilizes tumor type, staging, and laboratory values to assign risk. Low-risk disease is defined as less than 1% risk of developing TLS, intermediate risk as a 1% to 5% risk, and high risk as greater than 5% risk. See Tables 1 to 3 for a summary. TABLE 1. TLS Risk Assessment for Solid Tumors and Chronic Hematologic Malignancies Tumor Type
Risk Level
Solid tumor Myeloma CML CLL CLL treated with biologic therapies
LRD LRD LRD* LRD* IRD*
*Renal dysfunction increases risk level by 1 step. Uric acid, phosphate, or potassium level above the upper level of normal increases IRD to HRD. CML indicates chronic myeloid leukemia; CLL, chronic lymphocytic leukemia, LRD, low-risk disease; IRD, intermediate-risk disease; HRD, high-risk disease.
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pediatric Emergency Care • Volume 30, Number 8, August 2014
TABLE 2. Risk Assessment for Leukemia Tumor Type
WBC Count, 103/μL
LDH
Risk Level*
Tumor Lysis Syndrome Risk Factors, Diagnosis, and Management Rebekah A. Burns, MD,* Irina Topoz, MD,† and Sally L. Reynolds, MD‡ Abstract: Tumor lysis syndrome (TLS) is a potentially fatal complication of induction therapy for several types of malignancies. Electrolyte derangements and even downstream complications may also occur prior to the initial presentation to a medical provider, before an oncologic diagnosis has been established. It is therefore imperative that emergency physicians be familiar with the risk factors for TLS in children as well as the criteria for diagnosis and the strategies for prevention and management. Careful evaluation of serum electrolytes, uric acid, and renal function must occur. Patients at risk for TLS and those who already exhibit laboratory or clinical evidence of TLS require close monitoring, aggressive hydration, and appropriate medical treatment. Key Words: tumor lysis syndrome, oncologic emergencies, hyperuricemia, allopurinol, rasburicase (Pediatr Emer Care 2014;30: 571–579)
TARGET AUDIENCE This CME activity is intended for pediatric emergency room physicians, nurses, hospitalists, and general pediatricians.
LEARNING OBJECTIVES After completion of this article, the reader should be able to: 1. Describe the pathophysiology and risk factors for tumor lysis syndrome. 2. Explain preventive and treatment strategies for tumor lysis syndrome including hydration, allopurinol, and rasburicase.
T
umor lysis syndrome (TLS) consists of a set of metabolic derangements resulting from the rapid release of intracellular contents from the lysis of malignant cells. It is most commonly seen in patients suffering from hematologic malignancies such as lymphoma and leukemia but may occur in patients with solid tumors as well. Although TLS is usually seen within 12 to 72 hours of initiating chemotherapy, it can occur prior to treatment and may be present at a child’s initial diagnosis. Complications can be life-threatening, so it is imperative that emergency medicine physicians understand the pathophysiology of this syndrome, as well as the evaluation and management necessary to prevent or mitigate the consequences. Assistant Professor (Burns), *Division of Emergency Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle Children’s Hospital, Seattle, WA; Assistant Professor of Pediatrics (Topoz), †Section of Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO; Medical Director, ‡Emergency Department and Associate Professor of Pediatrics (Reynolds), Division of Pediatric Emergency Medicine, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Chicago, IL. The authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interest in, any commercial organizations pertaining to this educational activity. Reprints: Irina Topoz, MD, Section of Emergency Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, 13123 E 16th Ave, Box 251, Aurora, CO 80045 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0749-5161
Pediatric Emergency Care • Volume 30, Number 8, August 2014
CASE PRESENTATION A 6 year-old boy is transferred to a children’s hospital emergency department complaining of 2 weeks of leg pain and 3 days of vomiting, abdominal pain, and decreased activity. He has not had a fever, respiratory symptoms, or weight loss. On physical examination, he has diffuse petechiae and tenderness in the left upper quadrant of his abdomen with splenomegaly. Laboratory values include sodium of 142 mEq/L, potassium 4.4 mEq/L, chloride 98 mEq/L, carbon dioxide 29 mEq/L, blood urea nitrogen 21 mg/dL, creatinine 0.56 mg/dL, calcium 10.5 mg/dL, phosphorus 5.3 mg/dL, lactate dehydrogenase (LDH) 438 IU/L, and uric acid 19.2 mg/dL. A complete blood cell count shows a white blood cell count of 79 103/μL with 50% blasts, hemoglobin of 12.6 g/dL, and platelets of 46 103/μL. He is admitted to the oncology service for further workup for malignancy. His physicians are concerned that he has TLS for which he will need further monitoring and management.
Pathophysiology of Tumor Lysis Syndrome Tumor lysis syndrome is caused by the rapid breakdown of tumor cells resulting in a sudden release of intracellular contents including anions, cations, and nucleic acids into the bloodstream. This may lead to electrolyte disturbances including hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Consequences of these abnormalities can be serious and include acute kidney injury, cardiac arrhythmias, seizures, and death. Hyperuricemia results from the release and breakdown of purine nucleic acids. These compounds are metabolized to uric acid by xanthine oxidase via the intermediate compounds of hypoxanthine and xanthine (Fig. 1). Uric acid is poorly soluble in water, and when normal limits of excretion are surpassed, precipitation of crystals occurs in the renal tubules leading to renal insufficiency and, potentially, failure.1 Malignant cells often have a higher phosphate concentration than normal cells.2 Rapid lysis can lead to hyperphosphatemia when the normal homeostatic mechanisms are overwhelmed. Excretion of phosphate may be further impaired because of acute kidney injury either from uric acid crystal deposition or from tumor involvement of the kidneys.3 In the setting of hyperphosphatemia, calcium phosphate precipitation may also occur in renal tubules, contributing further to acute kidney injury.1,4 Hyperphosphatemia may also cause nausea, vomiting, diarrhea, lethargy, or seizures. Hypocalcemia in TLS is a consequence of hyperphosphatemia causing calcium phosphate precipitation in tissues. It may be clinically asymptomatic, or patients may present with neurologic, cardiovascular, or muscular symptoms including seizures, arrhythmias, and tetany.5 Hyperkalemia is a potentially life-threatening consequence of TLS, occurring when large quantities of potassium are released from necrotic tumor cells. Acute kidney injury, if present, can worsen hyperkalemia. A rapid increase in serum potassium levels may result in cardiac arrhythmias and cardiac arrest.6,7
Incidence and Risk Factors Tumor lysis syndrome is associated with malignancies that have high cell turnover rates, large tumor burdens, and high sensitivity www.pec-online.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
571
Pediatric Emergency Care • Volume 30, Number 8, August 2014
Burns
dysfunction have an increased risk of developing electrolyte abnormalities and acute kidney injury.5,20 Furthermore, if the kidneys have been infiltrated by a tumor, including hematologic malignancies, the child is at increased risk for developing TLS.21,22
Presentation Tumor lysis syndrome has been defined in the literature as occurring within 7 days of the initiation of treatment for malignancy, although it most often presents within 12 to 72 hours after starting chemotherapy.5,10,23 However, it has also been reported to occur after administration of steroids, radiation therapy for solid tumors, and total body irradiation.24–27 Electrolyte abnormalities and acute kidney injury may also be present before a malignant diagnosis has been established because of high tumor turnover. Spontaneous TLS and its consequences, including renal failure, have been reported in children with previously undiagnosed leukemia.20 Some children present with TLS in the setting of an infection, including urinary tract infection and pneumonia, suggesting that an inflammatory response can trigger the event.28–30 Spontaneous TLS has also been reported in a child with metastatic germinoma, and in adults, it has been seen in patients with undiagnosed lymphoma, AML, and nonhematologic solid tumors.31–37
Definition and Risk Stratification
FIGURE 1. Purine catabolism.
to treatment.8 It occurs most often in patients with non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). Incidence rates of TLS in patients with high-grade non-Hodgkin lymphoma have been reported at up to 42%, although clinically significant derangements were present in only 4.4% to 6.1% of patients.6,9,10 In children with Burkitt lymphoma and preB ALL, the incidence of TLS was 8.4%.9 Tumor lysis syndrome was found in 17% of patients undergoing initial chemotherapy for AML, with 5% developing clinically significant consequences.11 The risk of TLS is also dependent on certain presenting features of the malignancy. In children with a new diagnosis of ALL, age 10 years or older, presence of a mediastinal mass, splenomegaly, or an initial white blood cell count of 20 103/μL or greater have all been shown to be independent risk factors for the development of TLS.12 In patients with AML, an initial white blood cell count of 25 103/μL or greater or an LDH level more than 2 times the upper limit of normal has been shown to be risk factors.11 Although TLS is most often associated with hematologic malignancies, it has been reported with solid tumors as well, especially in the presence of high tumor burden or metastases.13 Tumor lysis syndrome has been seen in children with several forms of solid malignancies including hepatoblastoma, neuroblastoma, thymoma, and neuroectodermal tumors.7,14–19 Although reported cases are rare, the risk is still present. In addition to a malignancy-specific risks, patient factors may also contribute to the development of TLS. Patients who present with dehydration, oliguria, or anuria or those with preexisting renal
572
www.pec-online.com
There have been several proposed definitions for TLS in the literature. Laboratory TLS (L-TLS) refers to specific electrolyte and metabolite abnormalities in the absences of clinical manifestations. Hande and Garrow10 defined L-TLS as a change in at least 2 of 5 measured values, including a 25% increase in serum phosphate, potassium, uric acid, or urea, or a 25% decrease in calcium within 4 days of initial treatment for a malignancy. The CairoBishop5 definition, on the other hand, requires 2 or more laboratory changes to occur between 3 days before and up to 7 days after initial cytotoxic therapy. Criteria for TLS diagnosis under this definition include uric acid of 8 mg/dL or greater, potassium 6.0 mmol/L or greater, phosphorus 2.1 mmol/L or greater, calcium 1.75 mmol/L or less, or a 25% change from baseline in any of these electrolytes. Clinical TLS is defined as presence of L-TLS and at least 1 clinical manifestation including a creatinine 1.5 times the upper limit of normal or greater, arrhythmia/sudden death, or seizure.5 Multiple risk stratification modules have been proposed.8,38,39 Cairo et al23 proposed a single stratification system inclusive of both pediatric and adult patients presenting with all types of malignancy. This system utilizes tumor type, staging, and laboratory values to assign risk. Low-risk disease is defined as less than 1% risk of developing TLS, intermediate risk as a 1% to 5% risk, and high risk as greater than 5% risk. See Tables 1 to 3 for a summary. TABLE 1. TLS Risk Assessment for Solid Tumors and Chronic Hematologic Malignancies Tumor Type
Risk Level
Solid tumor Myeloma CML CLL CLL treated with biologic therapies
LRD LRD LRD* LRD* IRD*
*Renal dysfunction increases risk level by 1 step. Uric acid, phosphate, or potassium level above the upper level of normal increases IRD to HRD. CML indicates chronic myeloid leukemia; CLL, chronic lymphocytic leukemia, LRD, low-risk disease; IRD, intermediate-risk disease; HRD, high-risk disease.
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pediatric Emergency Care • Volume 30, Number 8, August 2014
TABLE 2. Risk Assessment for Leukemia Tumor Type
WBC Count, 103/μL
LDH
Risk Level*
