What is Tumor Lysis Syndrome?
Tumor lysis syndrome (TLS) is a medical condition that can either occur by itself or after starting chemotherapy. It’s associated with certain metabolic imbalances, including high potassium levels (hyperkalemia), high phosphate levels (hyperphosphatemia), low calcium levels (hypocalcemia), and high levels of uric acid (hyperuricemia) in your blood. These imbalances can eventually harm your organs. It is more often seen in patients who have solid tumors.
Significantly, TLS is a metabolic and cancer-related emergency, commonly encountered in medical practice. It is often seen both in adults and children undergoing chemotherapy. Many of the symptoms seen in patients with this condition are due to the release of chemicals from inside the cells which interfere with the normal functioning of targeted organs. Serious complications can develop from TLS, like acute kidney injury (sudden damage to your kidneys), deadly heart rhythm disorders (arrhythmias), and even death.
Cancer is one of the leading causes of sickness and mortality in the United States, and second leading cause of death. The nature of cancer is incredibly diverse, with different types of cancer having different effects on the body. Furthermore, cancerous cells also have different points of origin in the body and have different life cycles. This variability can significantly disrupt the body’s metabolic functions or response.
Usually, TLS develops after one starts chemotherapy treatment. However, there have been cases where TLS developed spontaneously, particularly with advanced blood cancer related diseases. Because this condition can be quite dangerous, it’s crucial to identify patients who are at high risk of developing TLS and initiate preventive therapy as soon as possible. Quick and early recognition of the kidney and metabolic imbalances associated with TLS and starting treatment can save a patient’s life.
What Causes Tumor Lysis Syndrome?
Tumor Lysis Syndrome (TLS), a condition where a large number of cancer cells die rapidly, is often found in patients with leukemia, a type of blood cancer, who have a high white blood cell count. It can also occur in lymphomas, a type of blood cancer affecting the lymphatic system, especially after strong chemotherapy treatment begins. Other types of cancer like hepatoblastoma (a rare liver cancer predominantly in children) or neuroblastoma (a type of cancer often found in the adrenal glands) can also cause TLS. Interestingly, instances have been reported where TLS happens even before the chemotherapy started.
Specialists from around the globe have classified tumors according to their risk of leading to TLS. High-risk tumors include advanced types of Burkitt lymphoma (a fast-growing type of lymphoma) and leukemia, early-stage leukemia or Burkitt lymphoma with elevated lactate dehydrogenase (an enzyme found in the body, high levels of which can indicate tissue damage), and other conditions detailed above.
Intermediate-risk tumors include cases of acute myeloid leukemia (a cancer of the blood and bone marrow) with a certain white cell count, acute lymphocytic leukemia (a type of blood and bone marrow cancer) with a specific white cell count and lactate dehydrogenase level, among others as listed above.
Low-risk tumors include solid cancers, several myelomas (a type of blood cancer), slow-developing lymphomas, chronic lymphocytic leukemia (a type of leukemia in which the bone marrow makes too many lymphocytes, a type of white blood cell), chronic myeloid leukemia (a cancer of the white blood cells), and acute myeloid leukemia with a specific white blood cell count and lactate dehydrogenase level.
In some rare instances, TLS is linked to the use of steroids, biological immunomodulators (drugs that help regulate the immune system), and monoclonal antibodies (laboratory-produced molecules that can precisely target cancer cells). Some specific medications associated with the development of TLS include Thalidomide, Bortezomib, Hydroxyurea, Paclitaxel, Fludarabine, Etoposide, and Zoledronic acid.
In rare cases, TLS has been seen in patients undergoing surgery while under general anesthesia. There have also been unusual instances of TLS in pregnant individuals or in cases of high fever.
Risk Factors and Frequency for Tumor Lysis Syndrome
The exact number of cases of Tumor Lysis Syndrome (TLS), a condition that happens when a lot of cancer cells die all at once, is unknown. However, some factors can increase the risk of this happening. These include having a large number of cancer cells, fast-growing cancer cells, cancer cells very responsive to treatments, and pre-existing kidney ailments. It’s important to note that anyone, regardless of their gender or racial background, can develop TLS.
In a study exploring hospital records, the most common types of cancer associated with TLS were found to be non-Hodgkin lymphoma, solid tumors, acute myeloid leukemia, and acute lymphocytic leukemia. TLS can also happen when cancer treatments like chemotherapy are started. In some rare cases, it can even be triggered by radiation therapy.
Research shows the likelihood of developing TLS varies depending on the type of cancer. Here’s a breakdown of the chances based on different cancer types:
- High-Risk Tumors
- Acute lymphocytic leukemia: 5.2% to 23%
- Acute myeloid leukemia with a WBC count more than 75,000: 18%
- B-cell acute lymphoblastic leukemia: 26.4%
- Burkitt lymphoma: 14.9%
- Intermediate-Risk Tumors
- Acute myeloid leukemia with WBC counts between 25,000 and 50,000: 6%
- Diffuse large B-cell lymphoma: 6%
- Low-risk Tumors
- Acute myeloid leukemia with WBC count less than 25,000: 1%
- Chronic lymphocytic leukemia: 0.33%
- Chronic myelogenous leukemia: mentioned in few cases
- A solid tumor: mentioned in few cases
Signs and Symptoms of Tumor Lysis Syndrome
Tumor Lysis Syndrome (TLS) is a condition that commonly occurs as a result of cancer, specifically when cancerous cells break down at a rapid rate. When examining patients for TLS, doctors focus on understanding when the cancer first appeared and whether there are any general symptoms such as losing weight or losing appetite. Further, respiratory issues like shortness of breath, or difficulty breathing while lying down, can indicate a possible tumor affecting the airway. Urinary symptoms, such as painful urination, pain in the lower back or blood in urine, might also be present. Some symptoms are linked to low calcium levels in the blood, such as nausea, vomiting, seizures, muscle spasms, or mental state changes. TLS may also trigger other symptoms such as fainting, palpitations, fatigue, swollen limbs, a puffy face or a bloated abdomen.
During a physical check, doctors focus on looking for signs of electrolyte imbalance, a common occurrence in TLS. Here’s a list of symptoms related to different imbalances:
- Low Calcium Levels:
- Hand spasms
- Foot spasms
- Overall muscle spasms
- Chvostek sign (facial spasms)
- Trousseau sign (arm spasms)
- Wheezing due to spasms in the airway
- Seizures
- High Levels of Uric Acid and Kidney Blockage:
- Weakness
- Fatigue
- Feeling unwell
- Nausea
- Vomiting
- Metallic taste in the mouth
- Irritability
- Itching all over the body
- Abnormal lung sounds due to fluid overload
- Dulled heart sounds due to inflammation from uric acid
- Joint pain
- Kidney pain
- Skin deposits of calcium phosphate crystals
- Itching
- Gangrene
Symptoms of TLS can appear on their own, or around 72 hours after the start of chemotherapy treatment.
Testing for Tumor Lysis Syndrome
Tumor Lysis Syndrome (TLS) is usually diagnosed based on specific criteria formulated by Cairo and Bishop. However, these criteria have some limitations. The most important one is that these guidelines require chemotherapy to start before diagnosing TLS. Unfortunately, TLS can also occur naturally without the start of chemotherapy. Another limitation is the diagnosis includes high creatinine levels specific for age and gender, but this may not be accurate, especially for patients with Chronic Kidney Disease (CKD) who already have elevated creatinine levels. Lastly, the Cairo-Bishop criteria also take into account how severe the TLS is, ranging from no symptoms (grade 0) to death (grade 4).
To diagnose TLS in a lab, the patient needs to meet two or more of the following criteria within 24 hours, from three days before to seven days after starting chemotherapy:
* An increase in uric acid by 25% from baseline or greater than or equal to 8.0 mg/dL
* An increase in potassium by 25% from baseline or greater than or equal to 6.0 mEq/L
* An increase in phosphorus by 25% from baseline or greater than or equal to 4.5 mg/dL in adults, or 6.5 mg/dL in children
* A decrease in calcium by 25% from baseline or less than or equal to 7.0 mg/dL
The clinical diagnosis of TLS includes lab results plus one or more of the following: creatinine being 1.5 times higher than the normal limit, seizure, cardiac arrhythmia, or sudden death. Any other causes of Acute Kidney Injury (increase in kidney damage markers in a short period of time) must be ruled out.
During the evaluation of TLS, some tests must be carried out:
Imaging, such as X-ray and CT scans of the chest to check if there is a mass and fluid in the chest cavity. CT scan and ultrasound of the abdomen to check if the mass lesion is present in the abdomen or behind it. However, care must be taken with injection of contrast dye due to its potential kidney damage, especially in TLS.
Electrocardiography (ECG) is used to observe heart activity and identify any heart rhythm problems related to high potassium and low calcium levels, which are common symptoms of TLS.
A Complete Blood Count (CBC) can help diagnosing the cancer linked to TLS. High white blood cell count along with low platelet and red blood cell count is often a sign of many cancers.
Comprehensive Metabolic Panel (CMP) should be tested 2 to 3 times a day before and after starting treatment. This test measures blood levels of potassium, calcium, phosphorus, and uric acid, as well as markers of kidney function, all of which are usually abnormal in TLS.
Finally, analysis of the patient’s urine is also important to detect presence of uric acid salt, which can cause blockage and damage to kidneys. Regular urinalysis with an assessment of urine pH, concentration, and volume is required during treatment of TLS.
Treatment Options for Tumor Lysis Syndrome
Treatment of Tumor Lysis Syndrome (TLS), a complication following aggressive cancer treatments, starts with quickly replenishing body fluids. This process, called rapid volume expansion, uses substances known as crystalloids. The goal is to make the kidneys filter more blood (increasing Glomerular Filtration Rate or GFR), helping them filter out toxins associated with TLS. However, for this to work, the kidneys must be functioning correctly. This process should begin two days before chemotherapy and continue for two days afterwards. Proper hydration is essential: 3-3.5 liters/m2 per day or 4-5 liters per day might be necessary, maintaining around 3 liters of daily urine output.
Several medications can also be used in treatment:
Allopurinol – This medication turns into oxypurinol in the body, which helps to reduce the production of uric acid, a compound that can aggravate TLS. However, it doesn’t effectively treat high levels of uric acid that might already be present. It’s mainly beneficial in preventing TLS rather than treating it once it has developed. Side effects may include skin rash, high levels of a type of white blood cell called eosinophils, and sudden inflammation of the liver (acute hepatitis).
Recombinant Urate Oxidase – This medication works by breaking down uric acid into simpler substances thereby controlling high uric acid levels in the blood. It is commonly used in patients undergoing chemotherapy for leukemia, lymphomas, and solid tumors. However, it can potentially cause serious side effects like severe anemia due to its breakdown product, hydrogen peroxide, especially in patients with a condition called glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Sodium Bicarbonate for Urine Alkalinisation – Making urine more alkaline (increasing the pH) can make uric acid more soluble, helping to flush it out of the body. This is achieved by adding sodium bicarbonate to the hydration fluids. However, it can lead to lower calcium levels in the body, which might result in muscle twitching or irregular heartbeat, and might worsen the kidney damage caused by TLS. Therefore, it’s usually only used when Recombinant Urate Oxidase is not readily available, and calcium levels need to be monitored regularly.
Calcium Treatments – Calcium chloride and calcium gluconate can be given through IV to treat low calcium levels. Using Calcium can potentially worsen kidney damage and soft tissue complications caused by the build up of calcium phosphate crystals, so it’s use may necessitate dialysis.
Dialysis or continuous renal replacement therapy might be needed if potassium and phosphorus levels rise dangerously high, combined with kidney injury from TLS. This life-saving treatment cleans your blood of waste products when your kidneys can’t. However, it may lead to sudden, severe overproduction of these substances after the procedure.
Febuxostat – This is a newer medication that can also inhibit uric acid formation, similar to allopurinol. Although more expensive, it doesn’t cause hypersensitivity reactions often associated with allopurinol. In trials, Febuxostat showed good effectiveness at controlling uric acid levels in TLS.
What else can Tumor Lysis Syndrome be?
TLS, or Tumor Lysis Syndrome, can be mistaken for a number of other health conditions that have similar symptoms. These conditions could cause a variety of imbalances in the body’s electrolytes such as:
- High potassium levels (Hyperkalemia)
- High phosphate levels (Hyperphosphatemia)
- High uric acid levels (Hyperuricemia)
Each imbalance could be a sign of other conditions:
High potassium levels could indicate:
- Low levels of calcium (Hypocalcemia)
- Metabolic changes (Metabolic acidosis)
- Adrenal gland disorders (Congenital adrenal hyperplasia)
- Digitalis toxicity
- Kidney damage (Acute tubular necrosis)
- Effects of electrical burn or head trauma
- Muscle breakdown (Rhabdomyolysis)
- Thermal burns
High phosphate levels could be a sign of:
- Monoclonal gammopathy
- Conditions like Waldenstrom macroglobulinemia or multiple myeloma
- Other conditions to consider include pseudohypoparathyroidism, rhabdomyolysis, vitamin D intoxication, misuse of oral saline laxative (Phospho-soda), or false high phosphate levels (Pseudohyperphosphatemia)
High uric acid levels may suggest:
- Hyperparathyroidism or Hypothyroidism
- Kidney stones (Nephrolithiasis)
- Alcoholic or diabetic ketoacidosis
- Conditions like Gout, Pseudogout, or type 1 a glycogen storage disease
- Hemolytic anemia
- Conditions like Hodgkins lymphoma or Uric acid nephropathy
What to expect with Tumor Lysis Syndrome
Information about the long-term outcomes of TLS, either before beginning chemotherapy or after completing it, is somewhat scarce. However, a medication called recombinant urate oxidase has been shown to greatly reduce the occurrence of acute kidney failure that requires dialysis. As our understanding of how TLS works (its pathophysiology) has grown, so have our treatment outcomes improved.
Current procedures and treatments are being amended based on a more comprehensive understanding of how the disease progresses. This newfound knowledge has led to a meaningful reduction in unfavorable outcomes linked with TLS.
