Introduction 

Tumour Lysis Syndrome (TLS) is a potentially life-threatening condition that is caused by various metabolic abnormalities which can take place after the initiation of cancer treatment. It is when malignant cells break down rapidly and release their contents into the bloodstream, such as potassium, phosphate and nucleic acids.¹ This results in metabolic disturbances such as:

• Hyperkalemia - increased potassium levels in the blood
• Hyperphosphatemia - increased phosphate levels in the blood
• Hypocalcemia - low calcium levels 
• Hyperuricemia - increased uric acid levels from nucleic acid breakdown

TLS can result in severe complications such as acute kidney injury, acute seizures and cardiac arrhythmias.² They can be fatal if not treated; therefore, early diagnosis is important. This will help with management and treatment for the improvement of patient outcomes. Management strategies may include electrolyte correction, excessive hydration and administration of uric acid-lowering agents, such as allopurinol or rasburicase.³

Management strategies may include electrolyte correction, excessive hydration and use of medications such as rasburicase or allopurinol for treatment and improvements in patient outcome.  

Classification of tumour lysis syndrome

TLS can be classified under two categories: Laboratory Tumour Lysis Syndrome or Clinical Tumour Lysis Syndrome. Segregating patient under appropriate classification upon addressing their clinical manifestations helps with management and treatment.

Laboratory tumour lysis syndrome (LTLS)

LTLS is characterised by metabolic abnormalities without clinical manifestation. The specific diagnostic criteria are based on the Cairo-Bishop definition,  where LTLS refers to the presence of abnormalities in two or more of the following laboratory markers within three days before or seven days after initiating chemotherapy under adequate hydration and use of a uric acid-lowering agent.⁴

• Hyperuricemia: Uric acid > 8 mg/dL or > 476 μmol/L or 25% increase from baseline
• Hyperkalemia: Potassium > 6 mmol/L or a 25% increase from baseline
• Hyperphosphatemia: Phosphate > 4.5 mg/dL in adults or > 6.5 mg/dL in children or a 25% increase from baseline
• Hypocalcemia: Corrected calcium < 7 mg/dL or ionized calcium < 1.12 mmol/L, or a 25% decrease from baseline

Clinical tumour lysis syndrome (CTLS)

Clinical TLS occurs when laboratory abnormalities develop into life-threatening clinical manifestations which require a critical response.⁵ According to the Cairo-Bishop criteria, cTLS is diagnosed when LTLS is accompanied by at least one of the following complications:

Acute kidney injury (AKI), aka acute renal failure, acute kidney failure

A condition characterised by abrupt damage to the kidneys’ ability to work properly due to uric acid or calcium phosphate crystal deposition in renal tubules, leading to obstruction and dysfunction (6). Key clinical indicators of AKI include:

• Serum creatinine will be elevated  ≥ 1.5 times the upper limit of normal (ULN) or baseline.
• Oliguria (< 400 mL/day) or anuria (< 50 mL/day).

Cardiac arrhythmias or sudden death

Hyperkalemia and hypocalcemia can affect cardiac electrical activity in the heart, leading to arrhythmias like fibrillation or ventricular tachycardia. Severe cases may lead to sudden cardiac arrest.^7,8 Symptoms of hyperkalemia may include palpitations, irregular heartbeat, dizziness, or sudden collapse.⁹ Whereas for hypocalcemia, symptoms may include muscle twitching, cramps, numbness or tingling (especially around the mouth or fingers), and even seizures in severe cases.¹⁰

Hyperkalemia 

• Mild (5.5 – 5.9 mmol/litre)
• Moderate (6.0 – 6.4 mmol/litre)
• Severe ( ≥ 6.5 mmol/litre) 

Normal ranges : 3.5–5.0 mmol/L  (7).

TLS threshold is - Potassium > 6 mmol/L or a 25% increase from baseline.

Hypocalcemia (low calcium level in the blood)

• Normal ranges for adults are usually 8.5 to 10.2 milligrams/deciliter (2.15 to 2.55 millimoles/litre) (10)

TLS Threshold - Corrected calcium < 7 mg/dL or ionised calcium < 1.12 mmol/L.

A patient with hyperkalemia and hypocalcemia can significantly increase the risk of life-threatening arrhythmias.

Seizures 

Seizures can be caused by hypocalcaemia or severe metabolic imbalances affecting neuronal excitability (11). Clinical signs include status epilepticus, tonic-clonic seizures or focal seizures in severe cases.

Risk stratification for TLS

To minimise TLS diagnosis, it is crucial to identify the high-risk patients. For instance, patients with:

Hematologic malignancies

Haematological malignancies refer to various types of cancers that are associated with the blood-lymphatic system and bone marrow.^12,13 Patients who undergo chemotherapy are at a high risk of developing hematologic malignancies, such as high-grade lymphomas like Burkitt’s Lymphoma or patients diagnosed with acute leukaemias.¹⁴ 

• Burkitt’s Lymphoma - a high-grade lymphoma characterised by rapid growth of cancer cells in the lymphatic system, predominantly affecting B lymphocytes and can be life-threatening if untreated¹⁵
• Acute Leukaemias - (acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)) is a rapidly progressing cancer that originates in blood-forming tissues such as the bone marrow and the lymphatic system^16,17

Large tumour burden

The presence of significant amounts of cancerous tissue within the body is commonly seen in patients with leukaemia, lymphoma or solid tumours. It increases the risk of TLS, especially after initiating treatment such as chemotherapy.¹⁸

The characteristics of a large tumour burden can include the following:

• High tumour mass: A high volume of tumour tissue is present, which may be detectable through imaging studies such as CT scans, MRIs, or X-rays
• Elevated Tumour Markers: High levels of lactate dehydrogenase (LDH), white blood cell count (WBC), or uric acid in the blood. Elevated LDH levels are indicative of tumour cell turnover, while high WBC counts suggest a large number of malignant cells

Patients with a large tumour burden are at a higher risk of developing TLS due to the rapid breakdown of malignant cells during chemotherapy or other treatments.

Rapid cell proliferation 

Tumours with fast-paced cell breakdown (lysis) release a significant amount of intracellular contents (e.g., potassium, phosphate, uric acid) into the bloodstream, increasing the risk of TLS.¹⁹

Pre-existing conditions

Patients with pre-existing conditions, such as renal dysfunction or baseline metabolic abnormalities, are at increased risk of being diagnosed with TLS

Risk assessment tool and scales for TLS

Risk assessment tools and scales for TLS can help clinicians to understand and determine the patient’s risk of developing TLS. It is crucial for management and identification at an early stage to prevent life-threatening situations.

1. Cairo-Bishop TLS Classification (2004 and 2010): Presents laboratory and clinical features like elevated creatine levels. It can be used to determine if a patient has metabolic abnormalities 
2. TLS Risk Index (Risk Stratification Score): Clinical tool with an index of risk category that is divided into low, moderate or high based on tumour type, tumour burden, blood counts, and pre-existing medical conditions²⁰
3. The NCCN (National Comprehensive Cancer Network) Guidelines for TLS: A guideline that provides preventative, diagnostic and treatment for hematologic malignancies. It determines whether a patient is at high, intermediate, or low risk for TLS and recommends appropriate interventions based on the patient's risk category²¹

Diagnostic tools for TLS

Laboratory monitoring 

1. Serum electrolytes

Identifies intracellular contents, including hyperkalemia, hyperphosphatemia, and hypocalcemia.³

2. Renal function tests (e.g., creatinine, BUN)

Tests assess serum creatinine levels and blood urea nitrogen levels.²²

3. Uric acid levels

Elevated uric acid (hyperuricemia) is monitored alongside identification of the risk of kidney damage²³

Imaging studies (if applicable)

• Ultrasound of the kidneys: Assess hydronephrosis or urinary obstruction
• X-rays or CT Scans: Detection for renal calcification or other TLS complications (tumour mass)
• Chest X-ray: Patients with Burkitt lymphoma must undergo a chest X-ray to identify any large tumour masses that can put the patient at risk of TLS

Differential diagnosis

Metabolic disturbances can occur in many conditions. Therefore, it is essential to rule out these alternative conditions. This can be done by evaluating patients' history, clinical findings and laboratory results.¹ Examples of differentials can be:

1. Acute Kidney Injury (non-TLS causes)
2. Rhabdomyolysis 
3. Sepsis
4. Primary Hyperparathyroidism
5. Hypocalcemia from Vitamin D Deficiency

Summary 

It is essential to recognise TLS at an early stage to prevent further complications. By using the classification systems (LTLS and cTLS), risk assessment tools and diagnostic tests, the clinicians can identify to what extent the patient is at risk. This will enable them to initiate preventative methods to improve patient outcomes. 

FAQs

What is tumour lysis syndrome (TLS)? 

TLS is a condition that is caused by the breakdown of cancer cells after cancer therapy takes place. This process can lead to the release of intracellular content, resulting in metabolic abnormalities such as hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. 

Who is at risk of developing TLS?

Patients who have a risk of:

• Hematologic malignancies
• High tumour burden 
• Elevated tumour markers
• Pre-existing renal disease

What are the symptoms of TLS?³

• Muscle cramps (due to hypocalcemia)
• Weakness or fatigue
• Heart arrhythmias (due to hyperkalemia)
• Decreased urine output or dark-coloured urine (indicating kidney injury)
• Seizures or confusion in severe cases

What are the long-term effects of TLS?

• Chronic kidney disease from kidney damage.
• Risk of secondary infections 
• Cardiovascular problems from severe electrolyte imbalances

Is TLS common in all types of cancers?

No, it is most common in hematologic malignancies.