Oncologic emergencies

Oncologic emergencies are a group of potentially life-threatening conditions that can manifest as a result of malignant disease and/or their treatment. These conditions include, but are not limited to, leukostasis, tumor lysis syndrome (TLS), superior vena cava (SVC) syndrome, malignant hypercalcemia, and neutropenic fever. Symptomatic patients must be rapidly assessed with early specialist intervention. Therapeutic goals in the treatment of the underlying oncologic condition (e.g., palliative care) should always be taken into account during management. TLS results from rapid destruction of tumor cells releasing intracellular components into the bloodstream that can damage the kidneys and cause potentially fatal electrolyte imbalances. Management of TLS consists of hydration, correction of electrolyte disturbances and reduction of serum uric acid to preserve kidney function. Leukostasis results from massive amounts of leukocytes that cause microcirculatory obstruction leading to organ ischemia and failure. Management of leukostasis consists of cytoreduction, hydration, and prophylaxis against TLS. SVC syndrome results from impaired blood flow from the SVC into the heart, which leads to venous congestion in the head and upper extremities. Management of SVC syndrome depends on the underlying etiology and is aimed at reducing symptoms (e.g., fluid restriction), treating complications (e.g., cerebral edema), and restoring blood flow pharmacologically, radiologically, or mechanically.

This article covers tumor lysis syndrome, leukostasis, and superior vena cava syndrome. Neutropenic fever and hypercalcemia are discussed in separate articles.

Definition ^[1][2]

A potentially life-threatening oncologic emergency; resulting from the rapid destruction of tumor cells, which leads to a massive release of intracellular components; , e.g., potassium (K+), phosphate (PO₄^3-), and uric acid, that can damage the kidneys and cause renal failure.

Etiology ^[1][2]

• TLS most commonly occurs after initiating cytotoxic treatment in patients with hematologic malignancies (e.g., ALL, AML, or NHL).
• Can also manifest unrelated to therapy in patients with a very high tumor burden

Pathophysiology

• Tumor cell lysis → release of intracellular components (e.g., K⁺, PO₄^3-, nucleic acids) into the bloodstream
  • ↑ Nucleic acid → conversion to uric acid → hyperuricemia → urate nephropathy and risk of acute kidney injury
  • ↓ Ca²⁺ secondary to PO₄^3- binding → hypocalcemia → neuronal excitability → risk of seizures
  • Hyperphosphatemia: PO₄^3- binds Ca²⁺ and forms calcium phosphate crystals that obstruct renal tubules → acute kidney injury
  • Hyperkalemia: changes in resting membrane potential → risk of cardiac arrhythmias

Think of “PUKE calcium” to remember the electrolytes affected in tumor lysis syndrome: Phosphorus, Uric acid, and potassium (K⁺) are Elevated; Calcium is decreased.

Clinical features ^[3]

Signs and symptoms are closely related to the degree of electrolyte abnormalities and acute kidney injury.

• Renal failure: e.g., edema, lethargy, oliguria
• Hyperkalemia: : e.g., cardiac arrhythmias; , nausea, vomiting, and diarrhea
• Hypocalcemia: : e.g., tetany, muscle cramps, seizures

Electrolyte abnormalities in TLS can lead to seizures, cardiac arrhythmias, and sudden cardiac death. ^[1]

Diagnostics ^[1]

Consider TLS in any patient with hematological malignancies and hyperleukocytosis who have electrolyte imbalances, kidney failure, or recently initiated cytotoxic therapy.

• Routine tests
  • BMP
    • ↑ Creatinine: may indicate AKI
    • ↑ K⁺
    • ↓ Ca²⁺
  • CBC
    • WBC count: often ≥ 50,000–100,000/mm³
    • Possibly ↓ hemoglobin and ↓ platelets
  • Urinalysis : presence of uric acid crystals
  • ECG: to detect cardiac arrhythmias due to electrolyte abnormalities (see “Diagnostics” in “Hyperkalemia” and “Hypocalcemia”)
• Other important markers of cell lysis
  • ↑ LDH
  • ↑ PO₄^3-
  • ↑ Uric acid

Diagnostic criteria

Although there is no universally established classification of TLS, the Cairo-Bishop definition is widely used to help confirm the diagnosis and guide management. ^[2][4]

Management of TLS ^[1][2][4][5]

• Identify patients with established TLS and those at high risk (e.g., hematological malignancy, chemotherapy) ^[6]
• Start intensive fluid therapy, uric acid reduction, and correction of electrolyte imbalances.
• Consider notifying ICU, nephrology, and oncology early on.

Renal replacement therapy is indicated if the following complications are intractable: fluid overload, electrolyte imbalances, or hyperuricemia.

Fluid management

Hydration is the mainstay of TLS prophylaxis and treatment.

• Low-risk patients: oral hydration, monitor fluid balance, consider IV hydration
• Intermediate and high-risk patients, or established TLS: aggressive IV hydration (see “IV fluid therapy”)
  • Hyperhydration with isotonic crystalloids (e.g., 0.9% NaCl ) ^[7]
  • Close monitoring for fluid overload
    • Target urine output: ≥ 2 mL/kg/hour
    • To maintain adequate urine output, consider administering loop diuretics (e.g., furosemide ) once the patient is hydrated.

Hydration is the most effective preventive measure.

Avoid nephrotoxic drugs (e.g., NSAIDs) and fluids with added potassium due to the risk of hyperkalemia.

Electrolyte imbalances

Monitor electrolytes regularly, as they can be also be affected by fluid therapy.

• Hyperkalemia: cardiac monitoring and standard therapy for hyperkalemia if K⁺ ≥ 6 mEq/L, e.g., glucose and insulin (rapid action)
• Hyperphosphatemia: hydration and possibly oral phosphate binders, e.g., sevelamer
• Hypocalcemia: Treat only if symptomatic and give the lowest calcium dose to relieve symptoms (see “Hypocalcemia”)

Hyperuricemia

• Allopurinol
  • Indicated as prophylaxis in patients at low to intermediate risk
  • No additional benefit to combining with rasburicase
• Rasburicase: recombinant uricase that catalyzes the breakdown of uric acid to allantoin
  • Indications and dosing
    • Treatment of established TLS: rasburicase infusion .
    • Prophylaxis for intermediate to high-risk patients: rasburicase infusion OR single fixed-dose rasburicase
  • Contraindications: G6PD deficiency, which can precipitate hemolytic anemia
• Urinary alkalinization: no longer routinely recommended

Rasburicase is indicated for patients with established TLS or those at intermediate to high risk for TLS.

Acute management checklist for established TLS

• Continuous cardiac monitoring
• Consult ICU and oncology.
• Start vigorous hydration with IV isotonic crystalloids.
• Treat electrolyte imbalances: hyperkalemia, hyperphosphatemia, hypocalcemia.
• Give rasburicase unless contraindicated.
• Stop nephrotoxic medications (e.g., NSAIDs).
• Order frequent electrolytes, kidney function, and markers of cell lysis.
• Monitor urine output every hour and fluid balance frequently.
• Nephrology consult for hemodialysis if there is intractable hyperkalemia, hyperuricemia, or fluid overload.

Definitions ^[8]

• Leukostasis: a medical emergency characterized by tissue hypoxia and hypercoagulability due to an excessive number of immature leukocytes causing microvascular obstruction
• Hyperleukocytosis: a leukocyte count > 100,000/mm³ that may or may not be accompanied by leukostasis ^[8]

Etiology ^[8][9]

• Most commonly occurs in acute leukemia: more common in AML than ALL ; ^[10]
  • AML: with WBC > 150,000/mm³
  • ALL: with WBC > 400,000/mm³
• Rarely seen in chronic leukemia
  • CML: almost exclusively in accelerated phases or blast crisis
  • CLL: with extremely high WBC (> 1,000,000/mm³).

Pathophysiology

• Very high number of leukemic blasts → increased viscosity of blood → increased risk of vascular obstruction → tissue hypoxemia and infarction → clinical features of leukostasis
• Contributing factors: endothelial activation and high metabolic activity of the dividing immature leukocytes ^[5]

Clinical features ^[5][9]

Clinical features depend on the affected system or organ. Although the lungs and the CNS are most commonly affected; , leukostasis can also cause TLS and DIC (a frequent complication of APL).

• Respiratory ^[9]
  • Dyspnea and tachypnea
  • Pulmonary crackles
  • Hypoxemic respiratory failure
• Neurological
  • Headache, confusion
  • Dizziness, vertigo, focal neurological deficits
  • Seizures
• Ophthalmological: blurry vision, retinal hemorrhages, papilledema
• Others
  • Fever (common)
  • Acute kidney injury symptoms
  • Deep venous thrombosis, myocardial infarction, priapism
  • Symptoms of concomitant TLS or DIC

Diagnostics ^[5][9]

• Leukostasis is primarily a clinical diagnosis.
• High index of suspicion in oncologic patients with clinical features suggestive of end-organ damage
• Hyperleukocytosis is commonly present but not mandatory for diagnosis.

Laboratory studies ^[5][9]

Findings are nonspecific and vary widely depending on the organ system involved and the underlying condition.

• Routine tests
  • CBC with peripheral blood smear (PBS)
    • ↑ WBC count, hyperleukocytosis
    • Anemia
    • Overestimated platelet count
  • BMP
    • Signs of renal failure and electrolyte imbalances
    • Pseudohyperkalemia may occur due to WBC death that occurs after sampling.
  • Coagulation studies: signs of DIC (see “Diagnostics” in “Disseminated intravascular coagulation”)
• Additional tests
  • ABG (in dyspneic patients)
    • True hypoxemia as a sign of pulmonary involvement
    • Spuriously decreased PaO₂ (pseudohypoxemia) ^[9]
  • Diagnostic microbiology (e.g., blood cultures): in patients with suspected infection ^[9]

Hyperleukocytosis can lead to falsely normal platelet counts, falsely reduced PaO₂, and falsely elevated potassium levels.

Imaging and additional studies ^[9]

Additional diagnostics should be guided by clinical symptoms and pretest probability and should not unnecessarily delay treatment.

• Chest x-ray (if pulmonary symptoms are present): Findings include pulmonary infiltrates, pleural effusion, or normal CXR
• CT head or MRI head (if neurological symptoms are present): Findings include ischemia, hemorrhage, masses
• Direct fundoscopy: Findings include papilledema, retinal hemorrhages, and dilation of the retinal blood vessels. ^[9]
• Bone marrow examination: required prior to initiating induction chemotherapy ^[9]
• Histopathology : Microvascular occlusion by leukocyte plugs confirms the diagnosis. ^[5]

Leukostasis is a clinical diagnosis in leukemia patients with a markedly elevated WBC count and signs of end-organ damage (particularly the CNS and the lungs). ^[9]

Leukostasis is a medical emergency. Diagnostic studies should not delay treatment.

Treatment ^{[9] [8]}

General principles

• Treatment aims to reduce the WBC count (cytoreduction) and control symptoms.
  • Induction chemotherapy is the only treatment option that improves the survival rate.
  • Leukapheresis and hydroxyurea are bridging therapies that provide rapid symptom control.
• Admit to ICU and involve specialists early.

Cytoreduction

Individualize cytoreductive treatment regimens and involve specialists early.

• Induction chemotherapy: treatment of choice for curative intent ^[8][9]
  • Regimen depends on the underlying condition.
  • Provides sustained response on WBC
  • Usually requires concurrent TLS prophylaxis
• Leukapheresis
  • Indications
    • Symptoms of leukostasis or a WBC ≥ 100,000/mm^{3 [8]}
    • Severe pulmonary and neurological manifestations ^[9]
    • Patients awaiting further diagnostic workup before chemotherapy ^[8][9]
  • Acute promyelocytic leukemia is usually considered a contraindication. ^[8][11]
• Hydroxyurea ^[5][9]
  • Indications
    • Bridging to induction chemotherapy (e.g., while awaiting results of diagnostic studies)
    • Contraindications for induction chemotherapy

Additional measures

• Intravenous fluid resuscitation with IV isotonic crystalloids
• TLS prophylaxis according to risk (see “Tumor lysis syndrome”) and monitoring for DIC
• Avoid blood cell transfusions, if possible.
• Cranial radiotherapy: not routinely recommended ^[5]
• ICU level of care with continuous cardiac monitoring

Acute management checklist for leukostasis

• ABCDE assessment
• Fluid resuscitation
• Order routine laboratory studies, PBS, and coagulation panel.
• Consider differentials (e.g., infection) and order diagnostic studies as needed.
• Start cytoreduction therapy (in consultation with hematology, oncology).
• Discuss individual treatment goals, consider ICU admission.
• Frequent evaluation for signs of TLS and DIC

Definition ^[12]

Venous congestion of the head, neck, and upper extremities resulting from impaired venous flow through the superior vena cava (SVC) to the right atrium.

Etiology ^[13]

Conditions that obstruct the SVC intraluminally (e.g., neoplastic invasion, thrombosis) or due to extraluminal compression (e.g., Pancoast tumors, mediastinal masses). The etiology of SVC syndrome is the basis for its classification.

• Malignant SVC syndrome (most common) ^[12][14]
  • The following entities account for > 80% of all SVC syndrome cases:
    • Non-small cell lung cancer (NSCLC)
    • Small cell lung cancer (SCLC)
    • Non-Hodgkin lymphoma (NHL)
  • Less common: metastatic cancer (usually breast cancer), germ cell tumors, thymoma, mesothelioma
• Nonmalignant SVC syndrome ^[13]
  • Most commonly caused by thrombosis associated with an intravascular device (e.g., dialysis catheter, pacemaker wire) ^[13]
  • Can also be due to other conditions that cause compression of the SVC

Clinical features ^[12][14][15]

Symptoms usually progress over weeks, but rapid deterioration causing emergency presentation can occur. Evaluate patients for signs of increased ICP.

• Hemodynamic symptoms
  • Edema of the upper extremities and face (facial plethora)
  • Prominent venous pattern on the chest, face, and upper extremities
  • Jugular venous distension
  • Orthostatic hypotension
  • Syncope
  • Renal failure
• Symptoms and signs of congestion of the neck
  • Dyspnea
  • Cough and hoarseness
  • Stridor
  • Dysphagia
• Neurological symptoms ^[16]
  • Headache
  • Dizziness
  • Confusion and mental obtundation
  • Visual impairment

Evaluate frequently for signs of laryngeal edema, hemodynamic instability, and ↑ ICP.

Diagnostics ^[13][14]

• Unstable or severely symptomatic patients : invasive venography with or without stent placement (gold-standard)
• Stable patients
  • CT chest with CT venography: modality of choice for most patients ^[17]
    • Findings
      • SVC obstruction
      • Dilated collateral vessels
      • Signs of an underlying condition
  • Doppler ultrasound: initial investigation for suspected catheter-associated thrombosis ^[18]
    • Findings
      • Abnormal flow pattern (e.g., retrograde flow in the internal thoracic vein)
      • Visualization of a thrombus or venous incompressibility in central veins
• Additional investigations
  • MRI chest with MR venography (MRV): if CT is contraindicated (e.g., in pregnancy)
  • Chest x-ray: not routinely recommended ^[19]
    • Nonspecific findings or signs of an underlying condition, including:
      • Mediastinal enlargement
      • Hilar lymphadenopathy
      • Pleural effusion

Management ^[13][20]

General principles

• Patients with severe symptoms usually require emergency endovascular treatment. ^[5]
• Definitive treatment depends on the underlying condition.
  • Malignant SVC syndrome: tumor-specific management
  • Nonmalignant SVC syndrome: directed therapy if possible, anticoagulation if thrombosis is present
• Specialists should be involved early to provide an individualized treatment strategy.

Patients with severe or life-threatening SVC syndrome require emergency treatment (e.g., invasive venography with stent placement).

Supportive measures ^[13][20]

• Head elevation
• Oxygen therapy and pain management
• Consider fluid restriction and/or loop diuretics. ^[12][14]
• Consider removal of intravascular device if catheter-associated thrombosis is present.

Invasive treatment

• Stent placement: for unstable patients or patients with severe symptoms, regardless of the underlying cause
• Surgical bypass or SVC reconstruction: individual decision ^[15][17]

Medical treatment ^[13][14][21]

Radiotherapy and chemotherapy usually require prior histologic confirmation of the underlying malignancy.

• Radiotherapy: radiosensitive tumors
• Chemotherapy: tumors with rapid response to chemotherapy
• Glucocorticoids: steroid-responsive tumors , laryngeal edema or prophylaxis of radiation-induced edema ^[20]
  • E.g., dexamethasone
  • Should be initiated after a histologic sample has been obtained to avoid altering it.
• Antithrombotic therapy
  • Initial parenteral anticoagulation (e.g., enoxaparin ): in SVC syndrome due to thrombotic disease ^[12][14][17]
  • Thrombolysis (systemic or catheter-directed): case-by-case decision ^[17][22]

Acute management checklist for SVC syndrome

• ABCDE assessment
• Elevate the head.
• Supplementary oxygen if needed
• Check for signs of severity (e.g., cerebral edema).
• If unstable, prepare for emergency venography and endovascular treatment.
• Restrict fluids.
• Consider loop diuretics.
• Order routine laboratory studies.
• Order first diagnostic imaging study.
  • Usually CT with CT venography
  • Consider doppler ultrasound if catheter-associated thrombosis is suspected.
• Involve specialists early (vascular surgery, oncology, radiation oncology, interventional radiology).