1 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
2 Icahn School of Medicine at Mount Sinai, New York, NY, USA
Background
Definition of disease
Tumor lysis syndrome (TLS) involves massive tumor cell lysis releasing intracellular products into the systemic circulation causing electrolyte derangements including hyperkalemia, hyperphosphatemia, secondary hypocalcemia, and hyperuricemia, often leading to acute kidney injury.
Superior vena cava syndrome (SVCS) results from obstruction of blood flow through the SVC, either by direct tumor invasion or extrinsic compression, thus causing edema and retrograde flow.
Neutropenic fever is a single oral temperature of >38.3°C (101°F) or a temperature of >38°C (100.4°F) sustained for >1 hour occurring in a patient with neutropenia (absolute neutrophil count (ANC) <500 cells/μL), either from chemotherapy or direct myelodysplasia from cancer. It may be the only sign of infection in these immunosuppressed patients and is critical to recognize and act upon it to avoid worsening sepsis and potential death.
Symptomatic leukostasis (SL) occurs in the setting of hyperleukocytosis, commonly seen in patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) in blast crisis, in which leukocyte plugs in the microvasculature decrease tissue perfusion.
Incidence/prevalence
TLS is most commonly associated with hematologic malignancies. The reported incidence rates for patients with non‐Hodgkin’s lymphoma, AML, and acute lymphoblastic leukemia (ALL) are 28%, 27%, and 19%, respectively.
SVCS occurs in approximately 15 000 people in the USA every year. SVCS develops in 5–10% of patients with right‐sided malignant intrathoracic mass lesions.
Neutropenic fever most commonly occurs in patients undergoing chemotherapy; 10–50% in solid tumor and >80% in hematologic malignancies will develop fever associated with neutropenia during one or more chemotherapy cycles. An infectious etiology is only identified in 20–30% of febrile neutropenic episodes.
The incidence of leukostasis varies by leukemia type; it affects up to 10–20% of patients with new AML and 10–30% of patients with new ALL.
Etiology
TLS is most commonly induced by chemotherapy or radiation therapy. TLS also occurs spontaneously, typically in hematologic malignancies with high tumor cell proliferation rates and/or large tumor burdens (bulky disease or high WBC count).
In SVCS, intrathoracic malignancy accounts for 60–85% of cases, along with other benign etiologies, such as thrombosis. Non‐small cell lung cancer (NSCLC) is the most common malignant etiology, causing 50% of cases, followed by small cell lung cancer (SCLC) (25%) and non‐Hodgkin’s lymphoma (10%).
Neutropenic fever is caused by immune suppression from the chemotherapy and directly from the underlying malignancy, which leads to higher susceptibility to various infections.
SL occurs most commonly due to blast crisis in a patient with either AML or CML
Pathology/pathogenesis
TLS occurs in malignancies (most commonly hematologic) with large tumor burdens, high cell proliferation rates, or high sensitivities to treatment.
Initiation of therapies (chemotherapy, radiation, and/or corticosteroids) can induce rapid lysis of tumor cells which causes massive release of intracellular components, such as potassium, phosphate, and nucleic acids (which are metabolized to uric acid). This ultimately can cause hyperkalemia, hyperphosphatemia, hyperuricemia, secondary hypocalcemia, and acute kidney injury.
SVCS occurs due to obstruction caused by direct tumor invasion, external compression by processes involving the apical right lung, lymph nodes, or other structures in the mediastinum, or thrombosis.
As blood flow is obstructed, collateral venous circulation forms; however this process develops over several weeks and is generally insufficient for complete venous drainage, thus causing a marked elevation in upper body venous pressure.
Consequences of this include edema of the head and neck, which can lead to respiratory impairment (dyspnea, cough, stridor) and dysphagia. Life‐threatening complications include cerebral edema and, rarely, hemodynamic compromise.
Neutropenic fever is caused by both direct effects of chemotherapy on the immune system and on mucosal barriers as well as abnormalities in the host immune system due to the malignancy. The risk for specific types of infections is dictated by the specific type of immune deficit (humoral versus cellular).
SL occurs due to increased blood viscosity from large leukemic blasts, exaggerated by cytokine leak and endothelial injury.
Prevention
Screening
There are multiple forms of prevention for patients at high risk for TLS. High risk malignancies include Burkitt’s leukemia, ALL and AML with WBC count >100 000/μL, stage III or IV lymphoblastic lymphomas, or any disease with a serum lactate dehydrogenase (LDH) level greater than two times the upper limit of normal.
Patients at high risk for neutropenic fever are those expected to be profoundly neutropenic (ANC <100 cells/μL) for more than 7 days. Those with ongoing comorbidities including significant renal or hepatic dysfunction are also considered high risk.
No screening exists for SVCS or SL.
Primary prevention
The mainstay of prevention in patients at high risk for TLS is administration of aggressive intravenous hydration (2–3 L/m2/day of IV fluid) as well as prophylactic rasburicase prior to initiation of treatment.
For those at intermediate risk, allopurinol should be given prophylactically as long as uric acid levels are not severely elevated (<8 mg/dL).
The Infectious Disease Society of America guidelines recommend consideration of fluoroquinolone prophylaxis in patients at high risk for profound prolonged neutropenia (anticipated ANC ≤100 cells/μL for >7 days).
Prophylaxis against Candida is recommended in those undergoing allogeneic hematopoietic stem cell transplantation or intensive chemotherapy for leukemia. Prophylactic antibiotics are not recommended in low risk patients.
No interventions have been demonstrated to prevent the development of SVCS or SL.
Secondary prevention
Patients with a history of prior invasive fungal infections (particularly Aspergillus) are at high risk for recurrence with further chemotherapy.
For patients with a history of prior invasive aspergillosis who receive myelosuppressive chemotherapy, voriconazole is recommended for secondary prophylaxis of disease reactivation.
For patients with a history of Candida infections, secondary prophylaxis should be chosen based on prior susceptibilities. HSV‐seropositive patients should receive acyclovir antiviral prophylaxis.
Diagnosis
Clinical diagnosis
History
Regarding TLS, any history of a hematologic malignancy with a large tumor burden (either bulky disease >10 cm in diameter or WBC count >100 000/μL) is relevant. Symptoms associated with metabolic abnormalities, such as nausea, vomiting, diarrhea, fatigue, palpitations, muscle cramps, and syncope, should be sought out.
Regarding SVCS, any history of lung cancer or lymphoma and any prior instrumentation involving the SVC are important. Dyspnea, cough, chest pain, dysphagia, and/or facial swelling and head fullness are common complaints.
Patients at risk for neutropenic fever are those with anticipated prolonged (>7 days), profound neutropenia (<100 cells/μL). Patients with significant comorbidities, such as hypotension, pneumonia, abdominal pain, or neurologic changes, should be started on empiric antimicrobial therapy.
Regarding SL, neurologic symptoms such as visual changes, headache, dizziness, tinnitus, and confusion are common. Pulmonary symptoms such as dyspnea should also be investigated.
Physical examination
Patients with TLS should be evaluated for arrhythmias and tetany.
In patients with neutropenic fever, a thorough evaluation for potential sites of infection including sinuses and oropharynx/dentition, a lung exam (pleural effusion, consolidation), a skin exam (abscesses, joint space infections), and an abdominal exam (any quadrant, suprapubic, or cerebrovascular accident tenderness) should be performed. Rectal exams must be avoided.
Patients with SVCS should be evaluated for facial edema and erythema along with distension of the neck and chest wall veins. Arm edema, facial plethora, and cyanosis are also seen.
Patients with SL may have an abnormal neurologic exam and hypoxia.
Useful clinical decision rules and calculators
Clinical TLS is defined as laboratory TLS plus one or more of the following, not attributable to a therapeutic agent: increased serum creatinine (> than 1.5 times the upper limit of normal), cardiac arrhythmia/sudden death, or a seizure.
Laboratory TLS is defined as any two or more abnormal serum values (uric acid >476 mmol/L or 8 mg/dL, potassium >6.0 mmol/L or 6 mEq/L, phosphorus >1.45 mmol/L or 4.5 mg/dL, calcium <1.75 mmol/L or 7 mg/dL) present within 3 days before or 7 days after instituting chemotherapy in the setting of adequate hydration and use of a hypouricemic agent.
The Multinational Association for Supportive Care in Cancer (MASCC) score can be used to identify patients with neutropenic fever who are low risk for serious medical complications and poor outcome (Table 58.1). Those with a score <21 are high risk and should be admitted to the hospital or ICU for empiric antibiotics.
The severity of TLS can be graded using the Cairo–Bishop clinical TLS grading scale (Table 58.2).
The severity of SL can be graded on the basis of pulmonary, neurologic, or other organ system involvement (Table 58.3).
The severity of SVCS can be graded based on the extent and severity of edema (Table 58.4).
There are no risk scores for SVCS or SL.
Neutropenic fever
High risk patients are those considered to be at high risk for serious complications during fever and neutropenia. They are defined as either those with a MASCC score of <21 or those who have any of the following criteria:
Profound neutropenia (ANC <100 cells/mm2) anticipated to extend >7 days.
Hemodynamic instability.
Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea.
Gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea.
New pulmonary infiltrate, hypoxemia, or underlying chronic lung disease.
Evidence of hepatic insufficiency (defined as aminotransferase levels >5× normal values) or renal insufficiency (defined as a creatinine clearance of <30 mL/min).
Radiographic SVC obstruction in the absence of symptoms
1
Mild
25
Edema in head or neck, cyanosis, plethora
2
Moderate
Edema in head or neck with functional impairment (cough, mild dysphagia, visual disturbance)
3
Severe
10
Mild or moderate cerebral edema or laryngeal edema, diminished cardiac reserve
4
Life‐threatening
5
Significant cerebral edema or laryngeal edema; significant hemodynamic compromise
5
Fatal
<1
Death
Note: Each sign or symptom must be thought due to SVC obstruction
Laboratory diagnosis
List of diagnostic tests
In TLS, serologic testing with LDH, BMP (creatinine, potassium, calcium), and phosphorus is indicated.
In neutropenic fever, one must obtain a CBC with differential, BMP, liver enzymes, at least two sets of blood cultures (with a set collected simultaneously from each lumen of an existing central venous catheter, if present, and from a peripheral venous site) as well as cultures from other sites as clinically indicated.
In SL, PaO2 can be falsely low (due to enhanced metabolic activity of malignant cells). Other important laboratory tests are a CBC with differential, BMP, and labs to evaluate disseminated intravascular coagulation. Pathologically, a biopsy of involved tissue will show white cell plugs in the microvasculature (rarely obtained).
There are no diagnostic tests for SVCS.
List of imaging techniques
When SVCS is suspected a CXR and a CT scan of the neck and chest should be obtained to evaluate for obstructing mass.
In neutropenic fever, a CXR should be ordered to evaluate for possible pulmonary infectious etiology. Further imaging should be ordered as dictated by the clinical picture.
There are no imaging techniques for TLS or SL.
Treatment
Treatment rationale
The best treatment for TLS is prevention, employing continuous cardiac monitoring, serial laboratory evaluations (electrolytes, renal function, uric acid) every 4–6 hours, and rasburicase 0.2 mg/kg with repeated dosing as needed in high risk patients.
In those who develop TLS, the management is largely supportive and consists of correction of electrolyte abnormalities, aggressive hydration, and renal replacement therapy as indicated.
There are multiple modalities used to treat SVCS, depending on the clinical situation (type of tumor, severity of symptoms, patient comorbidities/preferences) (Algorithm 58.1).
In cases of neutropenic fever, broad spectrum antibiotics should be given as soon as possible, most critically within 1 hour of presentation. The initial antibiotic choice is an antipseudomonal beta‐lactam agent (which should be tailored based on clinical picture). A thorough infectious investigation should be pursued (Algorithm 58.2).
With SL, cytoreductive therapy is paramount. Induction chemotherapy should be given immediately. For those who are asymptomatic and unable to receive chemotherapy, hydroxyurea (50–100 mg/kg/day orally) is given. For those who are symptomatic and unable to receive chemotherapy, leukapheresis is used.
When to admit to the ICU
TLS and SL are medical emergencies and typically warrant emergent hospitalization.
Neutropenic fever may warrant ICU admission when symptoms of sepsis are present.
Table of treatment
Disease
Treatment
Tumor lysis syndrome
Conservative: The best treatment is prevention including continuous cardiac monitoring, serial labs (electrolytes, renal function, uric acid) every 4–6 hours, and rasburicase 0.2 mg/kg with repeated dosing as needed in high risk patients
Medical: The management of TLS remains largely supportive with management of electrolyte abnormalities, aggressive hydration, and renal replacement therapy as indicated
SVC syndrome
Combination of conservative, medical, surgical, radiological methods
Neutropenic fever
Medical: Broad‐spectrum antibiotics should be given as soon as possible, most critically within 1 hour of presentation. Initial antibiotic choice is an antipseudomonal beta‐lactam agent (which should be tailored based on clinical picture). A thorough infectious investigations should be pursued
Surgical: If any abscess is identified, it should be drained. Any indwelling catheters or hardware thought to be the source of infection should be removed immediately
Symptomatic leukostasis
Medical: Cytoreductive therapy is paramount. Ideally, induction chemotherapy is given immediately. For those who are asymptomatic and unable to receive chemotherapy, hydroxyurea (50–100 mg/kg/day orally) is given. For those who are symptomatic and unable to receive chemotherapy, leukapheresis is used
The in‐hospital mortality in neutropenic fever is approximately 10%. If critically ill, mortality increases to as high as 50%.
The initial mortality rate for AML and leukostasis is 20–40%. If patients survive initially, they generally have lower rates of remission.
Reading list
Abner A. Approach to the patient who presents with superior vena cava obstruction. Chest 1993; 103(Suppl 4):S394–7.
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127(1):3.
Coiffier B, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence‐based review. J Clin Oncol 2008; 26:2767.
Higdon ML, Higdon JA. Treatment of oncologic emergencies. Am Fam Physician 2006; 74(11):1873–80.
Novotny JR. Grading of symptoms in hyperleukocytic leukaemia: a clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome. Eur J Haematol 2005; 74(6):501–10.
Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome: clinical characteristics and evolving etiology. Medicine (Baltimore) 2006; 85(1):37.
Yu JB. Superior vena cava syndrome – a proposed classification system and algorithm for management. J Thor Onc 2008; 3(8):811.
Guidelines
National society guidelines
Title
Source
Date and reference
Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients With Cancer: 2010 Update by the Infectious Diseases Society of America
Infectious Diseases Society of America
2011 Clin Infect Dis 2011;52(4):e56
Recommendations for the Evaluation of Risk and Prophylaxis of Tumour Lysis Syndrome (TLS) in Adults and Children With Malignant Diseases: An Expert TLS Panel Consensus
TLS Expert Panel
2010 Br J Haematol 2010;149(4):57
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