Tumor lysis syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Nazia Fuad M.D.

Synonyms and keywords: TLS; Laboratory Tumor Lysis Syndrome; LTLS; Clinical Tumor Lysis Syndrome; CTLS

Tumor lysis syndrome (TLS) is cosidered to be an oncologic emergency that develops after chemotherapy or radiotherapy. Tumor lysis syndrome is more common in highly proliferative lymphomas and leukemias, and sometimes even without treatment. As evident by its name, tumor cells breakdown with chemotherapy releases potassium, nucleic acids, and phosphorus into the circulation, resulting in hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acute renal failure. The complications of tumor lysis syndrome include nausea, vomiting, diarrhea, anorexia, hematuria, tachycardia, and muscle cramps. Screening for tumor lysis syndrome is not recommended. However, patients with malignancies undergoing treatment or with acute renal failure should be considered for tumor lysis syndrome workup. The essential component in TLS treatment include aggressive hydration and diuresis, treating hyperuricaemia with allopurinol prophylaxis and rasburicase and close monitoring of electrolyte abnormalities.

Tumor lysis syndrome is classified according to the 1993 Hande-Garrow classification system into two groups i.e. laboratory tumor lysis syndrome (LTLS) and clinical tumor lysis syndrome (CTLS).

Tumor lysis syndrome (TLS) is cosidered to be an oncologic emergency that develops after chemotherapy or radiotherapy. Tumor lysis syndrome is more common in highly proliferative lymphomasand leukemias, and sometimes even without treatment. As evident by its name, tumor cells breakdown with chemotherapy releases potassium, nucleic acids, and phosphorus into the circulation, resulting in hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acute renal failure. Hyperuricaemia results from rapid release and catabolism of intracellular nucleic acids. Hyperphosphataemia results from the rapid release of intracellular phosphorous from malignant cells. The malignant cells contain as much as four times the amount of organic and inorganic phosphorous as compared to normal cells. Hyperkalaemia results from breakdown of tumor cells and then becomes exacerbated by the development of renal failure. Hypocalcaemia results from hyperphosphataemia and the precipitation of calcium phosphate crystals in the renal tubules. When the calcium phosphorus levels rises up there is a significant risk of calcium phosphate deposition in the kidney and other tissues. This secondarily leads to systemic hypocalcaemia.

Development of tumor lysis syndrome is the result of initiation of chemotherapy or radiotherapy in cancer patients. The most common causes of tumor lysis syndrome are Burkitt’s lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia and chemotherapy including methotrexate. Sometimes it can occur spontaneously without administration of treatment primarily in patients with non-Hodgkin lymphoma (NHL) or acute leukemia.

Tumor lysis syndrome must be differentiated from other diseases that cause hyperuricemia, hyperkalemia, and hyperphosphatemia, such as acute kidney injury.

The exact incidence of tumor lysis syndrome has not been established. There is no racial or sex predilection for tumor lysis syndrome.

The most potent risk factor in the development of tumor lysis syndrome after initiating chemotherapy is kidney disease. Other risk factors include dehydration, hematologic tumors, and solid tumors.

Screening for tumor lysis syndrome is not recommended. However, patients with malignancies or acute renal failure should be considered for tumor lysis syndrome workup.

If left untreated, patients with tumor lysis syndrome may progress to develop nausea, vomiting, diarrhea, anorexia, hematuria, palpitations, and muscle cramps. Common complications of tumor lysis syndrome include hyperkalemia, hypocalcemia, and hyperphosphatemia. Prognosis is generally good, if not associated with acute renal failure.

The diagnosis of tumor lysis syndrome is based on the Cairo–Bishop criteria, which includes uric acid, potassium, phosphorous, and calcium.

Symptoms of tumor lysis syndrome include nausea, vomiting, diarrhea, oliguria, confusion, delirium, and seizure.

Common physical examination findings of tumor lysis syndrome include edema, cardiac arrhythmia, and tetany.

Laboratory findings consistent with the diagnosis of tumor lysis syndrome include high serum uric acid, potassium, phosphorus, and low calcium.

Electrocardiogram (ECG) may be helpful in the diagnosis of arrhythmias associated with tumor lysis syndrome.

There are no chest x-ray findings associated with tumor lysis syndrome. However, chest x-ray may be useful to detect mediastinal tumors.

There are no CT findings associated with tumor lysis syndrome. However, abdominal CT may be useful to detect abdominal tumors or renal masses.

There are no MRI findings associated with tumor lysis syndrome. However, abdominal MRI may be useful to detect abdominal tumors or renal masses.

There are no ultrasound findings associated with tumor lysis syndrome. However, abdominal ultrasound may be useful to detect abdominal tumors or renal masses.

There are no other imaging studies available for the diagnosis of tumor lysis syndrome.

There are no other diagnostic studies available for the diagnosis of tumor lysis syndrome.

Tumor lysis syndrome is a medical emergency and requires prompt treatment. Patients who develop TLS should receive intensive care with continuous cardiac monitoring and measurement of electrolytes, creatinine, and uric acid every four to six hours. Special attention should be given to correct the electrolyte abnormalities. Hyperurecemia should be treated with rasburicase at 0.2 mg/kg with repeated doses as needed, to wash out the obstructing uric acid crystals with fluids with or without a loop diuretic, and then the appropriate use of renal replacement therapy is also required

There is no surgical intervention for the management of tumor lysis syndrome.

Effective measures for the primary prevention of tumor lysis syndrome include intravenous hydration and administration of either allopurinol or rasburicase.

There are no secondary preventive measures available for tumor lysis syndrome.

The cost-effectiveness of administration of a singe low dose (3 mg) of rasburicase for tumor lysis syndrome prevention in cancer patients may be superior to the daily intravenous allopurinol.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Tumor lysis syndrome was first discovered in 1929 in patients with chronic leukemia. Spontaneous tumor lysis syndrome was first discovered by Crittenden and Ackerman in 1977.

Tumor lysis syndrome was first discovered in 1929 in patients with chronic leukemia.^[1] Spontaneous tumor lysis syndrome was first discovered by Crittenden and Ackerman, in 1977.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Tumor lysis syndrome (TLS) may be classified according to the 1993 Hande-Garrow classification system into two groups: laboratory tumor lysis syndrome (LTLS) and clinical tumor lysis syndrome (CTLS).

Tumor lysis syndrome may be classified according to the 1993 Hande-Garrow classification system into two groups:^[1][2]

• Laboratory tumor lysis syndrome: patients have positive laboratory findings with no signs or symptoms
• Clinical tumor lysis syndrome: patients have life threatening medical signs and require urgent medical interventions

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Nazia Fuad M.D.

Tumor lysis syndrome (TLS) is cosidered to be an oncologic emergency that develops after chemotherapy or radiotherapy. Tumor lysis syndrome is more common in highly proliferative lymphomasand leukemias, and sometimes even without treatment. As evident by its name, tumor cells breakdown with chemotherapy releases potassium, nucleic acids, and phosphorus into the circulation, resulting in hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acute renal failure. Hyperuricaemia results from rapid release and catabolism of intracellular nucleic acids. Hyperphosphataemia results from the rapid release of intracellular phosphorous from malignant cells. The malignant cells contain as much as four times the amount of organic and inorganic phosphorous as compared to normal cells. Hyperkalaemia results from breakdown of tumor cells and then becomes exacerbated by the development of renal failure. Hypocalcaemia results from hyperphosphataemia and the precipitation of calcium phosphate crystals in the renal tubules. When the calcium phosphorus levels rises up there is a significant risk of calcium phosphate deposition in the kidney and other tissues. This secondarily leads to systemic hypocalcaemia.

• Tumor lysis syndroms develops after chemotherapy or radiotherapy usually lymphomas and leukemias, and sometimes even without treatment.^[1][2]
• Massive cells destruction will lead to a rapid release of intracellular anions, cations and metabolic products of proteins and nucleic acids into the bloodstream. As consequences of their high intracellular concentration, potassium, calcium, phosphates and uric acid will be released in the extracellular space.
• Hyperuricaemia results from rapid release and catabolism of intracellular nucleic acids.
• Purine nucleic acids are catabolized to→ hypoxanthine→ xanthine → uric acid by xanthine oxidase.
• Uric acid excretes through the kidney, and approximately 500 mg of uric acid is excreted through the kidneys each day.
• Hyperphosphataemia results from the rapid release of intracellular phosphorous from malignant cells.
• The malignant cells contain as much as four times the amount of organic and inorganic phosphorous as compared to normal cells.
• Initially, the kidneys are able to respond to the increased concentration of phosphorous from tumour lysis by increased urinary excretion and decreased tubular re‐absorption of phosphorous.
• Later on the tubular transport mechanism becomes saturated and serum phosphorous levels rise.
• The development of hyperphosphataemia may be further exacerbated by acute renal insufficiency associated with uric acid precipitation or other complications of tumour therapy,
• Hyperphosphataemia can lead to the development of acute renal failure after the precipitation of calcium phosphate in renal tubules during TLS.
• Hyperkalaemia may also be a life‐threatening consequence of TLS and is partly because of the kidneys inability to clear the large quantities of potassium released after breakdown of tumor cells
• Hyperkalaemia results from breakdown of tumor cells and then becomes exacerbated by the development of renal failure
• The rapid rise in serum potassium may result in severe arrhythmias and sudden death.
• Hypocalcaemia may be asymptomatic or symptomatic.
• Hypocalcaemia results from hyperphosphataemia and the precipitation of calcium-phosphate crystals in the renal tubules.
• When the calcium phosphorus levels rises up there is a significant risk of calcium phosphate deposition in the kidney and other tissues.
• This secondarily leads to systemic hypocalcaemia.
• Uraemia is another common manifestation of TLS
• The most common cause of uraemia during TLS is uric acid crystal formation in the renal tubules secondary to hyperuricaemia.
• Other mechanisms of uremia during TLS include calcium phosphate deposition, tumor infiltration in the kidney, tumor‐associated obstructive uropathy, drug associated‐nephrotoxicity and/or acute sepsis..
• Pretreatment spontaneous tumor lysis syndrome is associated with acute renal failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphomas and leukemias.
• The important distinction between this syndrome and the post-chemotherapy syndrome is that spontaneous tumor lysis syndroms is not associated with hyperphosphatemia. One suggestion for the reason of this is that the high cell turnover rate leads to high uric acid levels through nucleoprotein turnover but the tumor reuses the released phosphate for resynthesis of new tumor cells. In post-chemotherapy tumor lysis syndroms, tumor cells are destroyed and no new tumor cells are being synthesized.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Nazia Fuad M.D.

Development of tumor lysis syndrome is the result of initiation of chemotherapy or radiotherapy in cancer patients. The most common causes of tumor lysis syndrome are Burkitt’s lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia and chemotherapy including methotrexate. Sometimes it can occur spontaneously without administration of treatment primarily in patients with non-Hodgkin lymphoma (NHL) or acute leukemia.

The most common causes of tumor lysis syndrome are:^[1][2]

• Burkitt’s lymphoma
• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Chemotherapy including methotrexate

• Solid tumor
• Myeloma
• Chronic myeloid leukemia CML
• CLL chronic lymphocytic leukemia
• Hodgkin lymphoma
• Small lymphocytic lymphoma
• Marginal zone B cell
• MALT
• Nonblastoid mantle cell
• Cutaneous T cell
• Adult T-cell leukemia

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Bortezomib, Carfilzomib, Cytarabine, cytotoxic chemotherapy, Doxorubicin Hydrochloride etoposide, fludarabine, glucocorticoids, hydroxyurea, Ibrutinib, imatinib, lenalidomide , Nelarabine, Nilotinib, Ofatumumab, paclitaxel, Pralatrexate, rituximab, thalidomide, Vincristine sulfate liposome zoledronic acid
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Acute lymphoblastic leukemia , acute myeloid leukemia, adult T-cell leukemia/lymphoma , anaplastic large cell lymphoma, breast cancer , Burkitt’s lymphoma, chronic myeloid leukemia, diffuse large B-cell lymphoma, gastrointestinal stromal tumors, germ cell tumors , hepatoblastoma, hepatocellular carcinoma, hodgkin’s disease, isolated plasmacytomas, mantle cell lymphoma, medulloblastoma, melanoma, metastatic colorectal cancer , multiple myeloma, neuroblastoma, Non-Hodgkin lymphoma, ovarian cancer , rhabdomyosarcoma, sarcoma, small cell lung cancer, squamous cell carcinoma of the vulva, thalidomide, transformed lymphoma, urothelial cancer
Ophthalmologic	No underlying causes
Overdose/Toxicity
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte
Rheumatology/Immunology/Allergy	No underlying causes|-
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Tumor lysis syndrome must be differentiated from other diseases that cause hyperuricemia, hyperkalemia, and hyperphosphatemia, such as acute kidney injury. The common conditions are hereditary hyperuricemia, Insulin resistance, Hypertension, Obesity, Gout, Alcoholism and renal insufficiency. Patients taking ACE inhibitor, NSAIDs and Antibiotics such as trimethoprim are more prone to hyperkalemia. Hyperphosphatemia is usually seen in Acute kidney injury, Hypoparathyroidism, vitamin D supplementation and also in sarcoidos.

Tumor lysis syndrome must be differentiated from other diseases that cause electrolytes disturbance.^[1]

• Hyperuricemia:^[2]

• Hereditary hyperuricemia
• Insulin resistance
• Hypertension
• Obesity
• Gout
• Alcoholism
• Renal insufficiency
• Medications:

• Diuretics
• Salicylates
• Pyrazinamide
• Ethambutol
• Nicotinic acid
• Ciclosporin

• Hyperkalemia:^[2]

• Renal insufficiency
• Medications

• ACE inhibitor
• angiotensin receptor blockers
• Potassium-sparing diuretics such asamiloride and spironolactone
• NSAIDs such as ibuprofen and naproxen
• Ciclosporin
• Tacrolimus
• Antibiotics such as trimethoprim
• Antiparasitic drugs such as pentamidine

• Mineralocorticoid deficiency or resistance:

• Addison’s disease
• Aldosterone deficiency
• Some forms of congenital adrenal hyperplasia
• Type IV renal tubular acidosis

• Gordon’s syndrome (pseudohypoaldosteronism type II)

• Hyperphosphatemia^[2]

• Acute kidney injury
• Hypoparathyroidism
• Vitamin D
• vitamin A intoxication
• Sarcoidosis
• Immobilization
• Osteolytic metastases
• Milk-alkali syndrome
• Severe hypermagnesemia or hypomagnesemia
• Pseudohypoparathyroidism
• Acromegaly
• Extensive cellular injury or necrosis:

• Crush injury
• Rhabdomyolysis
• Hyperthermia
• Fulminant hepatitis
• Severe hemolytic anemia

• Transcellular phosphate shifts:

• Metabolic acidosis
• Respiratory acidosis

Organ system Conditions Distinguishing features Additional findings Symptoms Signs Labs Tissue break down Tumor lysis syndrome[3] Fever, weight loss, symptoms related to underlying malignancy Altered mental status, lymphadenopathy, muscle weakness Hyperkalemia, hyperphosphatemia, hypocalcemia History of underlying malignancy Rhabdomyolysis[4] Myalgia, fatigue Altered mental status, hypotension Hyperkalemia, increased muscle enzymes (CK, aldolase) History of seizure, drug overdose, or trauma Renal Acute kidney injury[5] Nausea, vomiting, decreased urine output, fatigue, dyspnea, edema Tremor, confusion, edema Hyperkalemia, increased BUN and Cr, metabolic acidosis Recently developed symptoms Chronic kidney disease[6] Nausea, vomiting, decreased urine output, fatigue, dyspnea, edema Tremor, confusion, edema Hyperkalemia, increased BUN and Cr, metabolic acidosis, hypocalcemia, hyperphosphatemia Chronic underlying disease (DM, HTN), duration of symptoms ≥ 3 months Renal tubular acidosis type-4[7] Usually asyptomatic Signs of underlying disease Hyperkalemia, normal anion gap metabolic acidosis, urine PH< 5.5 History of diabetes mellitus Endocrine DKA[8] Change in mental status, abdominal pain Decreased skin turgor, dry oral mucosa, tachycardia Hyperglycemia, increased anion gap metabolic acidosis, ketonemia Rapidly developing polyuria, polydipsia, and weight loss HHS[9] Change in mental status, abdominal pain Decreased skin turgor, dry oral mucosa, tachycardia Severe hyperglycemia, normal anion gap, increased serum osmolality Polyuria, polydipsia, and weight loss develop more insidious Congenital adrenal hyperplasia (CAH)[10][11] Poor feeding, failure to thrive, precocious puberty, short statue, hirsutism, weight loss Ambiguous genitalia, hypotension Hyperkalemia, increased 17 hydroxyprogestrone, hyponatremia Salt wasting Addison’s disease Skin hyperpigmentation, fatigue, salt craving, nausea and vomiting, amenorrhea, depression Hyperpigmentation, hypotension, pubic and axillary hair loss Hyperkalemia, decreased serum cortisol level Diagnosis by cosyntropin test

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

The exact incidence of tumor lysis syndrome has not been established. There is no racial or sex predilection for tumor lysis syndrome.^[1]

The exact incidence of tumor lysis syndrome has not been established.^[1]

There is no racial prediction for tumor lysis syndrome.^[1]

There is no sex prediction for tumor lysis syndrome.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Nazia Fuad M.D.

The most potent risk factor in the development of tumor lysis syndrome after initiating chemotherapy is kidney disease. Other risk factors include dehydration, hematologic tumors, and solid tumors.

The followings are risk factors for developing tumor lysis syndrome after initiating chemotherapy:^[1]

• Common risk factors in the development of tumor lysis syndrome include:^[2]
  • acute lymphoblastic leukemia
  • Non-Hodgkin lymphoma
  • Burkitts lymphoma
  • Older age
  • Dehydration
  • Non-steroidal anti-inflammatory drugs
  • Angiotensin converting enzyme inhibitors
  • angiotensin receptor blockers

• Less common risk factors in the development of TLS include:^[2]
  • Multiple myeloma
  • Melanoma
  • Breast cancer
  • Ovarian cancer
  • Hepatocellular carcinoma
  • Lung cancer
  • Sarcomas

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Screening for tumor lysis syndrome is not recommended. However, patients with any hematologic malignancies or acute renal failure should be considered for tumor lysis syndrome workup.

• Screening for tumor lysis syndrome is not recommended.^[1]
• Patients with malignancies or acute renal failure should be considered for tumor lysis syndrome workup.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

If left untreated, patients with tumor lysis syndrome may progress to develop nausea, vomiting, diarrhea, anorexia, hematuria, palpitations, and muscle cramps. Common complications of tumor lysis syndrome include hyperkalemia, hypocalcemia, and hyperphosphatemia. Prognosis is generally good, if not associated with acute renal failure.^[1]

If left untreated, patients with tumor lysis syndrome may progress to develop nausea, vomiting, diarrhea, anorexia, hematuria, heart palpitations, and muscle cramps. Eventually, tumor lysis syndrome may lead to death.^{[1] [2]}

• Life-threatening conditions may result in death or permanent disability within 24 hours if left untreated.^[1]
• Acute kidney injury
• Arrhythmia
• Seizures
• Tetany

The prognosis of tumor lysis syndrome is good with treatment and if not associated with renal failure. Without treatment, tumor lysis syndrome will result in cardiac arrhythmia and electrolytes disturbance.^[1]

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