Several complications of childhood leukemia and neuroblastoma — and of the treatment given for them — can become life-threatening within hours, and a child can die of one of them before the cancer itself has been treated. They are recognized from the history and the examination rather than from a test that arrives in time, and each turns on one or two decisions: fluid, antibiotics, position, cytoreduction, steroids. Six of them account for most of the early danger, and they fall into three groups:
- problems caused by the leukemic cells themselves — what they release when they die in large numbers, how they crowd small vessels, and what they do to clotting: tumor lysis syndrome, leukostasis, and the coagulopathy of acute promyelocytic leukemia;
- a mass pressing on a vital structure: the mediastinal mass that compresses the airway, and spinal cord compression;
- infection when treatment has left the child with too few neutrophils: febrile neutropenia.
Tumor lysis syndrome
Tumor lysis syndrome (TLS) is the metabolic consequence of leukemia cells dying in large numbers at once. It can begin spontaneously in bulky disease, but it usually follows the start of chemotherapy, when the breakdown of a large, rapidly dividing population of cells releases potassium, phosphate and nucleic acids into the blood. Four abnormalities follow — hyperkalemia, hyperphosphatemia, hyperuricemia and secondary hypocalcemia — and together they cause acute kidney injury, arrhythmia, seizures and death.
Laboratory tumor lysis syndrome is defined by at least two of these abnormalities occurring in the same 24-hour period, from 3 days before to 7 days after treatment starts:
| Value | Threshold in children | Alternative criterion |
|---|---|---|
| Uric acid | ≥8.0 mg/dL (476 µmol/L) | ≥25% increase from baseline |
| Potassium | ≥6.0 mmol/L | ≥25% increase from baseline |
| Phosphate | ≥6.5 mg/dL (2.1 mmol/L) | ≥25% increase from baseline |
| Calcium | ≤7.0 mg/dL (≤1.75 mmol/L) | ≥25% decrease from baseline |
The phosphate threshold is the one that differs from adult practice, where it is 4.5 mg/dL (1.45 mmol/L). Clinical tumor lysis syndrome is laboratory tumor lysis syndrome plus at least one of: a creatinine at or above 1.5 times the age-adjusted upper limit of normal, an arrhythmia or sudden death, or a seizure.
Management is anticipatory, because the risk can be estimated from the tumor burden before any blood result is abnormal. It consists of intravenous hydration without potassium; frequent measurement of potassium, phosphate, calcium, uric acid, creatinine and lactate dehydrogenase; the uric acid-lowering drugs allopurinol or rasburicase according to risk; and dialysis when hyperkalemia, hyperphosphatemia or renal failure are refractory.
Two details change what is done at the bedside. Rasburicase is not given to a child with glucose-6-phosphate dehydrogenase (G6PD) deficiency, in whom it causes hemolysis and methemoglobinemia. And asymptomatic hypocalcemia is not corrected reflexively, because the added calcium can precipitate with phosphate and worsen the renal injury.
Hyperleukocytosis and leukostasis
Tumor lysis is a problem of too many cells dying; leukostasis is a problem of too many cells circulating. Hyperleukocytosis conventionally means a white cell count above 100 × 10⁹/L. It is a laboratory number, and what it signals is leukostasis: blasts sludging in the small vessels of the brain and lungs, producing organ dysfunction. Leukostasis can occur below that count, and it is more common in acute myeloid leukemia (AML) than in acute lymphoblastic leukemia (ALL), with some myeloid leukemias carrying the risk from a count of about 50 × 10⁹/L.
The findings are neurological or respiratory — headache, confusion, visual disturbance, priapism, a focal deficit, a seizure or altered consciousness at one end, and dyspnea, hypoxemia and diffuse pulmonary infiltrates at the other. The same child often has tumor lysis syndrome and disseminated intravascular coagulation (widespread activation of clotting that uses up platelets and clotting factors) at the same time, and all three are managed together.
The intervention that changes the outcome is leukemia-directed cytoreduction — treatment that lowers the blast count — which is not delayed for anything else. Alongside it, hydration is given cautiously with prophylaxis against tumor lysis, red cell transfusion is avoided or minimized where possible because it raises blood viscosity, platelet support is maintained above about 50 × 10⁹/L, and any coagulopathy is corrected. Leukapheresis, the mechanical removal of white cells from the blood, is used in selected symptomatic children but is not routine, because the evidence that it improves outcome is limited; it is also avoided in suspected acute promyelocytic leukemia (APL), where the procedure can worsen the coagulopathy.
The coagulopathy of acute promyelocytic leukemia
The coagulopathy that leukapheresis can worsen belongs to acute promyelocytic leukemia, a subtype of AML, and it is an emergency of its own. It is present at diagnosis in almost every child with the disease, and it can worsen during the first days of therapy. The leukemic promyelocytes release procoagulant material that activates clotting and fibrinolysis at the same time, so bleeding and thrombosis appear together, and early deaths in APL are usually hemorrhagic.
Any child with a new acute leukemia and abnormal clotting is therefore treated as if they have APL until the translocation result is available: platelets and fibrinogen are replaced, and tretinoin (all-trans retinoic acid) is started on suspicion alone. The lumbar puncture that would otherwise be part of the workup waits until the coagulopathy has resolved.
A mediastinal mass that compresses the airway
The remaining two emergencies are mechanical: a mass that presses on a structure the child cannot do without. The mediastinal mass of T-cell ALL can compress the trachea, the bronchi, the superior vena cava, the pulmonary artery or the heart, and the compromise can progress abruptly, particularly when the child lies flat or is sedated.
The warning signs are a child who cannot lie flat because of breathlessness, stridor or wheeze, facial or upper-limb swelling, distended neck veins, syncope or hypotension. Raising both arms to the sides of the face and producing facial congestion and distress — Pemberton’s sign — points to superior vena cava obstruction. A muffled heart sound with a raised jugular venous pressure and a falling blood pressure raises the possibility of pericardial effusion or tamponade.
Management is mostly a matter of disturbing as little as possible. The child stays in the position of comfort and is not forced to lie flat; oncology and intensive care are involved early; imaging is obtained only in a position the child tolerates; and sedation, general anesthesia and invasive procedures are planned in advance with an anesthetist, because those are the moments at which such children deteriorate. The diagnostic sample should be the least invasive one that will answer the question — peripheral blood flow cytometry, pleural fluid or a marrow aspirate — rather than a deep biopsy. Corticosteroids shrink the mass but can make the diagnosis impossible to confirm, so they are started only after discussion with oncology.
Spinal cord compression
Spinal cord compression is the one emergency in this group that comes from a solid tumor pressing on nervous tissue rather than from the chemistry of the disease or from its treatment. A paravertebral neuroblastoma grows through an intervertebral foramen into the spinal canal as a dumbbell tumor and presses on the cord; neuroblastoma is the tumor most often responsible in children under 5 years, and compression complicates a few percent of childhood cancers overall.
The first signs are easy to miss — back pain, a limp or a refusal to walk, limb weakness, or loss of bladder or bowel control — and the deficit present when treatment starts is what determines the child’s future function. Imaging of the spine is urgent, corticosteroids are given early to limit cord edema, and the tumor is then treated according to its extent and biology, with chemotherapy, surgery or radiotherapy.
Febrile neutropenia
Febrile neutropenia is the most familiar of these emergencies, because it follows routine chemotherapy rather than an unusual tumor burden. Both halves of the term have a working definition:
- Neutropenia means an absolute neutrophil count (the number of neutrophils per litre of blood) of 0.5 × 10⁹/L or less — or 1.0 × 10⁹/L or less when the count is expected to fall below 0.5 × 10⁹/L within the next day or two.
- Fever in this setting is a single temperature of 38.3 °C or above, or 38.0 °C or above sustained for at least an hour.
The combination is treated as possible sepsis: cultures are taken but do not delay treatment, and intravenous antibiotics active against Pseudomonas and other Gram-negative organisms are started without waiting — within 30 minutes if the child has signs of sepsis, and within 60 minutes if not.
Fever itself can be absent, however. A child receiving corticosteroids may be seriously infected without a fever, so an afebrile presentation does not exclude it.
Acting before the result
None of the six can wait for the diagnosis to be complete. Each is treated on suspicion, and each has a decision — fluid, antibiotic, position, cytoreduction or steroid — that is made before the confirmatory result comes back.