Audra L. McCreight
Jonathan E. Wickiser
• Acute leukemia is the most common malignancy in childhood and may present with a variety of symptoms including fever, fatigue, bleeding, adenopathy, or bone pain.
• Most oncologic emergencies arise from metabolic, hematologic, structural, or toxic chemotherapy effects.
• Findings associated with inflammation may be absent in the neutropenic patient, with fever the only sign of serious infection.
• Infection may progress rapidly in the neutropenic host; evaluation and initiation of antibiotic therapy must be done urgently.
• Tumor lysis syndrome (TLS) results from the death of tumor cells and release of their intracellular contents leading to hyperuricemia, hyperphosphatemia, and hyperkalemia.
• Mediastinal compression from the tumors may result in superior vena cava syndrome (SVCS) or superior mediastinal syndrome (SMS), resulting in an airway emergency.
Approximately 10% of childhood deaths are related to cancer.1 The leukemias, central nervous system (CNS) tumors, and lymphomas account for more than one-half of all childhood malignancies. Advances in cancer treatment have led to improvement in survival rate. However, much of this progress has come with increased intensity of treatment regimens. It is important for the emergency physician to be aware of the common malignancies that occur in children and to be ready to treat the complications of cancer at presentation and during treatment.
COMMON PEDIATRIC MALIGNANCIES
Leukemia is a condition in which there is uncontrolled, clonal proliferation of an immature white blood cell (WBC) within the bone marrow, with subsequent suppression of normal hematopoiesis. Acute leukemia is the most common childhood malignancy, representing approximately 30% of newly diagnosed cancers.2 Acute lymphoblastic leukemia (ALL) accounts for approximately 75% of pediatric leukemia, with acute myelogenous leukemia (AML) accounting for the other 25%. Chronic myelogenous leukemia (CML) accounting for less than 1% of all childhood cancers.
The peak incidence of ALL in children occurs between the ages of 3 and 5 years. Overall, approximately 80% of patients survive more than 5 years beyond diagnosis, with many patients considered cured of the disease.3 Unlike ALL, the incidence of AML is relatively constant throughout childhood and has a much poorer prognosis with approximately 60% of patients surviving at 5 years from diagnosis.4
The signs and symptoms of acute leukemia reflect replacement of bone marrow or extramedullary collections of leukemic blasts. Common presentations include pallor, fatigue, petechiae, purpura, and infection as a result of defective hematopoiesis from marrow replacement. Lymphadenopathy, hepatomegaly, splenomegaly, and mediastinal or testicular masses may represent extramedullary involvement. Bone pain results from leukemic involvement of the periosteum and bone, causing patients to limp or even refuse to walk. Leukemia may be present in the CNS, leading to cranial nerve deficits, headache, or changes in vision. The leukocyte count at diagnosis varies greatly and may be high, low, or normal. Even in the absence of neutropenia at diagnosis, patients should be considered immunocompromised as the WBCs produced may not be functional. Most patients will be anemic and/or thrombocytopenic. Despite hematologic abnormalities in the peripheral blood, the diagnosis of leukemia is confirmed by evaluation of the bone marrow. Further morphologic and cytogenetic characterization of the leukemic blasts determines the particular treatment regimen.
Hodgkin lymphoma (HL) is a malignancy of the lymph nodes. The Reed–Sternberg cell is considered to be the malignant cell in classical HL.5 Approximately 5% of pediatric malignancies are HL, with a peak incidence in adolescents and young adults.1 The majority of pediatric patients have painless supraclavicular or cervical lymphadenopathy. Nodes are rubbery, matted, and unlike reactive nodes, do not decrease in size. The abdominal examination may reveal hepatomegaly or splenomegaly. Mediastinal involvement is common, and a chest radiograph should be obtained. Systemic or “B” symptoms may occur in one-third of the patients and include fever, weight loss, and night sweats. The differential diagnosis of HL includes other causes of lymphadenopathy, such as infectious mononucleosis, mycobacterial infections, or other metastatic malignancies. Abnormalities may be seen on complete blood count (CBC) secondary to metastatic disease in the bone marrow. Biopsy of an affected lymph node is required for diagnosis. Treatment regimens include multidrug chemotherapy and/or radiation, with 5-year survival rates of >90%.
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignancies of the lymphatic tissue. Unlike HL there is no peak age incidence, but cases increase steadily with age. Compared to the indolent nature of many adult lymphomas, childhood NHLs are rapidly proliferating and are often disseminated in extranodal tissues at the time of presentation. The most common types of NHL seen in children are Burkitt, Burkitt-like, and large B cell lymphoma (all of mature B cell origin), lymphoblastic lymphoma (predominately of precursor T cell origin), and anaplastic large cell lymphoma (ALCL). Clinically, children with NHL present with clinical symptoms that correlate with the histologic subtype. Lymphoblastic lymphomas often present with a mediastinal mass or supraclavicular adenopathy leading to cough, wheeze, chest pain, airway obstruction, or signs and symptoms of superior vena cava obstruction. Burkitt lymphomas most often present with abdominal involvement causing pain, nausea, vomiting, distension, ascites, or bowel obstruction. Right lower quadrant pain reflects distal ileal, appendiceal, or cecal involvement and may mimic appendicitis. Abdominal lymphoma may be a lead point for an intussusception. Bone, bone marrow, and the CNS are common sites of metastasis. ALCL have a broad spectrum of clinical presentations including lymphadenopathy, skin and bone involvement. Patients presenting with NHL often require emergency management owing to the rapid doubling time and growth rate of the tumor (Burkitt lymphoma) or owing to tumor mass encroachment on vital structures (lymphoblastic lymphoma). Initial laboratory studies include a CBC to assess for marrow involvement as well as electrolytes, creatinine, calcium, phosphorous, and uric acid to evaluate for TLS (discussed later). A chest radiograph may reveal a mediastinal mass (Fig. 107-1). Patients with an abdominal mass are evaluated with abdominal ultrasound or computed tomography (CT) scan. Multiagent chemotherapy with/without radiation is the mainstay of treatment, with up to 80% or higher long-term, disease-free survival depending on histologic type.
FIGURE 107-1. Large mediastinal mass in an 11-year-old boy. Lymphoblasts were seen in the peripheral blood, confirming the diagnosis of T-cell lymphoblastic lymphoma.
CENTRAL NERVOUS SYSTEM TUMORS
Tumors of the CNS account for up to 20% of cancers in childhood.6 Factors increasing the risk of developing a CNS malignancy include various genetic disorders, such as neurofibromatosis or tuberous sclerosis, and exposure to ionizing radiation. Classification of CNS tumors is generally based on histologic type. Tumors arising in the supratentorial region include cerebral astrocytoma, optic glioma, and craniopharyngioma. These occur more commonly in neonates and infants. Infratentorial tumors such as cerebellar astrocytoma, medulloblastoma, ependymoma, and brain stem glioma are more commonly seen after 2 years of age.
Supratentorial tumors may cause headache, seizures, or visual impairment. However, compared to adults, seizure is rarely the initial presenting sign of a CNS tumor. Truncal ataxia or incoordination is typical of infratentorial tumors. Impingement of the brain stem may lead to cranial nerve palsies or Horner syndrome. Raised intracranial pressure (ICP) in infants and toddlers may manifest as vomiting, anorexia, irritability, developmental regression, or impaired upward gaze (“sunsetting” sign). There may be excessive enlargement of the head circumference and persistently palpable cranial sutures. Parents may note a change in behavior or personality in their child. Older children may complain of headache, fatigue, or vomiting. Headaches that are recurrent, intense, associated with vomiting, or that awaken patients from sleep should raise the suspicion of a malignancy. In addition, patients may have back pain, bladder or bowel dysfunction, or focal neurologic deficits that suggest spinal cord or cauda equina involvement.
Other conditions that may present with raised ICP or neurologic deficits include brain abscess, chronic subdural hematoma, and vascular malformations. Tumors of the CNS may be diagnosed by CT; however, magnetic resonance imaging (MRI) is more sensitive.
Wilms tumor (nephroblastoma) arises from embryonal renal cells. The peak age of diagnosis is 2 to 3 years with most cases diagnosed before 5 years of age. Most children appear well at diagnosis with a nontender abdominal mass. Systemic symptoms are rare. Hematuria is uncommon with Wilms tumor, and if present is usually microscopic. Other uncommon features at diagnosis include pain, hypertension, polycythemia, or an acquired von Willebrand disease. Rarely, cases are associated with an underlying genetic predisposition syndrome such as Beckwith–Wiedemann, Denys–Drash, or Wilms tumor, aniridia, genitourinary anomalies, mental retardation (WAGR syndrome).7 Tumor may be present in both kidneys at diagnosis in 5% to 10% of cases. The differential diagnosis includes other conditions that present with abdominal or pelvic mass. Initial workup includes a CBC, urinalysis, and imaging of the chest and abdomen. Ultrasound or CT will often reveal a large, encapsulated mass arising from the kidney (Fig. 107-2). Patients suspected of having a Wilms tumor are referred for further evaluation and management, which includes surgical resection and chemotherapy or radiation. Nephrectomy or biopsy should only be performed by a surgeon experienced with Wilms tumor in order to avoid rupture and subsequent upstaging of the tumor.
FIGURE 107-2. CT scan of a 3-year-old girl with a large encapsulated mass arising from the right kidney. The patient underwent a right nephrectomy and pathology confirmed the diagnosis of Wilms tumor.
Neuroblastoma is a malignant tumor arising from neural crest cells, originating anywhere along the sympathetic chain or the adrenal medulla It is the most common extracranial solid tumor in childhood, with almost all cases diagnosed before 5 years of age.7 Presenting signs and symptoms are most often related to the local effects of the primary or metastatic tumor. Two-thirds of neuroblastomas arise in the abdomen and pelvis and may present as an abdominal mass. Impingement of renal vasculature may lead to renin-mediated hypertension. Cervical or thoracic primary tumors are more often seen in infants. Horner syndrome, with unilateral ptosis, miosis, and anhidrosis, may occur with cervical or high thoracic involvement. Tumors of the paraspinal ganglia may grow around and through the intervertebral foramina, causing spinal cord or nerve root compression. Metastatic disease may be present at diagnosis in up to half of the cases, most often in bone, bone marrow, liver, or skin. Lung or brain involvement is rare and usually represents end-stage or relapsing disease. Retrobulbar involvement can cause proptosis or periorbital ecchymosis. Bone pain and limping may be related to bone and bone marrow disease. Massive hepatomegaly due to liver involvement, more common in infants, can cause respiratory compromise or liver failure. Skin manifestations appear as bluish, nontender, subcutaneous nodules. Opsoclonus–myoclonus is a paraneoplastic syndrome characterized by myoclonic jerking and random eye movements seen in a small percentage of neuroblastoma patients at diagnosis. A CBC may reveal cytopenias due to marrow involvement. Abdominal ultrasound or CT scan may reveal a suprarenal mass, often with calcifications (Fig. 107-3). Lytic lesions and periosteal reaction may be seen on radiographs of painful areas of bone. The catecholamine metabolites homovanillic acid and vanillylmandelic acid are elevated and detectable in the urine in greater than 90% of patients.
FIGURE 107-3. CT scan of a 2-year-old boy who presented with 2 weeks of bruising, pallor, and abdominal distension. Compared to the Wilms tumor shown in Figure 107-2, this mass is not encapsulated and displaces normal structures (note the position of the abdominal aorta). Biopsy confirmed the diagnosis of neuroblastoma.
Common musculoskeletal tumors in children include osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma.8 Rhabdomyosarcoma is a malignant solid tumor from mesenchymal tissue that normally forms striated muscle, and may arise anywhere. Osteosarcoma is the most common malignancy of bone, with a predilection for the metaphysis of long bones, particularly the distal femur and proximal tibia. Ewing sarcoma occurs equally between long bones and flat bones; it may also present as a soft tissue mass without bone involvement. Rhabdomyosarcoma most often presents as a painless mass, and signs and symptoms are location dependent. Genitourinary tract involvement may manifest with hematuria or urinary obstruction. Vaginal tumors may present with hemorrhagic discharge and may mimic a foreign body. The most common presenting symptom of osteosarcoma and Ewing sarcoma is pain in a bone or joint, often after an injury. Other presentations include a palpable mass or pathologic fracture. Initial imaging of a soft tissue mass suspected to be rhabdomyosarcoma is dependent on location. Plain radiographs should be the first step in the initial evaluation of a suspected bone tumor. In osteosarcoma, the tumor may extend through the periosteum, causing new malignant bone deposition resulting in the characteristic radiographic “sunburst” pattern. Ewing sarcoma may cause a multilaminar periosteal reaction resulting in an “onionskin” appearance on plain film. Each of these tumors may metastasize to the lung and bone marrow.
Retinoblastoma is the most common intraocular tumor of childhood. It is strongly linked to genetic mutation.9 Disease may be bilateral in 30% of cases. Most cases are diagnosed before 4 years of age. Retinoblastoma most commonly presents with leukocoria or strabismus. A CT or MRI is needed to determine the presence of choroidal or optic nerve spread and orbital, subarachnoid, or intracranial involvement. Unilateral disease is often treated with enucleation.
COMMON COMPLICATIONS OF CHILDHOOD CANCER
The emergencies encountered in children with cancer may arise at any time in the course of care, from the initial diagnosis through treatment to the time of tumor recurrence. Complications may result from the tumor itself or treatment directed at the malignancy.
TLS results from the death of tumor cells and the subsequent release of intracellular contents resulting in hyperuricemia, hyperphosphatemia, and hyperkalemia. Uric acid may crystalize within the renal tubules leading to obstruction, oliguria, and renal failure. The release of intracellular potassium leads to hyperkalemia, which may be exacerbated by declining renal function. Hyperkalemia may lead to life-threatening arrhythmias. Hyperphosphatemia will lead to secondary hypocalcemia. Severe hypocalcemia may cause tetany, seizures, and arrhythmias. Precipitation of calcium phophate crystals in the renal tubules leads to renal failure.10 TLS occurs most often with hematologic malignancies, particularly Burkitt lymphoma and T-cell lymphoma or leukemia. TLS is rare with nonlymphomatous solid tumors. TLS may occur prior to initiation of therapy but usually begins within the first few days of treatment. TLS may be precipitated by the administration of corticosteroids to a patient not initially thought to have a malignancy. All patients with possible TLS require the following studies: CBC, creatinine, electrolytes, glucose, calcium, phosphate, and uric acid. An electrocardiogram should be obtained if hyperkalemia is found. Early recognition or anticipation of TLS is important. Hydration is the most important initial intervention, improving renal perfusion, minimizing acidosis, and promoting excretion of uric acid and phosphorous. Intravenous (IV) fluid is administered at 1.5 to 2 times the patient’s maintenance rate. Alkalinization of the urine with sodium bicarbonate may be considered as this increases uric acid solubility and excretion. However, given that hyperuricemia may be easier to correct than hyperphosphatemia, the need for alkalinization of the urine needs to be carefully considered. Over alkalinization may lead to crystallization of calcium phosphate in the kidneys. Fluids should not contain potassium unless symptomatic hypokalemia exists. Allopurinol inhibits xanthine oxidase, the enzyme that promotes the degradation of purine to uric acid, and may be used to prevent hyperuricemia. Recombinant urate oxidase given intravenously will rapidly convert uric acid to allantoin and may be indicated in the place of allopurinol in patients with an elevated uric acid, tumors of a high proliferative rate such as Burkitt lymphoma, or with a large tumor burden. Calcium supplementation for hypocalcemia is indicated only in patients who are severely symptomatic with a normal serum phosphate. Giving calcium in the face of hyperphosphatemia may increase the precipitation of calcium phosphate. Hyperkalemia may be reduced by sodium bicarbonate, albuterol aerosol, and insulin/glucose infusion. Sodium polystyrene sulfonate (Kayexalate) should not be an initial choice for hyperkalemia due to its slow onset of action and desire to avoid per rectum route of administration in neutropenic patients. Dialysis is indicated with persistent oliguria or electrolyte abnormalities that do not correct with medical management. Nonperfusing dysrhythmias resulting from hyperkalemia should be treated with IV calcium.
Hypercalcemia is more commonly associated with adult malignancies, but it may occur with ALL, NHL, neuroblastoma, and Ewing sarcoma. Disruptions in calcium homeostasis or excessive bone resorption by parathyroid hormone secreting tumors are the usual causes. Clinically, patients may experience constipation, weakness, polyuria, and drowsiness. Treatment begins with IV hydration with normal saline, followed by furosemide to promote calcium excretion.
Hematologic complications include anemia, hemorrhage, and hyperleukocytosis. Management of anemia includes transfusion therapy with packed red blood cells (PRBC). Patients who are symptomatic will often have a hemoglobin of <6 to 8 g/dL and experience malaise, decreased activity, headache, or irritability due to reduced oxygen-carrying capacity. They warrant transfusion with 10 to 12 mL/kg PRBC given over 3 to 4 hours. Those with a hemoglobin <5 g/dL that has developed gradually may require transfusion with multiple smaller aliquots (3–5 mL/kg) to avoid congestive heart failure. Patients with signs of fluid overload may be given furosemide. Blood products given to chemotherapy or stem cell transplant patients should be irradiated and leukoreduced to minimize the occurrence of posttransfusion graft-versus-host disease. Leukoreduction decreases the occurrence of transfusion reactions as well as the transmission of CMV.
Hemorrhage may occur due to thrombocytopenia secondary to leukemia, chemotherapy, or disseminated intravascular coagulation (DIC). Petechiae, bruising, and mucosal bleeding may be seen with platelet counts <20,000/mm3, but significant spontaneous hemorrhage is more likely with platelet counts <10,000/mm3. Platelet transfusions are warranted for patients who have significant bleeding, such as epistaxis, gingival bleeding, or gross gastrointestinal hemorrhage. Prophylactic use of platelet transfusions for nonbleeding patients with a platelet count <20,000/mm3 is controversial but may be justified in the presence of infection or prior to an invasive procedure. Hemorrhage can also be secondary to DIC, which causes a prolongation of the prothrombin time and partial thromboplastin time, reduced fibrinogen level, thrombocytopenia, and elevated fibrin degradation products. DIC may occur in the setting of sepsis, newly diagnosed or relapsing AML, and hyperleukocytosis. Initial management includes treatment of the underlying condition and replacement of coagulation factors with fresh frozen plasma (10 mL/kg). Platelet and PRBC transfusions may be necessary.
Hyperleukocytosis may be seen with acute leukemia. Unlike RBCs and platelets, WBCs are larger and not easily deformed, contributing significantly to blood viscosity. Leukemia cells tend to aggregate and impair tissue perfusion. Patients may be dyspneic, confused, agitated, or experience blurred vision. The level of leukocytosis leading to symptoms is variable and depends on the type of leukemia. Patients with AML may be symptomatic at a lower WBC than those with ALL; symptomatic hyperleukocytosis is rarely seen in CML despite very high WBC counts. Physical examination may reveal plethora, cyanosis, papilledema, retinal hemorrhage, ataxia, priapism, or focal findings on neurologic examination. The CBC will confirm an elevated peripheral WBC count. The chest radiograph may show a diffuse interstitial infiltrate. Patients with hyperleukocytosis are at risk for TLS. Thrombocytopenia is corrected to a platelet count of at least 20,000/mm3, as there is a significant risk of intracranial hemorrhage with hyperleukocytosis. Leukopheresis prior to initiation of chemotherapy will decrease viscosity and help correct electrolyte abnormalities and may be indicated in patients with symptomatic hyperleukocytosis.
Infection complicated by neutropenia is one of the most common complications in the treatment of children with cancer and is a significant cause of morbidity and mortality. The best estimate of production of neutrophils is the absolute neutrophil count (ANC) (total WBC × [% Bands + % PMNs]). Patients are defined as being neutropenic if their ANC is <500/mm3 or if it is <1000/mm3 with predicted decline to <500/mm3. Fever is defined as a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) for ≥1 hour.11 These patients are at significant risk of bacteremia or fungemia. Impaired cell-mediated immunity results in a greater risk for fungal, mycobacterial, and viral infections. In addition, mechanical barriers such as the skin and mucous membranes may be broken down by infection, chemotherapy, or long-term indwelling venous access devices (IVAD). Patients are at risk of infection from their own endogenous flora, as well as nosocomial pathogens from recent hospitalizations. It is important to promptly evaluate and treat immunocompromised patients with fever since their infections can be life threatening. The common pathogens are listed in Table 107-1.
Common Pathogens in Children With Cancer
Particular attention is paid to occult sites of potential infection, such as the oropharynx, axillae, groin, perineum, and sites of previous procedures, as well as along the tract of any IVAD. It is important to note that fever may be the only positive sign. Because of a decreased number of neutrophils, the inflammatory response is blunted; hence, other findings, such as exudates, adenopathy, fluctuance, warmth, and swelling, may be absent. Children with early pneumonia may not have cough or sputum production.
Initial investigations include a creatinine, CBC, and blood cultures sent for bacterial and fungal culture. A chest radiograph is required if respiratory symptoms are present. If an IVAD is present, a blood culture should be obtained from the line. Debate exists as to whether a culture from a peripheral vein as well as from the IVAD is necessary. Institutional standards should be followed. An aspirate for Gram stain and culture is sent from any other areas suggestive of focal infection.
Prompt initiation of empiric antibiotic therapy in febrile neutropenic children is critical as infection may progress rapidly. Antibiotic delivery should not be delayed while awaiting blood count results. All febrile neutropenic patients are admitted to the hospital for continuation of IV antibiotics. The outpatient management of the febrile neutropenic child is not well established, and should only be done in coordination with a pediatric oncologist. The choice of antibiotic regimen must consider the microbial sensitivity patterns in the institution. Combination therapy has been the usual approach to provide broad-spectrum antibiotic coverage (Table 107-2), which includes an aminoglycoside and an antipseudomonal beta lactam. The development of broad-spectrum antibiotics has made monotherapy an option in some institutions. Ceftazidime, imipenem, cefipime, and meropenem have good activity against Pseudomonas aeruginosa, and may be as efficacious as the standard combination therapy. The routine use of vancomycin in the initial empiric regimen has not shown to be of added benefit. However, vancomycin is warranted if there is evidence of IV catheter-related infection, methicillin-resistant Staphylococcus aureus colonization, severe chemotherapy-induced mucosal damage, fluoroquinolone prophylaxis, recent administration of high-dose cytarabine, or septic shock.
Empiric Antibiotic Therapy for Febrile Neutropenic Patients
Modifications to Therapy Patients with a focus of infection may require modifications in therapy. Signs or symptoms suggestive of an infection along the gastrointestinal tract warrant extended anaerobic coverage with either metronidazole or clindamycin. The presence of a pulmonary infiltrate may represent a bacterial, viral, fungal, or parasitic infection.
Fungal Infections Cancer patients who are febrile and neutropenic are at risk for fungal infections, particularly Candida and Aspergillus species. In pediatric patients, the oral cavity is the most common site for fungal infection. It may present asymptomatically as punctate foci or diffuse erythematous mucosal plaques and ulcerations. Any patient with difficulty breathing, hoarseness, or stridor should be considered to have epiglottic or laryngeal candidiasis. A scraping from the base of a lesion is sent for fungal and viral culture. Neutropenic patients who are afebrile and able to tolerate oral medication may be treated with topical antifungal agents such as clotrimazole. Empiric IV antifungal therapy is not initially indicated for febrile patients but may be added after several days of fever in a persistently neutropenic patient.
Pneumocystis jirovecii (formerly known as Pneumocystis carinii) is the infectious organism that causes pneumocystis pneumonia (PCP). Children with hematologic malignancies are at the highest risk. Typically, patients will have fever, dry cough, tachypnea, and intercostal retractions without detectable rales. Hypoxia may be present and out of proportion to the degree of tachypnea. The chest radiograph may be normal in early disease but later progresses to bilateral alveolar infiltrates. Diagnosis is confirmed by bronchoalveolar lavage or open lung biopsy. Immunocompromised patients should be started on empiric therapy with TMP-SMX pending definitive diagnosis. The incidence of PCP has been greatly reduced with the routine use of prophylaxis with TMP-SMX, pentamidine, or dapsone in immunocompromised patients.
Viral Infections Herpes simplex virus (HSV) infections tend to be localized, even in the immunocompromised patient, and commonly involve the mouth, nares, esophagus, genitals, and perianal region. Pain is the predominant presenting symptom. Disruption of the mucosa may promote secondary bacterial infection. Immunocompromised patients with mild mucocutaneous disease may be started on oral acyclovir. Patients with moderate or severe HSV infection should be admitted for IV acyclovir therapy.
Varicella zoster virus (VZV) infections in immunocompromised patients are associated with significant morbidity and mortality, including potential dissemination. Diagnosis of VZV infection is usually based on the characteristic vesicular lesions and history of recent exposure. Laboratory confirmation is by positive culture of the virus from scraping of the base of the lesions. A chest radiograph is obtained to assess for pneumonia. Immunocompromised patients with VZV infection are admitted for IV acyclovir.
Fever in the Nonneutropenic Oncology Patient The evaluation of the nonneutropenic oncology patient should be the same as that for the neutropenic patient. Nonneutropenic patients remain at risk for infection from an IVAD and therapy related immune dysfunction outside of neutropenia. If the nonneutropenic febrile patient has an IVAD, antibiotic therapy with a third-generation cephalosporin such as ceftriaxone (75 mg/kg q24h) should be given. The patient should be observed for some time after receiving antibiotics, and if stable, outpatient management may be arranged with the child’s oncologist. Hospitalization may be warranted in children whose ANC is expected to decline below 500 in the next few days or in the septic appearing patient. In the absence of an IVAD or focus of infection, the febrile nonneutropenic patient may be observed after obtaining a blood culture without the initiation of an antibiotic.
SUPERIOR VENA CAVA SYNDROME AND SUPERIOR MEDIASTINAL SYNDROME
Several pediatric malignancies, including NHL, HL, neuroblastoma, germ cell tumors, and acute lymphoblastic lymphoma may present with a mediastinal mass potentially resulting in SVCS or SMS. SVCS refers to the signs and symptoms resulting from obstruction, compression, or thrombosis of the SVC. SMS occurs with compression of the narrow, more compliant trachea in children. SMS and SVCS usually occur together in pediatrics. Patients may present with edema and plethora of the face, conjunctivae, neck, and upper torso. Tortuous collateral veins can appear on the chest and upper abdomen. Headache, papilledema, seizures, coma, cerebral hemorrhage, and engorgement of retinal veins may result from cerebral venous hypertension. Compression of the tracheobronchial tree may cause tachypnea, wheezing, stridor, orthopnea, or cyanosis. Death may occur as a result of airway obstruction, cerebral edema, or cardiac compromise. Chest radiography reveals superior mediastinal widening and occasionally a pleural or pericardial effusion (Fig. 107-4). The trachea may appear deviated or narrowed. A CBC with differential may show evidence of leukemia or lymphoma. Electrolytes may show evidence of tumor lysis. Management of these patients is challenging as complete obstruction of the airway may be precipitated. Securing the airway may be difficult, particularly if the obstruction is at or below the distal trachea. Attempts at intubation (either tracheal or selective bronchial intubation) or emergent tracheostomy after airway collapse may not be possible. Even if intubation is achieved, collapse of the airway below the level of the endotracheal tube may lead to inadequate ventilation. Several cases of death due to airway collapse at induction of anesthesia have been reported. Peak expiratory flow rates and CT determined tracheal cross-sectional area have been suggested as means to judge anesthetic risk. However, patients with a critical mass may not tolerate the supine positioning needed for the CT scan or cooperate with obtaining flow rates. If intubation is required, it is recommended that the patient should be awake with spontaneous respiration. The use of extracorporeal membrane oxygenation (ECMO) has been reported in patients at high risk of lower airway collapse.12 Patients with significant respiratory compromise may require the initiation of therapy with either radiation or chemotherapy prior to definitive tissue diagnosis.
FIGURE 107-4. Chest radiograph of a 6-year-old boy who presented with wheezing and tachypnea. The large mediastinal mass is causing deviation of the trachea and compression of the lower airway. The child became hypoxic in the supine position. Chemotherapy was begun emergently. Biopsy of the mass several days later confirmed the diagnosis of T-cell lymphoblastic lymphoma.
SPINAL CORD COMPRESSION
Spinal cord compression may occur with extradural metastatic tumors such as soft-tissue sarcomas, neuroblastoma, germ cell tumors, and HL, or rarely with an intradural cord tumor. Pain is the most common initial presenting symptom. The pain is usually worse when supine; there may be tenderness with palpation. Muscle weakness, which is usually symmetric, is a later finding. Most patients with weakness will already have extradural spinal cord compression at the time of diagnosis. Sensory deficits are less common than weakness and present with ascending numbness and paresthesias. Changes in bladder or bowel function may also occur. Hydrocephalus may result from physical obstruction of cerebrospinal fluid flow. Most patients will usually have objective neurologic deficits at the time of presentation.13
Plain spine radiographs will show an abnormality in some patients with spinal cord compression; however, an MRI provides a more definitive study. Spinal cord compression is a true neurologic emergency. Consultation with an oncologist and neurosurgeon should be obtained immediately. Treatment begins with dexamethasone to reduce tumor-related edema. MRI should be done immediately in those patients with progressive neurologic deficit. Patients should be promptly referred for possible surgery or radiation therapy. Chemotherapy is an option for chemotherapy-sensitive diseases such as HL, NHL, neuroblastoma, or germ cell tumors.
CENTRAL NERVOUS SYSTEM EMERGENCIES
Children with cancer may have CNS complications, such as altered mental status, intracranial hemorrhage, and seizures. Electrolyte abnormalities, hypoxia, renal or hepatic failure, DIC, hyperleukocytosis, and sepsis may lead to altered level of consciousness. Primary CNS tumors and metastatic lesions may present with acute mental status changes. Cerebrovascular accidents may complicate acute leukemia as a result of thrombosis or hemorrhage. Occasionally, hemorrhage can occur at the site of intracerebral metastases. Subdural and subarachnoid hemorrhage may occur due to thrombocytopenia or coagulopathy. Thrombosis may occur after CNS irradiation or chemotherapy. Seizures may arise from electrolyte abnormalities, infection, metastatic disease, or as a complication of CNS therapy. Recent administration of chemotherapeutic agents, either IV or intrathecal, such as methotrexate, cytarabine, corticosteroids, and ifosfamide may cause neurologic toxicity. Laboratory evaluation includes a CBC, electrolytes, glucose, creatinine, phosphate, calcium, uric acid, magnesium, blood culture, and coagulation studies. A CT scan of the head without contrast should be done to quickly assess for tumor or intracranial bleeding. MRI may be performed when the child is stable. Treatment for patients with altered mental status begins with support and protection of the airway and breathing. If necessary, endotracheal intubation is performed utilizing medications that do not increase ICP in conjunction with lidocaine. If raised ICP is suspected, controlled ventilation to a PCO2 of 35 mm Hg can be helpful. Corticosteroids are given to patients with an intracranial tumor in order to decrease cerebral edema. Hyperosmolar agents, such as mannitol and 3% sodium chloride solution (hypertonic saline), may help to reduce cerebral edema by creating an osmotic gradient between the blood and the brain with an intact blood–brain barrier. Use of a diuretic (furosemide) in conjunction with mannitol may enhance the reduction in ICP. Prompt neurosurgical consultation is recommended. If meningitis is suspected, lumbar puncture is deferred, but antibiotics are initiated prior to the CT scan. Thrombocytopenia and coagulopathy are corrected, especially in the presence of an intracranial hemorrhage.
Esophagitis, typhlitis, enterocolitis, and perirectal abscess may occur as a result of immunosuppression and infection. Typhlitis is a severe necrotizing colitis of the cecum in neutropenic patients; it may mimic signs and symptoms of acute appendicitis. Gastrointestinal hemorrhage can result from thrombocytopenia, coagulopathy, mucosal ulceration, or abnormal tumor vessels. The use of high-dose corticosteroids in the treatment of leukemia and lymphoma places patients at high risk of upper GI bleeding. Obstruction may be caused by tumor mass at presentation, adhesions from previous resection of an abdominal tumor, or paralytic ileus from medications such as vincristine. The use of asparaginase in the treatment of leukemia may cause pancreatitis. Venoocclusive disease presents with tender hepatomegaly, ascites, weight gain, and hyperbilirubinemia. It most often occurs during stem cell transplant, but may be a complication of some chemotherapy regimens. Common causes of an acute abdomen, such as appendicitis, must also be considered. Determining the etiology of the abdominal pain may be difficult in neutropenic or immunosuppressed patients. The inflammatory response may be reduced due to leukopenia and normally localized processes may be generalized. Examination of the perineum and rectum is important in detecting pelvic and perirectal disease, neutropenia is not necessarily a contraindication to this maneuver. Laboratory workup includes a CBC, blood and urine cultures, urinalysis, electrolytes, glucose, amylase, and lipase. A chest radiograph is done to assess for pneumonia, while abdominal films may reveal bowel obstruction, perforation, or pneumatosis intestinalis. An abdominal CT may be helpful if plain films are nondiagnostic.
Patients with an acute abdomen should be admitted and started on IV hydration. Nonneutropenic patients with esophagitis and presumptive gastric stress ulcers may benefit from H2 antagonists. Thrombocytopenia and coagulopathies are corrected in the presence of hemorrhage. Patients with typhlitis must be started on broad-spectrum antibiotics to cover both gram-negative pathogens as well as gastrointestinal anaerobes. Early surgical consultation is recommended. Indications for laparotomy with typhlitis include evidence of perforation, persistent gastrointestinal hemorrhage despite correction of existing coagulopathies, and clinical deterioration.
1. Scheurer ME, Bondy ML, Gurney JG. Epidemiology of childhood cancer. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
2. Pearce JM, Sills RH. Childhood leukemia. Pediatr Rev. 2005;26(3):96–104.
3. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030–1043.
4. Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin North Am. 2008;55(1):21–51.
5. Kuppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest. 2012;122(10):3439–3447.
6. Packer RJ, MacDonald T, Vezina G. Central nervous system tumors. Pediatc Clin North Am. 2008;55(1):121–145.
7. Golden CB, Feusner JH. Malignant abdominal masses in children: quick guide to evaluation and diagnosis. Pediatr Clin N Am. 2002;49(6):1369–1392.
8. Arndt CA, Rose PS, Folpe AL, Laack NN. Common musculoskeletal tumors of childhood and adolescence. Mayo Clinic Proc. 2012;87(5):475–487.
9. Melamud A, Rakhee P, Singh A. Retinoblastoma. Am Fam Physician. 2006;73(6):1039–1044.
10. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844–1854.
11. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52(4):e56–e93.
12. Wickiser JE, Thompson M, Leavey PJ, Quinn CT, Garcia NM, Aquino VM. Extracorporeal membrane oxygenation (ECMO) initiation without intubation in two children with mediastinal malignancy. Pediatr Blood Cancer. 2007;49(5):751–754.
13. Prasad D, Schiff D. Malignant spinal-cord compression. Lancet Oncol. 2005;6(1):15–24.