Chapter 11. Hematology and Oncology

Clinical Summary

Fever in a child with sickle cell disease (SCD) is a medical emergency, because of the possibility of overwhelming Streptococcus pneumoniae sepsis. By age 1 year, 30% to 50% of infants with homozygous sickle cell anemia (HbSS) have diminished or absent spleen function, more than 90% by age 4 years. Though splenic hypofunction occurs less commonly and at a later age in children with hemoglobin SC (HbSC) and sickle β0-thalassemia, they should also be considered at risk. Although availability of conjugated pneumococcal vaccines (most recently Prevnar 13) has reduced the prevalence of invasive pneumococcal disease, prompt empiric therapy with an appropriate antibiotic remains critically important. To some extent, use of Prevnar 7 resulted in emergence of nonvaccine, penicillin-sensitive serotypes as causes of invasive disease, and children less than age 5 should be receiving prophylaxis with penicillin. Patients with pneumococcal bacteremia are often well-looking for a period of several hours prior to sudden circulatory collapse and death; the presence of otitis media or other localized infection does not exclude the possibility of bacteremia. Children with high fever (T >40°C) and/or headache may require lumbar puncture. Although children with acute chest syndrome (ACS) may present with obvious respiratory distress, presentation may be subtle, and careful clinical and radiographic assessment is required. Moreover, although parents are advised to bring children to the hospital because of risk of fulminant sepsis, the fever is often due to viral illness.

Emergency Department Treatment and Disposition

Children presenting with fever should be urgently triaged and immediately seen by a physician. After brief examination, blood should be obtained for a complete blood count (CBC) with a reticulocyte count, blood culture, and any other indicated tests and, if there is no allergy, a dose of a long-acting cephalosporin (eg, ceftriaxone) should be administered intravenously (IV). If penicillin resistance is common in the community, and especially if meningitis is present, treatment with vancomycin is recommended. Patients should then be observed carefully for at least 2 hours as laboratory results are retrieved and any additional evaluation completed. All patients should have a chest x-ray as part of their assessment. Even immunized children taking penicillin should be managed urgently and receive empiric therapy. Children with high fever, pain, and/or ACS should be admitted to the hospital. The majority of children with fever can be managed on an ambulatory basis; clinical criteria published in 1993 were highly effective in identifying a higher-risk group of children best hospitalized and should be utilized by emergency department (ED) physicians for appropriate disposition of febrile children. Children with any of the following characteristics should be hospitalized to continue antibiotics pending results of the culture:

1. “toxic” appearance

2. temperature at or above 40°C

3. infiltrate on chest x-ray, abnormal oxygen saturation, tachypnea in excess of that attributable to fever, clinical signs of consolidation

4. white blood cell (WBC) count greater than 30 000/mm or less than 5 000/mm

5. platelet count less than 100 000/mm

6. hemoglobin less than 5 g/dL or more than 2 g/dL below baseline

7. history of sepsis due to S pneumoniae

8. poor oral intake, signs of dehydration

9. concurrent pain episode

Others who require admission include: any child without a reliable caretaker, source of primary care and/or hematology follow-up; no telephone or poor access to the hospital; unimmunized, noncompliant children. Others generally can be sent home. A hematologist should be called to ensure adequate follow-up and to obtain any further critical information that may be available. If discharged, the child must be reevaluated in the ED or at the hematology clinic 24 hours after administration of parental antibiotics. Depending on culture results and other factors, a second dose of cephalosporin, an oral course of antibiotics, or discontinuation of antibiotic therapy might be recommended. This decision should be made in conjunction with the hematologist.

Pearls

1. Fever in a child with SCD must be considered a medical emergency to permit prompt empiric antibiotic therapy and prevent death/morbidity from pneumococcal sepsis.

2. Prompt empiric therapy is required even if the child has been immunized, is taking prophylactic penicillin, and/or has a “source” for the fever.

3. Criteria are available that permit most children to be discharged and managed on an ambulatory basis.

Clinical Summary

Pain is one of the most common manifestations of sickle cell anemia, and can occur in any part of the body. It is often associated with bone marrow infarction and may be accompanied by prominent inflammatory changes (warmth, tenderness, erythema) over the painful area, or there may be minimal or no physical findings. Pain may be due to “sludging” of sickle cells in the capillary bed with vascular obstruction and tissue ischemia/infarction; sickle cell vasculopathy and inflammatory mediators may contribute to tissue injury. However, the subjective complaint of pain is often unaccompanied by objective physical findings, and the patient must be relied on to assess analgesic response. There are no clinical, radiographic, or laboratory parameters proven to confirm or refute pain. Radiographs are generally not useful in assessment of acute pain; even with acute infarction, bone films will be normal for 7 to 10 days after onset. Nuclear medicine scans (gallium, indium, and bone or bone marrow) have been used to attempt to differentiate acute bone infarction from osteomyelitis but are also often not definitive and should not be ordered in the ED. Other potential causes of pain should be assessed. Patients with chest pain should be examined carefully for clinical findings of consolidation. They also must be continuously monitored for splinting/hypoventilation as a precipitant of ACS. Careful performance of the physical examination with auscultation for rales or diminished breath sounds is critical; clinical findings often precede radiographic findings. Tachypnea may be subtle, with shallow but rapid respiratory rate. Sickle cell patients with concurrent asthma may be at increased risk for ACS. Abdominal pain and/or distension may be a presenting symptom of ACS or sometimes a complication. Any patient with abdominal pain requires careful monitoring of pulmonary status and oxygen saturation. Other potential causes of abdominal pain need to be considered, both sickle cell–related (ie, cholecystitis, “gallstone,” pancreatitis) and those occurring in the general pediatric population. If appendicitis is suspected, hematology consultation must be obtained before surgery. Although acute infarction of cranial bones can occur, severe or persistent headache should prompt a careful neurologic assessment for meningitis or acute cerebral infarction and/or hemorrhage. Low-grade fever can complicate pain episodes, especially in patients with local inflammatory findings. A workup for possible infection should be done and empiric antibiotic therapy may be required. Prior to antibiotic administration, it may be appropriate to consult orthopedics regarding aspiration of the inflamed bone or joint to attempt to obtain material for culture.

Emergency Department Treatment and Disposition

The patient’s assessment is the only tool available for adequate pain management and they should be asked to quantitate their pain using an assessment scale (eg, a numerical pain intensity scale [Visual Analogue Scale] or the Wong-Baker FACES scale for younger children). A numerical goal should be agreed upon, and patients reassessed and retreated at intervals until adequate control is achieved. Patients receiving opioid analgesia should also be assessed with a sedation scale and have the dosage modified as required. Patients should be monitored, most commonly with a pulse oximeter. Patients will often suggest what medications and dosages have provided relief on previous episodes; this information should be utilized in designing a treatment regimen. IV fluids are administered at least at a maintenance rate; most children with pain are somewhat dehydrated. If the patient is drinking liquids, decrease the IV fluid accordingly. However, aggressive hydration may be a risk factor for ACS, and patients with concurrent ACS generally receive only maintenance fluids or less. Most patients should receive ibuprofen every 6 hours by mouth and an initial dose of IV morphine sulfate. A patient should be reassessed in 30 minutes and if pain is poorly relieved and sedation acceptable, additional morphine should be given. Once relief is achieved, morphine should be given at 2- to 4-hour intervals to maintain adequate analgesia. An alternative to morphine is hydromorphone, which has a slightly longer duration of action given every 3 to 4 hours. Both morphine and hydromorphone are also used via patient-controlled analgesia (PCA), allowing the patient to titrate medication himself or herself to achieve pain control, avoiding dependence upon care providers and potential pseudo-addiction. The optimal dosing for PCA (generally a continuous infusion supplemented by demand doses by the patient) has not been established for children with SCD and use should be restricted to physicians/pain teams with experience. Ketorolac is a nonsteroidal anti-inflammatory medication that is not a respiratory depressant and may thus be especially useful in patients with chest or back pain. It is only approved for IV use in adolescents older than age 15 years. It should not be used with ibuprofen or by patients with renal disease. If pain is poorly controlled on usual doses of opioids and/or the need for parenteral analgesia continues, the patient should be admitted. If pain is, in the assessment of the patient, under control, it may be appropriate to substitute an oral analgesic prior to discharge to ensure continued adequacy of analgesia on discharge. The dose of morphine when changed from parenteral to oral administration needs to be increased 3-fold and hydromorphone 4-fold to achieve comparable analgesia. Alternatives include oxycodone for older children or codeine. A substantial minority of patients may not metabolically activate codeine and it may be ineffective. Codeine is often dispensed in combination with acetaminophen; parents should be reminded not to supplement with additional acetaminophen. Ibuprofen and/or acetaminophen should generally be continued with the oral opioid preparation. Patients should be provided with sufficient analgesia to last several days and be encouraged to follow up with the hematologist or primary care physician. Those who utilize the ED primarily and do not show evidence of an ongoing relationship with a health care provider should be referred for psychosocial assessment. Nonpharmacologic interventions should be encouraged, including psychosocial strategies (distraction or psychotherapy), behavioral strategies (deep breathing, relaxation, self-hypnosis), and physical strategies (heat, massage). Regular (10 puffs every 2 hours while awake) use of incentive spirometry is proven to reduce the incidence of nosocomial ACS and, especially if a prolonged stay in the ED is anticipated, should be prescribed. Patients with recurrent episodes of pain and/or ACS may be candidates for hydroxyurea therapy (after consultation with hematologist). Hydroxyurea is safe and effective in reducing the frequency of pain and ACS in children as young as age 9 months and convincingly improves life expectancy in adults.

Pearls

1. The patient is the only person who can assess his or her pain and may have a useful opinion as to the most effective analgesic regimen. Listen to the patient!

2. Do not administer placebo; response to placebo does not prove that the patient is not in pain.

3. Meperidine is a less effective pain reliever, has a higher potential for toxicity (neurotoxic), and its use is discouraged except perhaps in patients who are truly allergic to morphine (and thus hydromorphone and codeine as well).

4. Patients who received opioids for pain relief in the recent past or for more than a few days may develop pharmacologic tolerance to the drug and require higher doses for pain relief. Rapid cessation of opioid therapy after several days of treatment may result in withdrawal symptoms, sometimes manifested as recurrent pain. Opioid dosage should be tapered over several days in such cases.

5. Causes of pain other than those attributable to acute vasoocclusion should be excluded.

Clinical Summary

Acute chest syndrome (ACS) is defined as acute pulmonary findings in a child with sickle cell disease (SCD). These findings may include tachypnea, which is sometimes subtle; retractions; diminished (often asymmetrical) breath sounds; rales, vesicular sounds, or other signs of consolidation. Hypoxemia is often present and new pulmonary findings may be seen on chest radiograph. However, many patients present with clinical findings of ACS that precede abnormal radiographic findings by 24 to 48 hours. Because of multiple and sometimes overlapping etiologies, all children with ACS should be treated for both infectious and sickle cell–related etiologies. The most common identifiable infectious pathogens are atypical bacteria (Mycoplasma pneumoniae and Chlamydia pneumoniae); bacterial infection (including S pneumoniae) may occur in approximately 5% of cases. The most common identifiable noninfectious cause of ACS is pulmonary fat embolization from infarcted bone marrow; marrow infarction is a frequent cause of an acute pain episode. Transfusion therapy may be important in preventing multiorgan failure and death due to severe fat embolization syndrome (approximately 70% of children are ultimately transfused during a course of ACS). Abdominal pain and/or distension may be a presenting symptom of ACS or sometimes a complication. Any patient with abdominal pain requires careful monitoring of pulmonary status and oxygen saturation. Neurologic problems may occur because of embolization of bone marrow fat from the lungs to the brain or ischemia/infarction due to systemic hypoxemia and underlying cerebrovascular disease. There is a temporal association of ACS with stroke.

Emergency Department Treatment and Disposition

Examine patients carefully, especially those with fever, chest or back pain, and abdominal pain or distension; an accurate respiratory rate is simple and critical. A CBC with reticulocyte count is required. It often shows a significant drop in hemoglobin value from baseline, a decrease in platelet count, and an elevated number of nucleated RBCs. Other tests include arterial blood gases; an arterial-alveolar gradient measured in room air greater than 30 mm Hg suggests risk for a more severe clinical course, and it must be remembered that a normal Pco2 in a patient with respiratory distress is ominous and may indicate impending respiratory failure. Chest radiograph may initially be normal or involve one or several lobes and rapidly progress to “white-out” of one or both lungs. Pleural effusions may be present. As radiologic findings may lag behind clinical findings, treatment should precede confirmatory radiograph in children with symptoms and signs of ACS. A specimen for type and screening should be sent to the blood bank with the alert that the patient has SCD. Many blood banks will have a complete red cell phenotype on file to extend the compatibility profile; at a minimum, patients should receive red cells compatible with types C, E, and Kell (historically the most antigenic in sickle cell populations). Because most Rh (D)–negative Caucasian donors are C and E negative as well, if the need for blood is urgent Rh- and Kell-negative units can generally be released promptly and safely. Preserve hydration by offering maintenance fluids or less with close monitoring of intake and output (avoid pulmonary edema–induced worsening of ACS). Careful choice and dosing of analgesic therapy is needed to prevent hypoventilation secondary to splinting and/or sedation/respiratory depression (hypoventilation may lead to atelectasis and hypoxemia); ketorolac use may be desirable in older patients. Incentive spirometry, as prescribed for pain, should be offered, especially if a prolonged stay in the ED is anticipated. All patients with ACS should receive macrolide therapy to cover possible atypical bacteria. Though bacteria, including S pneumoniae, are uncommon pathogens, younger patients (especially nonimmunized) with high fever, high white cell count, or a toxic appearance may also be given antipneumococcal therapy pending culture results. Simple transfusion with packed RBCs is often given for a moderate to severe episode, especially when associated with a drop in hemoglobin concentration. Unless a prolonged stay in the ED is required and a patient is clinically distressed, transfusion should best be administered in the inpatient area. Simple transfusion rather than exchange should be the front-line therapy unless a patient is less anemic than average (ie, Hb > 9 g/dL) and thus cannot safely be given a simple transfusion because of viscosity concerns (posttransfusion Hb should never exceed 11 g/dL in an acutely ill, urgently transfused patient). Activation of various cytokines and upregulation of adhesion molecules are particular manifestations of an often robust and sometimes deleterious inflammatory response. Use of dexamethasone (given every 12 hours for four doses) attenuates the course of ACS but appears to be associated with a high readmission rate for pain shortly after recovery from ACS. An “asthma regimen” of prednisone for 5 to 7 days may be less associated with readmission and perhaps efficacious in reducing the need for transfusion; however, this regimen has not been assessed prospectively and should NOT be initiated in the ED. Because of its variable and often severe clinical course, all patients with ACS should be hospitalized, preferably in an ICU or well-observed bed with oxygen therapy and continuous cardiac and pulse oximetry monitoring. A pediatric hematologist should be consulted for management of a patient with ACS and in decisions about antibiotic coverage, transfusion, and steroid therapy. All patients who experience even a single episode of ACS should be made aware of the role of hydroxyurea therapy in potentially reducing the risk of recurrent ACS and other sickle cell complications.

Pearls

1. A careful physical examination, with particular attention to respiratory rate and effort, is critical in diagnosis of ACS.

2. Fever may be the only early manifestation of ACS; all febrile sickle cell patients should have a chest radiograph as part of their evaluation, even if respiratory signs and symptoms are not identified.

3. Clinical or radiologic diagnosis of ACS mandates hospitalization. Radiographic findings may lag and need not be present to make a clinical diagnosis of ACS.

4. All patients with ACS and hypoxia and/or tachypnea should receive supplemental oxygen until (and after!) their transfer to the inpatient unit.

5. The blood bank should always be aware of a sickle cell diagnosis, so extended antigen-matching, at least to include C, E, and Kell antigens, is done.

6. Although corticosteroid therapy may be a useful adjunct to care, treatment should not be initiated in the ED without specific discussion with the pediatric hematologist.

Clinical Features

Stroke affects 5% to 10% of children with sickle cell disease (SCD). The majority of ischemic strokes are due to watershed infarcts resulting from sickle cell vasculopathy of major cerebral vessels. It is speculated that abnormal adherence of sickled red cells and white cells to the vascular endothelium and perhaps nitric oxide depletion result in vessel injury and intimal hyperplasia. Hyperplasia leads to gradual stenosis and ultimately occlusion of the large- and middle-caliber cerebral arteries, particularly the middle cerebral artery; often multiple vessels are involved. Approximately 70% to 90% of children with SCD who have strokes due to infarction have cerebrovascular disease of major vessels. An additional 10% to 30% may have microvascular disease; typically these lesions are in deep periventricular white matter. Hemorrhagic stroke (subarachnoid and/or intracerebral hemorrhage) occurs less commonly during childhood, but becomes progressively more common with increasing age. A sudden onset of hemiparesis is the most common presentation in children. Weakness or numbness of an extremity or a painless limp may be patient/parent complaints. Cranial neuropathies are sometimes seen, but infarction in the brainstem and areas fed by the posterior circulation (cerebellum) are uncommon. Patients may have bilateral findings at the time of initial diagnosis because of previously unrecognized infarcts. Intracranial hemorrhage can present with headache, although headache is not often seen in infarctive strokes. Patients with transient ischemic attacks (TIAs) may have similar symptoms that resolve spontaneously within 24 hours of onset. TIAs are associated with an increased risk of subsequent stroke, and patients with TIA should be investigated carefully for underlying cerebrovascular disease. Transcranial Doppler ultrasonography (TCD) is a screening method to identify children at increased risk for stroke, who can then receive preventive transfusion therapy. Screening appears to substantially reduce stroke incidence and is recommended at least annually for all children with HbSS or sickle β-thalassemia from age 2 through 16 years. Prompt TCD screening may be useful in an individual patient with TIA or equivocal neurologic findings to establish stroke risk but must be performed by an examiner familiar with the screening protocol and interpretation required for children with SCD.

Emergency Department Treatment and Disposition

A pediatric hematologist and a pediatric neurologist should be consulted emergently regarding a patient with suspected stroke to confirm the neurologic findings and initiate therapy. Patients should be given oxygen and specimens sent for CBC, coagulation screen, and alloantibody screening. A specimen should also be sent for complete red cell phenotyping to facilitate extended antigen-matching of blood and ultimately chronic transfusion therapy. A CT scan of the brain is generally done urgently to rule out intracranial hemorrhage. CT scans are relatively insensitive for infarction, although sensitivity improves after 3 to 4 days. Patients who are found to have intracranial bleeding on CT scan should have urgent neurosurgical consultation. If conventional angiography is needed, it is best done after exchange transfusion (see below) and using low ionic strength contrast medium. A diffusion-weighted magnetic resonance imaging (MRI) should be done to confirm cerebral ischemia/infarction, with a magnetic resonance angiography (MRA) done concurrently to establish the extent of cerebrovascular disease. It is convention that patients with newly diagnosed stroke be treated with exchange transfusion; recovery is often substantial after the procedure. Although no prospective trials have compared exchange transfusion to simple transfusion repeated at weekly intervals to achieve the traditional goal of <30% HbS, a retrospective review suggested patients exchanged promptly had a lower risk of stroke recurrence. A simple transfusion may be given to patients with Hb <9 g/dL while preparing for exchange. An exchange transfusion requires admission to the hospital, most appropriately to an intensive care unit, and can be done manually or by erythrocytapheresis. TIA patients should be transfused while awaiting complete evaluation for cerebrovascular disease and the decision as to whether to continue a chronic transfusion program. Most patients who are found to have a new acute cerebral infarction, or TIA with significant vascular disease, are placed on a chronic transfusion program for at least several years. Although anticoagulation and thrombolytic therapy are increasingly used in adults with acute stroke, appropriate use of these therapies has not been established in patients with SCD; standard therapy is exchange transfusion.

Pearls

1. The most common cause of stroke in children with SCD is cerebral infarction due to vasculopathy of the major cerebral vessels.

2. A painless limp or weakness (hemiparesis) is the most common presentation of stroke. In younger children, a limp or unwillingness to walk may occasionally be mistakenly diagnosed as a pain episode. A lack of complaint of pain, local tenderness or inflammatory findings in the extremities should prompt neurologic assessment.

3. All patients with SCD presenting with a seizure or neurologic symptoms and signs must be assessed for possible stroke.

4. Stroke in patients with SCD usually develops as an isolated event; however, it may occur during other types of crisis (eg, aplastic crisis, ACS, or splenic sequestration).

Clinical Summary

Priapism is defined as an unwanted painful penile erection. Clinically it can be a single prolonged (24 hours to several days) episode or shorter, often recurrent, “stuttering” episodes. Prolonged episodes are generally low-flow and ischemic, presumably because of sludging and stasis of blood in the cavernosal spaces. Ischemia and infarction will injure cavernosal smooth muscle and ultimately result in fibrosis and impotence. The pathophysiology of high-flow priapism is not clear. It may be related to vascular disease and autonomic dysfunction and/or nitric oxide depletion with derangement of normal regulatory pathways. Stuttering episodes are more commonly seen in prepubertal males and the prognosis is probably better than in older patients with low-flow episodes; however, in a large series from Jamaica, all patients with stuttering ultimately did have a prolonged episode lasting longer than 24 hours. Noninvasive methods used to assess penile perfusion include radionuclide penile scan and Doppler ultrasonography. The glans and corpus spongiosum are generally spared in sickle cell–related priapism, providing a rationale for surgical shunting. Tricorporal priapism is associated with a more prolonged, difficult course and more severe systemic disease.

Emergency Department Treatment and Disposition

Emergent consultation with urology and pediatric hematology is needed for patients who have a priapism episode lasting >2 hours; many of these episodes will extend to 24 hours and beyond without intervention. Episodes lasting more than 48 hours are associated with a high incidence of subsequent impotence; intervention should begin as early as possible after a patient appears in the ED. Patients should be treated with fluids at 1.5 times maintenance and given adequate analgesia (ie, morphine sulfate). Aspiration of the corpora cavernosum and irrigation with approximately 10 mL of a 1:1 000 000 dilution of epinephrine should be performed by an experienced urologist within a few hours of presentation as it nearly always achieves at least temporary detumescence. Depending on the patient, it is performed with local or regional anesthesia and/or moderate sedation; younger children may require admission to the hospital for deep sedation/general anesthesia. The first blood aspirated may be sent for analysis of pH, Pco2, and Po2 to establish cavernosal flow status. If aspiration fails or priapism recurs after brief detumescence, the patient should be hospitalized. Although there is no proven benefit from blood transfusion in the acute management of priapism, it may be useful to transfuse (simple transfusion in most cases) after an unsuccessful aspiration and prior to a repeat; subsequent aspiration will then allow “normal” transfused blood to enter the cavernosal spaces. Blood transfused to a patient during a low-flow episode will not enter the cavernosae and is unlikely to be effective. If detumescence occurs after initial aspiration, the patient may be discharged from the ED. Pseudoephedrine 30 to 60 mg at night may reduce risk of recurrent stuttering episodes. Recurrent priapism episodes that resolve spontaneously or with aspiration should be referred to a hematologist and/or urologist familiar with the disorder. Additional preventive treatment for recurrent priapism may include chronic transfusion therapy to maintain HbS <30% for 6 to 12 months, hydroxyurea therapy, stilbestrol therapy (unacceptable side effects), injections of leuprolide (suppresses production of testosterone), or oral finasteride.

Pearls

1. Priapism is a persistent, painful erection associated or unassociated with sexual stimulation.

2. A common complication of priapism is impotence. The risk of impotence increases with the number of recurrent episodes and increased duration of episodes. Patients who have persistent priapism for >48 hours prior to intervention often are left impotent.

3. Penile aspiration/irrigation with epinephrine should be done within several hours of presentation and is usually effective in achieving detumescence.

Clinical Features

The combination of jaundice and right upper quadrant pain, tenderness, and sometimes hepatic enlargement is termed right upper quadrant syndrome (RUQ syndrome). Although children with sickle cell disease (SCD) have normal susceptibility to viral or immune hepatitis, generally the differential diagnosis of concern in children presenting with RUQ syndrome is obstructive choledocholithiasis versus “sickle cell hepatopathy.” Gallstones are extremely common in children with SCD, with estimates that 30% of children age 2 to 10, 50% of adolescents, and 80% of adults with SCD likely have gallstones. These are often bilirubinate stones and not calcified; 90% are not radiopaque. Although stones are most commonly asymptomatic, stones will occasionally occlude the common bile duct and cause obstructive jaundice; pancreatitis can sometimes accompany common bile duct obstruction. In spite of this risk, most do not recommend routine cholecystectomy for asymptomatic stones. “Sickle cell hepatopathy” is due to intrahepatic sickling and cholestasis. In children, this most often is an “extreme benign hyperbilirubinemia”; children generally look fairly well, with or without liver enlargement or tenderness, in spite of sometimes markedly elevated levels of total and direct bilirubin, and mild elevation of hepatic transaminases. Symptoms generally resolve in a few days, though jaundice may persist for weeks. Adults and (usually) older children may be at risk for a more dangerous form of hepatopathy in which hyperbilirubinemia is accompanied by signs of hepatic dysfunction (coagulation abnormalities, hyperammonemia, central nervous system changes). Children who have hepatic dysfunction at presentation may have a severe or life-threatening course and require transfusion (perhaps exchange transfusion) to avoid a mortal outcome. Of note, children with the more fulminant direct hyperbilirubinemia often have serum bilirubin levels of 30 to 80 mg/dL, whereas those with the more benign hyperbilirubinemia generally have levels from 10 to 30 mg/dL. It is important to note that children with sickle cell anemia frequently have mild unconjugated hyperbilirubinemia due to hemolysis. In addition, a significant subgroup of children have a total serum bilirubin level greater than 4 mg/dL, which cannot be attributed to hemolysis alone. Nearly all such children have Gilbert syndrome and are homozygous for mutations in the glucuronosyl transferase gene (UGT1A). The incidence of Gilbert syndrome in sickle cell populations is 12% to 25%; an additional 50% may be heterozygous with somewhat higher bilirubin levels than individuals with the normal genotype. Higher indirect bilirubin levels are associated with increased risk for gallstones.

Emergency Department Treatment and Disposition

Patients should be examined with attention to hepatic enlargement and/or tenderness, mental status, and presence or absence of asterixis. Blood work should include CBC and reticulocyte count, coagulation profile, liver enzymes with total and direct bilirubin, and serum amylase, lipase, and ammonia. Patients found to have only indirect hyperbilirubinemia but with levels above 4 mg/dL require no further evaluation and can be informed they likely have inherited Gilbert syndrome and which contributes to their jaundice. All patients with direct hyperbilirubinemia should be hospitalized for diagnostic imaging and IV hydration. Abdominal ultrasound is generally the initial imaging but can miss common bile duct stones (up to 30%). Sensitivity is improved by magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasonography. Children found to have obstructive choledocholithiasis (dilated common bile duct/hepatic ducts) may spontaneously pass obstructing stones, but are candidates for endoscopic retrograde cholangiopancreatography (ERCP) for confirmation of the diagnosis and therapeutic commissurotomy. Elective laparoscopic cholecystectomy is usually done 4 to 6 weeks after the acute episode (timing is somewhat dependent on the institution). Patients found to have no evidence of obstruction on imaging and who do not have hepatitis have sickle cell hepatopathy and can generally be managed conservatively. However, those with hepatic dysfunction should be transfused promptly, perhaps with exchange transfusion, to lower the HbS to less than 30% of the total.

Pearls

1. All children with direct hyperbilirubinemia should be hospitalized for evaluation and at least conservative management.

2. For patients with common bile duct obstruction: ERCP should be offered if available for relief of obstruction to be followed by elective laparoscopic cholecystectomy.

Clinical Summary

There are 3 causes of acute exacerbations of anemia in children with sickle cell disease (SCD): acute splenic sequestration, transient aplastic crisis (TAC), and hyperhemolysis. The latter is relatively unusual, is often seen in association with the viral illness, and is associated with reticulocytosis and a lower than baseline hemoglobin. It may be due to activation of the reticuloendothelial macrophage system by an infectious agent, with enhanced removal of sickle cells and generally appropriate response by the bone marrow. It is not apparently related to concurrent glucose-6-phosphate dehydrogenase deficiency (as previously thought). Transient aplastic crisis is 70% to 90% of the time due to infection by parvovirus B19. This virus is the cause of erythema infectiosum (fifth disease) in the general population. Infection results in transient, profound inhibition of erythropoiesis because of viral incorporation into red cell precursors after entry via the P blood antigen receptor (also known as globoside). In individuals with normal hemoglobin, this results in reticulocytopenia for 7 to 10 days but no clinically significant drop in hemoglobin concentration. Patients with SCD may a have much shorter red cell life span and thus become profoundly anemic and reticulocytopenic (reticulocyte count less than 1%, often less than 0.1%). Usually these patients compensate well because of the gradual progression of anemia and often complain of nonspecific symptoms of tiredness, headache, or malaise at presentation. The prodromal symptoms and rash associated with parvovirus infection in the general population are often not observed in children with SCD. Leukoerythroblastosis, sometimes extreme, is often seen during the recovery phase of TAC; such patients are sometimes misdiagnosed as having hyperhemolysis and generally will not require transfusion (or even hospitalization).

Emergency Department Treatment and Deposition

Infants and children presenting with pallor and/or tachycardia should be seen immediately by a physician with assessment for cardiovascular compromise. Blood should be drawn for CBC, reticulocyte count and type, and screen. Patients who have severe anemia and profound reticulocytopenia due to clinically suspected parvovirus P19 infection should be provided oxygen and hospitalized for cautious transfusion to achieve near-baseline hemoglobin levels and to relieve symptoms, perhaps 7 to 9 g/dL. These patients often show minimal cardiovascular compromise, but are at risk for high-output congestive heart failure if transfused too rapidly. Transfusions should ideally be phenotype compatible for at least C, E, and Kell antigens. Hematology consultation would assist in such decisions. During hospitalization, patients should be isolated from other sickle cell children, immunocompromised patients (may acquire chronic parvoviremia), and pregnant women (increased fetal loss, hydrops fetalis) until reticulocytes recover, indicating resolution of parvoviremia and infectivity. Family should be advised to bring siblings with SCD to be checked for reticulocytopenia.

Pearls

1. Infants/children with acute splenic sequestration crisis are generally hypovolemic and require fluid resuscitation and urgent, rapid transfusion, whereas those with TAC are generally well compensated and require very cautious transfusion therapy.

2. Diagnosis of aplastic crisis with B19 infection can be confirmed by B19 IgM serology only after reticulocytosis has returned. Diagnosis during the aplastic episode requires detection of viral DNA.

Clinical Summary

Acute splenic sequestration crisis (ASSC) is a life-threatening complication seen most commonly in infants with sickle cell disease (SCD) under age 4 years. It can occur in any of the common genotypes, but in older children becomes more common in those with SC, sickle β-thalassemia, or Hb SS with α-thalassemia. In many patients today, SCD is diagnosed by newborn screening programs, allowing early instruction of parents in splenic palpation; studies have shown that this intervention increases the frequency of diagnosis of ASSC but reduces mortality. ED personnel must be aware that parents often become proficient at splenic palpation and should take their observation seriously. Patients who present with severe ASSC often have massive splenomegaly, tachycardia, and hypovolemia; hemoglobin levels below baseline; reticulocytosis; and often thrombocytopenia. Subacute presentations with mild to moderate exacerbation of anemia and newly discovered splenomegaly also occur. The differential diagnosis of acute exacerbations of anemia in children with SCD includes ASSC, transient aplastic crisis and hyperhemolysis.

Emergency Department Treatment and Deposition

Infants and children that present with pallor, tachycardia, or parental complaint of splenic enlargement should be seen immediately by a physician with assessment for cardiovascular compromise and splenic enlargement. Blood should be drawn for CBC, reticulocyte count and type, and screen. After stabilization of vital signs, often requiring fluid resuscitation, and provision of oxygen therapy, patients should be hospitalized to PICU or to a monitored bed. These patients usually need urgent transfusion to achieve something approaching baseline hemoglobin levels. Patients should not be overtransfused, as cells trapped in the spleen surprisingly often recirculate after transfusion and the hemoglobin level may increase to levels above that predicted based on volume transfused. Transfusions should ideally be phenotype-compatible for at least C, E, and Kell antigens. A hematology consultation would assist in such decisions. Patients presenting with subacute presentations may also require hospitalization for careful monitoring of splenic size, vital signs, and hemoglobin for 24 hours. After a first episode of ASSC, parents are reeducated regarding splenic palpation and warned that recurrences are common (50%–90%). After a second episode, splenectomy may be recommended by the hematologist, especially since the risk of pneumococcal sepsis has diminished because of availability of conjugated pneumococcal vaccines. Some may recommend splenectomy after a first episode if there are concerns about adequate parental monitoring of spleen size or lack of proximity to a hospital.

Pearls

1. Patients with ASSC may rapidly progress to cardiovascular collapse and death.

2. Infants/children with ASSC are generally hypovolemic and require fluid resuscitation and urgent, rapid transfusion, whereas those with transient aplastic crisis are generally well compensated and require very cautious transfusion therapy.

3. Parents may be quite proficient at splenic palpation. Their complaint of a newly palpable or enlarged spleen should be taken seriously.

4. Children with less common genotypes of SCD (SC, sickle thalassemias) may be at risk for ASSC throughout childhood.

Clinical Summary

Newly diagnosed immune thrombocytopenia (ITP) is characterized by sudden onset of skin and/or mucosal bleeding in otherwise healthy children. These include petechiae, ecchymosis, oral mucosal bleeding, epistaxis, and hematuria. Menorrhagia may be seen in adolescent females. Central nervous system bleeding is seen in 0.1% to 0.5% of children with ITP. Peak age at presentation is from 2 to 6 years with equal gender prevalence in contrast to female preponderance in adolescents and adults with ITP. Often, there is history of a viral illness in the weeks prior to onset of the illness. Physical examination is unremarkable except for skin and mucosal bleeding. Lymphadenopathy and hepatosplenomegaly are not seen except when ITP is associated with infectious mononucleosis. The platelet count is generally less than 20 000/mm in nearly 80% of children although the severity of thrombocytopenia is variable. Blood smear shows some large platelets indicative of increased platelet turnover. Hemoglobin level may be low due to bleeding; WBC count and differential are usually normal. Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and fibrin split products, though generally not done, are normal. Antinuclear antibody and tests for HIV infection are done mostly in an adolescent or as indicated. Bone marrow aspiration is not needed for diagnosis in most patients but it is recommended in patients with atypical features of acute ITP and in children who respond poorly to initial therapy. It shows normal erythroid and granulocytic series with normal to increased numbers of megakaryocytes.

Newly diagnosed ITP is a clinical diagnosis reached by exclusion of other causes of thrombocytopenia such as leukemia or aplastic anemia. Acute leukemia almost never presents with isolated thrombocytopenia. Immune thrombocytopenia can be a presenting manifestation of systemic lupus erythematosus, Evans syndrome, or AIDS, particularly in adolescents.

Emergency Department Treatment and Disposition

In the absence of significant mucosal hemorrhages, patients with platelet counts between 20 000 and 50 000/mm can be observed without specific therapy and followed as an outpatient with once or twice weekly evaluation and blood count. Hospitalization and hematology consultation are recommended for patients with severe mucosal bleeding and platelet count <20 000/mm3. These patients may receive intravenous immune globulin (IVIG) or glucocorticoid. Advantages of IVIG include rapid onset of action and increase in platelet count in 80% to 90% of recipients. It can be given without bone marrow examination. IVIG administration may not be suitable for ED administration since IV infusion takes 6 to 8 hours. Other treatment options are IV methylprednisolone or oral prednisone (4 mg/kg for 7 days followed by 2 mg/kg with tapering over next 2 weeks or 4 mg/kg/day for 4 days without tapering). Advantages of prednisone therapy include inexpensive therapy, oral administration, and effectiveness in 75% to 80% of patients. A bone marrow exam is recommended by some pediatric hematologists before starting corticosteroids. Immune globulin against D-antigen of Rh blood group system, when given to Rh+ children with ITP, produces a rapid rise in platelet count. The advantages are that it can be given by IV infusion over 3 minutes. A recent FDA recommendation mandates observation of patients prior to discharge for 6 to 8 hours after anti-D immune globulin administration for evidence of intravascular hemolysis. Premedication with prednisone and acetaminophen prior to anti-D is known to result in higher platelet count with fewer side effects. The most common adverse effect is a fall in hemoglobin concentration by 1 to 2 g/dL. For life-threatening hemorrhages (eg, intracranial bleeding or retroperitoneal bleeding), the patient needs to be hospitalized and managed in an ICU setting. The treatment that may be started in the ED prior to admission in such patients include IV methylprednisolone, beginning of IVIG infusion and a slow IV push of anti-D immune globulin (if the patient is D positive). The dosing will be recommended by a hematologist. Platelet transfusions are given every 6 to 8 hours. Although platelet survival following platelet transfusion is poor, it is better when combined with corticosteroids and IVIG or anti-D immune globulin.

Pearls

1. Newly diagnosed ITP typically presents with sudden onset of petechiae and ecchymoses in an otherwise healthy child.

2. Newly diagnosed ITP is a diagnosis of exclusion. Bone marrow aspiration is not required for diagnosis if patients are observed without specific therapy or receive IVIG or IV anti-D immune globulin.

3. Newly diagnosed ITP is a self-limiting disease (˜90% of patients recover by 6 months from the diagnosis).

Clinical Summary

Hemophilia is an X-linked recessive disorder due to deficiency of Factor VIII (hemophilia A) or Factor IX (hemophilia B). Hemophilia A affects 1 in 5000 to 10 000 males and hemophilia B affects 1 in 30 000 males. Bleeding manifestations are identical in patients with factor VIII or IX deficiency. Patients with mild (factor level 6%-30%) and moderate hemophilia (factor level 1%-5%) usually bleed after trauma. Those with severe hemophilia (factor level <1%) bleed either spontaneously or after minor injury. Hemarthrosis and bleeding into the muscle are characteristic of bleeding in patients with hemophilia. Other manifestations include oral bleeding, hematuria, gastrointestinal, or central nervous system bleeding. One to 2% of patients with hemophilia may experience intracranial bleeding. Only a third of hemophilia patients bleed after circumcision. In most patients, diagnosis is made at birth because of family history; in nearly a third of the patients, hemophilia is due to a new mutation. When diagnosis of hemophilia is suspected, the following laboratory studies should be done; PT, PTT, mixing studies and assay for factor VIII and IX, and studies to diagnose von Willebrand disease.

Emergency Department Treatment and Disposition

Urgent hematology consultation is recommended for all children with hemophilia who present with bleeding. Patients presenting with severe or life-threatening bleeding (CNS, GI, or airway) need stabilization of vital signs. For patients with hemophilia A, factor VIII 50 units/kg IV (to achieve 100% factor VIII level) is started in the ED followed by 3 to 6 units/kg/h by continuous IV infusion for 24 hours, and the patient is admitted to the ICU for ongoing monitoring and additional therapy. For patients with hemophilia B, 80 to 100 units/kg of factor IX is given IV followed by 20 to 40 units/kg every 12 hours. Additional therapy is continued in ICU. A history of head injury should be taken seriously. Even in the absence of external bleeding, the patient should be given appropriate clotting factor in a dose of 50 units/kg (factor VIII) or 80 units/kg (factor IX) prior to any imaging studies. Obtain a head CT scan soon after factor infusion. Any patient with significant head injury (eg, loss of memory, hematoma, or laceration) should be hospitalized after factor replacement in the ED and receive factor replacement for 3 to 5 days even if head CT scan is negative. Monitoring the levels of coagulation factor is mandatory in patients receiving factor replacement for serious and life-threatening bleeding.

In patients with hemophilia A and hemarthrosis/muscle or large subcutaneous hematoma, give factor VIII concentrate (preferably recombinant factor VIII) 50 units/kg slow IV push initially and 20 units/kg on the next day; additional doses are given if clinically indicated. For hemophilia B patients, infuse factor IX (concentrate or recombinant factor IX) in a dose of 80 units/kg followed by 40 units/kg the next day.

For oral bleeding/dental extraction in patients with Hemophilia A, administer 20 units/kg factor VIII or 40 units/kg factor IX for molar extraction and antifibrinolytic therapy (ϵ-amino caproic acid or Amicar) by mouth pre-extraction and 4 to 5 days post-extraction. For patients with hemophilia B, administer 40 units/kg factor IX (80 units/kg if molar extraction) along with antifibrinolytic therapy as in hemophilia A.

Intravenous desmopressin (DDAVP) or nasal desmopressin (Stimate) is recommended to treat hemarthrosis in mild to moderate hemophilia A. An IV infusion of desmopressin is given over 30 minutes and may be repeated at 24-hour intervals for 2 or 3 days. Stimate nasal spray requires 1 spray in 1 nostril (150 μg) for patients less than 50 kg in weight or 1 spray in each nostril (total dose 300 μg) for patients who are more than 50 kg in weight. During the acute phase, immobilization is recommended as required by bed rest, ice, compression, and elevation.

Pearls

1. Accurate diagnosis of the type of hemophilia (factor VIII or IX deficiency) is essential for the proper management of the patient.

2. It is also important to know if patient has history of inhibitors to factor VIII or IX. Patients with inhibitors are treated with either prothrombin complex concentrates (like FEIBA) or recombinant factor VIIa.

3. For patients with mild to moderate hemophilia A, do not prescribe DDAVP nasal spray (used to treat patients with diabetes insipidus); instead prescribe Stimate nasal spray.

4. CT scan of the head must be done if there is a history of head trauma—even if symptoms are minimal. All head injuries should be treated aggressively with factor infusion, even if there are no signs of intracranial bleeding.

5. If a patient with hemophilia is on home therapy and brings in his factor to the ER, it may be used for treating the patient if the product is not readily available in the ER.

6. Aminocaproic acid or tranexamic acid is an important medication when treating oral bleeding in patients with hemophilia.

Clinical Summary

Any abdominal mass in a child requires urgent medical attention because it may be a presenting manifestation of a malignant tumor and these masses tend to be retroperitoneal in origin. In infants, most abdominal masses tend to be due to benign conditions. Any mass detected during a routine well child visit may increase the chance of early diagnosis and treatment of a malignant tumor and a favorable outcome. It is essential to obtain detailed history including the duration of the mass and rapidity of increase in the size of the mass, pain, constipation (suggests either a tumor compressing the bowel or that the mass is stool), diarrhea, fever, and weight loss and perform thorough physical exam in each patient. An irritable or cachectic child may have malignancy; high blood pressure suggests Wilms tumor, neuroblastoma, hydronephrosis, or multicystic kidney. Proptosis and periorbital ecchymosis suggest metastatic neuroblastoma. Sporadic aniridia or hemihypertrophy may be associated with Wilms tumor. Marked pallor and petechiae suggest marrow infiltration by the tumor, typically neuroblastoma. Fecal masses are usually mobile, multiple, and palpable in the left lower quadrant or on the entire left side corresponding to the course of the descending colon. Rectal examination confirming rectum filled with stool suggests that the abdominal mass may be a stool mass. Fecal masses usually disappear after a cleansing enema. Less common abdominal masses include intussusception (mass in right lower or upper quadrant) or incarcerated hernia; imperforate hymen with an abdominal mass suggests hydrocolpos, hydrometrocolpos, hematocolpos, or hematometrocolpos.

In differential diagnosis of abdominal masses in children, the age of the child is an important consideration. Greater than 50% of masses are of renal origin in neonates (and of these, most are caused by multicystic kidney disease or congenital hydronephrosis). Abdominal masses in infants and children are either retroperitoneal tumors (eg, Wilms tumor or neuroblastoma) or enlarged liver and spleen (often from diseases like leukemia or lymphoma). Laboratory evaluation includes CBC, comprehensive metabolic panel, serum lactate dehydrogenase (LDH), uric acid, calcium, phosphate, urinalysis, and pregnancy test, particularly when dealing with a midline abdominal mass in an adolescent female. Severe anemia or pancytopenia suggests bleeding into tumor or extensive marrow infiltration respectively. Anemia with thrombocytosis is a frequent finding in neuroblastoma. LDH is elevated most often in lymphoma, neuroblastoma, and germ cell tumors. High uric acid, potassium, and phosphate (evidence of tumor lysis syndrome) prior to therapy is seen typically in Burkitt lymphoma. Hypercalcemia is seen in some patients with lymphoblastic leukemia, mesoblastic nephroma, and rhabdoid kidney tumor. Hematuria may be seen in patients with Wilms tumor or renal cell carcinoma.

Emergency Department Treatment and Disposition

Plain chest radiograph is done for evidence of mediastinal adenopathy (eg, lymphoma), posterior mediastinal mass (eg, neuroblastoma), or pulmonary metastasis (eg, Wilms tumor, rhabdomyosarcoma, or hepatoblastoma). Plain radiograph of abdomen is obtained for evidence of intestinal obstruction (eg, intussusception presenting with an abdominal mass) or calcification in a solid mass (eg, neuroblastoma, Wilms tumor, hepatoblastoma, or ovarian teratoma). Abdominal ultrasound will determine the structure of origin and whether the mass is solid or cystic. A CT scan with contrast will provide details of the extent of the mass, invasion of adjacent structures, and presence or absence of enlarged nodes. MRI is superior in evaluating paraspinal masses such as neuroblastoma that may invade the spinal canal. If mass is thought to be secondary to constipation, enema may resolve the problem. Pediatric hematology/oncology, pediatric surgery, and pediatric nephrology service consultations are obtained depending on the probable clinical diagnosis. Management of abdominal mass usually depends on the underlying etiology. Most patients with abdominal mass due to clinically suspected malignancy need hospitalization for prompt evaluation and treatment. Hymenotomy is performed for abdominal mass due to imperforate hymen with hydrometrocolpos (abdominal mass will disappear as the secretions/menstrual products are drained). Barium enema may reduce (or if indicated, surgical reduction) an intussusception and result in disappearance of the mass.

Pearls

1. Any abdominal mass in a child requires urgent medical attention because it may be a presenting manifestation of malignancy.

2. A history of fever, bone pain, and weight loss suggests metastatic neuroblastoma or lymphoma.

Clinical Summary

Lymphadenopathy is defined as painless enlargement of the lymph nodes measuring >1 cm in diameter in the neck and axillary region and 1.5 cm for inguinal nodes. In the supraclavicular or epitrochlear region, nodes >5 mm can be considered lymphadenopathy. Regional lymphadenopathy involves 1 or 2 contiguous regions; generalized lymphadenopathy involves more than 2 noncontiguous regions and is usually due to systemic disease. The etiology is determined by whether adenopathy is regional or generalized, presence or absence of signs of local inflammation, and whether there are systemic symptoms (eg, fever, weight loss). Clinical features depend on the cause of lymphadenopathy. During evaluation location, size, consistency, and signs of inflammation (warmth, tenderness, erythema, fluctuance) of lymph nodes are noted. Erythema of skin over the node and tenderness indicate acute infection. Matted or fixed nodes to the skin or underlying structures may be seen in tuberculosis or malignancy. Cervical lymphadenopathy may be seen in oropharyngeal infections, cat-scratch disease, leukemia, lymphoma, metastatic neuroblastoma, infectious mononucleosis, tuberculosis, histiocytic disorders, and autoimmune lymphoproliferative disease. An enlarged thyroid gland with cervical adenopathy suggests thyroid carcinoma. Supraclavicular adenopathy (right supraclavicular adenopathy is usually due to an intrathoracic malignancy or infection in the mediastinum; left supraclavicular adenopathy is usually due to an intra-abdominal malignancy). Lymph node biopsy is indicated if there is no decrease in size of lymph nodes in 4 to 6 weeks or no regression to normal size in 8 to 12 weeks. Lymph node biopsy in the majority of patients reveals nonspecific lymphoid hyperplasia. In such cases, close follow-up for persistent signs and symptoms is essential and a repeat lymph node biopsy may be needed to make the diagnosis if the problem is not resolved. Lymph node biopsy should be considered in patients whose adenopathy persists or increases in size. Some examples include age of the child, especially >10 years; associated signs and symptoms of persistent or unexplained fever; weight loss; night sweats; lymph nodes that are hard, rubbery in consistency, matted together, fixed to the surrounding structures, or to the overlying skin; and mediastinal adenopathy.

Emergency Department Treatment and Disposition

Hematology/oncology and surgery consultations are recommended for suspected malignancy. Tests, as clinically indicated, include CBC (screening for anemia, thrombocytopenia, abnormal WBCs), peripheral blood smear to look for atypical lymphocytes or any abnormal morphology (eg, lymphoblasts), throat culture for Streptococcus pyogenes, intradermal uberculin (5 TU PPD) test, serology tests for Epstein-Barr virus (EBV), cytomegalovirus (CMV), HIV, toxoplasmosis, erythrocyte sedimentation rate (ESR), comprehensive metabolic panel including serum LDH and uric acid, and a chest radiograph (hilar or mediastinal adenopathy). Needle aspiration of the affected node, if clinically indicated, may be done and aspirate sent for Gram stain and acid-fast stains and aerobic and anaerobic cultures. Patients with suppurative adenitis (painful, enlarged, tender nodes) require antibiotics after appropriate laboratory evaluation (CBC with differential, blood culture). If the patient is febrile and looks ill, he or she may be admitted for IV antibiotic therapy and for possible incision and drainage. Patients with significant leukocytosis, an abnormal differential, hyperuricemia, high serum LDH, or mediastinal or hilar adenopathy should be admitted with urgent consultation from the hematology/oncology service and pediatric surgery. A diagnosis of leukemia/lymphoma may be made at times by bone marrow aspiration/biopsy, thus avoiding the need for lymph node biopsy.

Pearls

1. The majority of patients with lymphadenopathy have benign, self-limited disease that resolves without specific therapy.

2. Enlarged nodes anterior to the sternocleidomastoid muscle are usually benign (exception: thyroid cancer).

3. About 50% of masses in the posterior triangle or multiple masses extending across both the anterior and posterior triangles represent malignancies, the majority of which are of lymphoid origin.

4. Suspect malignancy in case of large, painless, firm, and rubbery lymph nodes in the posterior triangle.

5. Supraclavicular lymphadenopathy strongly suggests malignancy.

6. Bacterial lymphadenitis commonly presents with fever and painful, enlarged, tender lymph nodes with local signs of inflammation.

Clinical Summary

Osteosarcoma is the most common type of bone tumor followed by Ewing sarcoma, with a peak incidence of 16 years in girls and 18 years in boys. Derived from the mesenchyme, it occurs in the metaphyseal portions of rapidly growing bones such as the distal femur, proximal tibia, and proximal humerus; 5% are multifocal. It can also develop in the bones of the pelvis, chest wall, head and neck, and soft tissues. The axial skeleton is rarely affected. Etiology is undetermined but there is a strong association with radiation, treatment with alkylating agents, hereditary retinoblastoma, P53 gene mutations, and Li-Fraumeni syndrome. The most common symptom is dull aching pain at the site of the lesion. Constitutional symptoms of fever and weight loss are rare but may occur in patients with metastasis, especially to lungs. A soft tissue mass or deformity is noted over the primary site and there may be erythema, edema, tenderness, or limitation of movement. Painful limp that increases with weight bearing is a common finding. Regional and distant lymph nodes are not enlarged. The average duration of symptoms is about 3 months.

Emergency Department Treatment and Disposition

The initial evaluation of suspected osteosarcoma includes plain radiographs of the involved site and chest (90% of the metastases are to the lungs). Laboratory studies include CBC, ESR, comprehensive metabolic panel, and serum phosphorus. Serum values of alkaline phosphatase are elevated in 40%, and LDH is elevated in 30% of patients. Common radiographic findings are destruction of the bone with lytic lesions. Periosteal new bone formation with lifting of the cortex (Codman triangle) are characteristic findings. As the tumor erodes the medullary cavity, a soft tissue mass is observed and a pathologic fracture may be seen. Ossification of the soft tissue can be seen in a radial or sunburst pattern. These findings are seen in the metaphyseal region of the long bones as opposed to Ewing sarcoma, which occurs in the diaphysis. Additional radiographic studies include MRI to assess the intraosseous extent of the tumor and chest CT for the lung metastasis. These studies are essential in planning surgery. Radionuclide bone scan is indicated to detect skip lesions and distant bone metastasis. Patient should be admitted after consultations with orthopedic surgeon, oncologist, and radiologist for further workup and management. Although the radiographic findings are highly suggestive, a biopsy is always required to confirm the diagnosis. Biopsy should be done by the same orthopedic surgeon who will later do the definitive surgery. It can be a fine-needle biopsy or core or open biopsy. Treatment includes preoperative chemotherapy followed by amputation or limb salvage surgery and postoperative chemotherapy. There is no role for radiation in the treatment of osteosarcoma. Chemotherapeutic agents include methotrexate, cisplatinum, ifosfamide, doxorubicin, and etoposide. Echocardiogram is needed before chemotherapy as some chemotherapy drugs are cardiotoxic. The most important prognostic factor is the degree of tumor necrosis in response to preoperative chemotherapy. Overall survival is 70%.

Pearls

1. Osteosarcoma is the most common malignant bone tumor in children and adolescents, with a peak incidence in the second decade of life.

2. Pathologic fracture occurring with minor trauma is suggestive of an underlying bone pathology, including malignant bone tumors.

3. The appearance of the bone lesion in osteosarcoma may be mixed lytic and blastic, with a characteristic sunburst pattern of new bone formation.

Clinical Summary

Ewing sarcoma is the second most common primary bone tumor in children and adolescents seen with a peak incidence between 10 and 15 years of age. Majority arises in a bone but extraosseous tumors may occur in soft tissues and neural crest. They typically occur in the diaphysis of long bones, chest wall, paraspinal region, scapula, vertebrae, and pelvis. Ewing sarcoma family of neoplasms includes the primitive neuroectodermal tumors with similar chromosomal translocations involving the EWS gene on chromosome 22q12. It is a small round cell tumor with rosette formation. The signs and symptoms are related to the site of origin. Patients present with bone pain or symptoms related to a mass. The pain may be severe enough to wake up the child from sleep. The swelling is tender and erythematosus. Fracture may be present within the bony involvement. Serum LDH values are elevated. Metastasis is seen in 25% of patients at diagnosis and sites include lungs, bone, bone marrow, and lymph nodes. Fever, anemia, and pancytopenia (bone marrow infiltration) may occur. Differential diagnosis of bone pain related to malignancies includes osteogenic sarcoma, leukemia, lymphoma, and neuroblastoma.

Emergency Room Treatment and Disposition

All clinically suspected cases of a malignant bone tumor require hospitalization for further workup and management by a multidisciplinary team, including hematology/oncology, radiology, orthopedic, and radiation oncology services. The plain radiographs of the involved site show cortical destruction and onion skin periosteal reaction, which is highly suggestive of a malignant bone tumor. Laboratory studies include CBC with a differential, comprehensive metabolic panel, ESR, and LDH. Additional studies include MRI of the involved site, chest CT for the lung metastasis, bone marrow aspiration, and biopsy of the mass. Treatment of localized disease is surgery and radiotherapy for non resectable or inadequately resected tumors. Neo adjuvant chemotherapy is necessary for extensive disease. Chemotherapeutic agents include vincristine, doxorubicin (Adriamycin), etoposide, cyclophosphamide, and ifosfamide. Prognosis depends on the tumor size, location, stage, surgical resection, and response to chemotherapy.

Pearls

1. Ewing sarcoma is unusual in African Americans.

2. Bone pain severe enough to wake up a child from sleep deserves further evaluation.

3. Radiographic appearance of Ewing sarcoma is a primarily lytic bone lesion with a characteristic onion-skinning periosteal reaction.

Clinical Summary

Acute leukemia is the most common malignancy in childhood. Of the 2000 cases diagnosed in the United States every year, 75% are acute lymphoblastic leukemia (ALL) and the remaining are acute nonlymphoblastic leukemia (ANLL). Childhood ALL has a peak between 2 and 6 years of age, and occurs more commonly in boys. It may be T or B cell in origin. There are a variety of predisposing or contributing factors like environmental carcinogens, viral infections, genetic syndromes, Bloom syndrome, Fanconi anemia, immunodeficiency states such as Wiskott-Aldrich syndrome, ataxia telangiectasia, and ionizing radiation. The presenting signs and symptoms reflect the degree of bone marrow infiltration with lymphoblasts and the extent of extramedullary spread. Low-grade unexplained fever is present in 80% of patients. Pallor and fatigue due to anemia and epistaxis, petechiae, and purpura due to thrombocytopenia may be seen. Anorexia is common but significant weight loss is uncommon. The duration of symptoms varies from days to weeks. There is multiorgan involvement due to leukemic infiltration with differing signs and symptoms. Bone pain is present in 25% of patients. Long bones are affected with involvement of the periosteum. Patient presents with limping and tenderness and the condition may be misdiagnosed as rheumatoid arthritis or osteomyelitis. Extramedullary spread leads to lymphadenopathy and hepatosplenomegaly. Hepatic dysfunction from liver infiltration is mild with LDH elevation. T-cell ALL usually presents with a high WBC count and a mediastinal mass. Compression of the trachea or superior vena cava causes dyspnea, plethora, and facial edema (superior mediastinal or superior vena cava syndrome). Infiltration of the kidneys causes renal enlargement. Hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia due to tumor lysis may lead to uric acid nephropathy and subsequent renal failure. Central nervous system involvement is rare at presentation. Differential diagnosis of ALL includes ITP, aplastic anemia, infectious mononucleosis, and other malignancies such as neuroblastoma and lymphoma.

Emergency Department Treatment and Disposition

All clinically suspected patients with ALL require hematology consultation and hospitalization for confirmation of the diagnosis by a bone marrow examination and further management. Laboratory tests include CBC with a differential and peripheral smear, blood culture, renal and liver function tests, uric acid, LDH, PT, PTT, type and cross match, and urine analysis. Chest radiograph is obtained to look for hilar lymphadenopathy and/or mediastinal mass. Intravenous hydration is initiated with the anticipation of tumor lysis syndrome. Although leukemic blasts may be identified in the peripheral smear in some patients, bone marrow examination is mandatory for establishing a definitive diagnosis, to identify the immunologic subtypes (T-ALL and B-ALL), and for cytogenetic evaluation. These are all necessary for risk stratification and treatment. Lumbar puncture is done after admission to look for blasts in CSF and for administration of intrathecal chemotherapy. A traumatic tap will confuse the cytologic assessment and potentially seed the central nervous system with lymphoblasts. Supportive care includes packed red blood cell and platelet transfusions (especially for bleeding and prior to lumbar puncture), prevention and treatment of infections, and treatment of tumor lysis syndrome. Multiagent chemotherapy is given for 2 to 3 years after risk stratification. Five-year event-free survival is 85% for children with standard-risk ALL.

Pearls

1. Tumor lysis syndrome and superior mediastinal syndromes are medical emergencies and require immediate intervention.

2. Unexplained fever, weight loss, lymphadenopathy, and bone pain require investigations for malignancy.

3. Patients with ALL may have leukopenia or leukocytosis at presentation.

Clinical Summary

Ovarian tumors and rhabdomyosarcoma are the two common pelvic tumors in girls. Ovarian tumors are rare, accounting for 1% of childhood malignancies and are of different pathological subtypes. Two-thirds of pediatric ovarian tumors are of germ cell origin. Most ovarian tumors are cystic and benign. Malignant ovarian tumors are uncommon in childhood and are seen in adolescence with a peak incidence at 19 years of age. The commonest malignant ovarian tumor is dysgerminoma, which is rapidly growing but curable with surgery and chemotherapy. Next are teratomas, majority of which present in the premenarchal age. These arise from the three germ cell layers and can be solid or cystic with or without calcifications. The immature teratomas contain fetal immature tissue, which is neuroectodermal in origin and can be malignant. Mature teratomas can present with ovarian torsion and can rupture spontaneously, leading to peritonitis in 1% to 3% of cases. Endodermal sinus or yolk sac tumors are associated with an increase in serum α-fetoprotein (AFP) level and can present with metastases to the lung, liver, or lymph nodes. In embryonal carcinoma, human chorionic gonadotrophin (HCG) level is increased and precocious puberty, amenorrhea, or hirsutism may be seen. Choriocarcinoma is rare in children and may present with an increase in serum HCG level and metastases to the lung and liver. Other rare tumors are mixed germ cell tumors and gonadoblastomas that are associated with dysgenetic gonads and sexual maldevelopment. The most common signs and symptoms of ovarian tumors are abdominal mass, abdominal distention, and abdominal or back pain. Pain can be chronic but may mimic an acute abdomen, especially if presenting with torsion. Fever, constipation, amenorrhea, vaginal bleeding, urinary frequency, or dysuria may be present. Differential diagnosis includes appendicitis, ovarian cyst, ovarian torsion, tubo-ovarian abscess with PID, urinary tract infection, and ectopic pregnancy.

Emergency Room Treatment and Disposition

Any patient presenting with an abdominal or pelvic mass needs an immediate sonogram as most ovarian tumors can be identified by ultrasonography. A CBC, comprehensive metabolic panel, LDH, ESR, and levels of AFP, HCG, and CA-125 should be obtained. Radiographic studies include MRI of the abdomen and pelvis, chest radiograph, and CT scan. Surgical and hematology consultations should be obtained and the patient should be admitted. Treatment is surgical resection of the tumor followed by chemotherapy for malignant tumors. Chemotherapeutic agents used are cisplatinum, vinblastine, bleomycin, and etoposide. Radiation therapy is avoided if possible for preservation of fertility.

Pearls

1. Abdominal mass, pain, and irregular menstrual periods need immediate abdominal and pelvic ultrasound for evaluation.

2. Ovarian tumors may rupture and present as acute abdomen and peritonitis.

3. Increased HCG in choriocarcinoma may result in a falsely positive pregnancy test.

4. Aim of treatment of ovarian tumors is cure with development of normal puberty and future fertility.