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 Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, and acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. 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 AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
  • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma
  • Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma

Risk factors

Malignancy characteristics:

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

Concurrent conditions:

  • Preexisting renal insufficiency
  • Oliguria
  • Dehydration
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. 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 Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia and hyperphosphatemia
    • Nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids 
  • Calcium sequestration by phosphate to create calcium phosphate → hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). 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 Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. 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 Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. 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 Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, hyperphosphatemia, hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, and hyperuricemia.

  • Neurological symptoms:
    • Altered mental status
    • Muscle weakness
    • Muscle spasms
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Tetany
    • Paralysis
  • Cardiac symptoms:
    • Palpitations (from cardiac dysrhythmias)
    • Syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
    • Sudden death
  • GI symptoms:
    • Anorexia
    • Nausea and vomiting
    • Abdominal cramps
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Urinary symptoms:
    • Dysuria
    • Oliguria
    • Flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. 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 Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of 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 Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis, hyperaldosteronism Hyperaldosteronism Hyperaldosteronism is defined as the increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Hyperaldosteronism may be primary (resulting from autonomous secretion), or secondary (resulting from physiological secretion due to stimulation of the RAAS). Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Hyperaldosteronism, and medications. Though mostly asymptomatic, hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia can be associated with palpitations, muscle pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, weakness, and fatal cardiac arrhythmias. The diagnosis is made with a serum potassium level. Emergency management of hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia includes administering calcium, IV insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism, crush injuries, rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. 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 Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout, nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. 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 Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. 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 Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis. Management is mostly supportive, including vigorous hydration.   
  • Diabetic ketoacidosis Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises: a life-threatening complication of diabetes characterized by hyperglycemia and ketoacidosis. Symptoms include polyuria, polydipsia, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia, metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis, and acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury. Management includes fluid resuscitation, insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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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