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Tumor lysis syndrome is an oncologic emergency that is caused by excessive destruction (lysis) of tumor cells leading to the release of nucleic acids, proteins and intracellular metabolites from tumor cells that cause electrolyte imbalance, harm to the Kidneys and other organs of the body. Tumor lysis syndrome was first described by Bedrna and Polcak in 1929 while treating patients with Chronic Leukemia who are undergoing radiotherapy.
Tumor lysis syndrome Epidemiology
Clinical Tumor lysis syndrome is a rare event affecting about 3 to 6% of people with high grade tumors and occurs more with hematological malignancies such as Leukemia. Tumor lysis syndrome has an overall mortality rate of more than 15%.
Tumor lysis syndrome Causes
- Spontaneously induced by highly proliferative malignancies (tumors)
Tumor lysis syndrome is a metabolic syndrome that is caused by the breakdown of malignant cells and hence, excessive breakdown of these tumor cells by any of the methods use in treating malignancy may cause Tumor lysis syndrome. Even when it is not induced by therapy; Tumor lysis syndrome may still occur when the tumor grows excessively and the rate of growth is higher than the supply of blood to the tumor, this causes some blood deficient parts of the tumor to become destroyed and release of the metabolites occur causing Tumor lysis syndrome.
Tumor Lysis Syndrome Risk Factors
- High grade tumor with rapid cell turnover: a tumor that grows excessively
- High tumor burden/bulky tumor: an overly large tumor that may outgrow its blood supply
- Volume depletion
- Elevated lactate dehydrogenase level of more than twice the normal value
- Treatment with highly active cell cycle specific agents
- Pre-existing renal impairment leading to impaired excretion of body waste
- Increased age
- Concomitant use of drugs that increase uric acid levels such as aspirin, ascorbic acid and thiazide diuretics
These risk factors for Tumor lysis syndrome are related to volume depletion and increased rate of cell breakdown.
Tumor lysis syndrome Types
- Laboratory Tumor lysis syndrome: in this, there is electrolyte imbalance immediately before treatment or during therapy or after treatment for cance
- Clinical Tumor lysis syndrome: when organ failure has occurred or symptoms caused by the electrolyte disturbance occur.
Risk stratification for Tumor lysis syndrome
Principles for risk stratification include:
- To assess whether there is evidence of Tumor lysis syndrome
- To asses if the tumor itself confers high risk of developing Tumor lysis syndrome
- To assess other factors that impact on the risk of development of Tumor lysis syndrome
According to the International Expert Consensus Panel, there are 3 categories of risk stratification with their respective treatment approach.
High risk category
- Acute lymphoblastic leukemia (ALL) or Acute myeloid leukemia (AML) with White Blood Count > 100 x 109/L
- Burkitts lymphoma or lymphoblastic lymphoma
- High-grade lymphoma (Diffuse Large B-Cell Lymphoma or T-cell Non-Hodgkins Lymphoma) with bulky disease
Intermediate risk category
- AML or ALL with WBC 25 100 x 109/L; with Lactate dehydrogenase (LDH) <2x
- Early stage Burkitts or Lymphoblastic lymphoma with LDH <2x or Diffuse Large B-Cell Lymphoma with LDH <2x; or no bulky tumor.
Low risk category
- Indolent lymphomas
- AML with WBC < 25 x109/L and LDH <2x
- Chronic Lymphocytic Leukemia (CLL) or Chronic Myeloid Leukemia (CML)
Tumor lysis syndrome Pathophysiology
Massive destruction of cancer cells causes excessive release of intracellular anions, cations and metabolic products of proteins and nucleic acid into the blood stream that result in organ failure because of electrolyte disturbances.
Types of Electrolyte imbalance in Tumor lysis syndrome
Primary components of Tumor lysis syndrome
- Hyperuricaemia (elevated levels of uric acid)
- Hyperkalemia (raised level of Potassium in the blood)
- Hyperphosphatemia (increased levels of phosphates in blood above normal)
Secondary component of Tumor lysis syndrome include hypocalcemia due to hyperphosphatemia.
Complications caused by Electrolyte imbalances in Tumor lysis syndrome
- Hyperuricaemia: this causes acute urate and xanthine nephropathy. The Uric acid crystals produced cause micro obstruction and decreased Glomerular Filtration Rate (GFR). Also, high uric acid levels cause reduction in Nitric oxide leading to vasoconstriction with subsequent ischemia and Kidney injury may occur.
- Hyperkalemia: this is the first to electrolyte disturbance to occur and it is the most life threatening. In the face of acute kidney injury or chronic kidney disease, there will be limited excretion of potassium and further compound and worsen the complications caused by Tumor Lysis Syndrome.
- Hyperphosphatemia: this leads to binding of calcium and causing secondary hypocalcemia (low levels of calcium in blood). There is formation of calcium-phosphate salts that get deposited in soft tissues including the kidney causing nephropathy or organ failure.
- Hypocalcemia: this is life threatening and is caused by high levels of phosphate in blood. This may persist even after phosphate levels have normalize
Tumor Lysis Syndrome Symptoms and Signs
- Muscle weakness
- Arrhythmia (abnormal heart rate)
- Sudden death
- Paraesthesias (abnormal sensations)
- Tetany (uncontrollable muscle spasm)
- Carpopedal spasms due to low calcium levels
- Acute kidney injury or Oliguria(low urine output of < 0.5ml/kg/hr)
- Lethargy (lack of energy)
- Anorexia (loss of appetite)
- Ecchymoses (bleeding under the skin)
- Gangrenous skin changes
- Malaise (feeling of sickness)
Clinical presentation is a spectrum ranging from symptoms or features of dyselectrolytemia to organ death.
Tumor Lysis Syndrome Laboratory Investigations and findings
- Urea and Electrolyte assessment will show elevated levels of Phospahtes, uric acid, potassium and low levels of calcium.
- Imaging studies such Ultrasound scan, Chest radiograph, CT/MRI scans may help visualize the tumors and their sizes and also outline any deposition of calcium in the kidneys
- Diagnosis of ALL, AML, CLL, CML and other Hematological malignancies could be made by bone marrow aspirations, blood film and full blood count.
- Electrocardiogram to assess the heart electrical activity to check for arrythymia
- Enzymes assay such as LDH used in assessing the risk stratification category
Tumor Lysis Syndrome Treatment
Treatment of Tumor Lysis Syndrome is a multidisciplinary approach and requires a high index of suspicion. The Key to management is to identify patients at risk of developing Tumor Lysis Syndrome and using prophylactic measures to prevent the occurrence.
The best management involves preservation of kidney function, prevent arrythmias and neuromuscular irritability.
Management of Tumor Lysis Syndrome
Prevention of Acute Kidney Injury
- Maintenance of Fluid balance
- Maintain urine output at > 4ml/kg/hr or 100ml/m2/hr (for older children)
- Prophylactic uricosuric agents (drugs that increase the excretion of uric acid in the urine) to prevent crystals formation.
Kidney injury can be prevented by use of drugs such as Xanthine oxidase inhibitors (e.g Allopurinol) or Urate oxidase (e.g Rasburicase)
Prevention of cardiac dysrhythmias and neuromuscular irritability
Treat Hyperkalemia: by limiting the intake of potassium, use of Beta agonists such as albuterol nebules, Oral polystyrene sulfonate and hemodialysis in the presence of intractable hyperkalemia, hyperphosphatemia and fluid overload.
Treat Hypocalcemia: Treat only when it is symptomatic by use of Calcium gluconate or calcium chloride at lowest dose.
Treat Hyperphosphatemia: by use of Phosphate binders, Rasburicase or dialysis
Tumor Lysis Syndrome guidelines
- Alkalinization of urine is not recommended in treatment of Tumor lysis syndrome
- Allopurinol is not a drug of choice in treatment of Tumor lysis syndrome
- Patients with allopurinol allergy should receive rasburicase
- Patients with G6PD deficiency should not receive rasburicase
- Patients with established Tumor lysis syndrome should receive rasburicase
- Peritoneal dialysis is not recommended for treatment of Tumor lysis syndrome
Tumor lysis syndrome Monitoring
- Monitor urine output and fluid balance
- High risk group should be monitor in the Intensive Care Unit especially cardiac monitoring
- Daily monitoring of electrolyte and Uric acid levels
Tumor lysis syndrome Complications
- Fluid overload/pulmonary edema
- Cardiac failure
- Renal impairment
- Multiple organ dysfunction
Tumor lysis syndrome Prevention
- High index of suspicion
- Early diagnosis of malignancies
- Proper risk stratification
- Proper fluid balance: hydration and diuresis
- Prophylactic uricosuric agents
- Early treatment of complications
- Follow up of complications
Tumor lysis syndrome Prognosis
Tumor lysis syndrome has a poor prognosis with acute kidney injury, metastatic tumor and high cell turnover of tumors. There is a higher chance of survival with prevention than with treatment.