Secrets – Pediatric: Oncology

Secrets – Pediatric: Oncology

CHEMOTHERAPY AND RADIATION THERAPY
1. What was the first cytotoxic chemotherapeutic agent used for the treatment of children with leukemia?
In 1948, Sidney Farber reported success using aminopterin (4-aminopteroyl-glutamic acid) in 16 children with acute leukemia. Aminopterin was a precursor to the antifolate drug, methotrexate, which is commonly used today.

Farber S, Diamond LK, Mercer RD, et al: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-amino-pteroylglutamic acid (aminopterin), N Engl J Med 238:787–793, 1948.

2. Name the common cytotoxic chemotherapeutic drug classes.
Chemotherapeutic drugs are usually classified by their primary site and mechanism of action or source. The most common are the alkylators, antimetabolites, antitumor antibiotics, and plant toxins.
3. We can thank the guinea pig for a major (albeit serendipitous) breakthrough in the treatment of childhood acute lymphoblastic leukemia (ALL). What role did our rodent friend the Cavy play?
In 1953, investigators discovered that whole guinea pig serum could bring about regression of certain transplanted lymphosarcomas in inbred mice. By 1961, it was determined that the fraction of guinea pig serum responsible for its antileukemic effect contained significant asparaginase activity. Most leukemic lymphoblasts were then found to be asparagine autotrophs, requiring exogenous asparagine for survival. A bacterial source (Escherichia coli) of asparaginase was identified, and pharmaceutical production of L-asparaginase began, increasing the complete remission rate for children with ALL from about 80% to more than 95%.
4. Which chemotherapeutic agents are cell cycle dependent? In which phase are they most active?
See Figure 14-1.

Vinblastine Vincristine
M
Phase

Bleomycin G2
Etoposide Phase

G0
Phase

G1
Phase

L-Asparaginase

Doxorubicin Daunorubicin

Cytarabine

S Phase

Flourouracil

Actinomycin-D Prednisone

Methotrexate Mercaptopurine Vincristine

Hydroxyurea Thioguanine Vinblastine

Figure 14-1. Phases in which cell cycle–dependent chemotherapy agents are most active. G0, resting phase (nonproliferation);
G1, gap1 (pre-DNA synthesis with diploid RNA and protein synthesis); S, DNA synthesis; G2, gap2 (post-DNA synthesis);
M, mitosis. (From Weiner MA, Cairo MS: Pediatric Hematology/Oncology Secrets. Philadelphia, 2000, Hanley & Belfus, p 96.)
558

5. What is the difference between adjuvant and neoadjuvant chemotherapy?
ADJUVANT chemotherapy is administered after the primary treatment of a tumor (surgical resection or radiation therapy), when there is no remaining gross tumor that can be assessed for response to the chemotherapy.
NEOADJUVANT chemotherapy is administered before the delivery of definitive local treatment and then continues afterward in the adjuvant setting. For children with solid tumors, several cycles of neoadjuvant chemotherapy are often administered to improve the chances of achieving complete surgical resection and improved local control of a primary tumor.
6. Why are most chemotherapeutic drug dosages based on body surface area (BSA)?
In theory, BSA correlates better than body weight with cardiac output and hence hepatic and renal perfusion. Because most drug clearance occurs by hepatic and renal mechanisms, anticancer drugs that have a very narrow therapeutic index are usually dosed in a manner that is normalized to BSA. The exception is made for infants, who have a very high BSA-to-body weight ratio; infants receive chemotherapy based on body weight. BSA can be estimated using height and weight. One estimate can be obtained with the following formula:
BSA m2 ¼ pffi½ffiðffiffiwffiffiffieffiffiiffigffiffihffiffitffiffi×ffiffiffiffihffiffiffieffiffiiffigffiffihffiffitffiÞffiffi=ffiffi3ffiffiffi6ffiffi0ffiffi0ffiffiffi]ffi
7. What is the difference between pharmacokinetics and pharmacodynamics? Pharmacokinetics refers to the effect of the body on the drug. It is the study of how drugs are absorbed, distributed, metabolized, and eliminated from the body. Common parameters include elimination half-life, peak concentration, clearance, and area under the concentration-time curve.
Pharmacodynamics refers to the effect of the drug on the body. A pharmacodynamic effect can be a toxicity measurement (decrease in blood counts) or an anticancer measurement (decrease in the size of a tumor) after chemotherapy.
8. What are the phases of clinical trials?
• Phase I: The dose determination phase. This phase is designed primarily to recommend a dose for further testing in children, usually the maximal tolerated dose. Pharmacokinetic studies are performed during phase I trials to help learn whether children handle a drug differently than adults. Phase 1 trials typically enroll 18 to 30 children.
• Phase II: The efficacy phase. Usually a group of children with the same diagnosis are studied, and the percentage of patients in whom the drug causes a tumor to decrease in size is determined.
Phase II trials enroll 30 to 150 children, depending on how many different tumor types are being studied.
• Phase III: The COMPARATIVE phase. This phase studies whether a new drug (or a new combination of drugs) that was found to be efficacious in a phase II trial can improve therapy relative to the best current therapy. Phase III trials are randomized and can enroll hundreds to thousands of children.

Balis FM, Fox E, Widemann BC, Adamson PC: Clinical drug development for childhood cancers, Clin Pharmacol Ther
85:127–129, 2009.

9. What is the major dose-limiting toxicity for the alkylating agents?
Myelosuppression. Alkylating agents are chemically reactive compounds that covalently add an alkyl group; this is most important with regard to macromolecules involved in DNA synthesis, damaging templates, and inhibiting synthesis. Agents include the nitrogen mustards, oxazaphosphorines (including cyclophosphamide and ifosfamide), busulfan, and cisplatin.
10. If one had to choose a single laboratory test to obtain before administering high-dose methotrexate, which one should it be?
Determination of serum creatinine is essential before administering high-dose methotrexate.
The kidneys eliminate more than 90% of methotrexate. In the presence of abnormal renal function, high-dose methotrexate carries a high risk for severe or fatal toxicity.

Widemann BC, Adamson PC: Understanding and managing methotrexate nephrotoxicity, Oncologist
11:694–703, 2006.

11. What factors are associated with an increased risk for developing anthracycline-induced cardiotoxicity?
Total cumulative dose, mediastinal radiotherapy, young age, and female gender are associated with an increased risk for developing anthracycline (doxorubicin, daunorubicin)-induced cardiotoxicity.
Cumulative anthracycline dose has long been associated with an increased risk, with the incidence of clinically apparent congestive heart failure rising significantly with doxorubicin doses exceeding
450 mg/m2. Late cardiotoxicity appears to be more common in children than in adults because the heart is unable to grow in proportion to the child, resulting in a small, poorly compliant left ventricle. Thus, younger children, particularly children younger than 5 years, are at higher risk. There is also some evidence that girls have a higher incidence of abnormal cardiac findings at any given cumulative dose than boys. Trisomy 21 and black patients may also be at increased risk. Dexrazoxane, a cardioprotective agent, has been used in adults receiving anthracyclines, but the FDA has limited pediatric use because of possible higher rates of second malignancies and acute myelogenous leukemia (AML) in patients treated for different cancers.

Lipshultz SE, Sambatakos P, Maguire M, et al: Cardiotoxicity and cardioprotection in childhood cancer, Acta Haematol
132:391–399, 2014.
Barry E, Alvarez JA, Scully RE, et al: Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management, Expert Opin Pharmacother 8:1039–1058, 2007.

12. How did a periwinkle plant contribute to some longstanding chemotherapeutic agents?
Extractions from the pink Madagascar periwinkle plant have been used for centuries as natural remedies. When used (unsuccessfully) as a treatment for diabetes mellitus, myelosuppression was noted. In the 1950s, the active components were noted to be vinca alkaloids. This property led to studies in oncology with vincristine (one of the alkaloids) licensed by the Food and Drug Administration (FDA)
in 1963.

Moudi M, Go R, Yien CY, et al: Vinca alkaloids, Int J PREV Med 11:1231–1235, 2013.

13. What is the mechanism of action of vincristine?
Vincristine binds to tubulin, which disrupts microtubules and arrests mitosis in metaphase. Thus, it is most effective in rapidly dividing cell types. It is used in all phases of ALL therapy including induction, consolidation, and maintenance. It has also played a role in the treatment of a variety of other pediatric oncologic diseases, including non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms tumor, and neuroblastoma.

Liesveld J, Asselin B: It’s ALL in the liposomes: vincristine gets a new package, J Clin Oncol 20:657–659, 2013.

14. What agent can limit the complication of hemorrhagic cystitis that occurs in some chemotherapeutic regimens?
Mesna is the acronym for 2-mercaptoethane sodium sulfonate, a sulfhydryl compound. The oxazaphosphorines (cyclophosphamide, ifosfamide) are widely used in clinical practice for their antitumor activities. However, urinary excretion of their urotoxic metabolite, acrolein, can lead to hematuria and hemorrhagic cystitis. Mesna acts as a detoxifying agent. It is given as an adjuvant therapy and binds to acrolein in the urine, which creates an inert thioether that is excreted.

Andriole GL, Sandlund JT, Miser JS, et al: The efficacy of mesna (2-mercaptoethane sodium sulfonate) as a uroprotectant in patients with hemorrhagic cystitis receiving further oxazaphosphorine chemotherapy, J Clin Oncol 5:799–803, 1987.

15. What is a vesicant?
A VESICANT is an agent that produces a vesicle; in oncology, it is a chemotherapeutic drug that can cause a severe burn if the drug infiltrates around the intravenous catheter. The anthracyclines (doxorubicin, daunorubicin), dactinomycin, and the vinca alkaloids (vincristine, vinblastine) are all vesicants. These drugs must be administered either through a central venous catheter or through a newly placed,
free-flowing intravenous catheter that does not cross over a joint space.

16. Which classes of chemotherapeutic agents have most commonly been implicated in causing secondary leukemias?
The alkylating agents (e.g., cyclophosphamide) and topoisomerase II inhibitors (etoposide) increase the risk for developing secondary leukemia. Etoposide-induced leukemias tend to occur earlier, usually within 2 to 3 years of exposure.
17. Why is intrathecal chemotherapy dose based on patient age, whereas systemic (oral, intravenous) dosing is based on weight or BSA?
The brains of children grow disproportionately more quickly than their bodies (hence the tendency of infants who have recently learned to sit to readily tip over). The cerebrospinal fluid (CSF) increases in parallel with central nervous system (CNS) growth, such that by the age of 3 years, CSF volume is 80% that of adult CSF volume. Scaling intrathecal doses to body size would undertreat younger children, whereas scaling doses in adolescent patients, whose CNS size has plateaued relative to body size, would unnecessarily expose them to potentially more toxic drug concentrations.
18. What antiemetic agents are most effective in the management of chemotherapy- induced nausea and vomiting?
The serotonin receptor antagonists (ondansetron and granisetron) act as the foundation of prophylactic therapy for chemotherapy with significant emetogenic potential. The neurokinin (NK1) receptor antagonists (e.g., aprepitant), are the newest class of effective antiemetic agents and have shown extremely promising results. Aprepitant blocks the NK-1 receptors in the vomiting centers in the CNS, which are activated by substance P, released as an unwanted consequence of chemotherapy. Corticosteroids are useful for chemotherapeutic agents with low emetic potential; however, they are most effective when used in combination with other agents. Less effective agents include metoclopramide, phenothiazines, cannabinoids, and olanzapine, all of which have a greater potential for adverse side effects.

Hargreaves R, Ferreira JC, Hughes D, et al: Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, Ann NY Acad Sci 1222:40–48, 2011.
Hesketh PJ: Chemotherapy-induced nausea and vomiting, N Engl J Med 2008; 358:2482–2494, 2008.

19. Who develops the “somnolence syndrome”?
Transient symptoms attributed to temporary demyelination have been observed 6 to 8 weeks after completion of CNS radiation, most commonly for CNS prophylaxis for ALL. Children who develop the somnolence syndrome have lethargy, headache, and anorexia that last for about 2 weeks. Computed tomography (CT) and CSF studies show no consistent abnormality, but an electroencephalogram often reveals a slow-wave activity consistent with diffuse cerebral disturbance. The use of steroids during irradiation appears to minimize the occurrence of the syndrome.
20. What is radiation recall?
Radiation recall is a delayed effect that results from the interaction of certain chemotherapeutic agents (doxorubicin, daunorubicin, or actinomycin-D) with radiation. After radiation therapy, an erythematous rash in the previous radiation field develops. The rash is geographic, usually precisely following the outline of the radiation field. Many of these occur months after the radiation treatment.
21. What is a “fraction” of radiation? Radiation therapy is coordinated so that a patient receives a maximally tolerated total amount of radiation dose. However, exposure to large amounts of radiation in one instance does not necessarily result in optimal cellular destruction, and it may have significant side effects. As a result, radiation is “fractionated” into smaller doses. Patients may receive up to dozens of individual fractions to achieve total radiation doses. For solid tumors, radiation is delivered over 2 to 6 weeks.
22. A 10-year-old girl is being treated for AML with a combination of high-dose cytarabine and daunorubicin. Five days after the initiation of therapy, she develops the onset of nystagmus, ataxia, and dysmetria, and a brain CT reveals no focal abnormalities. What is the most likely cause of her symptoms?
High-dose cytarabine can result in an acute cerebellar syndrome leading to nystagmus, ataxia, dysmetria, and dysdiadochokinesia. Imaging at the onset of symptoms is typically normal. In most cases, neurologic symptoms resolve within a week, but as many as 30% of patients do not regain full cerebellar function. The risk for developing cerebellar syndrome is related to the dose and schedule of cytarabine, with the highest risk being observed with administration of high doses over 6 or more days.

23. What are the long-term sequelae of chemotherapy?
Today, approximately 80% of children with cancer are cured. However there are significant long-term effects from chemotherapy that have come to the forefront with a growing population of survivors.
The effects are based on the type of treatment received and the age at which the patient was treated. The major sequelae include cognitive defects, cardiac defects (particularly with anthracyclines), endocrinopathies (especially thyroid dysfunction and hypopituitarism), infertility, and unfortunately secondary malignancies. There is a significant component of psychosocial morbidity, including depression and anxiety, which has been reported.

Skinner R: Long-term effects of cancer therapy in children—functional effects, late mortality and long-term follow-up,
Paediatr Child Health 22(6):248–252, 2012.
Skinner R: Long-term effects of cancer therapy in children—organs, systems and tissues, Paediatr Child Health
22:201–206, 2012.

24. Radiation therapy: what are its long-term effects?
Radiation therapy is an important component of treatment for many pediatric cancers. However, it is associated with the development of secondary neoplasms (solid tumors), obesity following cranial radiation, thyroid dysfunction, and pulmonary and cardiac complications. The majority of these complications arise within the field of exposure. Limiting the dose and the extent of radiation exposure is key in reducing the long-term effects.

Armstrong GT, Stovall M, Robison LL: Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the Childhood Cancer Survivor Study, Radiation Res 174:840–850, 2010.

CLINICAL ISSUES
25. A patient has a central venous catheter and develops a fever. What should be done? The risk for bacteremia is increased in patients with central venous catheters. As such, any patient with an indwelling central venous catheter and a fever (temperature usually 38.5 °C) should have paired blood cultures drawn from the catheter (one or more catheter lumens) and from a peripheral vein before any antibiotic administration. Intravenous antibiotics are typically administered until evidence of a negative blood culture is provided. Removal of the catheter should be considered if the patient has signs of sepsis, significant worsening erythema, or purulence. Removal of the catheter is generally advised if blood cultures are positive with a suspected pathologic organism. If the catheter is left in place, it should be removed if bloodstream infection continues despite >72 hours of antimicrobial therapy to which the infecting microbes are susceptible. If catheter removal is required, the catheter tip should be cultured.

Mermel LA, Allon M, Bouza, et al: Clinical practice guidelines for diagnosis and management of intravascular catheter-related infection, 2009 update by the Infectious Diseases Society of America, Clin Infect Dis 49:1-45, 2009.
Rackoff WR, Ge J, Sather HN, et al: Central venous catheter use and the risk of infection with acute lymphoblastic leukemia: a report from the Children’s Cancer Group, J Pediatr Hematol Oncol 21:260–267, 1999.

26. Describe three different types of infection that are associated with central venous catheters, and how the treatment approaches to these infections differ.
For external catheters (e.g., Hickman, Broviac), an exit site infection, manifested as inflammation and occasionally exudate limited to where the catheter emerges through the skin, can usually be managed with a combination of local care and systemic antibiotics. Patients with indwelling catheters are at increased risk for bloodstream infections. Many bacterial blood infections associated with central lines can be cleared with intravenous antibiotics administered through the central catheter, rotating lumens for multiline catheters. The potentially most serious bacterial infection is a tunnel infection, manifested by inflammation and tenderness along the entire subcutaneous tract of the catheter. These infections mandate prompt removal of the catheter and administration of intravenous antibiotics.
27. A patient undergoing chemotherapy is neutropenic and has a fever. What should be done?
Because neutropenic patients are at risk for invasive bacterial infections, patients who are neutropenic (absolute neutrophil count <500/mm3 or <1000/mm3 and falling) should have blood

cultures obtained and receive broad-spectrum antibiotics. Antibiotic coverage should include both gram-negative and gram-positive organisms, including antibiotics that are active against Pseudomonas aeruginosa. Broad-spectrum antibiotics are continued until blood cultures have been negative
for 48 hours, a patient has been afebrile for at least 24 hours, and there is marrow evidence (with increasing neutrophil counts) that indicates signs of recovery.

Lehmbecher T, Phillips R, Alexander S, et al: Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation, J Clin Oncol 30:4427–4438, 2012.

28. A patient remains febrile and neutropenic despite appropriate antibiotics for several days. Is there cause for concern?
Although it is not uncommon for a neutropenic patient to remain febrile for many days despite administration of broad-spectrum antibacterial agents, persistent fever is associated with an increased likelihood of invasive fungal infection. Pediatric patients at particular risk for invasive fungal disease are those with AML or relapsed acute leukemia, those receiving highly myelosuppressive chemotherapy for other malignancies, and those undergoing stem-cell transplantation with fever
96 hours despite broad-spectrum antibiotic therapy and with neutropenia expected to continue
>10 days. Because the ability to recover fungi in routine blood cultures is limited, the approach to such patients is to empirically add antifungal coverage after a period of persistent fever. Choices of empirical antifungal therapy have expanded over recent years and now include liposomal formulations of amphotericin B, azoles (e.g., voriconazole), and echinocandins (e.g., caspofungin).

Lehmbecher T, Phillips R, Alexander S, et al: Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation, J Clin Oncol 30:4427–4438, 2012.

29. How should a patient who has oral candidiasis or esophageal candidiasis be treated? Candida species of yeast are a common cause of oral or esophageal infections in immunocompromised hosts. Topical antifungals (e.g., nystatin) may be tried in cases of simple oral candidiasis, and these can be added to regimens to treat esophageal candidiasis. However, systemic therapy is usually indicated in cases of esophageal candidiasis. Fluconazole is the first-line agent that can be used against candidal mucosal infections.
30. After receiving broad-spectrum antibiotic therapy for 4 days for fever and neutropenia, a patient develops a new fever that is associated with abdominal cramps and bloody diarrhea. What is the most likely diagnosis?
The patient most likely has Clostridium difficile colitis brought on by treatment with broad-spectrum antibiotics. The diagnosis should be confirmed by detection of the C. difficile toxins in the stool, and either metronidazole (preferred) or oral vancomycin should be initiated promptly.
31. A 10-year-old in her second year of treatment for ALL has had all medications voluntarily stopped by her parents for 8 weeks. What is the likely diagnosis when she presents to the emergency department (ED) with cough, tachypnea, hypoxia, and a chest x-ray that reveals widespread pulmonary infiltrates?
Pneumocystis JIROVECI pneumonia (PJP). Formerly called pneumocystis carinii, pneumocystis JIROVECI are yeast-like fungi that can result in opportunistic infections in individuals with compromised immune systems. Although classified as a fungus, PJP is nonresponsive to antifungal treatment. Children with cancer are immunosuppressed both because of their underlying diagnosis and the chemotherapy they receive. As a result, they require PJP prophylaxis (typically trimethoprim-sulfamethoxazole), which is given as 2 to 3 consecutive days of dosing per week. In this case, a compliance failure likely resulted in pneumonia. Clinical signs of pneumocystis pneumonia can be highly variable, but a classic feature is an arterial oxygen level (PaO2) that is distinctly lower than expected given the clinical findings.
32. What paraneoplastic syndromes can occur in childhood? Paraneoplastic signs or symptoms are those that are unrelated to a malignancy but that can herald cancer. They occur more commonly in adults than children. However, unexplained high calcium, watery diarrhea, polymyositis, dermatomyositis, unexplained high hemoglobins, hypertension, precocious puberty, encephalitis, and opsoclonus or myoclonus can be associated with childhood malignancies.

Wells EM, Dalmau J: Paraneoplastic neurologic disorders in children, Curr Neurol Neurosci Rep 11:187–194, 2011.

33. What are the metabolic abnormalities in the tumor lysis syndrome?
Tumor lysis syndrome is an oncologic emergency that occurs when there is spontaneous or chemotherapy-induced massive breakdown of tumor cells. The subsequent release of the cells’ contents into the circulation leads to hyperkalemia, hyperuricemia, hyperphosphatemia, and secondary hypocalcemia. Hyperkalemia is the most dangerous aspect of tumor lysis syndrome because of the high risk of sudden death. As such, patients at risk for tumor lysis syndrome should have no potassium placed in their IV fluids, have frequent electrolyte checks, and may need to be placed on
a cardiac monitor.

Howard SC, Jones DP, Pui CH: The tumor lysis syndrome, N Engl J Med 364:1844–1845, 2011.

34. In what settings is tumor lysis syndrome more likely to occur?
Tumor lysis syndrome has been most frequently observed in patients with non-Hodgkin lymphoma and other hematologic malignancies (such as ALL) after the initiation of cytotoxic chemotherapy. It may also occur in other tumor types with a high proliferative rate or high sensitivity to cytotoxic therapy, as well as in the presence of a large tumor burden. In addition, the presence of preexisting renal impairment is widely regarded as a contributory factor.

Cairo MS, Coiffier B, Reiter A, et al: Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus, Br J Haematol 149(4):576-586, 2010.

35. What are the current recommendations regarding management of tumor lysis syndrome?
PREVENTION is the key in the management of tumor lysis syndrome and is done through aggressive intravenous (IV) hydration. The goal of IV hydration is to quickly improve renal perfusion and glomerular filtration, which results in high urine output that minimizes the likelihood of uric acid or calcium phosphate precipitation in the tubules. There is no current consensus regarding the role of urinary alkalinization by using sodium bicarbonate in these patients. Reducing the level of uric acid through pharmacologic measures is also recommended.
36. What two pharmacologic agents can be used to prevent or treat hyperuricemia caused by tumor lysis syndrome? Allopurinol inhibits the enzyme xanthine oxidase, a key enzyme required for the formation of uric acid. Its administration blocks further uric acid production. Rasburicase is a recombinant enzyme that catalyzes the conversion of uric acid to allantoin, which is more soluble than uric acid, and more readily excreted by the kidney.
37. A child with newly diagnosed leukemia experiences a rapid decline in hemoglobin soon after administration of rasburicase. What is the basis for this drug-related adverse event?
Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because of the risk for hemolysis and development of methemoglobinemia.
38. A child undergoing induction chemotherapy for leukemia develops right lower quadrant pain and tenderness. What diagnosis should be considered?
Typhlitis. Although patients with cancer or those receiving chemotherapy may develop appendicitis, typhlitis is a severe necrotizing infection of the ileocolonic junction that occurs in neutropenic patients.
39. What is the difference between a Broviac and a Port-A-Cath?
Children who require repeated blood draws or intravenous medications often have a semipermanent central venous catheter placed.
• A Broviac catheter is tunneled through the subcutaneous tissues of the chest and emerges as a thin plastic tube, usually at the level of the second or third rib.
• A Port-A-Cath contains a subcutaneous reservoir and is implanted under the skin of the chest. It is not visible, but it must be accessed by inserting a small needle through the skin and into the reservoir.

Gallieni M, Pittiruti M, Biffi R: Vascular access in oncology patients, CA Cancer J Clin 58:323–346, 2008.

40. What is the differential diagnosis of an anterior mediastinal mass?
The five “T’s” can be used to remember the differential diagnosis of an anterior mediastinal mass:
teratoma (germ-cell tumor), thymoma, thyroid tumor, T-cell leukemia, and terrible lymphoma (Fig. 14-2).

Figure 14-2. (A) Frontal radiograph in a child with “leukemia/lymphoma” syndrome, demonstrating an anterior mediastinal mass (arrows). (B) Lateral film illustrates the anterior nature of the mass (arrows) with posterior displacement of the trachea. (From Blickman JG, Parker BR, Barnes PD: Pediatric Radiology: The Requisites, ed 3. Philadelphia, 2009, Mosby, p 42.)

41. What is superior mediastinal syndrome? How is it managed? Superior mediastinal syndrome, also called superior vena cava syndrome, results from the presence of an anterior mediastinal mass that compresses the trachea and the superior vena cava. Patients have a cough and dyspnea, particularly when supine, and they have swelling of the head and upper extremities as a result of venous compression. Patients with a large mediastinal mass must not be anesthetized because of the risk for complete airway obstruction and vascular collapse. The optimal management of a mediastinal mass is prompt diagnosis and the initiation of appropriate treatment. Irradiation of the mass may provide emergent relief while the diagnosis is being made.
42. Which tumor is the most common cause of superior mediastinal syndrome in children?
Non-Hodgkin lymphoma. Less frequent causes are Hodgkin disease, neuroblastoma, and sarcomas. Nonmalignant infectious causes are unusual but can include histoplasmosis or tuberculosis. The most frequent nonmalignant cause in children, however, is iatrogenic, resulting from vascular thrombosis after surgeries for congenital heart disease, shunting procedures for hydrocephalus, or central catheterization for venous access.
43. Why is a generous mediastinal shadow on a radiograph much more worrisome in a teenager than in an infant?
Among infants, the incidence of Hodgkin disease is extremely low. The thymus normally has a distinctive shape with flaring at the base and indentations from the ribcage (“sail sign”), which can usually be delineated on plain film. In teenagers, thymic enlargement has a higher likelihood of malignancy, particularly Hodgkin disease, which is usually accompanied by lymphadenopathy in other areas of the mediastinum, particularly the paratracheal, tracheobronchial, and hilar regions.
44. Which neoplasms are associated with hemihyperplasia?
Wilms tumor, hepatoblastoma, adrenal cortical carcinoma, and leiomyosarcomas are associated with hemihyperplasia (formerly called hemihypertrophy) either as part of a syndrome (such as Beckwith-Wiedemann syndrome) or in isolation. Hemihyperplasia results in one side or portion of the body being larger than the other. The difference can be subtle (noted only when a patient lies on a flat surface) or more obvious when posture or gait is observed. Between 1% and 3% of Wilms tumor patients have hemihyperplasia.

45. Which cancers are often associated with splenomegaly?
Acute leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, Hodgkin disease, and non-Hodgkin lymphoma are often associated with splenomegaly. Solid tumors rarely metastasize to the spleen to the point of causing splenomegaly.
46. What are the predictors of malignancy in the pediatric patient with peripheral lymphadenopathy?
A common clinical problem is determining which patients with enlarged lymph nodes require biopsy for diagnosis. Risk for malignancy is increased with increasing size (>1 cm in the neonatal period, >2 cm and increasing in older children despite antibiotic therapy), increasing number of adenopathy sites, and concurrent systemic symptoms (i.e., prolonged fever, night sweats, weight loss). Supraclavicular location, abnormal chest radiograph, abnormal complete blood count (CBC), and fixed nodes are also significantly predictive of malignancy.

King D, Ramachandra J, Yeomanson D: Lymphadenopathy in children: refer or reassurance? Arch Dis Child Educ Pract Ed 99:101–110, 2014.
Soldes OS, Younger JG, Hirschl RB: Predictors of malignancy in childhood peripheral lymphadenopathy, J Pediatr Surg
34:1447–1452, 1999.

47. What is the function of the Langerhans cells?
These are antigen-presenting immune cells, dendritic in appearance, that are found in all layers of the skin and mucosal surfaces and in lymph nodes. The ultrastructural hallmark of the cell is the Birbeck granule, a cytoplasmic organelle that is shaped like a tennis racquet.
48. What are the features of Langerhans cell histiocytosis (LCH)?
LCH is a multifaceted disorder and replaces the diseases grouped under the term histiocytosis X.
The presenting symptoms of LCH may be isolated bone lesions (eosinophilic granuloma), bone lesions with exophthalmos and diabetes insipidus (Hand-Sch€uller-Christian disease), or bone lesions with disseminated disease (Letterer-Siwe disease). Other features include skin rashes that resemble seborrheic dermatitis, chronic otitis externa, lymphadenopathy, hepatosplenomegaly, pancytopenia, neurologic deficits, and pulmonary disease. Mild forms of the disease tend to wax and wane even without treatment, whereas disseminated disease is often resistant to therapy.
49. What is an eosinophilic granuloma?
Eosinophilic granuloma is a lytic tumor of bone that is accompanied by pain and sometimes swelling. Its histology is identical to that of LCH, with which it is now classified. Biopsy of an isolated eosinophilic granuloma is often curative, although lesions may also regress spontaneously.
50. What are the common indications for transfusion support for children with cancer?
Although there are no absolute criteria, in most centers, packed red blood cells are given when a patient has a hemoglobin level in the range of 6 to 8 g/dL, even if asymptomatic, or at higher levels if a patient has symptoms or if ongoing marrow suppression is anticipated. Platelets are empirically administered for a platelet count of less than 10,000 to 20,000/mm3 in an otherwise well patient; a higher threshold may be used if there is active bleeding, disseminated intravascular coagulation (DIC), or a planned procedure. Granulocyte transfusions may be effective in neutropenic patients with a refractory infection caused by a gram-negative organism. Transfusions with plasma may be used for the treatment of coagulopathies.

Roseff SD, Luban NL, Manno CS: Guidelines for assessing appropriateness of pediatric transfusion, Transfusion
42:1398–1413, 2002.

51. What are the most common symptoms experienced by oncology patients receiving end-of-life care?
Fatigue, pain, and dyspnea. Parents report that these symptoms are managed effectively in less than one-third of children. As compared with adults, twice as many children die in hospitals (usually an ICU) during the final stages of disease, half on ventilators, and only 10% to 20% of dying children receive hospice care. This is despite the fact that 70% of families would choose for their child to die at home if

support were adequate. Insufficient attention to palliative care has been a large problem, although an appreciation of its importance is growing.

Epelman CL: End-of-life management in pediatric cancer, Curr Oncol Rep 14:191–196, 2012.
Wolfe J, Grier HE, Klar N, et al: Symptoms and suffering at the end of life in children with cancer, N Engl J Med
342:326–333, 2000.
National Hospice and Palliative Care Organization: www.nhpco.org/pediatrics. Accessed on Jan. 9, 2015.

EPIDEMIOLOGY
52. Although in psychic lore a “seer” can look into the future, SEER has a different connotation for cancer researchers. What is it?
SEER stands for the Surveillance, Epidemiology, and End-Results database. SEER collects cancer incidence, prevalence, and survival data in specific geographic areas in the United States. These areas represent about 26% of the U.S. population. SEER data are freely available to qualified investigators and can be used to study epidemiologic trends in cancer incidence, prevalence, and survival.

National Cancer Institute: www.seer.cancer.gov. Accessed on Jan. 9, 2015.

53. How do the types of cancers differ between adults and children?
As a general rule, in adults, most cancers are carcinomas (of epithelial origin). In children, the origin of most cancers are reticuloendothelial (e.g., leukemia, lymphoma), embryonal (e.g., blastomas)
or mesenchymal (e.g., sarcomas).
54. What is the most frequently occurring childhood cancer?
Leukemia is the most frequently occurring with ALL being the most frequent single cancer diagnosis.
55. How do the types and frequency of childhood cancers vary by age?
Children (Ages: 0 to 14 years) Adolescents (Ages: 15 to 19 years)
• Acute lymphoblastic leukemia: 26% • Hodgkin lymphoma: 15%
• Brain and CNS tumors: 21% • Thyroid carcinoma: 11%
• Neuroblastoma: 7% • Brain and CNS tumors: 10%
• Non-Hodgkin lymphoma: 6% • Testicular germ cell tumors: 8%
• Wilms tumor: 5% • Non-Hodgkin lymphoma: 8%
• Acute myeloid leukemia: 5% • Acute lymphoblastic leukemia: 8%
• Hodgkin lymphoma: 4% • Bone tumors: 7%
• Rhabdomyosarcoma: 3% • Melanoma: 6%
• Retinoblastoma: 3% • Acute myeloid leukemia: 4%
• Ovarian germ cell tumors: 2%

Ward E, DeSantis C, Robbins A, et al: Childhood and adolescent cancer statistics, 2014, Ca Cancer J Clin 64:83–103, 2014.

56. Where does cancer rank as a cause of death in younger children? While cancer is the leading cause of disease-related mortality in children 5 to 14 years of age, it is overall the second leading cause of death in this age group in the United States. It accounts for 12% of deaths in children younger than 14 years. Unintentional injuries, primarily motor vehicle accidents, are the most frequent cause of death in children ages 5 to 14 years.

Murphy SL, Xu J, Rochanek KD: Deaths: Final report for 2010. National Vital Statistics Report, Volume 62, No. 6, Hyattsville, MD, 2013, National Center for Health Statistics.

57. Is cancer the leading cause of death in teenagers and young adults? No. Unintentional injuries are the leading cause of death for adolescents and young adults, accounting for more than 40% of deaths. Homicides and suicides are responsible for almost 30% of deaths in this age group, with cancer being a distant third at 6.4%.

Murphy SL, Xu J, Rochanek KD: Deaths: Final report for 2010. National Vital Statistics Report, Volume 62, No. 6, Hyattsville, MD, 2013, National Center for Health Statistics.

58. What are the relative risks for children to develop leukemia?
See Table 14-1.

Table 14-1. Relative Risk for Children to Develop Leukemia
POPULATION AT RISK ESTIMATED RISK
U.S. white children 1 in 2800
Siblings of a child with leukemia 1 in 700
Identical twin of a child with leukemia 1 in 5
Children with:
Down syndrome 1 in 75
Fanconi syndrome 1 in 12
Bloom syndrome 1 in 8
Ataxia-telangiectasia 1 in 8
Exposures:
Atom bomb within 100 m 1 in 60
Ionizing radiation ?
Benzene 1 in 960
Alkylating agents 1 in 2000?
Data from Mahoney DH Jr: Neoplastic diseases. In McMillan JA, DeAngelis CD, Felgin RD, Warshaw JB, editors: Oski’s Pediatrics, Principles and Practice, ed 3. Philadelphia, 1999, JB Lippincott, p 1494.

59. Does cell phone usage increase the risk of cancers, specifically brain tumors? Any connection between cell phones and cancer is controversial. Studies have been conflicting. A number suggested a relationship between long-term use (>10 years) of mobile and cordless phones and the development of certain CNS tumors, primarily gliomas and acoustic neuromas. However, the largest study to date, the INTERPHONE study involving 13 countries, found no increased risk. Cell phones emit radiofrequency electromagnetic fields (RF-EMFs) and obviously the brain is proximate during typical usage. In 2011, the International Agency for Research on Cancer (IARC) classified RF-EMFs as “possible” human carcinogens. Data are currently epidemiologic. Theories on the role of RF-EMF as potential initiators and promoters of stages of carcinogenesis at present remain speculative, but certainly
do raise concern given the high degree of cell phone usage and exposure in younger children and teenagers.

INTERPHONE Study Group: Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case-control study, Int J Epidemiol 39:675–694, 2010.

60. Which cancers have a significant racial predilection? Wilms tumor has a higher incidence among black female infants. Ewing tumor is about 30 times more common in whites than in blacks. Hodgkin disease is rare in those of East Asian descent.
61. What cancers are most commonly associated with a second neoplasm?
See Table 14-2.

Table 14-2. Cancers Most Commonly Associated With a Second Neoplasm
PRIMARY TUMORS SECONDARY TUMORS
Retinoblastoma Osteosarcoma
Pineoblastoma
Hodgkin disease Acute nonlymphoblastic leukemia
Non-Hodgkin lymphoma

Table 14-2. Cancers Most Commonly Associated With a Second Neoplasm (Continued )
PRIMARY TUMORS SECONDARY TUMORS
Sarcoma (in radiation field)
Thyroid carcinoma
Breast carcinoma (in radiation field)
Acute lymphoblastic leukemia Brain tumors
Non-Hodgkin lymphoma
Sarcomas Sarcomas

62. Are there any known transplacental carcinogens?
Diethylstilbestrol, which was used to prevent spontaneous abortion, has been associated with an increased risk for vaginal cancer in the female offspring. It has also been reported that there is a 10-fold increased risk for monoblastic leukemia in the infants of mothers who smoke marijuana. It has been suggested that sedatives and a number of nonhormonal drugs are transplacental carcinogens, but this has not been proven. It also has not been proven if cigarette smoke and the use of oral contraceptives are transplacental carcinogens.
63. Is prenatal ultrasound associated with a risk for leukemia later in childhood?
No. In vitro, ultrasound has been shown to cause cell membrane changes, and thus concern has been expressed regarding potential effects on embryogenesis and prenatal and postnatal development.
However, the available evidence on both fetal development and neonatal outcomes following ultrasound exposure is strongly reassuring, including no increased risk of childhood cancer. Of note, the only known association of prenatal ultrasound with alterations in development has been a slight preference among males for non–right handedness (i.e., use of both hands equally or left handedness). One concern is that most of the longer-term outcome studies were begun before 1990, when ultrasound was not performed as frequently and when the allowable output potential of the ultrasound equipment was relatively reduced.

Houston LE, Odibo AO, Macones GA: The safety of obstetrical ultrasound: a review, Prenat Diagn 13:1204–1212, 2009. Salvesen KA, Elk-Nes SH: Ultrasound during pregnancy and subsequent child non-right handedness: a meta-analysis, Ultrasound Obstet Gynecol 13:241–246, 1999.

64. Do children living near electrical power lines have an increased risk for developing cancer?
Although a few small studies have suggested an association between power lines and an increased risk for ALL, evidence has been inconsistent, but largely negative.

Bunch KJ, Keegan TJ, Swanson J, et al: Residential distance at birth from overhead high-voltage power lines: childhood cancer risk in Britain, 1962-2008, Br J Cancer 110:1402–1408, 2014.
Linet MS, Hatch EE, Kleinerman RA, et al: Residential exposure to magnetic fields and acute lymphoblastic leukemia in children, N Engl J Med 337:1–7, 1997.

LEUKEMIA
65. What are the most common clinical findings in the initial presentation of ALL?
• Hepatosplenomegaly: 70% (10% to 15% of children have marked enlargement of the liver or spleen to a level below the umbilicus)
• Fever: 40% to 60%
• Lymphadenopathy: 25% to 50% with moderate or marked enlargement
• Bleeding: 25% to 50% with petechiae or purpura
• Bone and joint pain: 25% to 40%
• Fatigue: 30%
• Anorexia: 20% to 35%

KEY POINTS: ACUTE LYMPHOBLASTIC LEUKEMIA
1. Most common childhood malignancy
2. Increased risk: Patients with Down syndrome, congenital immunodeficiency syndrome, exposure to ionizing radiation; sibling of patient with acute lymphoblastic leukemia
3. Chemotherapy phases: Induction (to achieve remission), delayed intensification, maintenance
4. Survival (if in standard risk group) >80% at 5 years after completion of therapy
5. Most common sites of relapse: Bone marrow, central nervous system, testis

66. What are the typical hematologic findings noted during the presentation of ALL?
Leukocyte count (mm3)
• <10,000: 45% to 55%
• 10,000 to 50,000: 30% to 35%
• >50,000: 20%
Hemoglobin (g/dL)
• <7.5: 45%
• 7.5 to 10.0: 30%
• >10: 25%
Platelet count (mm3)
• <20,000: 25%
• 20,000 to 99,000: 50%
• >100,000: 25%
67. What studies of tumor cells are useful for determining a patient’s prognosis? Cytogenetics and ploidy (number of chromosomes): Cytogenetics and DNA index (ratio of DNA content in abnormal cells compared with normal reference cells) are determinants of the number and structure of chromosomes and chromosomal material in tumor cells. More than 50 chromosomes or a DNA index of >1.16 is favorable, whereas <46 is a poor prognostic indicator. Certain chromosomal translocations are unfavorable.
Immunophenotyping is also useful and involves the determination of B- or T-cell lineage, with maturity or immaturity of cells. Mature B-cell and precursor T-cell types have poorer prognosis.

Harrison CJ: Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia, Br J Haematol
144:147–156, 2009.
Pui C-H, Relling MV, Downing JR: Acute lymphoblastic leukemia, N Engl J Med 350:1535–1548, 2004.

68. Which patients with ALL have a poorer prognosis: younger or older children? The prognosis for children diagnosed with ALL 12 months has remained poor. Infant ALL appears to be a biologically distinct entity in comparison with ALL in older children, with infants generally having a conglomeration of adverse factors including MLL gene rearrangement (observed in up to 80% of infants with ALL, see question 69), high presenting leukocyte counts, hepatosplenomegaly, CNS disease,
and slow early response to therapy.

Silverman LB: Acute lymphoblastic leukemia in infancy, Pediatr Blood Cancer 49(7 Suppl):1070–1073, 2007.

69. What is the significance of translocations of the MLL gene?
The term MLL gene refers directly to the mixed lineage leukemia gene, present at chromosome 11, band q23. This region is frequently involved in a variety of chromosomal translocations and rearrangements in pediatric leukemia. Translocations involving the MLL gene are found primarily in infant ALL, where they confer a poor prognosis. They are also found in infant AML and confer an intermediate risk. The presence of MLL translocations results in increased intensification of chemotherapy.

Chowdhury T, Brady HJ: Insights from clinical studies into the role of the MLL gene in infant and childhood leukemia, Blood Cells Mol Dis 40:192–199, 2008

70. Although many prognostic factors have come and gone for childhood ALL, which two have remained significant for the past 40 years?
The two most consistent prognostic factors are age and elevation of presenting white blood cell count. Children <1 year or >10 years have a worse prognosis, as do those with a presenting white blood cell count of 50,000/mm3 or greater. Prognostic factors are important because, although 95% of ALL patients achieve remission (<5% lymphoblasts in bone marrow), 25% relapse.
Identifying patients at higher risk is important so that more aggressive or novel therapy can be considered.
71. Why do boys with ALL fare more poorly than girls?
In boys, after a full course of chemotherapy with remission, testicular involvement is a common site of relapse, occurring in up to 10% of cases. In older boys and teenage boys, there is a higher
incidence of T-cell disease than in girls. T-cell disease is associated with adverse prognostic factors (high white blood cell count, hepatosplenomegaly, and mediastinal masses) and alone carries a poorer prognosis. In girls, ovarian relapse is very rare.
72. Are race and ethnicity related to treatment outcome in patients with acute leukemia? Race and ethnicity appear to be related to outcome in ALL. Black, Hispanic, and American Indian/Alaskan Native children have a somewhat poorer outcome than white children. Asian/Pacific Islander children fare slightly better than white children. Although the reasons are not known, these differences may be the result of either host or leukemia characteristics.

Kadan-Lottick NS, Ness KK, Bhatia S, et al: Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia, JAMA 290:2008–2014, 2003.

KEY POINTS: HIGHER-RISK GROUPS WITH POORER PROGNOSIS OF PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA
1. Age: <1 year and >10 years
2. White blood cell count: >50,000/mm3
3. Chromosomal translocation abnormalities, specifically t(8;14), t(9;22), and t(4;11)
4. Hypoploidy (<45 chromosomes)
5. Malignant cells, with mature B-cell or T-cell immunophenotyping
6. Central nervous system involvement
7. Black and Hispanic patients
8. Males

73. In the United States, what are the four most common types of pediatric leukemia, and about how many children are diagnosed each year with each type?
ALL, with about 2500 new diagnoses yearly; AML, with about 500 new diagnoses yearly; chronic myelogenous leukemia (CML), with about 100 new diagnoses yearly; and juvenile myelomonocytic leukemia (JMML), with about 50 new diagnoses yearly.
74. What is MRD and how is it used?
MRD stands for minimal residual disease, which is typically detected by flow cytometry at several time points during therapy. In ALL, MRD detects patients who have a normal appearing bone marrow by light microscopy, but in fact have an increased risk for relapse owing to low-level, persistent disease. MRD use in AML is not as well defined as in ALL.
75. Is there a relationship between MRD and prognosis in children with ALL? Yes. A 2008 study indicated that MRD after induction therapy is the most important prognostic factor for outcome in children with ALL.

Borowitz MJ, Devidas M, Hunger SP, et al: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study, Blood 111:5477–5485, 2008.

76. What is the acute risk for a very elevated blast count noted at the time of the initial diagnosis of leukemia?
An elevated blast count at diagnosis may cause CNS leukostasis and stroke. The risk is higher in patients with AML because myeloblasts are larger and may have procoagulant activity that increases the risk for stroke or hemorrhage. Leukocytapheresis is sometimes used to reduce the blast count before initiating therapy, but its impact on improving outcome remains unproved.
77. What are the most common sites of extramedullary relapse of ALL?
The most common is the meninges, and this is followed by testicular relapse. Testicular disease is accompanied by painless testicular swelling (usually unilateral). The diagnosis must be confirmed by biopsy. Patients with testicular disease require irradiation in addition to intensive retreatment with chemotherapy.
78. What are known risk factors for acute myeloid leukemia?
See Table 14-3.

Table 14-3. Risk Factors for AML

GENERALLY ACCEPTED RISK FACTORS
SUGGESTIVE OF INCREASED RISK SUGGESTIVE OF DECREASED RISK

LIMITED EVIDENCE
• Down Syndrome
• Fanconi anemia
• Familial monosomy 7
• Ataxia
telangiectasia
• Shwachman- Diamond syndrome
• Bloom syndrome
• Ionizing radiation in utero • Older maternal age
• Increasing birth order
• Prior fetal loss
• Maternal alcohol use
• Maternal exposure to pesticides
• High birth weight
• Low birth weight • Long term breast-feeding • Paternal exposure to benzene
• Parental smoking
• Maternal exposure to benzene
• Maternal use of antibiotics
• Maternal dietary consumption of DNA topoisomerase II inhibitors
AML Acute myelogenous leukemia; DNA deoxyribonucleic acid.
From Puumala SE, Ross JA, Aplenc R, Spector LG: Epidemiology of childhood acute myeloid leukemia Pediatr Blood Cancer
60:728–733, 2013.

79. What is a chloroma?
A chloroma is a tumor that is formed by a coalescence of AML blasts. It may appear in bones, skin, soft tissue, or other sites. Its name is derived from its green appearance on its cut surface.
80. What are the two major classes of lymphomas? Lymphomas can be divided into Hodgkin and non-Hodgkin lymphomas (NHL). Lymphomas as a group are the third most common pediatric malignancy with NHL accounting for approximately 7% of pediatric cancers. Whereas lymphomas in adults generally are defined as low grade or intermediate, almost all lymphomas in pediatrics are high grade. Higher grade lymphomas are faster growing and more aggressive.
81. What is the malignant cell of Hodgkin disease?
The Reed-Sternberg cell. Its normal cell of origin remains unclear, with the predominance of evidence indicating a B or T lymphocyte. However, the cells alone are not pathognomonic of Hodgkin disease and may be seen in infectious mononucleosis, non-Hodgkin lymphoma, carcinomas, and sarcomas.
82. How is Hodgkin disease staged?
The Ann Arbor staging system with Cotswolds modifications is the current staging system for Hodgkin lymphoma. Individuals are defined as being in one of four different numeric stages (stages I to IV).
• Stage I: Involvement of a single lymph node region
• Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm
• Stage III: Involvement of lymph node regions on both sides of the diaphragm
• Stage IV: Diffuse or disseminated disease

Patients are then further subclassified based on the absence (A) or presence (B) of one or more of the following “B” symptoms: fever, night sweats, or unexplained weight loss.
83. What is the difference between clinical and pathologic staging as it relates to Hodgkin disease? Clinical staging refers to staging based on history, physical examination, and imaging (preferably PET-CT) following a single diagnostic biopsy. Pathologic staging was based on staging laparotomy with splenectomy, liver biopsy, multiple lymph node biopsies, and bone marrow biopsy. Pathologic staging is no longer performed.
84. What is the histologic classification of Hodgkin disease?
See Table 14-4.

Table 14-4. The Rye, New York, Histologic Classification*

TYPE

LYMPHOCYTES REED- STERNBERG CELLS

OTHER
INCIDENCE (%)
Lymphocyte predominant Many Few Histiocytes 10-15
Nodular
sclerosing Many Few or many Bands of refractile fibrosis 40-70
Mixed cellularity Many Few or many Eosinophils, histiocytes 20-30
Lymphocyte depletion Few Many No refractile fibrosis <5
*Based on the relative number of lymphocytes and Reed-Sternberg cells.

85. What is the prognosis for the various stages of Hodgkin disease? The prognosis for children with Hodgkin disease is excellent in that most are cured. For stages I and IIA, the 5-year relapse-free survival rate is higher than 80% for patients treated with radiation only, and
it may be higher than 90% for patients treated with radiation and chemotherapy. For stage IIB, prognosis is not as good, especially if there is a massive mediastinal tumor, but 5-year survival is
still higher than 80%. The same survival figures pertain to stage IIIA disease, but treatment generally is more extensive than that for a limited stage II disease. For stage IV disease, the 5-year relapse-free survival rate is 70% to 90%.
86. From what cells do non-Hodgkin lymphoma (NHL) derive?
NHL constitutes a variety of lymphoid malignancies with different cell types including B and T cell progenitors; mature B and T cells; and rarely, natural killer (NK) cells.
87. How is childhood NHL classified?
The 2008 World Health Organization (WHO) system for classification is the one most commonly used. It relies on (1) cell immunophenotype (i.e., B lineage, T lineage, or NK lineage) and (2) differentiation (i.e., precursor versus mature cell). Although a large number of subtypes are categorized on the basis of histology and genetic studies, NHL of childhood and adolescence falls into three main categories, which are based in large measure on the clinical features and the therapeutic response to treatment.
• Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma): These account for about 40% to 50% of U.S. NHL pediatric cases.
• Lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B- cell lymphoma): These account for about 20% of U.S. cases.
• Anaplastic large cell lymphoma (mature T-cell or null-cell lymphoma, which lacks characteristic markers of both T and B cells): These account for about 10% of U.S. cases.

Jaffe ES, Harris NL, Stein H, et al: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, editors: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues, ed 4. Lyon, France, 2008, International Agency for Research on Cancer, pp 157–166.

88. Are there specific chromosomal abnormalities in Burkitt lymphoma? Yes. Burkitt lymphoma is associated with three chromosomal translocations resulting in the inappropriate expression of the c-Myc oncogene. The translocations are t(8;14) (most frequent) and t(8;22) or t(2;8) (relatively rare), each of which juxtaposes the c-Myc gene located on chromosome 8 (specifically, 8q24) with an immunoglobulin heavy chain locus regulatory element. C-Myc is a proto-oncogene, which is involved in cellular proliferation.
89. What is the role of geography in the classification of Burkitt lymphoma?
The rapid onset of Burkitt lymphoma and its uneven geographic distribution has suggested a possible infectious etiology by a vectored pathogen as key to the disease. This peculiar epidemiology led the WHO to classify Burkitt lymphoma into three clinical entities: endemic (found primarily in countries where malaria is endemic, such as Africa and Papua New Guinea), sporadic (the predominant type found in the United States and in nonmalarial areas), and immunodeficiency-related (seen most often in individuals with HIV). Each entity has different clinical presentations and genetic features. The endemic variant most commonly presents as a jaw or facial bone tumor, while the sporadic form has an abdominal presentation with ascites. Epstein-Barr virus is found to be associated with almost all cases of the endemic variant, less frequently so with the immunodeficiency variant and rarely in the sporadic variant.

Molyneux EM, Rochford R, Griffin B, et al: Burkitt’s lymphoma, Lancet 379:1234–1244, 2012.

90. Who was Burkitt? Denis Burkitt was an Irish surgeon who, while living in Uganda, noted a series of children with swellings at the angles of the jaw and began to investigate the tumors. He published his case series in 1958, concluding that these represented a new previously unrecognized tumor complex. He later became a prominent proponent of increased dietary fiber, having noted that many Western diseases were rare in Africa. He was one of the first to suggest a fiber-depleted etiology for colorectal cancer, although subsequent epidemiologic studies did not support that hypothesis. He died in 1993 at the age of 82.

Smith O: Denis Parsons Burkitt (1911-93), Irish by birth, Trinity by the grace of God, Brit J Haematol 156:770–776, 2012.

91. What differentiates B- and T-cell precursor leukemia from lymphoma?
The bone marrow blast percentage is used to differentiate B- and T-cell precursor leukemia from lymphoma. If the bone marrow blast percentage is greater than or equal to 25%, the diagnosis of leukemia is given. If the blast percentage is less than 25% and the patient has other sites of malignant disease, the diagnosis of lymphoma is given.

NERVOUS SYSTEM TUMORS
92. How are CNS tumors classified?
Most are typically classified on the basis of histology:
• Glioma: Arises from supportive tissue (astrocytes)
• Ependymoma: Arises from the ependymal cells that line the ventricles
• Germ cell tumor: Arises from totipotent germ cells
• Rhabdoid: Arises from an unknown cell type
• Craniopharyngioma: Arises from embryonic precursors to anterior pituitary gland

KEY POINTS: CENTRAL NERVOUS SYSTEM TUMORS
1. Second most common neoplasm of childhood, after leukemia
2. Older children (>1 year): Most tumors are infratentorial (cerebellar or brainstem)
3. Younger children (<1 year): Most tumors are supratentorial
4. Gold standard for diagnosis: MRI with and without gadolinium enhancement
5. Back pain, extremity weakness, and/or bowel and bladder dysfunction suggestive of spinal cord lesions or metastases

93. Where is the most common area for each tumor to occur?
• Glioma: Cerebellum and optic pathway (more commonly benign and low grade); cerebrum or brainstem (more commonly malignant and higher grade)

• Ependymoma: Fourth ventricle; less commonly the spinal cord
• Germ cell tumor: Pineal or supracellar region
• Primitive neuroectodermal tumor (PNET) medulloblastoma: Midline of the cerebellum
• Rhabdoid: Posterior fossa
• Craniopharyngioma: Choroid plexus See Figure 14-3.

Hemispheric

Gliomas: 37%
Low-grade astrocytomas: 23%
High-grade astrocytomas: 11%
Other: 3%
Midline:
1. Chiasmal gliomas: 4%
2. Craniopharyngiomas: 8%
3. Pineal region tumors: 2%

2 3 Posterior fossa:
1. Brainstem gliomas: 15%
2. Medulloblastomas: 15%
3. Ependymomas: 4%
2 4 4. Cerebellar astrocytomas: 15%
1 3

Figure 14-3. Relative frequency of brain tumor histologic types and anatomic distribution. (From Kleigman RM, Stanton BF, Schor NF, et al: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, ELSEVIER Saunders, p 1748.)

94. What are the most common supratentorial brain tumors? What are their symptoms? Supratentorial tumors include tumors of the cerebrum, basal ganglia, thalamus, and hypothalamus. They can be gliomas, ependymomas, PNETs, germ cell tumors, choroid plexus tumors, or craniopharyngiomas. These tumors can show signs of increased intracranial pressure, such as headache and vomiting.
In addition, these tumors may be accompanied by focal deficits, such as memory loss, weakness, and visual changes.

Hawley DP, Walker DA: A symptomatic journey to the centre of the brain, Arch Dis Child Educ Pract Ed 95:59–64, 2010.

95. What are the most common infratentorial tumors? What are their symptoms? Infratentorial tumors include tumors of the cerebellum and brainstem. They can be astrocytomas, medulloblastoma, ependymomas, or gliomas. If infratentorial tumors block CSF outflow, headache and vomiting may be the presenting signs; they can also become apparent with localizing signs such as cranial nerve palsies or ataxia.
96. Which common parameters should be closely monitored in a child after resection of a brain tumor?
It is important to closely monitor urine output and serum sodium in children undergoing CNS surgery. Resection of a hypothalamic glioma, germ cell tumor, or craniopharyngioma can directly disrupt the function of the pituitary gland and lead to diabetes insipidus. Alternatively, some patients may develop a cerebral salt-wasting syndrome after resection.
97. Which cranial nerve abnormality is most common in children showing signs of increased intracranial pressure as the result of a posterior fossa tumor? Inability to abduct one or both eyes (cranial nerve VI palsy) may result from an elevation in intracranial pressure and can be a false localizing sign for the primary brain tumor.

98. What are the three “E’s” of the diencephalic syndrome? Diencephalic syndrome is the constellation of symptoms that result from the presence of a hypothalamic tumor: euphoria, emaciation, and emesis.
99. What is Parinaud syndrome?
Parinaud syndrome is the result of increased intracranial pressure at the dorsal midbrain, causing downgaze, papillary dilation, and nystagmus.
100. In addition to imaging studies, what should be included in the evaluation of a possible CNS germ cell tumor?
Both serum and cerebrospinal tumor α-fetoprotein and human chorionic gonadotropin should be obtained. Significant elevation of these markers is diagnostic of CNS germ cell tumor in a patient with an intracranial mass.
101. What are the key evaluations for a child with a newly-diagnosed medulloblastoma?
Medulloblastomas may spread contiguously to the cerebellar peduncle, to the floor of the fourth ventricle, into the cervical spine, or above the tentorium. In addition, medulloblastomas may disseminate through the CSF. Every patient should thus be evaluated with diagnostic imaging (magnetic resonance imaging [MRI]) of the spinal cord and of the whole brain. Examination of CSF should be performed after resection of the primary tumor.

Bartlett F, Kortmann R, Saran F: Medulloblastoma, Clin Oncol (R Coll Radiol) 25:36–45, 2013.

102. What is a “dropped met”? Most brain tumors do not metastasize; they are fatal because of local invasion. A dropped metastasis occurs when a primary brain tumor spreads through CSF pathways, thereby resulting in meningeal deposits along the spinal cord. These metastases have “dropped” from their original site down to the spinal cord or cauda equina.
103. What are the differences among a glioma, an astrocytoma, and glioblastoma multiforme?
• A glioma (from the Greek word glia for glue and the suffix -oma for tumor) is a neoplasm that is derived from one of the various types of cells that form the supporting interstitial tissue of the CNS, such as astrocytes, oligodendria, and ependymal cells. Of the gliomas, astrocytomas of variable malignancy are the most prevalent.
• Astrocytomas are subdivided into categories (grades) on the basis of the degree of tumor anaplasia and the presence or absence of necrosis. The juvenile pilocytic and subependymal astrocytoma are low-grade gliomas. Anaplastic astrocytomas (grade 3) grow more rapidly than the more differentiated astrocytomas.
• Glioblastoma multiforme is the highest grade astrocytoma (grade 4).

Ullrich NJ, Pomeroy SL: Pediatric brain tumors, Neurol Clin 21:897–913, 2003.

104. What is the most common benign brain tumor found in children?
Juvenile pilocytic astrocytoma (JPA). This is a type of low grade astrocytoma (glioma), most commonly found in the cerebellum. JPAs are associated with the genetic diagnosis of neurofibromatosis type I and involvement of the optic nerve is a classic finding. Fifteen percent of neurofibromatosis type I patients develop JPAs. The tumor is very slow growing.
105. Is resection curative for patients with juvenile pilocytic astrocytoma? If complete resection is possible, no additional treatment is required. However, for many patients a full resection is not possible because of the tumor’s location and size. In this situation, the surgical resection could have debilitating and neurologically devastating consequences. A number of chemotherapy and radiation regimens may be used to treat residual or recurrent tumors, but they are frequently noncurative.

Karajanis M, Allen J, Newcomb E: Treatment of pediatric brain tumors, J Cell Physiol 217:584-589, 2008.

106. Why is the prognosis for children with brainstem gliomas so poor? Location. A basic tenet of CNS tumors is that a gross total resection is necessary to achieve the greatest chance of long-term cure. Brainstem tumors most commonly are fully intrinsic to the pons and unresectable. Although radiation can improve symptoms, there currently is no known curative therapy for most children with brainstem gliomas.
107. What is leukocoria? White pupillary reflex. It can be obvious or it can be a subtle asymmetry on pupillary red reflex evaluation. Although other diagnoses can accompany leukocoria, the most significant one is retinoblastoma.
108. What is the heredity of retinoblastoma? Although most cases are sporadic, retinoblastoma can be inherited as an autosomal dominant trait with nearly complete penetrance. Of all cases, 60% are nonhereditary and unilateral, 15% are hereditary and unilateral, and 25% are hereditary and bilateral. Families of patients with retinoblastoma should have genetic counseling.
109. What is the “two-hit” hypothesis of cancer, particularly retinoblastoma?
Alfred Knudson’s “two-hit” hypothesis is a basic tenet of malignant transformation. In 1971, Knudson calculated the genetic probabilities of developing retinoblastoma and hypothesized that patients with bilateral disease first inherited a germline mutation and then underwent a second somatic mutation to develop the disease. Patients with unilateral or sporadic disease developed two somatic mutations during early childhood. The identification of the genes associated with the first of the “two hits” correctly predicted the presence of tumor suppressor genes.

Knudson A: Two genetic hits (more or less) to cancer, Nat REV Cancer 1:157–162, 2001.

110. In what age group does retinoblastoma usually occur?
Retinoblastoma most often occurs in younger children, with 80% of cases diagnosed before the age of 5 years. Retinoblastoma is usually confined to the eye, with more than 80% of children being cured with current therapy.

Shields CL, Shields JA: Basic understanding of current classification and management of retinoblastoma, Curr Opin Ophthalmol 17:228–234, 2006.

111. Patients with retinoblastoma are at increased risk for other tumors. How significant a risk is this?
Patients with the hereditary type of retinoblastoma have a markedly increased frequency of second malignant neoplasms. The cumulative incidence is about 26% 10% in nonirradiated patients and 58% 10% in irradiated patients by 50 years after diagnosis of retinoblastoma. Most of the second malignant neoplasms are osteosarcomas, soft tissue sarcomas, and melanomas.
112. What is the cell of origin of neuroblastoma? Neuroblastoma is an embryonal tumor of the autonomic nervous system. The tumors originate in tissues of the sympathetic nervous system, most frequently in the adrenal medulla or paraspinal ganglia. Hence neuroblastomas may present as mass lesions in the abdomen, pelvis, neck or chest.
113. What is the most common cancer in younger children?
While leukemias may constitute the most common group of pediatric cancer diagnoses overall,
neuroblastomas are the most commonly occurring cancer in children <1 year of age.

Maris JM: Recent advances in neuroblastoma, N Engl J Med, 362:2202–2211, 2010.

KEY POINTS: NEUROBLASTOMA
1. Most common pediatric extracranial solid tumor
2. Most common malignant tumor among infants
3. Majority of children <4 years old
4. Poorer prognosis: >1 year old, metastatic disease, Myc-N amplification
5. Most metastatic at diagnosis

6. Paraneoplastic syndromes: VIP syndrome (diarrhea as a result of increased vasoactive intestinal peptide), opsoclonus-myoclonus (“dancing eyes, dancing feet”), and catecholamine excess (with flushing, sweating, headache, and hypertension)

114. What are the most common presentations of neuroblastoma?
Children with disseminated neuroblastoma are irritable and ill, and they often have exquisite bone pain, proptosis, and periorbital ecchymoses. Seventy percent of neuroblastomas arise in the abdomen; half of these arise in the adrenal gland, and the other half arise in the parasympathetic ganglia and are distributed throughout the retroperitoneum and the paravertebral area in the chest and neck. The tumor produces and excretes catecholamines, which can on occasion cause systemic symptoms such as sweating, hypertension, diarrhea, and irritability. Children with localized neuroblastoma may have symptoms referable to a mass.

Maris JM: Recent advances in neuroblastoma, N Engl J Med 362:2202–2211, 2010.
115. What is Horner syndrome?
Ptosis, miosis (with unequal pupils), and anhidrosis (Fig. 14-4). The syndrome results from unilateral disruption of sympathetic neural pathways. The condition can occur from congenital

Figure 14-4. (A) Right Horner syndrome due to a T-cell lymphoma involving the right thalamus and hypothalamus.
(B) Ring-enhancement (arrow) and edema are seen on the axial CT scan. (From Liu GT, Volpe NJ, Galetta SL, editors:
Neuro-Ophthalmology: Diagnosis and Management, ed 2. Philadelphia, 2010, ELSEVIER, p 431.)

brachial plexus injury, but acquired Horner syndrome requires evaluation for intrathoracic (preganglionic); cervical (postganglionic); or intracranial (central) pathology, particularly neuroblastoma.

116. Where does neuroblastoma tend to metastasize?
Neuroblastoma spreads to the liver; the bone; the bone marrow; and less commonly, the skin.

117. What is meant by “dancing eyes, dancing feet”?
“Dancing eyes, dancing feet” is a descriptive term for opsoclonus-myoclonus, a condition in which children with neuroblastoma develop horizontal nystagmus and involuntary lower extremity muscle spasm. These symptoms are thought to arise from a nonspecific antibody reaction to neuroblastoma that cross-reacts with the motor end plate. These symptoms do not always improve, despite appropriate neuroblastoma therapy.

118. What urinary test aids in the diagnosis of neuroblastoma? Urinary concentrations of catecholamines and metabolites, including dopamine, homovanillic acid, and vanillylmandelic acid, are often increased (>3 standard deviations above the mean per milligram creatinine for age) in children with neuroblastoma.

119. Which molecular abnormality is associated with a more aggressive form of neuroblastoma?
Myc-N amplification is often seen in patients with stage 4 neuroblastoma. The presence of myc-N amplification renders a patient at higher risk for recurrence regardless of staging.

120. What does the S stand for in stage 4S neuroblastoma? Stage 4S is a “special” type of neuroblastoma that is found only in children <1 year of age. Along with a primary tumor, these infants also may have bone marrow, liver, and skin disease. Even without therapy, these cancers spontaneously regress and disappear over time. Treatment is only indicated if the patient is symptomatic from the underlying disease (e.g., large abdominal mass, liver disease).

121. How can the site of spinal cord compression be clinically localized?
Spinal tenderness on percussion correlates with localization in up to 80% of patients. In addition, neurologic evaluation of strength, sensory level changes, reflexes, and anal tone can help pinpoint the location in the spinal cord, the conus medullaris (the terminal neural portion of the spinal cord), or the cauda equina. Progression is rapid with spinal cord compression but may be rapid or variable with compression of the conus medullaris or the cauda equina. Spinal cord compression most commonly occurs in the thoracic area (70%) compared with the lumbar (20%) and cervical
(10%) regions.

SOLID NON-NERVOUS SYSTEM TUMORS
122. What are the peak ages of incidence of the most common solid tumors of childhood?
Neuroblastoma and Wilms tumor are tumors of early childhood. Ewing sarcoma and osteosarcoma are more prevalent during adolescence. Rhabdomyosarcoma occurs throughout childhood and the
teenage years.

123. What are “blastemal” tumors? Many pediatric solid tumors are thought to arise from a primitive blastemal cell. A blastema is a mass of embryonic cells from which an organ or a body part develops. Thus, these cells are undifferentiated and, if mutated, may develop into tumors such as neuroblastoma, pleuropulmonary blastoma, hepatoblastoma, or Wilms tumor, to name a few.

124. What is the average age of diagnosis for Wilms tumor? Wilms tumor is a primary malignant renal tumor of large histologic diversity. Average age of diagnosis is 3 to 4 years. The tumor becomes less common as children grow older and is an uncommon occurrence after 6 years of age.

125. What are the three histologic components of a Wilms tumor?
Wilms tumors are considered triphasic, consisting of a blastemal (immature) component, an
epithelial (tubular) component, and a stromal (muscular) component.

126. How is Wilms tumor distinguished radiographically from neuroblastoma?
• Wilms tumor: CT images will show intrinsic distortion of the kidney parenchyma and the collecting system. Only 10% of children with Wilms tumor have calcifications.
• Neuroblastoma: This is almost always extrarenal and causes displacement—not distortion—of the renal parenchyma and collecting system. Calcifications are seen in more than 50% of children with abdominal neuroblastoma.

127. Where does Wilms tumor tend to metastasize?
Locally, Wilms tumor can grow through the renal capsule, invade the renal veins, extend into the vena cava, and even progress into the chambers of the heart. The lungs, regional lymph nodes, and liver are the most common sites of metastasis.

128. What is a stage V Wilms tumor?
Bilateral Wilms tumor is known as a stage V tumor. Each tumor is staged independently; prognosis with bilateral disease is not necessarily poor.

129. What factors influence the prognosis of a patient with Wilms tumor?
Overall, Wilms tumor carries a good prognosis. Factors that influence the prognosis include tumor stage and histology, as well as chromosomal abnormalities such as loss of heterozygosity (LOH). LOH for markers on the distal arm of chromosome 16 has been found in about 20% of Wilms tumors, whereas loss of the short arm of chromosome 1 has been found in about 10% of cases. LOH of either locus portends an adverse prognosis, independent of tumor stage and histology.

130. “Small, round, blue cell tumor” is often used in the description of which childhood tumors?
Neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, lymphoblastic leukemia, and lymphoma. All appear as small, round, blue cells on low-power microscopic examination. High-power microscopic examination, usually in combination with a panel of immunohistochemical stains and molecular diagnostics, is required for definitive diagnosis.

131. Where are the most common locations of Ewing sarcoma? The pelvis, leg, upper arm, and rib. These tumors arise in extraskeletal (soft tissue) locations and can locally invade the bone.

132. What molecular abnormality is commonly seen in Ewing sarcoma?
The t(11:22) translocation is pathognomonic of Ewing sarcoma. This translocation results in the fusion gene EWS-FLI1, which is thought to disrupt transcriptional regulatory pathways. About 85% of Ewing sarcomas carry this translocation.

133. What are the two most common sites of metastases for patients with Ewing sarcoma?
Ewing sarcoma often metastasizes to the lungs and somewhat less frequently to other bones. In general, lymph nodes are not involved, which suggests that dissemination of this tumor is primarily hematogenous.

134. What type of tumor is an osteosarcoma?
An osteosarcoma is a malignant spindle cell tumor in which the cells produce neoplastic osteoid. It is the most common primary malignancy of bone in children.

135. Osteosarcoma generally arises in which part of the bone? The metaphyses of long bones of the extremities. Between 60% and 80% of tumors are located in the metaphyses of the knee (i.e., the proximal tibia or the distal femur) (Fig. 14-5).

Figure 14-5. Radiograph of an osteosarcoma of the distal femur with typical “starburst” appearance of bone formation. (From Kleigman RM, Stanton BF, Schor NF, et al: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, ELSEVIER Saunders, p 1764.)

136. Do all patients with osteosarcoma require surgical resection of the primary tumor? Surgical resection of the primary tumor is a requirement for curative treatment of osteosarcoma. In contrast to Ewing sarcoma, osteosarcoma is a relatively radiation-resistant tumor, and thus surgical resection after neoadjuvant chemotherapy is a mainstay of treatment.
137. For patients with localized osteosarcoma, what factor is most predictive of a favorable outcome?
Patients with more than 95% necrosis of the primary tumor (as determined by pathologic examination)
after neoadjuvant chemotherapy have a better prognosis than those with lesser amounts of necrosis.
138. What do Ewing sarcoma and osteosarcoma have in common?
Both are treated with neoadjuvant chemotherapy, which is an initial 2- to 3-month period of chemotherapy, followed by local control with surgery. For select cases of Ewing sarcoma, radiation therapy is also used. Both tumors can develop distant metastases in the lungs and in other bones, and both tumors are cancers of adolescence. Although both Ewing sarcoma and osteosarcoma appear to be soft tissue tumors arising in bone, only osteosarcoma is truly a tumor of bone, whereas Ewing sarcoma is a primitive neuroectodermal tumor.
139. In what solid tumor has the surgical resection of pulmonary metastases been shown to result in long-term cure?
Although many pediatric sarcomas metastasize to the lungs, only surgical resection of pulmonary metastases from osteosarcoma has been definitively shown to contribute to cure, and only, in general, when the metastases are few in number. The role of the surgical resection of pulmonary metastases arising from other sarcomas (e.g., rhabdomyosarcoma, Ewing sarcoma) is less clear and is only undertaken in select circumstances.

140. What is a limb salvage procedure?
In an attempt to save as much natural tissue as possible, patients with soft tissue sarcomas often undergo a “limb salvage” surgery, in which cancerous tumor is removed from the bone without amputation. Because of the proximity of osteosarcomas to the knee joint, this often results in the removal of the joint as well. Patients who undergo a limb salvage procedure will require a prosthesis or crutches to ambulate.
141. What type of tumor is a rhabdomyosarcoma?
A rhabdomyosarcoma is a soft tissue tumor that arises from cells that give rise to striated skeletal muscle. It is the most common soft tissue tumor of childhood.
142. Where do rhabdomyosarcomas usually arise?
The four most common areas are as follows: (1) head and neck; (2) genitourinary region;
(3) extremities; and (4) orbit. The survival rate for those with tumors in other areas is dependent on the amount, if any, of tumor left after resection and the presence or absence of metastatic disease.
143. What sites of disease are associated with the best outcomes for children with rhabdomyosarcoma?
Favorable locations include the orbit, the head and neck (except for parameningeal tumors), the vagina, and the biliary tract. Unfavorable locations include the extremities, retroperitoneum, and trunk.

Mazzoleni S, Bisogno G, Garaventa A, et al: Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma, Cancer 104:183–190, 2005.

144. What are the two major histologic subtypes of rhabdomyosarcoma?
Alveolar rhabdomyosarcoma, a name derived from its superficial appearance histologically to lung tissue, tends to occur in older children and adolescents. Most of these tumors carry the t(2;13) translocation, and they carry a higher risk for recurrence. Embryonal rhabdomyosarcomas tend
to occur in younger children, and they are the predominant histology associated with favorable site tumors.
145. Which germ cell tumor is usually seen in young children?
Most germ cell tumors that appear in young children are benign teratomas occurring in the sacrococcygeal region. In general, patients with mature teratomas are managed by surgical resection, with care taken for sacrococcygeal tumors to be sure that the entire coccyx is removed.
146. Why are tumor markers assessed before surgery for teratomas and other germ cell tumors?
Tumor markers (e.g., α-fetoprotein, β-HCG) are assessed in anticipation of postoperative monitoring for possible recurrence and malignant transformation. If elevated at diagnosis, these levels should be obtained monthly for the first 6 months because this is the highest risk period. If no elevation is noted, intermittent monitoring should be continued for a total of 3 years after resection.
147. Virilization may be associated with which childhood cancer?
Tumors that cause virilism are most commonly those that produce large quantities of dehydroepiandrosterone, a 17-ketosteroid. Tumors that produce testosterone may also cause virilization. Most commonly, these are benign tumors of the adrenal gland; rarely are they malignant. However, the distinction between carcinoma and benign adenoma is frequently difficult. Occasionally, males with primary hepatic neoplasms may become virilized because of the production of androgens by the tumor.
148. How great is the risk for malignant transformation in undescended testes? The risk for malignancy may be 5 to 10 times higher in the undescended testis than in a normal testis. The risk in the contralateral testis may also be increased. Orchidopexy decreases, but does not eliminate, the risk for subsequent malignant transformation.
149. What are the most common primary liver tumors of childhood? Hepatoblastoma and hepatocellular carcinoma. Hepatoblastomas usually develop in infants and young children, whereas hepatocellular carcinomas develop throughout childhood. Infection with hepatitis B and C virus is the greatest risk factor for the occurrence of hepatocellular carcinoma.

150. Which tumor marker is most likely to be elevated in children with hepatic tumors? Most patients with either hepatoblastoma or hepatocellular carcinoma have an elevated concentration of α-fetoprotein that parallels disease activity. Lack of a significant decrease of α-fetoprotein with treatment may signify a poor response to therapy. Occasionally, hepatoblastomas produce β-human chorionic gonadotropin and can result in isosexual precocity.
151. Lance Armstrong’s treatment for metastatic testicular germ cell tumor had an important modification from standard therapy. What was it and why did this seven-time winner (albeit later discredited) of the Tour de France find this important?
Lance Armstrong had a testicular germ cell tumor with metastases to the brain. The therapy for germ cell tumors is typically a combination of cisplatin, etoposide, and bleomycin. Bleomycin is a glycopeptide antibiotic that can result in pulmonary fibrosis and impaired lung function. Fortunately, a number of other agents have excellent activity in the treatment of germ cell tumors, including ifosfamide and etoposide, and thus Mr. Armstrong was effectively treated without administration of bleomycin. Pulmonary toxicity from bleomycin could certainly have affected bicycle climbs through the Pyrenees. In general, gonadal germ cell tumors, even when metastatic, have a good prognosis.

STEM CELL TRANSPLANTATION
152. What are the two main types of hematopoietic stem cell (HSC) transplant?
• Allogeneic: The recipient receives stem cells from an HLA identical, haploidentical, or mismatched donor.
• Autologous: The recipient and the donor are the same person.
153. What is the importance of HLA matching in HSC transplant recipients? The genes for HLA, the major histocompatibility complex, are closely linked on chromosome 6. Matching donor and recipient for human leukocyte antigen (HLA) class I (A, B, and C) and class II (DRB1 and DQB1) haplotypes is vital to successful allogeneic HSC transplant. There is a progressive decrease in posttransplant survival with each HLA allele mismatch.

F€urst D, M€uller C, Vucinic V, et al: High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis, Blood 122:3220–3229, 2013.

154. What is the chance of siblings having the same human leukocyte antigen (HLA) type?
The HLAs, which are located on chromosome 6, approximate simple Mendelian inheritance, with two siblings having a 1 in 4 chance of having the same typing. A 1% crossover of material may also occur during meiosis. The larger the family, the more likely a match becomes, as shown by the formula [1 – (0.75)n], with n being the number of siblings. Thus, a child with five brothers and sisters has a 76% chance of having a sibling with an HLA match.
155. What is the chance of finding an HLA-matched unrelated donor?
Although in theory the number of possibilities would equal or even exceed the world’s population, thereby making a match astonishingly unlikely, HLA types cluster in individuals of similar genetic and racial backgrounds. In one estimate of persons of European ancestry, about 200,000 individuals would need to be screened to reach a 50% chance of finding a match.

Gahrton G: Bone marrow transplantation with unrelated volunteer donors, Eur J Cancer 27:1537–1539, 1991.

156. What are the different sources of stem cells for transplantation? Stem cells may be obtained either from the peripheral blood, the bone marrow itself, or the umbilical cord blood of a newborn. Peripheral blood stem cells are collected by leukocytapheresis, whereas bone marrow stem cells are collected by multiple bone marrow aspirates. Cord blood is harvested from the placenta at the time of delivery. Stored placental or cord blood is a useful source for patients without a related histocompatible donor because of less graft-versus-host disease (GVHD).

Copelan EA: Hematopoietic stem-cell transplantation, N Engl J Med 354:1813–1826, 2006.

157. What are the advantages and disadvantages of umbilical cord blood as the source for a stem cell transplantation?
Advantages
• No risk to mother or infant
• Available on demand after cryopreservation
• Can target minority families
• Donors not lost as a result of age, illness, or relocation
Disadvantages
• Limited number of stem cells in collection
• Possible lack of availability of additional donor cells if graft failure or relapse occurs
• Undiagnosed medical condition may be present in newborns
158. How are stem cells collected? Bone marrow is collected by repeated bone marrow aspirates while the donor is under general or local anesthesia. Marrow is generally obtained from the posterior iliac crests. Peripheral blood contains low levels of circulating stem cells. However, the administration of hematopoietic growth factor (e.g., granulocyte-macrophage colony-stimulating factor [GM-CSF]), greatly increases this circulating number. Peripheral blood stem cells are generally obtained after the donor has been given G-CSF and with collection by apheresis. Umbilical cord blood contains high numbers of hematopoietic stem cells at the time of delivery. Cord blood is harvested from the placenta at the time of delivery and these cells can be processed and cryopreserved in cord blood banks.
159. What is the rationale behind an autologous transplant? Autologous transplants are used in situations where high dose chemotherapy will increase the response rate in chemosensitive tumors, but toxicity from the intense chemotherapy is a limiting factor. This limitation can be overcome by harvesting HSCs from the patient, cryopreserving and then subsequently reinfusing the HSCs once they have received the chemotherapy and/or radiotherapy.
160. Are there nonmalignant indications for an HSC transplant? The list of nonmalignant indications is growing, both for hereditary disorders that trace their origin to the hematopoietic stem cell (e.g., sickle cell disease, thalassemia major) and more recently for nonhematopoetic hereditary disorders in which engraftment of stem cells might ameliorate damage in target organs. These latter diseases have included epidermolysis bullosa and Fanconi anemia.

Tolar J, Mehta PA, Walters MC: Hematopoietic cell transplantation for nonmalignant disorders, Biol Blood Marrow Transplant 18(1 Suppl):S166–S171, 2012.
161. In transplant medicine, to what does the term “conditioning” refer? Conditioning refers to the preparative regimen necessary to achieve bone marrow ablation and immune suppression for successful donor engraftment to occur. This conditioning regimen is also important in eradicating the underlying disease for which the individual is receiving the transplant.
162. What are the three most common categories of conditioning regimens?
• Myeloablative: These are comprised of single or combination agents that completely destroy the HSCs in a patient’s bone marrow. The result is severe pancytopenia that is often irreversible and may be fatal without the infusion of a stem cell rescue. Current myeloablative regimens may include total body irradiation or high dose busulfan.
• Nonmyeloablative: This causes minimal cytopenia (but severe lymphopenia) and does not require stem cell support.
• Reduced intensity: An intermediate category of regimens, which may lead to prolonged cytopenias (although not frequently irreversible) and may require stem cell infusion for support.

Bacigalupo A, Ballen K, Rizzo D, et al: Defining the intensity of conditioning regimens: working definitions, Biol Blood Marrow Transplant 15:1628–1633, 2009.

163. What are the major side effects from total-body irradiation used in conditioning? In the short term, total-body irradiation may cause interstitial pneumonitis and nephritis. Over the long term, total-body irradiation may lead to cataracts, growth retardation, hypothyroidism, other endocrine dysfunction, infertility, and secondary malignancies. The long-term effects of total-body irradiation on pulmonary, cardiac, and neuropsychiatric function continue to be studied.

164. Which prophylactic measures should be taken after stem cell transplantation? Patients may receive antibiotics for gut decontamination. An oral antifungal agent such as fluconazole is also frequently administered. Patients should receive P. JIROVECI prophylaxis and replacement of immunoglobulins with intravenous immunoglobulin. Acyclovir may also be administered.
165. What is the most common early complication seen in patients after HSC transplant? Mucositis is the most common early complication seen in patients after autologous or allogeneic hematopoietic stem cell transplant. It frequently occurs in the setting of myeloablative preparative regimens and the use of methotrexate for GVHD prophylaxis. If the mucositis is severe enough, the patient may be unable to tolerate oral intake and may require total parenteral nutrition to maintain their daily caloric needs.
166. What are the major features of graft-versus-host disease (GVHD)?
Acute GVHD typically begins with a fever that is followed by a salmon-colored rash on the palms and soles. The rash may be pruritic and may desquamate. Hepatitis (with jaundice and transaminase elevation) and gastroenteritis (with diarrhea, weight loss, and abdominal pain) may also occur.
167. How is GVHD managed? Doses of methotrexate, cyclosporine, or tacrolimus during the immediate posttransplantation period may be given in an attempt to prevent the development of acute GVHD. T-cell depletion of the bone marrow graft also decreases the incidence of GVHD. For the treatment of acute GVHD, steroids, cyclosporine, or tacrolimus may be used alone or in combination, depending on the extent of
donor-recipient mismatch and the severity of GVHD.

Carpenter PA, MacMillan ML: Management of acute graft-versus-host disease in children, Pediatr Clin North Am
57:273–295, 2010.

168. What are the risk factors for GVHD?
There are multiple risk factors for GVHD. First and foremost is the relatedness of the donor to the recipient. An unrelated donor transplant will have a higher risk for GVHD than a matched related donor transplant. Second, the number of T cells received is a risk factor with higher T-cell numbers associated with a higher risk of GVHD. Donor age and parity status are also risk factors, with older donors and multiparous donors having higher risks of GVHD.
169. What is the most likely diagnosis for a patient who experiences weight gain, right upper quadrant pain, and hepatomegaly 10 days after stem cell infusion?
The patient most likely has venoocclusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS). VOD/SOS is due to damage to the hepatic endothelial cells that then leads to activation of the clotting cascade within the hepatic sinusoids and subsequent reversal of blood flow through the liver. Severe VOD/SOS may be characterized by more than 10% weight gain, respiratory failure, hepatorenal syndrome, and mental status changes. The treatment of VOD centers on maintaining adequate intravascular volume without compromising respiratory function and administration of defibrotide.
Acknowledgments
The editors gratefully acknowledge contributions by Drs. Richard Aplenc, Emily Lipsitz and Peter Adamson, as well as from all of the previous authors, that were retained from prior editions of Pediatric Secrets.

BONUS QUESTIONS
170. Which chemotherapeutic agents can be administered intrathecally to either treat or prevent meningeal malignancy?
Methotrexate, cytarabine, and hydrocortisone are commonly administered intrathecally to treat or prevent meningeal leukemia and lymphoma. Thiotepa and a novel formulation of carmustine (BCNU) are also used for nonhematologic malignancies with meningeal involvement. Most systemically administered anticancer drugs have limited penetration into the CSF. Intrathecal chemotherapy has the advantage of delivering high drug concentration to the CSF while minimizing systemic toxicities.
171. What are the common side effects of methotrexate?
Myelosuppression and mucositis. In high doses, the drug can be nephrotoxic and cause dermatitis, hepatitis, and mucositis. Most important, toxicity is primarily a function of duration of exposure. Because methotrexate can collect within fluid compartments (e.g., pleural or peritoneal effusions), it should be avoided in patients with significant third-space fluid collections.
172. In what way do the side-effect profiles of cisplatin and carboplatin differ? Carboplatin causes significant myelosuppression, primarily thrombocytopenia. Cisplatin causes only mild myelosuppression but is associated with significant nephrotoxicity, ototoxicity, and neurotoxicity.
173. What are the common complications of vincristine?
Constipation, alopecia, loss of deep tendon reflexes, and peripheral neuropathy have been reported frequently in patients receiving vincristine.

Carbone PP, Bono V, Frei E 3rd, Brindley CO: Clinical studies with vincristine, Blood 21:640–647, 1963.

174. What agent can limit the complication of hemorrhagic cystitis that occurs in some chemotherapeutic regimens?
Mesna is the acronym for 2-mercaptoethane sodium sulfonate, a sulfhydryl compound. The oxazaphosphorines (cyclophosphamide, ifosfamide) are widely used in clinical practice for their antitumor activities; however, urinary excretion of their urotoxic metabolite, acrolein, can lead to hematuria and hemorrhagic cystitis. Mesna acts as a detoxifying agent. It is given as an adjuvant therapy and binds to acrolein in the urine, which creates an inert thioether that is excreted.

Andriole GL, Sandlund JT, Miser JS, et al: The efficacy of mesna (2-mercaptoethane sodium sulfonate) as a uroprotectant in patients with hemorrhagic cystitis receiving further oxazaphosphorine chemotherapy, J Clin Oncol 5:799–803, 1987.

175. What are the differences between conventional external radiation, intensity-modulated radiation therapy (IMRT), and proton-beam radiation?
Both conventional radiation and IMRT use photon or electron beams to deliver radiation to the patient. IMRT uses many radiation fields, with each field having a unique radiation intensity profile that varies as a function of position within the field. This differs from conventional radiation, in which each field has a constant, or fixed intensity profile across the field area and thus allows for dose reduction to normal tissues or critical structures. Because of the physical properties of protons and their ability to deposit energy over a short distance, proton therapy may have the advantage of reducing radiation dose to nontarget normal tissues while allowing higher doses to be delivered to the tumor.
176. What treatment options exist for individuals who are allergic to sulfonamides and are unable to tolerate trimethoprim-sulfamethoxazole?
Atovaquone, dapsone, and pentamidine are accepted alternatives, but are less efficacious when compared with trimethoprim-sulfamethoxazole.

Prasad P, Nania JJ, Shankar SM: Pneumocystis pneumonia in children receiving chemotherapy, Pediatr Blood Cancer
50:896–898, 2008.

177. What PJP prophylactic agent has been associated with methemoglobinemia? Dapsone. Methemoglobinemia has been reported in up to 20% of pediatric patients with risks increasing with higher doses.

Esbenshade AJ, Ho RH, Shintani A, et al: Dapsone-induced methemoglobinemia: a dose-related occurrence? Cancer
117:3485–3492, 2011.

178. Is it true that the PEG-asparaginase was affectionately named after its inventor? Although a Peggy may certainly have been involved in its development, PEG stands for polyethylene glycol. By conjugating the native enzyme L-asparaginase to this large polymer, the half-life of the drug is greatly extended, and the exposed antigenic sites that can result in allergic reactions are diminished. Thus, instead of requiring up to nine intramuscular injections every other day, children with ALL can now be treated with a single injection.
179. Why are blood products irradiated and leukocyte depleted? Irradiation of blood products prevents transfusion-associated GVHD, which occurs when small numbers of T cells in the blood product are transferred into an immunocompromised patient. Leukocyte depletion (i.e., leukoreduction) removes other white blood cells that would increase the risk for febrile transfusion reactions, alloimmunization, and the transmission of cytomegalovirus.
180. What is the most well-documented risk factor for hepatoblastoma?
Multiple studies have demonstrated that low birth weight (<1000 g) is a risk factor for hepatoblastoma. It is not known whether this is due to other factors associated with low birth weight, such as hyperalimentation use, or the low-birth-weight condition itself.
181. Which distinct form of AML uses an analog of a common vitamin as a core component of its treatment? Treatment of acute promyelocytic leukemia (APL), or AML FAB subtype M3, includes oral administration of the vitamin A analog all-trans-retinoic acid (ATRA). ATRA can differentiate a malignant promyeloblast into a mature functioning neutrophil. Inclusion of ATRA in current treatment protocols has dramatically increased cure rates for patients with APL.
182. What is the consensus regarding appropriate treatment for CML?
CML is a rare entity in pediatrics, comprising only 3% of all pediatric leukemias, with very few cases seen yearly. As such, there has been difficulty in the ability to perform clinical trials to determine the best therapeutic option. Before the development of tyrosine kinase inhibitors (TKIs), allogeneic stem cell transplant was the established treatment. However, with the discovery of the molecular effects of the TKI imatinib on BCR-ABL, an ongenic fusion gene, the clinical discussion has changed. Imatinib is used as first-line therapy for adults with CML. Based on the adult data and results, a reasonable recommendation has been made to initially treat pediatric patients with imatinib and change to a second generation TKI (dasatinib, nilotinib) if there is relapse or an incomplete response. At the time of switch to a second generation TKI, an allogeneic hematopoietic cell transplantation (HCT) should be considered. The relatively low toxicity of TKIs makes them a favorable option; however the long-term effects and the possible need for lifelong treatment still require further study. In addition, although HCT is potentially curative, TKIs are not and require an extremely prolonged exposure. As such, the jury is still out and the need for clinical studies regarding therapeutic decisions remains.

Suttorp M, Yaniv I, Schultz KR; Controversies in the Treatment of CML in Children and Adolescents: TKIs versus BMT? Biol Blood Marrow Transplant 17(1 Suppl):S115–S122, 2011.

183. If you saw a car with the license plate, “FLT3 ITD,” what would the most likely interest of its driver be? Studying childhood AML would likely occupy most of this driver’s free time. FLT3 or “FMS-like tyrosine kinase 3” is a tyrosine kinase located on chromosome 13. Internal tandem duplications (ITD) of the juxtamembrane region of FLT3 protein are associated with an increased risk for relapse in AML. In pediatric AML, this increased risk for relapse is particularly evident for patients who have a high allelic ratio, or an increased number of the ITDs.

184. What nuclear medicine agent has been useful in both the diagnosis and treatment of neuroblastoma?
131I-metaiodobenzylguanidine (131I-MIBG) was developed by Wieland and colleagues at the University of Michigan in the 1970s for use as an antihypertensive agent. It is structurally similar to
norepinephrine and found to concentrate within the neurosecretory granules of catecholamine producing cells. In the 1980s, studies confirmed the usefulness of I-MIBG in localizing neuroblastoma; 90% of neuroblastomas have uptake of I-MIBG in both primary and metastatic sites. In the late 1980s, studies investigating the use of I-MIBG as a therapeutic modality came about and are ongoing.
185. Patients with high-risk neuroblastoma require treatment with virtually all
known therapeutic modalities to maximize the likelihood of cure. Can you name these modalities?
Therapy often requires administration of multiagent chemotherapy; surgical resection; stem cell transplantation; radiation therapy; differentiation therapy with 13-cis-retinoic acid (Accutane); and most recently, immunotherapy.
186. Do all transplant patients require complete ablation of their recipient bone marrow? No. Stem cell transplants that do not ablate the recipient bone marrow are called nonmyeloablative transplants. Such transplants require vigorous immune suppression to maintain the donor graft, as well as a disease that does not require intensive chemotherapy or full donor engraftment for success. Thus, patients with leukemias that respond well to a graft-versus-leukemia effect may benefit from the decreased morbidity and mortality of a reduced-intensity preparative regimen.
187. What is graft-versus-leukemia (GVL)?
GRAFT-VERSUS-LEukemia occurs when the donor marrow recognizes antigens on the leukemic blast cell as foreign and initiates immune-mediated clearance of the malignant cell. GVL is most easily obtained in patients who have been transplanted for CML, although patients with AML and ALL may also experience a GVL effect (AML usually more than ALL). Thus, GVL constitutes an important part of the antileukemic effect of transplantation, particularly for CML and AML. Current research is directed
at separating a graft-versus-host effect from a GVL effect.