Etiology

Tumor lysis syndrome (TLS) is most commonly associated with the initiation of chemotherapy, particularly regimens with highly active, cell cycle phase-specific drugs (e.g., etoposide, cytarabine).[1][2][16][24]​ There are increasing reports of TLS with targeted agents (e.g., venetoclax, sunitinib, bortezomib) and immunotherapy (e.g., monoclonal antibodies).[9][10][11][12][22][23][24][25][26]

There are reports of TLS occurring with other treatments, such as corticosteroids, hormonal therapy, intrathecal chemotherapy, and radiation therapy, but these are uncommon.[27][28][29][30][31]

Spontaneous TLS (i.e., occurring without initiation of cancer treatment) has also been reported, mainly in association with high-grade hematologic malignancies (e.g., B-cell acute lymphoblastic leukemia).[24] Spontaneous TLS is uncommon.

TLS most commonly develops in highly proliferative hematologic malignancies, particularly high-grade non-Hodgkin lymphoma (e.g., Burkitt lymphoma and diffuse large B-cell lymphoma), acute lymphoblastic leukemia, and acute myeloid leukemia.[1][12] It occurs less frequently in multiple myeloma and the indolent hematologic malignancy, chronic lymphocytic leukemia.[8][9][10][11][16][17]

Reports of TLS in solid (non-hematologic) tumors, such as renal cell cancer, breast cancer, small cell lung cancer, testicular cancer, and neuroblastoma, are uncommon.[19][20][21] However, the incidence of TLS is likely to increase across all malignancies, including solid tumors, due to advances in cancer treatment.[9][10][11][12][22][23][24][25][26][30]

The risk of developing TLS is increased if there is a large tumor burden (i.e., a bulky tumor mass consisting of rapidly dividing cancer cells) and if the tumor is sensitive to chemotherapy or other cancer treatments (e.g., targeted agents).[1][2]​​[3]​[24]​​ Elevated serum lactate dehydrogenase, leukocytosis, and hyperuricemia prior to initiation of cancer treatment correlate with large tumor burden and are considered independent risk factors for TLS.[2][13][32][33]

Pre-existing renal impairment (elevated serum creatinine ≥1.5 times the upper limit of normal), dehydration (with elevated blood urea nitrogen), and volume depletion are predisposing risk factors for TLS that may be modifiable and should be identified prior to initiation of cancer treatment.[1][3]

There is an increased likelihood of developing TLS with advancing age.[13] However, this is most likely related to a reduction in glomerular filtration rate that develops with advancing age. Increasing age is not, therefore, considered an independent risk factor for TLS.[13]

Pathophysiology

TLS is caused by rapid breakdown of large numbers of cancer cells and subsequent release of large amounts of intracellular content (potassium, phosphate, and nucleic acids) into the bloodstream, usually following the initiation of cancer treatment.

Cancer cells have a high turnover rate and contain large amounts of purine nucleic acids (which are metabolized to uric acid) and phosphate. The release of large amounts of intracellular content into the bloodstream overwhelms normal homeostatic mechanisms resulting in hyperuricemia, hyperphosphatemia, hyperkalemia, and/or hypocalcemia.[34]

Large amounts of cellular byproducts in the bloodstream can impair renal function and cause acute kidney injury.

  • Hyperuricemia: in combination with acidic urine and reduced urinary flow, may result in precipitation of uric acid crystals, renal tubular obstruction, and a decline in renal function. This is the most common mechanism of acute kidney injury in TLS.

  • Hyperphosphatemia: may lead to the formation of calcium phosphate crystals and precipitation resulting in nephrocalcinosis and urinary obstruction.

  • Secondary hypocalcemia: reported as a consequence of hyperphosphatemia; may be symptomatic if severe.

  • Hyperkalemia: related to massive cell degradation; may be exacerbated by the development of acute kidney injury or lactic acidosis.

The clinical manifestations of TLS are directly related to these pathophysiologic abnormalities. Hyperkalemia, hyperphosphatemia, and hypocalcemia may result in cardiac arrhythmias and sudden death. Hypocalcemia can lead to muscle cramps, tetany, and seizures. Acute kidney injury may lead to fluid overload and pulmonary edema.[2][35][6]

Classification

Cairo and Bishop definition of laboratory TLS and clinical TLS (2004)[2]

This classification groups patients with TLS into two categories:

  • Laboratory TLS: abnormality in two or more of the following, occurring 3 days before or 7 days after initiation of chemotherapy:

    • Uric acid ≥476 micromol/L (≥8 mg/dL) or 25% increase from baseline

    • Potassium ≥6.0 mmol/L (≥6.0 mEq/L) or 25% increase from baseline

    • Phosphate ≥2.1 mmol/L (≥6.5 mg/dL) in children or ≥1.45 mmol/L (≥4.5 mg/dL) in adults, or 25% increase from baseline

    • Calcium ≤1.75 mmol/L (≤7 mg/dL) or 25% decrease from baseline.

  • Clinical TLS: laboratory TLS plus one or more of the following:

    • Increased serum creatinine (≥1.5 times upper limit of normal)

    • Cardiac arrhythmia or sudden death

    • Seizure.

Etiological classification

Cancer treatment

  • TLS associated with initiation of cancer treatment (chemotherapy, targeted agents, immunotherapy [e.g., monoclonal antibodies], corticosteroids, hormonal therapy, or radiation therapy).

Spontaneous

  • TLS occurring prior to initiation of cancer treatment.

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