History and exam

Key diagnostic factors

common

haematological malignancy

Patients with highly proliferative haematological malignancies (e.g., acute lymphoblastic leukaemia and Burkitt's lymphoma) and large tumour burden (i.e., a bulky tumour mass consisting of rapidly dividing cancer cells) are at high risk of TLS.[1][2][4]​​[12][24]​​

Tumours that demonstrate high sensitivity to chemotherapy or other cancer treatments (e.g., targeted agents) are associated with a high risk of TLS.[1][2][4]​​[24]​​

TLS occurs less frequently in multiple myeloma and the indolent haematological malignancy, chronic lymphocytic leukaemia.[8][9][10][11][16][17]

recent cancer treatment (particularly chemotherapy)

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 radiotherapy, but these are uncommon.[27][28][29][30][31]

Clinical manifestations of TLS typically occur within 12 to 72 hours after initiation of cancer treatment.[2][7] Laboratory signs of TLS may appear as early as 6 hours after treatment initiation.[8][9][11]

pre-existing renal impairment

Pre-existing renal impairment (elevated serum creatinine ≥1.5 times the upper limit of normal), dehydration (with elevated urea), 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]

uncommon

cardiac arrhythmia (including syncope, chest pain, dyspnoea)

Cardiac arrhythmia may present as a manifestation of hyperkalaemia, hyperphosphataemia, or hypocalcaemia. It is the most serious manifestation of clinical TLS.

Signs and symptoms include syncope, chest pain, and dyspnoea. If unrecognised or untreated, this can result in sudden death.

seizures

Rarely, this can occur with severe hypocalcaemia or hyperphosphataemia. Seizures are a serious manifestation of clinical TLS that can be rapidly life threatening.

Other diagnostic factors

common

nausea and vomiting

Commonly related to chemotherapy, but may also be related to hyperuricaemia, hyperphosphataemia, or hyperkalaemia associated with TLS.

anorexia

May be due to hyperuricaemia or hyperphosphataemia.

diarrhoea

May be due to hyperuricaemia, hyperphosphataemia, hyperkalaemia, or hypocalcaemia.

muscle weakness

May be due to hyperkalaemia, hyperphosphataemia, or hypocalcaemia.

paralysis

Secondary to hyperkalaemia.[47]

muscle cramps and spasms

May be due to hyperphosphataemia or hypocalcaemia.

lethargy

A common finding that may be due to cancer treatment, underlying malignancy, biochemical abnormalities associated with TLS, or renal failure.

paraesthesia

May be due to hyperkalaemia or hypocalcaemia.

lymphadenopathy

Due to underlying malignancy. Lymphadenopathy may indicate a large tumour burden, which is associated with a high risk of TLS.[3]

splenomegaly

Due to underlying malignancy. Splenomegaly may indicate a large tumour burden, which is associated with a high risk of TLS.[3]

hypertension/hypotension

Volume depletion or excess may be due to acute kidney injury.

oliguria/anuria/haematuria

Manifestations of acute kidney injury.

cloudy urine

May be due to renal impairment.

joint pain/discomfort

May be due to hyperuricaemia.

uncommon

solid tumour malignancy

Rarely, TLS may develop in solid (non-haematological) tumours. (e.g., renal cell cancer, breast cancer, small cell lung cancer, testicular cancer, and neuroblastoma).[19][20][21] However, with advances in cancer treatment and the increasing availability of highly effective therapies (e.g., targeted agents), the incidence of TLS is likely to increase across all malignancies, including solid tumours.[12][22][23][24]

tetany

A sign of severe hypocalcaemia.

Trousseau sign

A sign of severe hypocalcaemia.

Chvostek sign

A sign of severe hypocalcaemia.

laryngeal spasm

Rarely, this can occur with severe hypocalcaemia.

peripheral or pulmonary oedema

May occur as a consequence of fluid overload due to acute kidney injury.

confusion/delirium/hallucinations

A sign of severe hypocalcaemia.

flank pain

Potential manifestation of acute kidney injury.

Risk factors

strong

haematological malignancy

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

large tumour burden

The risk of developing TLS is increased if there is a large tumour burden (i.e., a bulky tumour mass consisting of rapidly dividing cancer cells).[1][2][3]​​[24]​​

The destruction of cancer cells and subsequent release of large quantities of potassium, phosphate, and nucleic acids (which are metabolised to uric acid) into the bloodstream can impair renal function and the ability to excrete these byproducts. The larger the tumour burden, the more cancer cells are destroyed, and the higher the likelihood of developing TLS.[1][18][36]

Elevated serum lactate dehydrogenase, leukocytosis, and hyperuricaemia prior to initiation of cancer treatment correlate with large tumour burden and are considered independent risk factors for TLS.[2][13][32][33]

treatment-sensitive tumours

Tumours that demonstrate high sensitivity to chemotherapy or other cancer treatments (e.g., targeted agents) are associated with a high risk of TLS.[1][2][3]​​[24]​​

recent cancer treatment (particularly chemotherapy)

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][30]

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

Clinical manifestations of TLS typically occur within 12 to 72 hours after initiation of cancer treatment.[2][7] Laboratory signs of TLS may appear as early as 6 hours after treatment initiation.[8][9][11]

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

pre-existing renal impairment

Pre-existing renal impairment (raised serum creatinine ≥1.5 times the upper limit of normal) is a potentially modifiable risk factor predisposing to TLS.[1][3]

dehydration

Dehydration (with raised urea) is a potentially modifiable risk factor predisposing to TLS.[1][3]

volume depletion

Volume depletion is a potentially modifiable risk factor predisposing to TLS.[1][3]

use of nephrotoxic agents

Nephrotoxic agents (e.g., aminoglycoside antibiotics, non-steroidal anti-inflammatory drugs, and intravenous contrast agents) may cause or worsen existing renal impairment, and increase the risk of TLS.[1][3]

weak

advanced age

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]

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