Pediatric Oncology

EXECUTIVE SUMMARY

• Pain without injury, unexplained weight loss, headache present upon awakening, bal­ance or gait problems, and prolonged fevers absent an infectious source are among the most important symptoms suggestive of malignancy in children.
• On physical exam, findings of focal weakness, ataxia, palpable abdominal masses, diffuse lymphadenopa­thy (especially supraclavicular location), unexplained bruising, or testicular enlarge­ment are also very concerning and mandate further evaluation.
• The acute leukemias, which include acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), are among the most common cancer diagnoses in children. ALL has an excellent overall prognosis, with 95% of children attaining remission and more than 80% of children expected to be event-free survivors. Unfortunately, the remission and survival rates for AML are lower.
• Wilms tumor arises from embryonal renal cells and is the most common pedi­atric intra-abdominal tumor. A predisposition to Wilms tumor is seen in children with aniridia (congenital absence of the iris).
• Primary central nervous system tumors are more common in children than in adults, in whom metastatic lesions are more com­mon. Children are more likely than adults to have a posterior fossa tumor and a low-grade histologic type.
• Retinoblastoma presents frequently (but not always) with leukocoria, a white pupillary reflex. The disease is most frequently unilateral, but can be bilateral in about 25% of patients. Bilateral involvement is always related to a genetic abnormality.

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Editor’s Note: Many emergency department (ED) visits for children are driven by parental fears of serious illness, including concerns that a child may have cancer. Some presenting symptoms are high-risk and require serious inquiry, while others are less concerning and may be managed by reassurance alone. Additionally, children with established cancer diagnoses may present to the ED with complications of their cancer, an unexpected recurrence after a period of remission, or issues related to treatment. The authors review the presentations for the most common pediatric cancers and the complications associated with pediatric cancers and their treatment.

— Ann M. Dietrich, MD, FAAP, FACEP

Epidemiology

In 2014 alone, an estimated 15,780 new cases of pediatric cancer were diagnosed in the United States. That same year, 1,960 children younger than 20 years of age died from cancer. While that may seem excessive, rates of childhood cancer survival have improved dramatically over the course of the last 40 years. Overall, the five-year survival rate for all cancers diagnosed in children and adolescents has increased from 50% in 1975 to more than 80% in 2010.¹ Although the overall survival rate has improved, the degree of improvement varies depending on the location and type of disease and the age at diagnosis. For example, the most common childhood cancer is acute lymphoblastic leukemia (ALL), which in the 1960s had a five-year survival rate of 10%. By 2009, the survival rate for children with ALL was about 90%. The most common forms of childhood cancer are listed in Table 1.

ED Evaluation of Possible Malignancy in Children and Adolescents

Early diagnosis of childhood cancer is challenging, since the symptoms frequently are similar to those of more common and relatively benign diseases. Symptoms of malignancy in children and adolescents are often nonspecific and are related to tumor infiltration of organs by abnormal cells. Symptoms such as fever, musculoskeletal aches and pains, constipation, headaches, respiratory symptoms, or swollen glands are common childhood complaints and usually have a benign cause, but they can be indicators of a more serious underlying disorder. Symptoms that linger for weeks to months suggest a need for a more thorough workup.

Pain is one of the most common presenting symptoms of pediatric cancer, and it has been reported to be present in more than half of the children referred for evaluation at the National Cancer Institute. Pain was the only symptom in about one-third of cases, and it was severe enough to interrupt sleep in about half of cases.² Attribution of pain to “growing pains” or minor trauma may lead to delays in diagnosis.³ Musculoskeletal discomfort is a common presenting complaint in children with ALL and occurs about 40% of the time. In half of the children who presented with ALL and musculoskeletal complaints, the pain was noted to be severe.⁴

Fever is also a presenting symptom in children with cancer, as well as a very common issue in otherwise well children. Protracted duration of fever may be the consequence of cancer, but even in prolonged fever, fewer than 10% of cases can be attributed as such.⁵ Persistent fevers may be the only symptom of leukemia or Ewing sarcoma.

Other common complaints can be associated with new-onset cancers in patients presenting to the ED. Brain tumors can present as headaches that disturb sleep, nausea, or visual changes.⁶ Tumors in the abdomen can present as constipation. Unusual bruising patterns can occur as the consequence of bone marrow infiltration.⁷

Initial management of a patient with a suspected cancer should begin with a careful history and physical exam. Pain without injury, unexplained weight loss, headache present upon awakening, balance or gait problems, and prolonged fevers absent an infectious source are among the most important symptoms suggestive of malignancy in children. On physical exam, findings of focal weakness, ataxia, palpable abdominal masses, diffuse lymphadenopathy (especially supraclavicular location), unexplained bruising, or testicular enlargement are also very concerning and mandate further evaluation. Table 2 provides a list of findings associated with specific cancers.

Essential ED evaluation of possible malignancy includes a complete blood count (CBC) to evaluate for evidence of increased white blood cells (WBC), decreased platelets, or anemia. Other useful tests are serum electrolytes (including calcium, magnesium, and phosphorus), liver function tests, serum creatinine, lactate dehydrogenase, and uric acid. Depending on the suspected diagnosis, plain radiography, computed tomography (CT), or ultrasound may be ordered as initial imaging to determine the location and size of a tumor. In the presence of bruising or petechiae, coagulation studies also may be helpful. ⁸

If the workup indicates cancer is a likely diagnosis, informing the patient and the family is often an emotionally difficult next step. Delivering bad news about a child’s health is challenging and should be done with great sensitivity. It should be done in a calm manner, allowing the parents to express their feelings about the diagnosis. The discussion should be held in a quiet area when both parents or a parent and a support person are available together. The news should be delivered when all parties are seated, and facial tissues should be available. It is important to avoid using jargon and to involve a social worker or a chaplain if available. If the illness can be named specifically, write it down for the parents. A detached demeanor usually is perceived as offensive and, thus, should be avoided. Since it is difficult to absorb new information when given a shocking or tragic diagnosis, it is reasonable to keep information presented to a minimum.⁹

Leukemia

Approximately one in 1,000 children are diagnosed with leukemia by the age of 19 years.¹⁰ The acute leukemias, which include ALL and acute myelogenous leukemia (AML), are among the most common cancer diagnoses in children. Both ALL and AML are derived from cells in the bone marrow. ALL originates in the B- and T-lymphoblasts, whereas AML starts in the early forms of myeloid cells, which become non-lymphocytic WBCs, red blood cells (RBCs), and platelets. ALL accounts for one in four diagnoses of cancer in children younger than 15 years of age, and sharply increases in incidence in children between the ages of 2 and 4 years. ALL has an excellent overall prognosis, with 95% of children attaining remission and more than 80% of children expected to be event-free survivors. Unfortunately, the remission and survival rates for AML are lower.¹¹

Genetic abnormalities and environmental exposures to ionizing radiation are risk factors for developing ALL. Children with Down syndrome are also at a 20-fold increased risk of developing acute leukemia. Exposure to ionizing radiation or immunosuppressant drugs (including chemotherapy for another cancer diagnosis) both are associated with an increased risk of leukemia. (See Tables 3 and 4.)

Initial symptoms may be nonspecific and consist of fevers and malaise. Later, unusual bleeding and bruising may be present. Hepatomegaly or splenomegly in association with a protracted fever should increase suspicion for leukemia. Boys should be examined for painless testicular masses. Central nervous system (CNS) involvement in the form of nuchal rigidity, vomiting, and headaches, as well as palpable neck masses, can be present.

Blood test abnormalities frequently are found in children presenting with a new diagnosis of leukemia. About half of children will have WBC counts > 20,000/mm³ at the time of diagnosis, and the WBC count can increase to 100,000/mm³ in some. In addition, blast cells may be present. Up to 90% of children also will have an abnormal hemoglobin, platelet count, or both if the bone marrow is infiltrated at the time of diagnosis.

CT scanning of the brain should be performed in children with severe headaches, focal neurologic deficit, or suspected CNS infiltration or mass. A chest radiograph may reveal a mediastinal mass, especially in children with respiratory distress or stridor. In children with B-precursor ALL, bone pain and limping may be the only complaint 5% of the time.⁵

When a new diagnosis of leukemia is suspected, early involvement of a pediatric oncologist can be helpful to guide further workup and to ensure appropriate disposition and treatment.

Lymphoma

Lymphomas include a group of cancers that derive from lymphatic tissue. Therefore, a diagnosis of cancer should be considered when enlarged lymph nodes are found on physical examination. However, the majority of enlarged lymph nodes found in children are not the result of a malignancy. The size of the node and age of the child are critical factors in determining whether the finding of an enlarged node requires further investigation. Nodes > 1 cm present in the cervical chain or 1.5 cm in the groin are considered enlarged. Large nodes that are not associated with a local infection and that are nontender, firm, rubbery, rapidly growing, fixed, or in the supraclavicular area all require further evaluation.¹² In fact, palpable supraclavicular nodes of any size are concerning. A CBC and a chest radiograph may help further determine need for emergent evaluation. Presence of anemia (hemoglobin < 10.1), low WBC or platelet count, presence of blast cells, or a mass on the chest radiograph all indicate an increased risk of lymphoma and require emergent referral and discussion with a pediatric oncologist; however, absence of any abnormal findings does not rule out the possibility of malignancy.¹³

Non-Hodgkin lymphoma (NHL) accounts for 7% of all childhood and adolescent cancers. NHL is very rare in infants. Unlike Hodgkin lymphoma, which has a bimodal distribution with peaks in early and late adulthood, NHL rates increase steadily with age. Clinical presentations of NHL are variable and depend on the histology of the tumor and site of disease. Children with NHL often appear ill on presentation, with an acute (< 1 month) onset of symptoms. Childhood NHL proliferates quickly and often is found outside of lymph node tissue at the time of presentation. (See Table 5.)

The differential diagnosis of NHL is broad and includes other cancers as well as common childhood diseases. (See Table 6.)

Hodgkin disease is a cancer of the Reed-Sternberg cell of the lymph nodes. It accounts for 5% of all childhood malignancies, and reaches peak incidence in adolescents and young adults. Most patients present with painless, enlarged lymph nodes, frequently in the supraclavicular and cervical areas. About one-third of patients also will present with “B” symptoms of fever, night sweats, and weight loss. The differential diagnosis of Hodgkin disease is similar to that of NHL.

Wilms Tumor (Nephroblastoma)

Wilms tumor arises from embryonal renal cells and is the most common pediatric intra-abdominal tumor. The median age of diagnosis is 3.5 years of age, and it accounts for 6-7% of all pediatric cancers. A predisposition to Wilms tumor is seen in children with aniridia (congenital absence of the iris) due to a genetic abnormality.

Physical exam demonstrates an asymptomatic abdominal mass in 80% of children at presentation. The Wilms tumor can grow very large before it is found, and may be discovered by parents when they are bathing or holding their child. The lack of fat and muscle of the child’s trunk may allow the mass to be apparent. Hypertension, hematuria, abdominal pain, and symptoms from metastatic disease are rare. When hematuria does occur, it is usually microscopic. CT or ultrasound imaging demonstrates a large encapsulated mass arising from the kidney. Wilms tumor is bilateral in 5-10% of cases. Nephrectomy usually is followed by chemotherapy, with or without postoperative radiation. Survival rates vary based on tumor stage and histology. The four-year survival rate for children with favorable histology and stage I disease is 99%.¹⁴

Neuroblastoma

Neuroblastoma is the most common cancer in infancy. Neuroblastoma is a neuroendocrine tumor that arises from immature nerve cells. Most cases are sporadic, but neuroblastoma is found with increased prevalence in chil­dren with neurofibromatosis type I and Beckwith-Wiedemann syndrome. Children often present with nonspecific symptoms of abdominal pain, vomiting, fatigue, or bone pain. The median age at diagnosis is 19 months, and most cases are diagnosed before age 5 years.⁶ It is found most commonly in and around the adrenal glands and along the paraspinal sympathetic nerves in the neck, chest, abdomen, and pelvis.

An abdominal mass is the most common finding on exam. Palpable masses in the neck, abdomen, or pelvis may be felt on physical examination. Proptosis, periorbital ecchymoses, bladder dysfunction, hypertension, fever, and weight loss also may be present. Neuroblastoma can spread along the sympathetic nerve roots through the spinal foramina, compressing the spinal cord and causing paralysis. Horner syndrome also can be the consequence of sympathetic nerve compression in the neck from tumor burden, and presents with miosis, ptosis, and anhydrosis (small pupil, drooping eyelid, and dry skin of the face).¹⁵

Evaluation of possible neuroblastoma includes blood and urine assays for catecholamines (vanillylmandelic acid and homovanillic acid), CT imaging, or ultrasound. The most specific test for neuroblastoma is a metaiodobenzylguanidine (MIBG) nuclear medicine scan. Ninety percent of neuroblastomas are detected on MIBG scanning, identifying primary tumor and metastatic disease.¹⁶

Paraneoplastic processes occur more commonly in adults with cancer, but also are described as rare findings associated with neuroblastoma. Paraneoplastic phenomena occur when hormones or cytokines are excreted by the tumor or as a result of an immune response to the tumor. Intractable diarrhea can be the result of a paraneoplastic syndrome in children with neuroblastoma. One of the more dramatic findings of neuroblastoma is opsoclonus-myoclonus. It is characterized by random eye movements and jerking. The syndrome occurs almost exclusively in young children (6 months to 3 years of age) and generally is considered to occur in 2-3% of children with neuroblastoma. Survival in children with neuroblastoma presenting with opsoclonus-myoclonus is significantly higher than those without this finding.

Overall survival rates have improved over time to 95% for children younger than 1 year of age and 68% for older children.

Central Nervous System Tumors

Brain cancer is the most common solid tumor in pediatric patients. Ninety percent of CNS tumors are in the brain, with the rest present in the spinal cord and cranial nerves. Primary CNS tumors are more common in children than in adults, in whom metastatic lesions are more common. Children are more likely than adults to have a posterior fossa tumor and a low-grade histologic type.⁷ The most common brain tumor in children is an astrocytoma, and it usually is found in a low-grade form. In adolescents and adults, low-grade gliomas are far more likely to transform into higher-grade disease than in younger children. High-grade astrocytomas are the most malignant of all brain tumors. Surgical treatment for low-grade glioma usually is curative in younger children, while chemotherapy and radiation treatment are considered in those with diffuse or inoperable disease or in older children with refractory or recurrent tumors.

Sixty percent of childhood brain cancers occur in the posterior fossa. Medulloblastoma arises from the region of the fourth ventricle and cerebellum and is the most common posterior fossa tumor in children. It usually presents with unsteady gait and headache. The majority of infants with medulloblastoma can be cured with surgery and chemotherapy alone, without the additional risks associated with radiation.¹⁷ By contrast, ependymomas are often lethal in infants, who have a 50% mortality rate associated with the disease.¹⁸

Brain stem gliomas (diffuse intrinsic pontine gliomas) are almost exclusively a pediatric disease process and occur most commonly in school-aged children. Brainstem gliomas can cause abrupt and dramatic symptoms: double vision, difficulty swallowing, ataxia, or clumsiness.

Exposure to ionizing radiation and genetic syndromes like neurofibromatosis, tuberous sclerosis, and von Hippel-Lindau are associated with CNS neoplasms.

Symptoms are variable depending on the age of the patient and location of the lesion. The most common complaint in children older than 4 years of age is headache, but this is present only in about one-third of patients. Most children complaining of headaches do not have brain tumors, and 95% of children with headaches associated with brain tumors have other neurologic findings present on physical examination.¹⁹ (See Table 7.)

Other symptoms of brain tumors include: nausea and vomiting, abnormal gait and coordination, or seizures. Children younger than 4 years of age most frequently present with macrocephaly, nausea and vomiting, lethargy, and abnormal gait and coordination, all symptoms associated with hydrocephalus.²⁰ Papilledema may be present upon physical examination. CT imaging of the brain is a quick, relatively easy option for initial evaluation of a child with a suspected brain tumor, but MRI is more sensitive and provides more detail of the posterior fossa, where about half of childhood brain masses are located. (See Figure 1.) About 70% of children with primary brain tumors will survive five years after diagnosis.²¹

Retinoblastoma

Retinoblastoma is the most common malignancy of the eye in childhood. It presents frequently (but not always) with leukocoria, a white pupillary reflex. The disease is most frequently unilateral, but can be bilateral in about 25% of patients. Bilateral involvement is always related to a genetic abnormality, and is diagnosed earlier than in children with unilateral involvement, whose disease is more likely to be sporadic. The differential diagnosis of retinoblastoma includes other diseases that cause leukocoria, including retinopathy of prematurity, cataract, uveitis, and vitreous hemorrhage. Urgent consultation with ophthalmology should be obtained for a child with suspected retinoblastoma.

Sarcomas

Sarcomas are tumors that arise from embryonal mesenchymal cells and account for 12% of pediatric cancers. Rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma are some of the more common forms in children and adolescents. Rhabdomyosarcoma is the most common pediatric tumor of soft-tissue origin and occurs most commonly in children younger than 6 years of age. (See Figure 2.) Ewing sarcoma is primarily a disease of long and flat bones, and presents with bony pain that intensifies with exercise and is worse at night. Radiographs may show an “onion-peel” appearance to bone. Pathologic fractures are diagnosed at presentation about 10-15% of the time.⁸ Osteosarcoma is the most common sarcoma of bone in pediatric patients. The peak incidence of osteosarcoma is during the adolescent growth spurt. Most patients with osteosarcoma complain of waxing and waning pain over months, and constitutional symptoms are rare. Although not present in the majority of patients, palpable masses were noted to be the most impor­tant physical exam finding suggestive of a cancer diagnosis.²² The distal femur and proximal tibia are most commonly involved.

Frequently, there are delays in diagnosis of bony tumors. Pain related to strain was reported by the majority of patients with both Ewing sarcoma and osteosarcoma. Pain at night was relatively rare. Palpable masses were present in one study in 40% of patients with osteosarcoma and 34% of Ewing sarcoma patients.

Complications of Pediatric Cancer and Treatment

Pediatric oncology patients are at risk of serious health risks related to their tumors and to the treatment regimens employed to control their disease. These problems are:

• Chest emergencies
• Abdominal emergencies
• Neurologic emergencies
• Hematologic emergencies
• Metabolic emergencies
• Infectious emergencies

Chest Emergencies

Respiratory distress, stridor, and signs of venous congestion are signs of a chest emergency in a child with cancer. Children may complain of shortness of breath or chest pain. These signs and symptoms may occur as a result of:

• Pericardial or pleural effusions
• Superior vena cava (SVC) syndrome
• Pneumonia
• Cardiotoxicity from chemotherapy

In children, the most common etiology of pleural or pericardial effusions is a rapidly dividing cancer (such as lymphoma or leukemia) associated with a mediastinal mass. Large pleural effusions can cause respiratory distress, while pericardial effusions can cause cardiac tamponade. (See Figure 3.) Cardiomegaly may be present on chest radiography, but echocardiography is more sensitive for smaller effusions.

Chest masses in children may be the result of childhood cancer, most commonly leukemia, lymphoma, and neuroblastomas. Thrombosis from indwelling catheters may cause decreased venous return through the superior vena cava, causing SVC syndrome, which can manifest as:

• Swelling and vascular congestion of the head, neck, and upper extremities
• Nonproductive cough
• Shortness of breath
• Trouble swallowing
• Headache or mental status changes from increased intracranial pressure
• Hoarseness
• Edema of head and neck
• Prominent veins of the face/upper extremities

In a child with respiratory distress and a chest mass, allow the child to sit or lie in a position of comfort. Sedating medications may put patients at risk of respiratory failure, so should be avoided.

Chest radiography should be considered in any child with a concern for cancer and respiratory distress. Most mediastinal masses will be seen with plain films. Children with stridor from a mediastinal mass are at risk of respiratory failure. The child should be kept in an upright position and provided with supplemental oxygen; urgent transfer to an ICU setting at a pediatric oncology center is appropriate.

Abdominal Emergencies

Abdominal pain and masses are a presenting symptom of several common childhood cancers. Leukemia and lymphoma can present as enlarged lymph tissue in the wall of the bowel and form a lead point for intussusception. In older children, intussusception should prompt an evaluation for possible cancer. Bowel obstruction can be the consequence of adhesions from surgery or from a mass effect from a tumor. Both intussusception and bowel obstruction in children can present as colicky abdominal pain, vomiting, bloody stools, and palpable mass.

Gastrointestinal (GI) bleeding in pediatric cancer patients is most commonly seen in a rapidly growing lymphoma and is the result of perforation of a mass into a vessel. It can be exacerbated by coagulation abnormalities from the cancer or its treatment. The use of steroids in cancer treatment also can cause GI bleeding due to ulcer formation.

Typhlitis (neutropenic enterocolitis) is the result of bacterial and fungal invasion of the bowel wall during periods of neutropenia. In children with cancer, it may occur with induction therapy for ALL and AML, and during aggressive chemotherapy for solid tumors. Typhlitis should be suspected in any neutropenic patient (absolute neutrophil count < 500 cells/microL) who presents with abdominal pain and fever. CT is the preferred diagnostic test; barium enema should be avoided because of the risk of perforation. Broad-spectrum antibiotics and bowel rest are first-line treatment options.

Increased intra-abdominal pressures can occur as a consequence of an intra-abdominal tumor such as Wilms tumor, neuroblastoma, or a germ cell tumor. Hypertension within the abdominal cavity can lead to compartment syndrome and end-organ dysfunction. Ileus, fluid resuscitation, hemorrhage, and pancreatitis all contribute to an increased risk of abdominal compartment syndrome. Early recognition reduces mortality and morbidity from this condition. Head elevation, nasogastric and bladder drainage, and diuretics are appropriate ED medical therapies. Surgical consultation is ideally coordinated in the early stages of the condition, as acute surgical decompression may be needed.²³

Neurologic Emergencies

Catastrophic neurologic emergencies associated with childhood cancer are spinal cord compression/cauda equina syndrome and cerebral herniation: mechanical problems that result from tumor spread, and can be devastating if not detected and treated emergently. (See Figure 4.)

Spinal cord compression in children is most commonly the result of spread of the tumor from outside the spinal cord; neuroblastoma and soft tissue sarcomas are often the cause. Back pain is the most common complaint in these children. Constipation, urinary retention or incontinence, and fecal incontinence in a child who previously was potty trained should raise a red flag for consideration of spinal cord compression. Any child with cancer who has new-onset or worsening back pain should be considered to have cord compression until proven otherwise. Motor weakness and loss of sensation are later grave findings.

Plain radiographs are not sensitive enough to rule out the diagnosis, but occasionally may show findings and are a reasonable first step. MRI is more sensitive and specific, but may be more challenging to obtain in a pediatric patient. Steroids may be used to reduce neurologic damage, but local radiation may be a more appropriate treatment. Early consultation with pediatric oncology should be obtained to treat and disposition these patients appropriately.²⁴

Children with cancer may arrive to the ED with altered mental status or seizures. Intracranial complications can occur as a result of primary tumor, metastasis, or treatment-related problems. Intracranial hemorrhage, thrombotic stroke, or abscess should be considered in addition to extracranial causes of altered mental status such as hypoxia, electrolyte disturbance, renal or hepatic failure, sepsis, and hyperleukocytosis. Certain chemotherapeutic agents can cause neurotoxicity resulting in altered mental status or coma.

Stroke has a prevalence of about 1% in children with cancer, and hemorrhagic stroke occurs about as frequently as ischemic stroke. Those with leukemia and brain tumors are at the highest risk of stroke.²⁵ CT scanning may be used in the initial assessment but can miss significant pathology, so MRI is much more sensitive. Oncology and neurosurgical staff should be made aware of the patient early in their ED course.

Hematologic Emergencies

Hematologic problems in children with cancer are generally the result of underproduction of healthy blood cells and coagulopathy. Children may present with unexpected bruising and bleeding, and pallor from anemia either due to marrow infiltration or blood loss. The excessive cell burden of leukemia can result in increased viscosity of the blood, resulting in thrombosis.

Symptomatic anemia presents as malaise, headache, lethargy, or irritability in children. Generally, the serum hemoglobin in symptomatic children is < 6-8 g/dL. Children with anemia who are asymptomatic and hemodynamically stable and have a hemoglobin >7 g/dL may be managed without transfusion without an increase in adverse events.²⁶ Children with more severe anemia may require smaller volumes of packed RBCs over a longer time frame to prevent congestive heart failure from fluid overload. All patients on chemotherapy or with stem cell transplants should receive irradiated and leukocyte reduced RBCs.

Hemorrhage can result from low platelet counts due to chemotherapy, leukemia, or disseminated intravascular coagulation. Bruising, bleeding from mucous membranes, or petechiae may be present in children with platelet counts < 20,000/mm³. Children with platelet counts < 10,000/mm³ are at increased risk of life-threatening spontaneous bleeding. Use of prophylactic platelet transfusion in stable patients is a controversial topic and requires consultation with the patient’s oncologist.²⁷

Hyperleukocytosis occurs in 20% of childhood leukemias and has a WBC > 100,000/mm³. It is a poor prognostic factor in acute pediatric leukemias because of the increased risk of tumor lysis syndrome (TLS) and bleeding complications. Large, less deformable WBCs aggregate and impair perfusion, causing leukostasis. Patients may present with shortness of breath, confusion, focal neurologic deficits, or blurred vision. Patients with AML are at higher risk of developing this complication. Treatment in the ED should focus on supportive care, identification of the diagnosis, and emergent referral to treatment by oncology. Treatment may include the initiation of chemotherapy to reduce the peripheral WBC count.²⁸

Metabolic Emergencies

TLS, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and hypercalcemia are the most common high-risk metabolic problems in children with cancer, and require rapid detection and treatment to prevent morbidity and mortality.

TLS is a group of metabolic issues that occur when dying malignant cells release their intracellular contents; TLS can occur during initial presentation or with treatment for cancer. Patients with hematologic malignancies (leukemia, lymphoma) or solid tumors can suffer from TLS. It usually presents between 12-72 hours after the initiation of chemotherapy but may be part of a child’s initial presenting complaint of cancer. TLS results in the release of large amounts of potassium, phosphates, and uric acid into the serum, and is defined as two or more of the following abnormal lab values: hyperuricemia, elevated creatinine, hyperphosphatemia, hyperkalemia, and hypocalcemia. Prevention of this complication with adequate hydration is necessary to prevent kidney injury or sudden death from hyperkalemia.⁹ Patients with hyperuricemia (uric acid >8 mg/dL) were at significantly increased risk of developing TLS and renal failure compared to those with lower levels (< 4 mg/dL).²⁹

Usually, TLS presents very nonspecifically in children. Symptoms may include nausea, vomiting, diarrhea, flank pain or edema, lethargy, weakness, fatigue, or cramps. More severe cases may result in arrhythmias, seizures, or sudden death. Treatment strategies include early, aggressive hydration, and medication to reduce uric acid levels and to correct electrolyte abnormalities. Hydration should be given at a rate of 2-4 times maintenance with isotonic fluids. The goal of hydration should be urinary output of about 5 mL/kg/hour. Hypocalcemia should be treated only in symptomatic patients because of an increased risk of obstructive uropathy.

Treatment of hyperuricemia is controversial in children with cancer. Lower-risk patients may be managed with intravenous hydration and/or allopurinol alone. Higher-risk patients with TLS may benefit from the addition of rasburicase. Rasburicase metabolizes existing uric acid, as opposed to allopurinol, which merely prevents the formation of new uric acid in the body but does not break down existing stores. Although multiple studies have demonstrated that rasburicase effectively reduces uric acid levels in children with cancer, a 2010 Cochrane review did not show any difference in mortality or renal failure rates compared with treatment with allopurinol alone.³⁰

SIADH is usually the result of side effects from chemotherapeutic agents. Injury to the brain from surgery or radiation also may result in SIADH. The initial symptoms are nausea, weight gain, headache, decreased urine output, and weakness, which can progress to confusion and altered mental status when the sodium level drops below 120 mg/dL. Diagnosis is made on the basis of abnormal labs: low serum osmolality (< 280 mOsm/L) and high urine osmolality (> 500 mOsm/L) along with low serum sodium. Seizures and coma can be the result of unchecked hyponatremia. Fluid restriction is the mainstay of treatment. In patients with seizure or severe altered mental status, 3% saline may be administered.

Hypercalcemia in children with cancer is very rare. Compared to adults with malignancies, who may develop hypercalcemia during their disease process 20-30% of the time,³¹ the rate of hypercalcemia in children is less than 1%.³² Hypercalcemia is usually the result of bony destruction by marrow infiltration or metastases of solid tumors with release of calcium into the central circulation. Levels > 12 mg/dL cause symptoms of:

• Muscular weakness and pain
• Abdominal pain, vomiting, constipation
• Depression or altered mental status
• Polyuria
• Biliary or renal stones

Treatment of hypercalcemia should be undertaken with gentle hydration, with or without diuresis. Furosemide (1-2 mg/kg) may be added to increase renal excretion of calcium. Calcitonin may be used for short-term management of calcium levels > 14 mg/dL.

Infectious Emergencies

Fever is common in neutropenic patients undergoing chemotherapy. Neutropenia and immunosuppression result in an increased risk of infection in children with cancer. Fever is defined as a single oral or equivalent temperature > 38.3° C or two consecutive temperatures > 38° C in a 12-hour period lasting at least one hour. Rectal temperature measurements are discouraged because of the risk of translocation of bacteria during insertion of the thermometer. Neutropenia is defined as an absolute neutrophil count < 500/mm³ or < 1,000/mm³ with an expected decline.³³ Fever and neutropenia in children with cancer has a mortality rate of 1%.³⁴ Common pediatric pathogens, opportunistic organisms, normal flora, and dormant viral infections may cause fevers. Febrile neutropenia (fever > 38° C associated with an absolute neutrophil count of < 500 cells/microL) should be addressed aggressively. Cultures of blood, urine, and stool (if warranted) should be obtained, and early broad-spectrum antibiotic treatment should be initiated with guidance from the patient’s oncologist. If an indwelling catheter is present, a blood culture should be obtained through the line.¹⁰

SUMMARY

Although pediatric cancers are rare, emergency physicians need to be able to recognize them when they present to the ED. Unfortunately, the symptoms, such as headaches, rashes, swollen lymph nodes, and fatigue, are also common symptoms of benign childhood illnesses. Nonetheless, an astute physician should at least include leukemias, lymphomas, and solid tumors in their differential when evaluating any child who presents with any of these symptoms and know how to rule out such illnesses, either through simple deduction or additional testing.

The authors would like to thank Cleveland Clinic librarian Irene Szentkiralyi for her assistance with research for this article.

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