Nuclear Oncology, 1 Ed.

CHAPTER 25

PEDIATRIC TUMORS

Reza Vali • Martin Charron

INTRODUCTION

Cancer is relatively rare in childhood with an overall incidence of approximately 130 per million children in the United States.1 Because of the relatively low frequency of childhood malignancy, the incidence rate is quoted per million rather than per 100,000 persons. The incidence of childhood cancers overall is about 140 per million in Europe for young children (0 to 15 years old) and approximately 157 per million for children and adolescents (0 to 19 years old).2 The total incidence of childhood malignancy varies slightly between different regions of the world and in different ethnicities with a cumulative risk of 1 to 2.5 per thousand.3,4 Approximately, 1 out of 500 to 600 children develops some forms of cancer by 15 years of age.5

Although cancer is rare in childhood, it is the second most common cause of death (after accidents) in children aged 1 to 14 years, accounting for 18% of all deaths in this age group. Over the last 30 years, the overall incidence has increased 0.5% to 1% every year.2,6 Notable increases are recorded for carcinomas, lymphomas, and germ cell tumors. However, the mortality rate has decreased dramatically, probably caused by early detection and improved treatment. The 5-year survival has increased from 58% for children diagnosed between 1975 and 1977 to 83% for those diagnosed between 2001 and 2007.7

Adult neoplasms are largely categorized according to the anatomical site of the tumor. Childhood cancers, however, are more naturally classified based on both histology and anatomical site of the cancer. The International Classification of Childhood Cancer (ICCC) divides these cancers into 12 main diagnostic groups, with further subgroups and divisions.8 These 12 diagnostic groups are summarized in Table 25.1. The three most common cancers in children are leukemia, central nervous system (CNS) tumors, and lymphoma, accounting for approximately two-thirds of pediatric cancers.

TABLE 25.1

AGE-ADJUSTED AND AGE-SPECIFIC SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS (SEER) CANCER INCIDENCE RATES, 2005–2009

Each specific tumor type exhibits a different age-distribution pattern (Table 25.1). Overall, leukemia (30%) is the most common malignancy in children, and brain tumors (20%) are the most common solid malignancy of childhood. Nonmalignant CNS tumors are also categorized as CNS tumors because they have the same presentation as the malignant CNS tumors and are generally treated in the same way. Lymphomas (14%) are the next most common malignancy in children followed by neuroblastoma (NB) (7%), soft tissue sarcomas (7%), Wilms tumor (6%), bone tumors (5%), germ cell tumors (3%), retinoblastoma (3%), carcinomas and melanoma (3%), hepatic tumors, (1%) and other unspecified malignant tumors (1%).

The overall incidence rates are higher for boys than for girls in all age groups; however, some tumors are more frequent in girls, notably germ cell tumors in specific age groups, infant leukemia, renal cancer, melanomas, and thyroid carcinomas. The type of malignancy is slightly different among 15- to 19-year-old patients in whom Hodgkin disease and germ cell tumors are more common and there is an increased incidence of non-Hodgkin lymphoma, osteosarcoma (OS), Ewing sarcoma, thyroid cancer, melanoma, and soft tissue sarcoma other than rhabdomyosarcoma (RMS).1

Because of the relatively low frequency of childhood malignancy, limited data are available about the etiology and risk factors of most childhood cancers. Overall, the risk factors can be categorized as genetic or environmental, though in many instances a more likely etiology is the result of exposure to an environmental risk factor in a genetically susceptible individual.5 In adults, except in some instances like hereditary nonpolyposis colorectal cancer (HNPCC) and multiple endocrine neoplasia (MEN), environmental factors have a greater role.

To a greater degree than in adults, genetic factors may play a major role in childhood malignancy. A number of inherited genetic syndromes are associated with childhood cancer. Down syndrome, neurofibromatosis type 1, ataxia telangiectasia, Fanconi anemia, MEN 2B, Bloom syndrome, Gardner syndrome, Li–Fraumeni syndrome, and Beckwith–Wiedemann syndrome are some examples. Radiation, chemotherapeutic agents, diethylstilbestrol, dietary exposure to N-nitroso compounds, atmospheric pollution, pesticides, tobacco, alcohol, recreational drugs, and anemia during pregnancy are among the environmental factors that may induce cancer during the prenatal period or childhood.

Early detection of childhood malignancy is essential for more effective treatment. Moreover, improving survival in childhood cancer requires an increasing need for long-term follow-up of late effects and complications. Diagnostic imaging has a pivotal role for diagnosis, staging, evaluation of the response to therapy, and surveillance of pediatric cancers. Imaging in children requires special considerations and techniques. Interpretation of images often differs from the adult population.

SPECIAL CONSIDERATIONS IN PEDIATRIC ONCOLOGY IMAGING

Success in obtaining high-quality studies in children is both challenging and rewarding. It is essential to know that in pediatric nuclear medicine, the physician and technologists are working not only with a child who is anxious or frightened but also with anxious parents. With careful planning, good communication and a quiet and friendly atmosphere create the right environment. The following should be kept in mind when dealing with the pediatric patients.

• Importance of communication appropriate for the child’s stage of development

• Need for flexible scheduling

• Appropriate injection techniques

• Imaging environment, including the use of immobilization devices or safety restraints, distraction techniques, and the possibility of sedation when necessary

Usually it takes about twice as long to complete a procedure on a pediatric patient as on an adult.9

SEDATION

Sedation should be performed only if necessary. Sedation is not a substitute for patient preparation or to decrease the time of acquisition. Many strategies are available to avoid sedation including maximizing co-operation with the child, allowing the parents to be with their child, using the child’s nap time and distracters (decorating the room, reading a story, television, pacifier, bottle, or stuffed animal). Each center should follow their own institutional guidelines for sedation. However, guidelines to monitor sedation of children were published by the American Academy of Pediatrics (AAP) and are helpful to develop the best strategy. The commonly used medications for sedation are chloral hydrate, pentobarbital sodium, and midazolam. APP recommends using oral chloral hydrate (50 to 70 mg/kg; maximum 100 mg/kg) for infants and young children (usually less than 15 kg) and a parental sedation like pentobarbital sodium (Nembutal) (2 to 6 mg/kg) for older children and patients with mental deficiencies. Nembutal is contraindicated in patients with porphyria and the dosage should be adjusted for seizure patients. Midazolam (nasal: 0.2 mg/kg; oral: 0.5 to 0.75 mg/kg) is also suggested because of its amnestic effect in children.

It should be kept in mind that recommended drugs and route of administration depend on the patient’s age, history of underlying illness (e.g., mental deficiency, cardiac or respiratory illness), experience and familiarity with certain drugs, institutional protocols, length of procedure, and availability of support (reversal drugs). The nuclear medicine physician should always consult with the anesthesiology department especially in patients with a history of significant snoring, abnormal airway, congenital heart disease, reactive airways disease, and increased intracranial pressure.

RADIATION DOSE

The radiopharmaceutical dose to children is different from the adult dose for several reasons, especially the patient size. A child is not simply a small adult. Because the organs of children are smaller and closer together, the absorbed dose to different organs differs from those of adults. Children are developing and growing. Exposure to environmental harmful factors may result in more profound damages than adults. Radiation is considered to be a factor that may increase the risk of cancers and other diseases. Epidemiologic and biologic research suggest that ionizing radiation may increase the risk of malignant cell transformation.

The effect of low-dose radiation has been well described recently by Hendee et al.10,11 Most of the epidemiologic information about the radiation effect on humans are based on the Hiroshima and Nagasaki atomic bomb survivor studies as reported by the Radiation Effects Research Foundation.12,13 Extrapolating from this information to the low-dose consequences of radiation in humans may not be a true reflection of the effect of low-dose radiation and may be an overestimate. Miller et al. found that the probability of malignant transformation from N particles hit on a cell is much greater than N times the probability of transformation to malignancy from a single hit.9,14 According to the epidemiologic data, the lowest dose of x- or γ-radiation for which good evidence exists of increased cancer risks in human is about 10 to 50 mSv for an acute exposure and approximately 50 to 100 mSv for a protracted exposure.15The effective dose estimation for many pediatric nuclear medicine procedures is less than 10 mSv. There are even some theories about the protective effect of low-dose radiation on humans (hormesis).16,17

In light of these controversies, it is recommended to select a more conservative approach for children. A study should be performed only if necessary and the radiation dose should be kept as low as possible without adversely affecting the quality of images. Conventionally the pediatric injected dose was calculated from the adult dose with different formulas adjusting for weight ((body mass (kg) × adult dose)/70 kg), body surface area (BSA (m2) × adult dose)/1.73 m2), or age (Webster’s formula; age (years) + 7) × (adult dose)/(age (years) + 1)).18,19 However, in some cases, the adult dose is based on the institutional experiences with a wide range of administered activities. With new technology and improved instrumentation, the optimum doses for the pediatric population can be changed. New North American consensus guidelines were published in 2010 to address this issue.20 Table 25.2 shows the recommended administered dose including the minimum and maximum doses of the commonly used radiopharmaceuticals in pediatric oncology.

TABLE 25.2

NORTH AMERICAN CONSENSUS GUIDELINES FOR ADMINISTERED RADIOPHARMACEUTICAL ACTIVITIES GENERALLY USED IN NUCLEAR ONCOLOGY IN CHILDREN AND ADOLESCENTS

Dosimetry associated with the CT on PET/CT and SPECT/CT should also be considered. The effective radiation dose to children from the CT portion is usually the same or slightly higher than the radiopharmaceutical dose. For the same CT acquisition parameters, the dose to a newborn is approximately twice that to a medium-sized adult. Therefore, CT acquisition parameters should be reduced for smaller patients.21 The radiation dose from the CT portion depends on various CT acquisition parameters, including the tube voltage (kVp) and the tube current–time product (mAs). The tube current could be adjusted based on the thickness of the body. In thinner parts or in areas with less attenuating tissues (e.g., the lungs) fewer x-rays can be emitted. Obtaining the CT over a limited field of view (over the area of interest), or using a higher pitch (faster bed speed) when using a helical CT will also decrease the radiation dose of CT part.

SPECIAL CONSIDERATIONS IN 18F-FDG PET/CT

PET/CT has become a standard component of medical imaging in oncology. The combination of the anatomic information from CT and the functional information from PET provides clinical information not attainable from either study alone. However, the widespread clinical application of PET/CT in pediatric oncology was slow for several reasons including the lack of availability of dedicated PET/CT in pediatric centers, the radiation dose and the relative rarity of childhood malignancies. The usefulness of PET/CT in the management of pediatric malignancies has been shown in several studies during the last decade. However, the physiologic variation in FDG biodistribution and potential pitfalls in pediatric population needs special attention.22

Standardized Uptake Value

One of the parameters commonly used in oncology for quantification of the intensity of FDG uptake is Standardized Uptake Value (SUV). SUV is a semiquantitative value representing the ratio of the radioactivity in a selected part of the body at a certain time point. Many factors influence the SUV including body composition and habitus, length of uptake period, blood glucose level, and partial volume effect.23,24 Consistency of SUV values is more challenging in the pediatric population because there are significant body changes during childhood. Fat has much lower FDG uptake than other tissues.23 The percentage of fat in the total body weight rises from 11% in the newborn to approximately 26% during the following 5 months, and then decreases gradually until 12 months of age.25 After that the amount of fat is variable and depends on many factors including diet, physical activity, and genetics. The pediatric SUV normalized to body weight is not exactly the same as that of adults. The clinical significance of SUV values in different pathologies and normal versus suspected malignancy reference numbers in the pediatric population should be interpreted cautiously and not just based on adult reference values.

Palatine and Lingual Tonsils

The palatine and lingual tonsils are lymphatic tissues that are very active during childhood. Therefore, it is not uncommon to see increased 18F-FDG activity in these structures, even without apparent inflammation (Fig. 25.1). Moreover, clinical or subclinical upper respiratory infection is more common in children than in adults especially in cold seasons. Lymphoma in the head and neck, posttransplant lymphoproliferative disorder (PTLD), and secondary malignancy in the nasopharyngeal area and tonsils may mimic the same pattern. The intensity of uptake and the symmetric/asymmetric pattern of activity may be helpful to differentiate a normal variant versus pathology. Symmetric pattern of uptake with similar shape is more likely to be physiologic uptake especially if there is no evidence of pathology on CT scan,26 whereas asymmetric areas should be considered suspicious for the presence of pathology. Comparison with the previous 18FDG PET study and correlation with the CT portion of PET/CT can be helpful for an accurate interpretation.

Thymus

The thymus is a specialized organ of the immune system localized in the anterior superior mediastinum, in front of the heart and behind the sternum extends from the brachiocephalic vessels toward the right cardiophrenic angle. The thymus “educates” T lymphocytes (T cells), which are critical cells of the adaptive immune system and becomes atrophic after puberty. The thymus has a more quadrilateral shape during early childhood and a more triangular shape during adolescence. The thickness and homogeneity of the gland is used to predict thymic disease on CT scan. Thickness of the gland measured perpendicular to the length of a lobe should be less than 1.8 cm in patients under 20 years old and 1.3 cm in older patients.27,28 In pediatric population, the thymus often shows mild to moderate homogeneous increased FDG uptake (Fig. 25.1) which decreases with age, notably at puberty, when the thymus undergoes fatty infiltration and involution.29

FIGURE 25.1. Axial and coronal PET and fused PET/CT images of a 20-month-old infant. Note the normal uptake in the area of the vocal cords (A), tonsils (arrows in B), and thymus (C).

Thymus uptake can also increase in thymus hyperplasia. Thymic hyperplasia may be seen after chemotherapy, particularly in young patients treated for lymphoma or testicular cancer. This is probably because of an immunologic rebound phenomenon characterized by infiltration of plasma cells after thymic aplasia in response to steroid-induced apoptosis and inhibition of lymphocyte proliferation.30

Differentiation of physiologic thymus uptake or thymus hyperplasia from malignancy is important. Correlative CT scan is useful to evaluate the homogeneity and the size of the gland. On 18FDG PET studies, the shape of the gland should be quadrangular or triangular with uniform uptake. Several investigators have studied the intensity of 18FDG uptake by means of SUV in normal thymus, thymic hyperplasia, and malignant infiltration of the gland. In a study by Brink et al.,30 the average SUV value of 2.7 (with a maximum of 3.8) was reported for thymic hyperplasia. Ferdinand et al.29 suggested that with an SUV value >4, further investigation should be performed before concluding that it is physiologic uptake.

The average SUV for thymic carcinoma has been found to be much higher (7.2 ± 2.9) in a study by Sasaki et al.31 This value was significantly greater than the values found for invasive thymoma (3.8 ± 1.3) and noninvasive thymoma (3 ± 1).29 By using an SUV of 5 as a cut-off, Ferdinand et al. achieved reasonable sensitivity (84.6%), specificity (92.3%), and accuracy (88.5%) in differentiating thymic carcinoma from thymoma. In summary, heterogeneous or focally increased activity, intense 18FDG uptake, or any changes in the shape of the thymus should be correlated with CT findings and needs further investigation.

Brown Fat

Brown fat is a type of adipose tissue with a thermoregulation function to control body temperature and energy expenditure. It is found in the neck region, shoulders, superior mediastinum, diaphragmatic hiatus, and perinephric area. The frequency of brown fat uptake in children is higher than in adults.32 Brown fat uptake is usually symmetric (except for diaphragmatic hiatus) mild to moderate activity which corresponds to hypodense regions on CT scan, similar to normal fat tissue (Fig. 25.2). There is a relationship between brown fat uptake and cold temperature. Some medications (e.g., propranolol, diazepam) are suggested to decrease the brown fat uptake. The use of these medications is not recommended routinely in clinical practice. Controlling the temperature of the injection room is the more practical way to decrease the brown fat uptake. Knowledge of the physiologic distribution of brown fat and the use of fused PET/CT images help to differentiate brown fat uptake from pathologic lesions. However, sometimes it is difficult to diagnose adjacent pathology or small lymph nodes (especially in the neck and upper mediastinum) in the context of high uptake in brown fat.

FIGURE 25.2. Intense 18F-FDG activity in brown fat tissues correlates with hypodense regions on CT.

Other Issues

Bone marrow may be more active in children than adults, probably because of greater red marrow component. Following chemotherapy or secondary to hematopoietic drug stimulators like granulocyte colony-stimulating factor (G-CSF), bone marrow often shows a diffuse intense 18FDG uptake (Fig. 25.3).33,34 Other conditions, including β-thalasemia, severe anemia (hyperplasic marrow), and diffuse metastasis (less likely), or drugs (interferon), have been reported to increase 18FDG uptake in bone marrow in both pediatric patients and adults.35,36

Children usually move during the uptake interval post-injection of tracer. Depending on the muscles involved, increased activity may be noted in a muscle or a group of muscles which could be symmetric or asymmetric. The pattern of uptake corresponding to the muscle/s on CT scan is helpful to differentiate physiologic uptake from pathology. However, especially in the head and neck region, sometimes it is difficult to differentiate focal uptake because of the physiologic activity in a small muscle and a pathologic lymph node, with a nondiagnostic CT scan or in cases of misregistration of PET and CT. Patient movement may also interfere with image acquisitions. Sedation during acquisition may be needed for some patients.

Children may also talk or scream during radiotracer injection or for a few minutes after during the uptake period. As a result, it is not uncommon to see increased physiologic activity in the vocal cords. The uptake is typically bilateral and symmetrical (Fig. 25.1) but it may be asymmetric. In cases of intense asymmetric vocal cord uptake, correlation with CT scan is useful to exclude any possible pathology or unilateral vocal cord palsy. Symmetric areas of mild FDG uptake may be seen in growth plates especially long bone physis which is more active in children. In girls of reproductive age, foci of increased FDG uptake may be seen in the pelvic region because of the physiologic activity in the ovaries.

FIGURE 25.3. Maximum intensity projection image in a patient 3 days after G-CSF administration. Note increased 18F-FDG uptake in bone marrow.

RADIOPHARMACEUTICALS

Many different radiopharmaceuticals have been used in pediatric oncology for the detection of tumors, metastases, and evaluation of response to therapy.

Gallium 67

Gallium scan has been used for staging, estimating prognosis, and assessing the treatment response as well as the evaluation of residual disease in lymphoma and soft tissue tumors (RMS), and also for the evaluation of metastatic melanoma and hepatocellular carcinoma. 67Ga decays by electron capture and emits several γ-rays: 93 (41%), 185 (23%), 288 (18%), and 394 (4%) KeV. Imaging with a large-field-of-view multipeak γ-camera equipped with a medium-energy parallel hole collimator is preferred. The physical half-life is 78 hours. The organ receiving the largest radiation dose is large bowel (0.72 mGy/MBq). The effective dose equivalent for a 5-year-old child is 0.4 mSv/MBq. The mechanism of 67Ga transport is similar to iron, initially binding to transferrin (an iron transport protein) after intravenous injection. However, 67Ga has one valence state (unlike Fe2+ or Fe3+) so the ultimate distribution is different. The mechanism of uptake in tumors may be caused by the leakage from the tumor vessels, intratumoral pH, or increased concentration of transferrin in tumors (transferrin receptors are upregulated in tumors with high proliferation ability). Because of the slow transfer of Ga-transferrin to the tumors and high background activity, imaging usually begins 48 hours after injection of 67Ga. However, imaging as early as 24 hours may also reveal the tumor. Delayed images for up to 7 days may be needed to differentiate bowel activity versus 67Ga-avid lesions in the abdomen. SPECT study is also suggested for the evaluation of chest and abdominal region. The usual administered activity in children is 1.5 to 2.6 MBq/kg (0.04 to 0.07 mCi/kg) with a minimum dose of 9 to 18 MBq (0.25 to 0.5 mCi).

Patients should be well hydrated and do not need to fast. Bowel preparation prior to imaging is suggested to decrease bowel activity. Knowledge of the patient’s history of recent infection (false-positive results for tumor), chemotherapy (will suppress 67Ga uptake; should wait 4 weeks after chemotherapy), radiation, and recent blood transfusion and iron injection (altered 67Ga biodistribution) is essential before the examination. 67Ga is normally observed in the liver, spleen, bone marrow, lacrimal and salivary glands, breast tissues, thymus, nasopharynx, gastrointestinal activity (because of both the small bowel excretion and biliary excretion), and kidneys (during the first 24 hours).

201Tl and 99mTc-MIBI

201Tl and 99mTc-methoxyisobutylisonitrile (MIBI) are taken up by a number of tumors and is indicative of viability. Either 201Tl or 99mTc-sestaMIBI is useful to assess treatment response in osteogenic sarcoma, RMS, Ewing sarcoma, and brain tumors. 201Tl decays by electron capture with a γ-ray ranging from 69 to 83 KeV (94% abundance) and two less abundant γs: 167 KeV (10% abundance) and 135 KeV (3% abundance). The physical half-life is 73 hours. The mechanism of tumor uptake depends on tumor blood flow and sodium–potassium ATPase pumping system of the cell membrane. The mechanism of uptake of 99mTc-MIBI depends on its lipophilic properties and passive diffusion into the cells. Then it attracts to negatively charged mitochondria inside the cells. The accumulation of 99mTc-MIBI is inversely related to the P-glycoprotein (PGP) in the cell membrane. PGP is a cellular membrane protein which is responsible for pumping out cationic and lipophilic substances from the cells. Malignant tumors have increased expression of PGP because of the multidrug resistance gene (MDR-1) which encodes for PGP. MDR-1 is responsible for resistance of tumors to chemotherapy agents. The washout of 99mTc-MIBI may be an indicator of the degree of expression of PGP and a predictor of chemotherapy resistance. The patient should be fast for 4 hours for both 201Tl and 99mTc-MIBI study. Imaging is usually performed 1 and 4 hours after the radiotracer injection with a low-energy high-resolution collimator. SPECT images over the lesion are also recommended. Normal biodistribution of 201Tl is salivary glands, thyroid, heart, liver, stomach, large bowel, kidneys, testes, muscles, eyes and slightly in choroid plexus of the lateral ventricles. The kidney is the critical organ for 201Tl, receiving 0.03 cGy/37 MBq. For 99mTc-MIBI, the normal biodistribution is heart, thyroid, liver, gallbladder, choroid plexus, lacrimal glands, lungs, salivary glands, bowel, spleen, kidneys, and muscles. The large bowel and gallbladder receive the highest dose. Increase uptake more than the background activity is considered a positive finding. For brain lesion comparing with the contralateral region is suggested. A baseline study before treatment is helpful for comparison.

MIBG Scintigraphy

Metaiodobenzylguanidine (MIBG) is a derivative of guanithidine, structurally similar to norepinephrine that enters neuroendocrine cells by an active type 1 uptake mechanism via the epinephrine transporter and is stored in the neurosecretory granules. MIBG scintigraphy with 131I or 123I has been used for the detection of neuroectodermal tumors including pheochromocytoma and NB for the last 30 years. MIBG has been labeled with 131I, 123I, and recently 124I.

131I MIBG is probably more commonly used in nuclear oncology because of its low cost and greater availability. Moreover, it may be preferred for dosimetric studies and treatment planning. 123I MIBG has the advantage of better physical characteristics, that is, shorter half-life (13 hours) and ideal energy of γ-rays (159 KeV), which reduces the radiation dose to the patient and allows SPECT imaging. Moreover, the study can be completed in a shorter period of time.37 Thus 123I MIBG is the preferred agent in pediatric population.

Patient preparation is important for MIBG scintigraphy. Thyroid blockade is necessary to reduce free iodine uptake by the thyroid gland. The pretreatment could be obtained by taking sodium or potassium perchlorate (300 to 600 mg/m2 BSA) daily (5 days before scanning with 131I MIBG or 1 day with 123I MIBG) or Lugol iodine solution (0.3 mL) three times a day (3 days before scanning with 131I MIBG or 1 day with 123I MIBG). These medications should be continued for 1 to 2 days for 123I MIBG, or 2 to 3 days for 131I MIBG scanning.38

A number of drugs are known to interfere with MIBG uptake. These drugs include tricyclic antidepressants, certain antipsychotics, CNS stimulants, calcium channel blockers, and α- and β-blocker labetalol. A list of interactive drugs and suggested time of withdrawal are summarized in Table 25.3. These medications should be discontinued with the supervision of the referring physician. It is also suggested that the patient is advised not to take some foods containing vanillin and catecholamine-like compounds (such as chocolate and blue-veined cheeses).38

The administered dose should be calculated based on the adult dose (40 to 80 MBq for 131I MIBG and 400 MBq for 123I MIBG) using standard formulas. The recommended minimum and maximum doses are 37 and 400 MBq for 123I-MIBG and 3.7 and 18.5 MBq for 131I MIBG, respectively.39 Slow infusion for at least 5 minutes is advised in a peripheral vein, followed by saline administration. Rapid injection or injection from a central intravenous line should be avoided because of the possibility of adverse reaction (vomiting, tachycardia, pallor, abdominal pain).39 Patient should be encouraged to drink water and fluids following injection and void frequently and before the imaging.

TABLE 25.3

DRUG INTERACTIONS WITH MIBG

The administered dose is 0.52 MBq/kg (3.7 to18.5 MBq) for 131I-MIBG and 5.2 MBq/kg (37 to 400 MBq) for 123I-MIBG. Imaging is performed at 24, 48, and 72 to 96 hours with 131I-MIBG and at 24 and 48 hours with 123I MIBG. SPECT views are usually obtained with 123I MIBG scan. The effective radiation dose for 123I MIBG is 0.037 mSv/MBq and 0.017 mSv/MBq for 5- and 15-year-old children, respectively. For 131I MIBG, it is 0.43 mSv/MBq and 0.19 mSv/MBq for 5- and 15-yearold children, respectively.38 Liver receives the highest radiation dose with both radiotracers (0.83 mGy/MBq for 131I MIBG and 0.067 mGy/MBq for 123I MIBG).

Images should be obtained 24 hours after 123I MIBG injection and 48 hours after 131I MIBG injection. SPECT study from chest, abdomen, and pelvis should be performed 24 hours after 123I MIBG administration. Delayed views may be obtained with equivocal finding on first images with both radiotracers.

After intravenous injection of MIBG, approximately 50% of the administered radioactivity appears in the urine by 24 hours. Thus, the bladder and urinary tract show intense activity. Physiologic activity is seen in the liver and to a lesser degree in spleen, lungs, salivary glands, skeletal muscles, and sometimes nasal mucosa, gallbladder, colon, uterus, muscles, and possibly brown fat tissues in the upper chest. Sometimes gastrointestinal tract and thyroid may be seen because of free iodine especially if the thyroid has not been blocked appropriately. Faint activity in the adrenal glands may be seen approximately in up to 15% of cases with 131I MIBG and up to 75% when using 123I MIBG.

The sensitivity and specificity of MIBG are different in different kinds of neuroectodermal tumors. The sensitivity of MIBG to detect NB (primary tumor and metastases) is about 80% on a lesion-by-lesion basis and 90% to 95% in terms of staging. MIBG is highly specific (∼100%) for the detection of primary tumor and metastases in NB.39,40

SYMPATHETIC NERVOUS SYSTEM TUMORS

Imaging

Sympathetic nervous system (SNS) tumors account for about 7% of all pediatric malignancies. NB, including ganglioneuroblastoma, is the most common form of all SNS tumors in children (approximately 97%). NB is the most common extracranial solid tumor in childhood and the most frequently diagnosed malignancy during infancy accounting for approximately a fifth (22%) of all cancers diagnosed below the age of 1 especially during the first 3 months of infancy. The incidence of NB is rare after the age of 5. Almost one-half (46%) of NBs develop in the adrenal gland followed by retroperitoneal paraspinal and mediastinal tumors. Mediastinal tumors are more frequent in infants than in older children.

The etiology of NB is not well understood. The higher incidence during infancy is suggestive of a genetic susceptibility or environmental exposure during conception and gestation. Medication during pregnancy (amphetamines, diuretics, tranquilizers, phenytoin, fertility drugs, etc.) has been reported to increase the incidence of NB.41,42 The effects of alcohol, smoking, and mothers’ occupational exposures on the incidence of neuroblastoma are controversial.4244

Overall, long-term survival of the patients with NB is less than 40%.45 A 5-year survival rate was improved from 35% during 1975 to 1984 to 55% during 1985 to 1994 for children aged 1 to 4 years at diagnosis whereas it was essentially unchanged over these time intervals among infants (83%) and children 5 years or older (40%).46

The diagnosis is usually based on histopathologic findings plus the high urinary levels of one of the catecholamines. In about 90% of cases of NB, elevated levels of catecholamines or their metabolites including dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA) can be detected in the urine or blood.47 On pathology, the tumor cells consist of neuroblasts, which are immature, undifferentiated, small, round-shaped sympathetic cells, with little cytoplasm, dark nuclei, and small indistinct nucleoli with pseudorosettes patterns (tumor cells around neutrophils).

The clinical behavior of the tumor is variable in different patients and different age groups. The tumor can regress spontaneously, or can mature into a benign lesion even without treatment, or progress and metastasize rapidly with poor outcomes despite aggressive therapy. Prognosis for neuroblastomas is dependent on the age, stage of disease, the molecular biologic and cytogenetic characteristics of the tumor and other parameters such as tumor proto-oncogenes, DNA content, and catecholamine synthesis.

Staging based on the International Neuroblastoma Staging System (INSS) is one of the variables that affect prognosis in patients with NB (Table 25.4). The classification evaluates the distribution of the disease using radiographic and scintigraphic studies, surgical operability, lymph node and bone marrow involvement. A new International Neuroblastoma Risk Group (INRG) classification system is also proposed based on 13 potential prognostic factors. The patients can be categorized into four groups (very low risk, low risk, intermediate risk, and high risk) with different 5-year event-free survival rates (>85%, >75% to ≤85%, ≥50% to ≤75%, and <50%, respectively).48

TABLE 25.4

INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM (INSS)

The clinical signs and symptoms depend on the size of the primary tumor, effect of hormone production, and the location of distant metastases. It may be found incidentally without any symptoms or present with abdominal pain and mass, generalized bone pain, anemia, malaise, fever, irritability, weight loss, encephalitic symptoms and even blindness, and paraneoplastic syndrome.

Because metastases are common at presentation, accurate staging depend on multimodality imaging. Initial imaging in children with NB is usually performed to confirm the diagnosis and investigate the presenting symptoms. Chest x-ray, abdominal radiographs, skeletal films, abdominal ultrasound or computerized tomography, spinal MRI (in cases of paraspinal NB), MIBG scintigraphy, and probably bone scan are among the investigations depending on the clinical findings.

Ultrasonography (US) is the initial imaging modality for the evaluation of abdominal mass in a child. It is useful for the diagnosis of abdominal mass, and the evaluation of local extent of the primary tumor. On US, NBs are heterogeneous solid lesions, mostly echogenic, with calcification and less commonly with cystic anechoic areas. CT scan shows lobulated nonuniform masses with heterogeneous or little enhancement. Calcifications, pseudonecrosis or hemorrhage may also be seen. Both CT and MRI are useful for assessment of the location and the size of the primary tumor, vascular encasement, tumor respectability, and retrocrural and paravertebral extension.49

MRI is superior to CT to assess bone marrow infiltration and intraspinal extension of tumor. Moreover, the lack of ionizing radiation and the absent necessity of using oral contrast are other advantages of MRI.49 On MRI, the tumor is typically heterogeneous with a variable enhancement pattern, prolonged T1 and T2 relaxation times with low signal intensity on T1W and high signal intensity on T2W images. Epidural invasion of NB and leptomeningeal involvement should be assessed with MRI on any patient with paraspinal NB.40,50

Bone metastasis is relatively common in NB. Detection of bone metastasis is important for staging (stage IV). Whole-body bone scan with 99mTc-MDP has been widely used in NB to evaluate bone metastasis. Bone metastases are usually present with focal increased uptake in the skeleton. However, cold defects and asymmetric metaphyseal increased activity may also reveal bone metastases. In children, detection of bone metastasis near the epiphysis is difficult. Even with a slightly blurring of the growth plate margins, bone metastasis should be ruled out.51 Involvement of the skull and facial bone including periorbital regions may be also seen with more advanced bone metastases. The sensitivity of MIBG to detect bone metastases is higher than bone scan (Fig. 25.4).52 Moreover, the specificity of the positive lesions in bone scan is lower than MIBG scintigraphy. However, there are some instances of positive bone scans with negative MIBG studies.53,54 Thus, bone scan is still needed for accurate staging at diagnosis. Omitting bone scanning in the diagnostic staging may lead to incorrect staging up to 10% of cases.55 On the contrary, in a clinically responding patient, bone scan is not recommended in the routine follow-up studies unless MIBG scan is not available, or with a negative MIBG scan and suspicious radiographic findings. Other incidental findings on bone scan are visualization of the primary tumor caused by calcification in approximately 40% of cases (Fig. 25.4) and visualization of a displaced or hydronephrotic kidney.

FIGURE 25.4. Bone scan in a 6-month-old boy with adrenal tumor confirmed to be neuroblastoma after biopsy. Note 99mTc-MDP uptake in the tumor.

MIBG shows variable uptake in neuroectodermal tumors; some authors have found greater uptake in tumors with high catecholamine excretion, whereas others have reported more intense uptake in more undifferentiated types of tumors. Thus, it is not possible to differentiate the different types of neuroectodermal tumors based on the positivity and intensity of MIBG uptake (40). MIBG scan has a high sensitivity (80% to 90%) and excellent specificity (∼100%) for the detection of primary tumor and metastases in NB.39,40

MIBG scintigraphy is a sensitive modality for the detection of bone marrow involvement in NB patients. It is as sensitive as MRI and bone marrow aspirate. The sensitivity of MIBG may be even better than bone marrow because it has the advantage of evaluation of the whole skeleton (Fig. 25.5).56 MIBG is more specific than MRI to assess response to treatment. However, still MIBG-negative NB tumors is a concern, which is usually seen in stage I and II tumors.53 If the tumor is MIBG avid at diagnosis, follow-up MIBG study is recommended to evaluate response to therapy and whenever the treatment regimen changes.

MIBG scan has also a prognostic value. Several scoring systems have been suggested to predict the response to therapy based on the number of MIBG uptake in different organs at diagnosis or during midcycle of therapy.5760 In addition, a negative MIBG scan after therapy in a patient with previous positive study indicates a good prognosis and longer disease survival.61 Evidence of residual disease and persistent positivity during and after induction suggest a poor prognosis.50 In summary, MIBG scan is indicated for the evaluation of NB at diagnosis, for staging, after completion of therapy, and whenever any changes in the therapeutic regimen is needed especially before decision about MIBG therapy.

NB tumors also exhibit somatostatin receptors. Thus 111In-DTPA-D-Phe1-octreotide (111In-octreotide; Octreoscan) or other somatostatin receptor radiotracers are potentially useful for the detection of NB tumors and metastases.62Many investigators compared the sensitivity of octreotide with MIBG in NB. The sensitivity of Octreoscan was 50% to 70% compared to 83% to 94% for MIBG.63 However, in most of those studies, only planar images were obtained for octreotide scintigraphy. With SPECT/CT, the sensitivity of Octreoscan will increase. They also suggested that a positive Octreoscan indicates a favorable prognosis.6466 New PET tracers for somatostatin receptors (68Ga-DOTA-Tyr3-octreotide), (68Ga-DOTA-TOC), (68Ga-DOTA-NOC), and (68Ga-DOTA-TATE) may have a higher sensitivity for the detection of NB lesions. 68Ga-DOTA-TOC PET has been shown to be superior to 111In-octreotide planar scintigraphy and SPECT imaging in neuroendocrine tumors (NETs).63,67 Kroiss et al. showed that 68Ga-DOTA-TOC PET has a high sensitivity (97.2%) compared to MIBG (90.7%) in a pilot study.68 Further studies with a larger number of subjects are needed to validate the findings and the exact role of somatostatin receptor scintigraphy in NB.

18F-FDG PET has been also used in patients with NB. 18F-FDG can accumulate in primary neoplasm and metastases even in the cases of MIBG-negative tumors. Sharp et al.69 compared the diagnostic utility of 123I MIBG and 18F-FDG PET in NB in 60 patients. They concluded that 18F-FDG PET was superior for stage I and II neuroblastomas, but 123I MIBG might be needed to exclude higher-stage disease. 18F-FDG PET also provided important information for patients with weakly positive MIBG scan and at major decision points during therapy (i.e., before stem cell transplantation or before surgery). They also concluded that 18F-FDG PET may be better for the detection of lesions in the chest, abdomen, and pelvis. In addition, the study can be completed in 2 hours. Because of the ability of MIBG to identify bone and bone marrow metastases, 123I MIBG was overall superior for stage IV NB, especially during initial chemotherapy. 18F-FDG PET may be of limited value for the detection of bone marrow and bone metastasis. Moreover, it is not a specific radiotracer and can be positive in other neoplastic lesions or inflammatory processes.

FIGURE 25.5. Bone scan in a 4-year-old boy with NB showed an abnormal activity in the skull (A) with no significant abnormal uptake in the vertebrae, pelvis, and femurs (B and C). 123I-MIBG scan (DF)revealed multiple bone metastases. 123I-MIBG scans 5 months after treatment (GI) and 4 years later on follow-up studies (J) were normal.

Kushner et al.70 proposed that 18F-FDG PET scan with bone marrow study may be sufficient for monitoring NB after resection of the primary tumor. However, in another comparative study by Taggart et al.,71 in 21 patients with relapsed NB, MIBG scintigraphy was significantly more sensitive for individual lesion detection than 18F-FDG PET, though 18F-FDG PET could sometimes play a complementary role, particularly in soft tissue lesions. The exact role of 18F-FDG PET should be clarified with further studies.

Other radiotracers have also been used in NB. Shulkin et al.72 used C11-hydroxyephedrine (HED) and 123I MIBG in seven patients with NB and found similar results in both studies. In two patients, detection of lesions was better visualized in the abdomen with MIBG scintigraphy because of the relatively less hepatic accumulation of MIBG than HED. Piccardo et al.73 showed that 3,4-dihydroxy-6-F-18-fluoro-L-phenylalanine (18F-DOPA) PET/CT has a higher sensitivity than 123I-MIBG scintigraphy to detect NB lesions. They prospectively evaluated 28 paired 123I-MIBG and 18F-DOPA PET/CT scans in 19 patients with stage III and IV NBs. NB lesions were confirmed in 17 of 19 patients. 18F-DOPA PET/CT and 123I-MIBG scintigraphy detected the lesions correctly in 16 (94%) and 11 (65%), respectively. On scan-based analysis, the sensitivity of 18F-DOPA PET/CT and 123I-MIBG were 95% and 68%, respectively, with similar specificity. In 9 of 28 paired scans (32%) 18F-DOPA PET/CT results influenced the patient management.74

Treatment

The treatment of NB depends on the stage of disease and the age of patient. In stage I and II surgical excision of the tumor is the first-line treatment. For stages III and IV, the treatment is usually a combination of surgery and chemotherapy and sometimes bone marrow transplantation with high-dose chemotherapy. However, despite an initial good response to therapy, 50% to 60% of patients with high-risk neuroblastoma have a relapse, probably because of drug resistance.48

131I-MIBG has been used for the treatment of NB cells since 1984.75 As 131I-MIBG has a high specificity in NB cells and because of a prolonged intracellular retention at tumor sites and in contrast to normal tissues, 131I-MIBG is a good radiotracer for the treatment of NB.

Usually, 131I-MIBG is used as a single agent in progressive or recurrent neuroblastoma after conventional therapy. In 1991, Hoefnagel et al.76 published a study in 49 children with high-risk progressive or relapsed NB patients after conventional therapy. They used a fixed dose of 100 to 200 mCi of 131I-MIBG for the treatment of NB. Seven patients showed complete responses and 23 showed partial responses. Similar results were shown by other investigators.77,78 131I-MIBG has also been used in combination with myeloablative therapy before autologous bone marrow transplantation (ABMT). Voute et al.79 combined 131I-MIBG therapy with hyperbaric oxygen in recurrent stage IV NB. They concluded that the survival rate at 28 months has increased compared to 131I-MIBG treatment alone.

Other investigators have combined 131I-MIBG therapy with chemotherapeutic agents.80,81 By adding chemotherapeutic agents to MIBG therapy, the hematologic toxicity will increase. Thus, in some of these studies, they followed the treatment by stem cell rescue or autologous bone marrow transplantation. 131I-MIBG therapy can also be used preoperatively, at diagnosis, for inoperable stage III and IV diseases for shrinkage of the tumor.

The protocol and indications for 131I-MIBG therapy is different in different centers. Intravenous infusion of fixed doses of 100 to 300 mCi 131I-MIBG in 1 to 4 hours is the most common approach. Patients should have MIBG-positive lesions in whole-body MIBG scintigraphy. Premedication with thyroid-blocking agent before and during the therapy is essential. The thyroid-blocking agents (sodium or potassium perchlorate or Lugol iodine solution) should be started 3 to 5 days before the therapy and continued for 10 days after the therapy. The interactive medication with MIBG uptake should also be discontinued (Table 25.3). It is suggested to discontinue these medications 1 or 2 weeks before the therapy. Pregnancy and breast-feeding, life expectancy less than 1 month, evidence of myelosuppression (Hb < 90 g, total white cell count <4 × 109, platelets <100 × 109), and rapidly deteriorating renal function (GFR < 30 mL/min) are contraindications for the MIBG therapy.

Hematologic toxicity is one of the main concerns after MIBG therapy. Thrombocytopenia is a common side effect probably caused by radiation to the bone marrow (possibly megakaryocytes) or uptake of MIBG by thrombocytes.82 The absorbed dose to bone marrow which is the critical organ should not exceed 2 to 2.5 Gy. The hematologic toxicity will increase when there is bone marrow involvement at the time of MIBG therapy. Other side effects are, decrease in erythrocytes and leukocytes (particularly with high-dose MIBG therapy), deterioration of renal function (in the cases of using chemotherapeutic agents affecting renal function, simultaneously), and hypothyroidism (in the cases of inadequate suppression before and during the therapy).

Isolation of patients is important for radiation safety. By inviting parents to be involved, explaining the procedure, increase the distance and decrease the time of exposure, and encouraging them to wear disposable gown, gloves and mask, isolation will be practical and safe. In addition, the external radiation dose to parents can be measured by a pocket dosimeter and probably urine sample if internal contamination is suspected.

PHEOCHROMOCYTOMA

Pheochromocytomas are rare in children and are seen primarily in adolescence or young adulthood. The average age of presentation is 11 years. These tumors arise from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. The majority of cases arise from adrenal medulla (85%), with the remainder occurring in extra-adrenal sites, like organ of Zuckerkandl and sympathetic ganglia surrounding the kidney. In children, approximately 40% of pheochromocytomas are associated with genetic mutations.83 Pheochromocytoma is seen in several familial syndromes: MENs (MENIIA and IIB), von Hippel–Landau syndrome, neurofibromatosis (NF-1), and familial paraganglioma syndromes.

The clinical presentation is variable from asymptomatic cases to symptoms caused by increased serum catecholamine level (hypertension, palpitations, headaches, pallor, and tremors). Elevated levels of plasma and urinary catecholamines are diagnostic. Localization studies should be performed after a conclusive biochemical diagnosis has been made. However, in patients with a hereditary predisposition for pheochromocytoma, even with lower or normal levels of catecholamines further diagnostic imaging may be needed because of a higher chance of developing paraganglioma or malignant disease.84

MRI has an excellent sensitivity (90% to 100%) for the detection of pheochromocytoma. However, additional imaging with a higher specificity like 123I-MIBG is needed to confirm the diagnosis and evaluate extra-adrenal metastatic involvement.85 18F-FDG PET/CT is also another modality which is useful to detect the lesion and its metastases. Pheochromocytomas are generally slow-growing tumors. Surgery is the mainstay of therapy with excellent response if the tumor is resected before becoming metastatic. However, in cases of metastatic disease, the treatment options are very limited and the disease can be eventually fatal.63,86

CENTRAL NERVOUS SYSTEM TUMORS

CNS neoplasms account for approximately 16% to 20% of all malignancies during childhood and adolescence. CNS cancer is the most common solid tumor in children and the second most common pediatric malignancy. Brain tumors are the leading cause of cancer deaths in pediatric oncology patients. Primary brain tumors in children are generally classified based on the cell type and location of origin in the brain. Brain cells arise in early development from primitive neuroectodermal tissue. Although there are some other cells in the brain, neurons and glial cells are two main cell types in the brain. Thus the majority of brain tumors are from neuroepithelial cells. Table 25.5 shows the WHO classification based on the histopathologic origin. In general, astrocytomas represent for approximately 52% of CNS malignancies, PNET accounts for 21%, other gliomas 15%, and ependymomas for 9%.87 In the posterior fossa (infratentorial), medulloblastoma, cerebellar astrocytoma, ependymoma, and brain stem gliomas (BSGs) are most common. Hypothalamic gliomas, craniopharyngiomas, and germ cell tumors are more common in the third ventricle. Astrocytomas (many of them low grade) are the most common neoplasms in the supratentorial region.

TABLE 25.5

WORLD HEALTH ORGANIZATION HISTOPATHOLOGIC CLASSIFICATION OF CENTRAL NERVOUS SYSTEM TUMORS

Unlike adults and older children, the frequency of cerebellar and the brainstem malignancy is relatively higher in young children. The frequency of brain tumors has slightly increased during the last two decades probably because of the improvement in diagnosis or changes in the environmental factors. In general the prognosis of brain cancer is not good. The prognosis is even worse in infants with ependymoma or PNET.

MRI and CT are the principal imaging modalities used in staging and surveillance of children with brain tumors. Their main limitation is the inability to differentiate between viable residual tumor or recurrence and postsurgical or postradiation changes. Functional imaging with 201Tl or 99mTc-MIBI has unique ability to determine viable residual tumor or recurrence. The sensitivity and specificity of 201Tl for the detection of childhood recurrence brain tumor are approximately 80% and 90%, respectively.88,89 However, evaluation of small residual tissues or tumors with a central necrosis and a rim of viable tissue may be difficult. The ratio of 201Tl uptake in the region of tumor versus contralateral brain tissue may be also helpful to determine a viable tumor versus postradiation changes. 99mTc-MIBI has the advantages of better image quality and no significant brain uptake. The sensitivity of 99mTc-MIBI has been reported to be similar to 201Tl, but the specificity is slightly higher. Brain tissue does not show any 99mTc-MIBI activity, however, mild physiologic activity may be seen in the choroids plexus. Both 201Tl and 99mTc-MIBI are lipophilic radiotracers and their uptake does not rely on alteration of blood brain barrier. Other radiotracers like 99mTc-labeled glucoheptonate (GHA), and 99mTc HMPAO/201Tl have also been used for the assessment of brain tumor recurrence.

Many studies have been reported the use of 18F-FDG PET in brain tumors for diagnosis, preoperative assessment, and to determine postoperative/radiation changes versus viable/recurrence tumor (Fig. 25.6).90 Increased activity in the tumor relative to background uptake is considered positive for tumoral involvement. However, because of the relatively high uptake in the brain tissue, detection of tumors with less metabolic activity is difficult especially with small tumoral foci. High-grade tumors usually show higher FDG uptake.91,92 However, the higher activity in 18F-FDG is not always correlate well with magnetic resonance spectroscopic imaging (MRSI). In a study by Hipp et al.93in 37 pediatric patients with brain tumor, the agreement between the intensity of activity in 18F-FDG PET and tumor metabolism based on the maximum choline: N-acetyl-asparate (Cho:NAA) on MRSI was low. Active tumor metabolism was observed more frequently using MRSI compared to 18F-FDG PET. The results indicated that 18F-FDG PET and MRSI detected similar but not identical regions of tumor activity.

FIGURE 25.6. 18F-FDG PET scan in a patient with PNET reveals multiple hypermetabolic lesions in the brain, spinal cord, and liver, as well as a bone lesion in the anterior superior iliac crest.

Increased activity in a low-grade tumor with low FDG uptake may indicate progression to a higher-grade tumor.72 The higher FDG uptake in the tumors may indicate a worse prognosis with a lower survival rate.74 Zukotynski et al.94 evaluated the associations between 18F-FDG uptake and progression-free survival (PFS), overall survival (OS), and MRI indices (tumor volume on fluid-attenuated inversion recovery, baseline intratumoral enhancement, diffusion and perfusion values) in 40 children with a newly diagnosed diffuse intrinsic BSG. Increased FDG uptake in at least half of the tumor associated with poorer survival than those with uptake in less than 50% of the tumor. Intense tracer uptake in the tumors, compared to gray matter, was also associated with decreased survival. Higher 18F-FDG uptake was seen in tumors with enhancement on MR images. Further studies are needed to confirm these findings. 18F-FDG PET may be also helpful to differentiate between post operation/radiation changes and viable tumor.95 However, increased FDG activity may be also seen after intensive radiation66 or shortly after radiation therapy.67

(11C) L-methionine [11C-MET] has also been used for pediatric brain tumors. The uptake of 11C-MET is minimal in the normal brain tissue thus allows a better tumor to background activity.96 11C-MET was useful for initial tumor assessment,97 for differentiation of recurrence/viable residual tumor versus scar,98 to predict prognosis99 and in combination with MRI for surgical plan in neurosurgery.97

LYMPHOMA

Lymphoma accounts for approximately 15% of pediatric cancers. It is the third most common type of cancer in children after leukemia and brain tumors with the peak age at 15 to 19 years. The percentage of lymphoma to the childhood malignancy is only 3% for children younger than 5 years of age to 24% for 15 to 19 years. Lymphoma can be simply categorized into Hodgkin disease and the non-Hodgkin lymphomas (NHL). For younger children NHL is more common than Hodgkin disease, whereas the reverse is true for adolescents. The 5-year survival rate is approximately 91% for Hodgkin disease for the patients younger than 20 years, compared to 72% for NHL. The 5-year survival rate for patients less than 20 years of age with NHL increased from 56% in 1975 to 1984 to 72% in 1985 to 1994.100

HL is less common than NHL and accounts for 6% of childhood malignancy. There are two peak ages for HL; 15 to 30 year old and >55 year old. The etiology of HL is not well understood. A genetic predisposition and prior viral infection have been proposed as the possible causes. According to the Revised European American Lymphoma Update of the WHO classification, HL is divided into two main categories: (1) Classical HL and (2) nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Classical HL is further divided into four histologic subtypes: (1) Nodular sclerosis (most common; approximately 70% of cases, with good prognosis), (2) mixed cellularity (intermediate prognosis), (3) lymphocyte rich (good prognosis), (4) lymphocyte depleted (worst prognosis; rare in children; more common in HIV patient and positive EBV). NLPHL has an excellent prognosis.

The incidence of NHL varies much less by age than Hodgkin disease. NHL incidence increases up until age 4 where it reaches a plateau and maintains until the second decade of life when rates increase again. Congenital immunodeficiency disorders (CIDs) and HIV are associated with an increased risk of NHL. The NHLs of children are a heterogeneous group of tumors which can be classified histopathologically into many subgroups. The major subgroups are: (1) Burkitt and Burkitt-like lymphomas (more common in 5 to 14 years old; often occur in the abdomen), (2) lymphoblastic lymphoma precursor T (usually mediastinal), (3) anaplastic large cell lymphoma, and (4) diffuse large B-cell lymphoma (DLBCL; most common subtype among 15 to 19 year old).

TABLE 25.6

HODGKIN DISEASE STAGING

In general, the patients with lymphoma present with only minor symptoms. Peripheral lymphadenopathy is the most common presentation. Sometimes mediastinal adenopathy can cause a cough or shortness of breath. B symptoms (fever, anorexia, weight loss, and night sweats), tiredness, pruritus, neurologic symptoms, anemia, and bone pain are other symptoms. The diagnosis will confirm with histopathology. Initial examinations usually include laboratory examination, chest x-ray, chest, abdominal, and pelvic CT scans, and 18FDG PET study. Bone marrow aspiration may be done when there are B symptoms, in stage III or IV and when there is evidence of bone marrow involvement like thrombocytopenia, anemia, and leukopenia.

67Ga citrate scan has been used as the most useful functional imaging modality for the evaluation of lymphoma (for staging and response to therapy) for decades. The sensitivity of 67Ga scintigraphy in detection of lymphoma depends on the grading and type of lymphoma (Tables 25.6 and 25.7). 67Ga scan is more positive in high-grade, B-cell or Burkitt lymphoma.101 The sensitivity and specificity of 67Ga scan to detect lymphoma and its metastases is approximately 80% to 90%, respectively.102 A baseline 67Ga scan is essential to evaluate the uptake of the tumor and to have a baseline for assessing response to therapy (Fig. 25.7). There are some reports on the use of gallium study for the evaluation of early response to therapy and restaging of lymphoma.103 Gallium study is especially useful for the evaluation of residual viable tumor after therapy versus nonviable scar tissue. MRI and CT scan have a limited role to differentiate viable residual/recurrence versus posttherapeutic fibrosis. 67Ga scan has also prognostic value after therapy; a positive scan may indicate a worse prognosis whereas a negative study (after treatment of a positive tumor) is suggestive of a good prognosis. Thyums rebound, reactive bilateral hilar uptake and activity in the parotid or salivary gland may be interpreted as a positive gallium scan.104,105 SPECT study and correlation with anatomical modality is helpful to diagnose these potential false-positive findings. Although 67Ga scan was used for a long time in lymphoma, 18F-FDG PET scan is now the preferred modality. With 18F-FDG PET study, the time of imaging is shorter, the radiation dose is less, and the image quality is much better.

TABLE 25.7

NON-HODGKIN LYMPHOMA STAGING

FIGURE 25.7. 67Ga scan in a 12-year-old boy with Hodgkin disease revealed Ga-avid tumor in the neck and mediastinum (A). After two cycles of chemotherapy (B), the lesions were not metabolically active indicative of a good response to therapy.

201Tl scintigraphy has also been used in combination with the 67Ga scan. 67Ga scan may be positive in inflammatory/infectious process and thymic rebound. A negative 201Tl scan is helpful in these cases. However, it should be kept in mind that some lymphomas are not 201Tl avid. A negative or low-level uptake in 201Tl scan in a previously positive 201Tl study is a reliable finding to differentiate tumor versus other inflammatory/infectious process. 201Tl shows more uptakes in low-grade lymphoma than 67Ga study, whereas 67Ga has a more uptake in high-grade lymphoma.106 Thus, 201Tl may have a role in 67Ga-negative tumors.

Bone involvement is relatively rare in primary lymphoma. However, it may be seen in up to 30% of disseminated HL. Whole-body bone scan with 99mTc-MDP can be useful for the detection of bone metastasis. Bone scan may show focal or diffuse uptake or areas of decreased activity. The sensitivity of bone scan for the detection of bone metastasis is more than radiography for HL. The usefulness of bone scan for NHL is controversial.107 67Ga, 18F-FDG PET, CT scan, and MRI are usually better for the detection of bone involvement in lymphoma (Fig. 25.8). 67Ga is better than bone scan for the evaluation of response to therapy.108

FIGURE 25.8. A 15-year-old girl with primary bone lymphoma. (A) Bone scan and (B)67Ga scan showed increased activity in the proximal right tibia and left ischium. Abnormal increased activity in the proximal right tibia has markedly decreased on the follow-up 67Ga scan (C) after treatment with normalization of the lesion in the left ischium.

18F-FDG PET has replaced 67Ga for the evaluation of lymphoma in recent years. It is especially useful in children because of the less radiation than 67Ga. Moreover, better image quality and the shorter time needed to complete the study are other advantages of 18F-FDG PET. The uptake of 18F-FDG also depends on the grading and type of lymphoma. 18F-FDG PET can be used at diagnosis for staging of lymphoma. According to the Revised Response Criteria for Malignant Lymphoma (RRCML), 18F-FDG PET is recommended (although is not mandatory yet) at diagnosis, for routine evaluation of FDG-avid lymphomas which are curable.109 18F-FDG PET shows increased uptake in most common types of lymphomas (e.g., diffuse large B-cell NHL, follicular NHL, mantle cell NHL, HL) with a sensitivity of more than 80% and a specificity of about 90% which is superior to CT scan.110,111 In many studies the use of 18F-FDG PET at diagnosis has led to change in disease stage and change of management approximately in 10% to 20% of cases.112114 The other purpose of initial study is to have a baseline for the evaluation of response to therapy (Fig. 25.9). However, 18F-FDG PET/CT at initial evaluation may be of interest not only for disease staging or posttherapy evaluation but also to guide the therapeutic strategy and sometimes to guide biopsy.115,116 18F-FDG PET at diagnosis may also have a prognostic value. In a study by Okada et al.117 in adult population, patients with recurrence had a higher FDG uptake pretherapy at diagnosis.

FIGURE 25.9. 18F-FDG PET/CT in a 7-year-old patient revealed multiple hypermetabolic lesions in the neck, mediastinum, and hilar regions (A) before treatment and resolution of the lesions after two cycles of chemotherapy (B)indicative of a good response to therapy.

18F-FDG PET has a validated role in response assessment following therapy in lymphoma. CT scan is a reliable method for staging and restaging of lymphoma. However, it has a low specificity to assess the response to therapy especially in patients with bulky disease before treatment in whom there is usually a residual mass after treatment.110 The residual tissue may be viable or it may be necrotic. 18F-FDG PET has a high sensitivity to detect viable residual tissue posttherapy. High negative predictive value of 18F-FDG PET after treatment makes it a reliable method to rule out any viable residual tumor or recurrence.118 However, there are some reports that 18F-FDG PET did not detect the microscopic viable tumors.117 The sensitivity of PET for the detection of residual tissue is approximately 90% to 100%. However, the specificity is only 57% to 75%. False-positive results were reported in 16% to 18% of the cases.119 The reasons for false-positive results were fibrosis, abdominal wall hernia, inflammatory process like appendicitis, thymus, and HIV-associated lymphadenopathy.

18F-FDG PET has been used during the therapy for the early assessment of the treatment and prediction of the future response. Based on RRCML, a routine 18F-FDG PET during therapy is not recommended. However, a routine restaging after completing the chemotherapy and/or radiotherapy is recommended especially for Hl and DLBCL. Because posttherapeutic inflammatory process may also show increased uptake on 18F-FDG PET, the study should be done at least 3 weeks after chemotherapy. In the cases of radiotherapy PET study should be performed at least 2 to 3 months later. 11C-MET PET has also been used in NHL with superior tumor to background contrast. 18F-FDG PET was superior to 11C-MET PET in differentiation between low-grade and high-grade tumors. Further studies with a higher number of patients are needed to confirm these findings.120 In summary, 18F-FDG PET is recommended for staging of lymphoma at diagnosis and evaluation of treatment response after completion of therapy. PET will probably play more role in future for the evaluation of therapy response during the treatment (between cycles 1 and 4), for monitoring the patients, radiation field planning, planning for biopsy, and evaluation of complications.

Other radiotracers have also been used in lymphoma. Somatostatin receptors have been found in HL. 111In-DTPA-D-Phe-Octreotide had a sensitivity of 94% in a study by Lugtenburg et al.121 Eighteen percent of stage I and II HL were upstaged after the Octreoscan results. Probably because of the introduction of 18F-FDG in recent years, somatostatin receptor scintigraphy has not found general acceptance. 99mTc LL2 monoclonal antibody to the CD22 receptor on B lymphocytes has also been introduced with similar result compared with 67Ga study.122 However, it is not generally accepted too. Lymphoma tumors can show 99mTc-sestaMIBI uptake. In a study by Kapucu et al.123 the uptake of 99mTc-MIBI was associated with the future response to therapy. However, the exact sensitivity and specificity of 99mTc-MIBI in lymphoma are not well established.

BONE TUMORS

Malignant bone tumors accounted for approximately 6% of childhood cancers reported by Surveillance, Epidemiology, and End Results (SEER) program of National Cancer Institute (NCI) areas from 1975 to 1995. OS and Ewing sarcoma are the most common types of malignant primary bone tumors in children. The incidence of OS is almost double that of the Ewing sarcoma. The incidence of bone cancers increases gradually between age 5 and age 10 and then a steeper rise is seen after age 11 until age 18 (peak age). Survival rates for OS were higher than those for Ewing sarcoma especially in the earlier time period. The 5-year relative survival for children with bone cancer improved from 49% in the period 1975 to 1984 to 63% in the period 1985 to 1994.

TABLE 25.8

SURGICAL STAGING FOR OSTEOSARCOMA

Osteosarcoma

OS is the most common primary bone tumor of childhood. OS originates from primitive bone-forming mesenchymal stem cells and most commonly involves the metaphyseal portion of the long bones. The peak age for OS in children is 11 to 18 years. The etiology is unknown. However, an association has been proposed with direct ionizing radiation, pre-existing benign disease (Paget disease) and genetic susceptibility (Li–Fraumeni, bilateral retinoblastoma, and Ruthmond–Thompson syndromes). The 5-year survival rate for children with OS is currently 70% to 80%. With the new advances in chemotherapy combined with surgery the survival rate has markedly improved. Advances in surgical techniques have led to better functional outcomes with limb salvage surgery. The tumor is not radiosensitive, thus radiotherapy is reserved for inoperable tumors. Staging usually depends on grading of the tumor (>15% risk of metastatic disease with a high-grade OS) and whether the tumor is contained within an anatomical compartment (Table 25.8). Most OSs are high grade and intracompartmental. If there are distant metastasis, compartment status is less important.

The most common presentation is pain and swelling around a joint. The first investigation is usually a plain x-ray followed by further evaluation with CT scan, MRI, chest x-ray, chest CT scan, bone scan, and probably FDG PET scan. The most common involved area is the metaphyseal portion of long bones. Nearly half of the cases occur around knees. Plain radiography usually shows a moth-eaten appearance of bone destruction with endosteal and periosteal sclerosis (resulting from malignant new bone formation). There is also extensive periosteal reaction with an adjacent soft tissue swelling. CT scan is useful for the evaluation of intramedullary extension, and to detect skip metastases in the bone. Chest CT scan is useful to detect pulmonary metastases. MRI is the best modality for the evaluation of marrow extension and adjacent soft tissue extension.

On the bone scan, the tumor is usually positive on flow and blood pool images (hyperemia) as well as an intense increased uptake on delayed views. Multifocal bone lesions or skip metastases may be detected by bone scan. However, the main indication for bone scan is to detect distant bone metastases (Fig. 25.10). Other findings that may be detected on bone scan include bone tracer uptake in pulmonary metastatic sites, the pattern of hypertrophic osteoarthropathy (with pulmonary metastasis), and postsurgical changes after amputation or surgical implants. Bone scan may be positive for a long time after radiation therapy. Other radiotracers like 201Tl or 18F-FDG may be more useful in this context.

201Tl usually accumulates in OS and can be used as a marker for the detection of viable tumor.124,125 Decrease 201Tl uptake after treatment is indicative of a good response to therapy. Rosen et al. described how serial 201Tl studies could be helpful to monitor the tumor response. In their study, 201Tl scan could differentiate responders versus nonresponders to chemotherapy and guided the oncologist for earlier amputation or limb salvage therapy.123 Although there are not many large studies with 99mTc-sestaMIBI, the result seems to be similar to 201Tl scintigraphy.126

FIGURE 25.10. Bone scan in a 12-year-old girl with osteosarcoma of the distal right femur (A) without distant bone metastases. (B) Follow-up bone scan after surgery.

The early result with 18F-FDG PET was promising. In a prospective multicenter study by Volker et al.127 on 46 pediatric patients (Ewing sarcoma family tumors = 23; OS = 11; RMS = 12) to evaluate the usefulness of 18F-FDG PET for initial staging and therapy planning, PET was as accurate as the combination of all conventional imaging modalities (CIMs) (including ultrasound, CT scan, MRI, and bone scintigraphy). 18F-FDG PET was superior to CIMs for the assessment of lymph node involvement (sensitivity, 95% versus 25%) and bone manifestations (sensitivity, 90% versus 57%), whereas CT was more accurate than 18F-FDG PET for lung metastases (sensitivity, 100% versus 25%). A combination of 18F-FDG PET with diagnostic CT from the chest may be the best option for the evaluation of these patients. 18F-FDG PET may be also useful to assess or predict the response to therapy.128 However, the usefulness of 18F-FDG PET for the evaluation of treatment response was not confirmed in a study by Huang et al.129 on 10 patients with OS. In their study, the average tumor necrosis rate determined by 18F-FDG PET was 22%, whereas it was 54.5% on histopathology. The use of 18F-FDG PET is still not recommended routinely for the evaluation of treatment response.

Ewing Sarcoma

The term Ewing sarcoma (EWS) describes a spectrum of small round cell tumors including Ewing sarcoma of bone, extraosseous Ewing sarcoma, and peripheral primitive neuroectodermal tumors (PNETs). EWS of bone is the second most common primary bone tumor in children (3% of all childhood malignancies). The EWS most likely originates from neural crest tissue and can involve both the extremities and the central axial skeleton. The etiology is unknown. In black children, the incidence is much less than in caucasian children. The overall 5-year survival is approximately 70%. The survival is better in younger children than in older children or adults. The prognosis depends on the size and surgical resectability of the tumor, the presence of metastases, and the response to chemotherapy. Almost 25% of patients have detectable metastases at diagnosis. Treatment involves intensive chemotherapy and surgical resection of tumor with or without radiation to the tumor site.

Patients may have variable symptoms depending on the site of origin of the disease. Generally, they present with local pain and swelling similar to osteomyelitis or OS. A plain film is usually the first diagnostic procedure. The plain film shows ill-defined, permeative bone destruction or lytic lesion of flat bone or diaphysis or metadiaphysis of tubular bone with periosteal reaction (“onion-skin” type pattern). Periosteal reaction may have a spiculated pattern. The CT scan shows the extent of cortical disruption and aids in surgical biopsy planning. The CT scan is not sensitive for the evaluation of intramedullary tumor extension. MRI is the most useful technique for the evaluation of intramedullary and soft tissue extent of disease including the relationship to surrounding normal structures such as the neurovascular bundle. MRI may also show skip metastases (bone metastases involving bone marrow in the same bone). Pulmonary metastasis can be assessed with a chest CT scan.

A radionuclide bone scan usually shows intense increased activity, although the lesion may also show no activity or only little uptake (probably more aggressive tumors) especially in the pelvic region (Fig. 25.11). Compared to OS, the uptake is more homogeneous and the location is more diaphyseal or metadiaphyseal (rather than nonhomogeneous uptake in the metaphyseal region which is commonly seen in OS). Bone scintigraphy is indicated at diagnosis because asymptomatic metastases may be detected by the radionuclide bone scan. Follow-up studies (including serial bone scans) are also needed during the first 2 years because of the high risk of bone metastases which were not detected initially. Detection of bone metastases on follow-up bone scan have been reported in 33% to 45% of patients who were free of metastasis at presentation.130,131 Decreased uptake at the site of tumor after treatment is indicative of a good response to therapy; however, increased or persistent activity may be suggestive of recurrence or superimposed complications (fractures, infection, etc). In a study by Erlemann et al.,132 the accuracy of bone scan for the assessment of therapeutic success was less than MRI (50% to 85%). Thus, further evaluation (with MRI or other methods) is indicated for equivocal bone scan findings.

67Ga uptake has been reported in EWS. 67Ga may also show soft tissue involvement (adjacent to the tumor or distant metastasis). 67Ga scintigraphy may be useful for evaluation of the response to therapy and appearance of recurrences.133 However, it is generally not used routinely in clinical practice. EWS may also show 201Tl uptake. However, the degree of 201Tl uptake in EWS is less than OS. Because the findings on 67Ga scintigraphy as well as bone scan are not specific, 201Tl scan may be more accurate to assess the response to therapy and for follow-up. The accuracy of 201Tl scan to differentiate recurrence versus posttherapeutic changes in EWS was approximately 96% in a study by Kostakoglu et al.134 18F-FDG PET/CT may be useful for the evaluation of local extension and distant metastases at diagnosis and restaging after therapy (Fig. 25.12).127 18F-FDG PET/CT may be also helpful for differentiation of recurrence versus posttherapy changes.135 Further investigations are needed to assess the exact accuracy of 18F-FDG PET in these scenarios.

RHABDOMYOSARCOMA

RMS accounts for approximately 4% to 8% of all malignant diseases in children less than 15 years old. The peak age of occurrence is 2 to 5 years; a second peak occurs at 15 to 19 years. RMS is the third most common extracranial solid tumor in childhood, after neuroblastoma and Wilms tumor. The overall survival rate is approximately 70%, which has increased from about 20% in the 1960s. The etiology is not well understood. The majority of cases are sporadic, however, a higher incidence has been reported in some congenital/genetic abnormalities (neurofibromatosis type 1, Beckwith–Wiedemann syndrome, Gorlin syndrome, hereditary retinoblastoma syndrome, Costello syndrome, Rubinstein–Taybi syndrome). Maternal or paternal use of marijuana and cocaine has also reported to increase the risk of RMS in their child. RMS can occur anywhere but it is more common in the head and neck (35% of cases; especially in the orbit and paranasal sinuses), genitourinary tract (about 20%), and extremities (about 20%). The presentation depends on the location of the tumor and is usually a mass or bulging with no history of trauma. Generally, a multimodality approach is needed for the treatment of RMS including surgery, radiation, and chemotherapy. The prognosis depends on many factors including the location, histology, and staging (Table 25.9). Unfavorable sites include parameningeal site, bladder/prostate, trunk, retroperitoneum, and extremities. Adverse prognostic factors include unfavorable sites, alveolar type, undifferentiated histology, distant metastases including bone or regional lymph node involvement, tumor size >5 cm, and older age.

For the evaluation of bone metastasis, a radionuclide bone scan is indicated. The sensitivity of the bone scan to detect bone metastasis in RMS is more than 95%.136 A soft tissue tumor may be seen on the bone scan, especially in early flow and blood pool images. 67Ga scintigraphy is also useful for the evaluation of RMS. In a study by Cogswell et al., 67Ga uptake was observed in 86% of the primary tumor. Although the sensitivity of bone scan was higher than 67Ga scintigraphy, the 67Ga study had a higher sensitivity for the detection of soft tissue metastases. If a tumor is 67Ga-avid, follow-up 67Ga scan is useful for the evaluation of recurrence in patients in whom recurrence is suspected. The incidence of late recurrence is low in RMS; thus a routine bone scan or 67Ga study is not indicated. MRI may be better for the follow-up evaluation. 201Tl scintigraphy has been also used for follow-up studies. However, lower sensitivity has been reported for 201Tl compared with 67Ga scan. Both 201Tl and 67Ga scan are usually negative in pulmonary metastases. The CT scan is a better modality to detect pulmonary metastases. Sentinel lymph node study is also useful for the evaluation of regional lymph node involvement especially for RMS of the extremities or paratesticular region.137139

FIGURE 25.11. Bone scan in anterior (A) and posterior (B) projection in a 13-year-old boy with pelvic Ewing sarcoma. Corresponding MRI axial images (C) revealed a big mass with invasion to the sacrum.

Rhabdomyosarcoma and other soft tissue sarcomas have been shown to be 18F-FDG avid.140 There is a wide range of SUVmax in RMS (Fig. 25.13). The 18F-FDG uptake is higher in high-grade RMS tumors. The majority of high-grade RMS tumors have an SUVmax of more than 1.6.141 Tateishi et al.142 showed the usefulness of 18F-FDG PET for staging and restaging of RMS by reporting a comparative study on 35 children using 18F-FDG and conventional imaging modalities (CT scan, MRI, and radionuclide bone scan). Using 18F-FDG PET/CT, the M stage was correctly assessed in 89%, whereas the accuracy of CIM to assess the M stage was 63%. TNM stage was correctly evaluated with 18F-FDG PET/CT in 86% and with CIM in 54% of the patients. Similar results were reported by other investigators.127,143,144 18F-FDG PET findings altered the therapy of patients mostly by detecting nodal disease and bone involvement.

The 18F-FDG PET scan is also useful to detect recurrent disease and to assess response to therapy. Arush et al.135 reported that 18F-FDG PET detected local relapse and distant metastases of sarcoma more accurately than CT/MRI/bone scan. However, the sensitivity of 18F-FDG PET is relatively low for pulmonary metastases.127 Evaluation with a diagnostic CT scan is recommended when pulmonary metastasis is suspected.

FIGURE 25.12. Bone scan (A) in a 14-year-old girl with Ewing sarcoma of the proximal right tibia with multiple bone metastases. 18F-FDG PET images (B) obtained 3 days later revealed numerous areas with abnormal FDG uptake in bones. Follow-up 18F-FDG PET/CT 6 months later (C) showed progressed disease with multiple bone and lung metastases.

TABLE 25.9

TNM STAGING OF RHABDOMYOSARCOMA

LEUKEMIA

Leukemias are the most common form of pediatric cancer accounting for more than one-quarter of childhood cancers. Acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are the most common forms, approximately 75% and 15% to 20%, respectively. The peak age is 2 to 4 years for ALL and neonate and teen ages for AML. The incidence of leukemia is substantially higher for white children than for black children. Survival of those diagnosed with ALL (80% to 90%) is higher than for those diagnosed with AML. ALL was a fatal disease in 1970s but survival for children with ALL has markedly improved during the last three decades because of improvements in treatment. Survival for children with ALL is very dependent upon age at diagnosis, and the most favorable outcome is seen for patients between 1 to 10 years old. The most important risk factors for ALL are prenatal exposure to radiation (x-rays) and specific genetic syndromes (e.g., Down syndrome). For AML, however, many risk factors have been proposed including Genetic syndromes (Down syndrome, neurofibromatosis type 1, etc.), immunodeficiency syndromes, ionizing radiation, chemotherapy agents (nitrogen mustard, cyclophosphamide, ifosfamide, chlorambucil, melphalan, etoposide), and benzene.

Skeletal involvement is common in leukemia; however, a routine bone scan is not indicated as it usually does not change the management. A bone scan may be indicated when there is skeletal pain especially with equivocal radiographic findings. The lesions could be seen on bone scan as focal or diffuse increased uptake. However, photopenic lesions may also be seen because of aggressive tumoral growth, bone necrosis or after methotrexate therapy, or radiation.145

FIGURE 25.13. 18F-FDG PET/CT in a 20-month-old baby with rhabdomyosarcoma of the left thigh showed moderate FDG uptake in the lesion. The study was negative for regional lymph node involvement or distant metastases.

TABLE 25.10

STAGING SYSTEM USED FOR WILMS TUMOR

WILMS TUMOR

Wilms tumor (nephroblastoma) is the fourth most common form of childhood cancer and the most common primary renal tumor in children (6% of all childhood cancer). Wilms tumor is by far the most common form of renal cancer in children (approximately 95% of renal cancers). Other types of renal cancers are much less common (renal carcinomas, the most common form of renal cancer in adults, accounts for only 2.6% of renal cancers in children). The peak age for Wilms tumor is 3 to 4 years. The etiology is unknown. However, in 5% of cases, Wilms tumor is associated with a number of genetic disorders (Beckwith–Wiedemann, Denys–Drash, and Perlman syndromes). In the majority of cases, Wilms tumor arises from a focal area in the kidney, but it may be multifocal within the same kidney (10%). In 5% of cases, it involves both kidneys. Invasion to the regional lymph nodes is not uncommon. The lung and the liver are the most common sites of metastases (Table 25.10). The overall 5-year survival for children with Wilms tumor is approximately 90%.

Ninety percent of patients present with an asymptomatic abdominal mass. In others, symptoms include abdominal pain, hypertension, fever, hematuria, anemia, and weight loss. Ultrasound usually shows a fairly homogeneous area with overall echogenicity similar to liver, sometimes with increased or decreased echogenic foci caused by hemorrhage or necrosis. Ultrasound is useful to identify extension of tumor to adjacent vessels and to evaluate bilateral disease and liver metastases. CT scan shows a heterogeneously enhancing mass, with foci of low attenuation caused by hemorrhage or tumor necrosis. Presence of high attenuation foci caused by calcification is very rare. CT scan is especially useful for the assessment of local extension into the adjacent tissues, evaluation of enlarged regional lymph nodes, intravascular extension, contralateral kidney for bilateral disease, and finally lung and liver for metastases. Because of the renal excretion of 18F-FDG, the usefulness of 18F-FDG PET/CT in diagnosis and evaluation of local extension of tumor is limited. It may have a role, however, for the evaluation of recurrence versus scars and assessment of distant metastases.

HEPATOBLASTOMA

Primary liver malignancies are rare in children, accounting for approximately 1% of neoplasms. Two histologic subtypes of primary liver cancers are most common: Hepatoblastoma (more than two-thirds of the cases) and hepatocellular carcinoma (most of the remaining cases). Hepatoblastoma occurs primarily in children younger than 5 years of age whereas hepatocellular carcinoma is more common after the age of 10 years. Treatment is a combination of radical surgery, chemotherapy, and sometimes radiotherapy. The 5-year survival rate for children with hepatoblastoma is approximately 60%. Survival rates are lower for children with hepatocellular carcinoma. The etiology of hepatoblastoma is not well understood.

In general, conventional imaging techniques (US, CT, and MRI) are the initial modalities for diagnosis and staging of hepatoblastoma. Liver and spleen scan with sulfur colloid or hepatobiliary scan with BrIDA may be useful to differentiate follicular nodular hyperplasia versus other tumors. 99mTc-labeled RBC scinitigraphy is useful to rule out liver hemangioma. 18F-FDG PET has a limited role in the initial diagnosis and staging of hepatic tumors. However, it may have a role for restaging and detection of recurrence. Tumor markers, including α-fetoprotein (AFP) and conventional imaging modalities are generally used for follow-up and detection of recurrence. In a study by Wong et al.,146 the 18F-FDG PET scan along with AFP measurement were useful to detect recurrence. In a study by Mody et al.147 on seven children with hepatic cancers for staging (one patient) or restaging (six patients), 18F-FDG PET was probably most useful to assess response to therapy, in following AFP-negative cases and to detect metastatic disease. However, large prospective studies are needed to confirm the result. 18F-FDG PET may also provide prognostic information. High 18F-FDG uptake in a tumor is suggestive of a less-differentiated tumor and, thus has poor prognosis.

THYROID CANCER

Thyroid cancer, the most common type of endocrine cancer, affected almost 60,000 people in the United States in 2013.148 Of these cases, only 5% occur in children and adolescents, representing about 1% to 1.5% of all pediatric malignancies.149 Thyroid cancer is very rare in early childhood; the incidence is higher in the 15- to 19-year-old group. The majority of thyroid cancers are of differentiated type, mainly papillary (85%) and to a lesser extent follicular cancer (10%).150 The anaplastic (undifferentiated) thyroid cancer and medullary cell carcinoma have poorer prognoses than other types. There is no documented single cause for thyroid cancer. However, there are many risk factors that are considered to increase the risk of thyroid cancer including ionizing radiation (from both environmental and therapeutic sources), family history of thyroid cancer, female gender, and sex hormones. The incidence is higher in females; however, the prognosis is slightly worse in males.

Long-term prognosis of differentiated thyroid carcinoma (DTC) is usually favorable, with overall survival rates of 80% to 95% at 10 years for middle-aged adults and about 95% for children. Local recurrence and distant metastases are not infrequent, particularly during the early years of follow-up, but may occur years later as well. Survival rates decrease to 40% with distant metastases.151,152 Unlike adults, children with thyroid cancer may present with more advanced disease and have a higher rate of local recurrence and distant metastases.153 The frequency of regional lymph nodes’ involvement at presentation is higher in children than adults. The risk of pulmonary metastases is also higher in children. In our experience, 18% of our patients with DTC had pulmonary metastases either at presentation or during follow-up. In children, because the response to treatment is better, the long-term surveillance of DTC recurrences and metastases is crucial throughout the patient’s life.154

The DTC patients can be categorized into low-, intermediate-, and high-risk groups based on the revised American Thyroid Association (ATA) management guidelines.155 Briefly, low-risk patients include those with: (i) no local or distant metastases, (ii) all macroscopic tumors resected, (iii) without aggressive histology or vascular invasion, and (iv) no evidence of any abnormal radioiodine uptake outside the thyroid bed on the first posttherapeutic whole-body scan (RxWBS). Patients are put into the intermediate-risk group when there is evidence of (i) microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery; (ii) cervical lymph node metastases or 131I uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation; or (iii) tumor with aggressive histology or vascular invasion. Finally, patients are categorized as high risk when they have (i) macroscopic tumor invasion, (ii) incomplete tumor resection, (iv) distant metastases, and possibly (v) elevated serum thyroglobulin (Tg) levels out of proportion to what is seen on the posttreatment scan.

Imaging

The incidence of thyroid cancer in single nodules is relatively high in children. Evaluation with thyroid ultrasound is indicated in every patient with a thyroid nodule.155 The use of thyroid scintigraphy for the evaluation of thyroid nodule is controversial. Thyroid scintigraphy with 99mTc or 123I can be helpful to determine the functional status of the nodule. As in the adult population, the risk of thyroid cancer is higher in cold nodules. However, unlike adults, the risk of thyroid cancer is not very low in hot nodules is children. Thus, fine needle aspiration is indicated for every child with a solitary thyroid nodule, regardless of the radionuclide imaging findings.

Conventionally, measurement of serum Tg level and diagnostic whole-body iodine scanning (DxWBS) are used to detect thyroid tissue remnant and recurrence in the follow-up of patients with DTC.156 RxWBS are usually obtained usually 7 to 10 days after the therapeutic dose of 131I, taking the advantage of high radioiodine activity that improves the sensitivity of scintigraphy.157,158 The sensitivity of diagnostic whole-body iodine for the detection of recurrence or distant metastases is approximately 70% and the specificity is more than 95%. Measurement of serum Tg level alone, although is very useful, may be misleading. Park et al.159 reported a 6.3% of false-negative Tg measurements using RxWBS as a reference standard. In 15% to 25% of cases, anti-Tg antibody may be high in DTC patients which may result in inaccurate Tg levels, falsely increased or decreased values. Some authors suggest following up low-risk DTC patients with ultrasound and Tg measurement. The sensitivity of ultrasound to detect regional lymph node involvement is greater than 90% but it is not a very specific modality, especially in children with a higher frequency of enlarged lymph nodes caused by inflammation. On the contrary, the whole-body iodine scan is useful to detect distant metastases (lung and bone) as well as regional lymph node involvement and is an essential component of the treatment plan.

In case of a positive Tg level (Tg > 1.5 ng/mL) and negative whole-body scan, further evaluation with 201Tl, 99mTc-sestaMIBI, or 18F-FDG PET is recommended. Sometimes, the lesions are only visible on imaging after whole-body iodine therapy (when the administered dose of radioiodine was high and background activity is low after 7 to 10 days).

The incidence of medullary thyroid cancer is very rare in children (approximately 2% of thyroid cancers). Thus the information about the diagnosis and treatment of medullary thyroid cancer in children is very limited and is based on adult data. In general, laboratory examination (serum calcitonin level, CEA measurement, etc.), ultrasound, CT scan, 201Tl scan, 111In-octreotide scintigraphy, 123I-MIBG scan, 99mTc(pentavalent)-DMSA study, 18F-FDG PET/CT, and 18F-DOPA PET/CT have been used to detect and follow up lesions.160162

Treatment

The main treatment of DTC consists of total or near-total thyroidectomy, with resection of involved regional lymph nodes and dissection of the central compartment followed by ablation of thyroid remnants and possible metastases using radioactive iodine and TSH suppression medication. The administered dose of radioiodine varies in different institutes from 1,110 to 7,400 MBq. The maximum administered dose depends on the radiation absorbed dose for the bone marrow and lungs (in the case of pulmonary metastases). The effective absorbed dose to bone marrow should not exceed 200 cGy and the cumulative exposure of the lungs should be less than 80 mCi (3,000 MBq) retained activity at 24 hours. In our center, low-risk patients are usually treated with 370 MBq 131I adjusted for their weight. Higher dosage may be used if the patient is high risk or if there are pulmonary or bone metastases. The patient should stop interfering medications (4 weeks prior to treatment for levothyroxine and 2 weeks for liothyronine) and have a low iodine diet for a week before the treatment. History of recent diagnostic imaging with contrast materials or any other iodine-containing medications should also be obtained. If thyroid hormones have been withdrawn, the patient should be hypothyroid before the iodine administration (TSH > 30 to 40 IU/mL). As an alternative, recombinant TSH injections have been used with similar results.163

Surgery is the main treatment for medullary thyroid cancer. Postsurgical ablation therapy with 131I has no role. If the tumor is MIBG avid, 131I-MIBG therapy may be useful for the treatment of metastases. Radioimmunotherapy with anticarcinoembryonic antigen (CEA) antibodies have also been used in advanced disease with promising results.164

FUTURE CONSIDERATIONS

The usefulness of 18F-FDG PET in the diagnosis, evaluation of treatment response, and surveillance of childhood cancers has been discussed in many studies with encouraging findings. However, the information remains very limited in pediatric malignancies. Further multicenter studies with a larger number of patients are needed to define the exact role of PET/CT in pediatric nuclear oncology. In addition to the well-established clinical data about the utility of 18F-FDG PET/CT in lymphoma, soft tissue tumors, neuroblastoma, etc, initial studies in other rare cancers were promising.

In a recent study, Cheuk et al.165 evaluated the usefulness of 18F-FDG PET/CT for the evaluation of nasopharyngeal carcinoma (NPC) in pediatric patients. They compared 18F-FDG PET/CT and MRI for restaging of disease in 18 patients with NPC. They found out that 18F-FDG PET/CT may underestimate tumor extent and regional lymphadenopathy compared with MRI at the time of diagnosis, but it helps to detect metastases and to clarify equivocal findings. 18F-FDG PET/CT was sensitive and specific for follow-up and enabled earlier determination of disease remission. They concluded that 18F-FDG PET/CT is a useful modality to evaluate and monitor NPC in children.

The use of 18F-FDG for the diagnosis and assessment of treatment in PTLD has been confirmed in adults. PTLDs are a heterogeneous group of diseases that occur after transplantation ranging from EBV-driven polyclonal proliferation similar to infectious mononucleosis to monomorphic proliferations that may be indistinguishable from aggressive types of lymphomas. It is very common in pediatric oncology especially during the first year following transplantation and occurs most frequently in multiorgan transplant recipients, followed by bowel, heart–lung, and lung recipients.136 It may involve any of the organ systems. The current classification system includes four subtypes that have different prognoses requiring different treatment strategies. PTLD is usually associated with EBV virus infection; however, it may occur in EBV seronegative patients. Tissue sampling is necessary for diagnosis and further subcategorization. The initial studies with 18F-FDG PET/CT were promising and showed that 18F-FDG PET/CT is a very useful method for diagnosis, assessment of the extent of disease, guide for biopsy, and evaluation of treatment response.166 Larger studies are needed to fully assess the exact role of 18F-FDG PET in pediatric PTLD.

Congenital hyperinsulinism is a relatively rare disease, which is mostly seen in newborn and infants and if it is not treated may lead to severe hypoglycemia and permanent brain damage. Glucose infusion and surgery should be done before any complications. However, exact detection and localization of the hyperfunctioning foci in the pancreas is of pivotal importance to decrease the chance of relapse or diabetes after surgery. Selective percutaneous pancreatic vein catheterization and measurement of the insulin level may detect the foci of hyperfunctioning pancreas in half of the patients. 18F-DOPA PET has been reported to have a high sensitivity and specificity for the detection of foci of hyperinsulinemia.167,168 18F-DOTA TATE may be also useful in these cases.

18F-FDG PET/CT has been used in adult germ cell tumors for detection and management of disease.169 However, limited data are available in pediatric populations. It seems that PET/CT is useful in these cases based on extrapolating the adult’s findings. Further evaluation will clarify the role of PET/CT in malignant germ cell tumors in children.

Although Langerhans cell histiocytosis (LCH) is no longer considered a malignancy, oncologists usually manage the patients. LCH is a disease of immune system previously named as histiocytosis X and is characterized by overproliferation of the Langerhans cell. These cells may accumulate in every organ in the body and present with a spectrum of disease from a local bone lesion to widespread visceral involvement. Radiography shows a typical lytic bone lesion. After confirming the diagnosis by biopsy, further evaluation includes bone scan, abdominal and chest CT scan, and brain MRI to evaluate the extent of disease. Initial experience with 18F-FDG PET/CT showed that the information provided by PET/CT was clinically useful to evaluate disease activity and response to therapy. This information was not provided by bone scan and radiography.170 In another study, Phillips et al.171 showed that 18F-FDG PET is useful for locating active or reparative LCH disease as well as response to therapy. In their study, changing in the intensity of FDG uptake (in terms of SUVmax) was a good tool to detect the activity of disease earlier than radiography or bone scan. PET was superior to detect all lesions except in the vertebrae where MRI was superior.

With the introduction of modern imaging techniques like PET/MRI or diffusion MRI, the application and indication of PET/CT may change in future. New radiotracers [e.g., 68Ga-DOTA TATE, 18F-DOPA, 18F azomycin-arabinoside (18F-FAZA), 18F-flourothimidine (18F-FLT) (Fig. 25.14)] are more specific and will probably change the management of cancers in children. Tumor receptor imaging will be probably more sensitive and specific for the evaluation of cancers and may open a new horizon in diagnostic imaging. Tumor receptor imaging techniques (tumor antigens, tumor cell surface receptors, and specific surface receptors of the endothelial cells of the tumor vessels) have the potential to significantly increase the sensitivity and specificity of imaging techniques by improving tumor detection and characterization. These new applied molecular imaging techniques are expected to develop our knowledge of the biology of pediatric cancers, and improve the diagnoses and therapies.172

FIGURE 25.14. 18F-FLT PET/CT in a 6-year-old patient with Hodgkin disease (upper row) showed foci of increased proliferation in the mediastinum (arrow). The SUVmax of the lesions was borderlined on 18F-FDG PET/CT (lower row) 2 days prior to the 18F-FLT PET. Note the difference in biodistribution of FLT (intense bone marrow and liver uptake with no cardiac or brain activity).

ACKNOWLEDGMENT

The authors express their thanks to Jeffrey Chan for his help with the PET/CT images.

REFERENCES

1. Davidoff AM. Pediatric oncology. Semin Pediatr Surg. 2010;19(3):225–233.

2. Steliarova-Foucher E, Stiller C, Kaatsch P, et al. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCISproject): An epidemiological study. Lancet. 2004;364(9451):2097–2105.

3. Pratt JA, Velez R, Brender JD, et al. Racial differences in acute lymphocytic leukemia mortality and incidence trends. J Clin Epidemiol. 1988;41(4):367–371.

4. Stiller CA, Parkin DM. Geographic and ethnic variations in the incidence of childhood cancer. Br Med Bull. 1996;52(4):682–703.

5. Birch JM. Genes and cancer. Arch Dis Child. 1999;80(1):1–3.

6. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.

7. SEER Cancer Statistics Review, 1975–2008. Bethesda, MD: National Cancer Institute [database on the Internet]; 2011.

8. Steliarova-Foucher E, Stiller C, Lacour B, et al. International classification of childhood cancer, third edition. Cancer. 2005;103(7):1457–1467.

9. Martin C. Practical Pediatric PET Imaging. New York, NY: Springer; 2006.

10. Becker GJ, Bosma J, Hendee W. Radiation exposure from medical imaging procedures. N Engl J Med. 2009;361(23):2289–2290; author reply 91–92.

11. Hendee WR, O’Connor MK. Radiation risks of medical imaging: Separating fact from fantasy. Radiology. 2012;264(2):312–321.

12. Preston DL, Shimizu Y, Pierce DA, et al. Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950–1997. Radiat Res. 2003;160(4):381–407.

13. Fahey FH, Treves ST, Adelstein SJ. Minimizing and communicating radiation risk in pediatric nuclear medicine. J Nucl Med. 2011;52(8):1240–1251.

14. Miller RC, Randers-Pehrson G, Geard CR, et al. The oncogenic transforming potential of the passage of single alpha particles through mammalian cell nuclei. Proc Natl Acad Sci U S A. 1999;96(1):19–22.

15. Brenner DJ, Doll R, Goodhead DT, et al. Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know. Proc Natl Acad Sci U S A. 2003;100(24):13761–13766.

16. Shadley JD, Dai GQ. Cytogenetic and survival adaptive responses in G1 phase human lymphocytes. Mutat Res. 1992;265(2):273–281.

17. Sanderson BJ, Morley AA. Exposure of human lymphocytes to ionizing radiation reduces mutagenesis by subsequent ionizing radiation. Mutat Res. 1986; 164(6):347–351.

18. Accorsi R, Karp JS, Surti S. Improved dose regimen in pediatric PET. J Nucl Med. 2010;51(2):293–300.

19. Gelfand MJ. Dose reduction in pediatric hybrid and planar imaging. Q J Nucl Med Mol Imaging. 2010;54(4):379–388.

20. Gelfand MJ, Parisi MT, Treves ST; Pediatric Nuclear Medicine Dose Reduction Workgroup. Pediatric radiopharmaceutical administered doses: 2010 North American consensus guidelines. J Nucl Med. 2011;52(2):318–322.

21. Frush DP. Radiation, CT, and children: the simple answer is … it’s complicated. Radiology. 2009;252(1):4–6.

22. Shammas A, Lim R, Charron M. Pediatric FDG PET/CT: Physiologic uptake, normal variants, and benign conditions. Radiographics. 2009;29(5):1467–1486.

23. Keyes JW Jr. SUV: Standard uptake or silly useless value? J Nucl Med. 1995; 36(10):1836–1839.

24. Ghanem MA, Kazim NA, Elgazzar AH. Impact of obesity on nuclear medicine imaging. J Nucl Med Technol. 2011;39(1):40–50.

25. Bemben MG, Massey BH, Bemben DA, et al. Age-related variability in body composition methods for assessment of percent fat and fat-free mass in men aged 20–74 years. Age Ageing. 1998;27(2):147–153.

26. Heusner TA, Hahn S, Hamami ME, et al. Incidental head and neck (18)F-FDG uptake on PET/CT without corresponding morphological lesion: Early predictor of cancer development? Eur J Nucl Med Mol Imaging. 2009;36(9):1397–1406.

27. Francis IR, Glazer GM, Bookstein FL, et al. The thymus: Reexamination of age-related changes in size and shape. AJR Am J Roentgenol. 1985;145(2): 249–254.

28. Nakahara T, Fujii H, Ide M, et al. FDG uptake in the morphologically normal thymus: Comparison of FDG positron emission tomography and CT. Br J Radiol. 2001;74(885):821–824.

29. Ferdinand B, Gupta P, Kramer EL. Spectrum of thymic uptake at 18F-FDG PET. Radiographics. 2004;24(6):1611–1616.

30. Brink I, Reinhardt MJ, Hoegerle S, et al. Increased metabolic activity in the thymus gland studied with 18F-FDG PET: Age dependency and frequency after chemotherapy. J Nucl Med. 2001;42(4):591–595.

31. Sasaki M, Kuwabara Y, Ichiya Y, et al. Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET. J Nucl Med. 1999;40(10):1595–1601.

32. Hong TS, Shammas A, Charron M, et al. Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging. Pediatr Radiol. 2011;41(6):759–768.

33. Sugawara Y, Fisher SJ, Zasadny KR, et al. Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol. 1998; 16(1):173–180.

34. Tang B, Patel MM, Wong RH, et al. Revisiting the marrow metabolic changes after chemotherapy in lymphoma: A step towards personalized care. Int J Mol Imaging. 2011;2011:942063.

35. Cone LA, Brochert A, Schulz K, et al. PET positive generalized lymphadenopathy and splenomegaly following interferon-alfa-2b adjuvant therapy for melanoma. Clin Nucl Med. 2007;32(10):793–796.

36. Aflalo-Hazan V, Gutman F, Kerrou K, et al. Increased FDG uptake by bone marrow in major beta-thalassemia. Clin Nucl Med. 2005;30(11):754–755.

37. Shapiro B, Gross MD. Radiochemistry, biochemistry, and kinetics of 131I-metaiodobenzylguanidine (MIBG) and 123I-MIBG: Clinical implications of the use of 123I-MIBG. Med Pediatr Oncol. 1987;15(4):170–177.

38. Bodei L, Lam M, Chiesa C, et al. EANM procedure guideline for treatment of refractory metastatic bone pain. Eur J Nucl Med Mol Imaging. 2008;35(10): 1934–1940.

39. Olivier P, Colarinha P, Fettich J, et al. Guidelines for radioiodinated MIBG scintigraphy in children. Eur J Nucl Med Mol Imaging. 2003;30(5):B45–B50.

40. Lonergan GJ, Schwab CM, Suarez ES, et al. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: Radiologic-pathologic correlation. Radiographics. 2002;22(4):911–934.

41. Kramer S, Ward E, Meadows AT, et al. Medical and drug risk factors associated with neuroblastoma: A case–control study. J Natl Cancer Inst. 1987; 78(5):797–804.

42. Michalek AM, Buck GM, Nasca PC, et al. Gravid health status, medication use, and risk of neuroblastoma. Am J Epidemiol. 1996;143(10):996–1001.

43. Kinney H, Faix R, Brazy J. The fetal alcohol syndrome and neuroblastoma. Pediatrics. 1980;66(1):130–132.

44. Bunin GR, Ward E, Kramer S, et al. Neuroblastoma and parental occupation. Am J Epidemiol. 1990;131(5):776–780.

45. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341(16):1165–1173.

46. Marc T, Goodman JGG, Malcolm A, et al. Sympathetic nervous system tumors, ICCC IV. In: Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR, eds. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995. Bethesda, MD: National Cancer Institute; 1999.

47. Strenger V, Kerbl R, Dornbusch HJ, et al. Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients. Pediatr Blood Cancer. 2007; 48(5):504–509.

48. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362 (23):2202–2211.

49. Papaioannou G, McHugh K. Neuroblastoma in childhood: Review and radiological findings. Cancer Imaging. 2005;5:116–127.

50. Kushner BH. Neuroblastoma: A disease requiring a multitude of imaging studies. J Nucl Med. 2004;45(7):1172–1188.

51. Howman-Giles RB, Gilday DL, Ash JM. Radionuclide skeletal survey in neuroblastoma. Radiology. 1979;131(2):497–502.

52. Shulkin BL, Shapiro B, Hutchinson RJ. Iodine-131-metaiodobenzylguanidine and bone scintigraphy for the detection of neuroblastoma. J Nucl Med. 1992; 33(10):1735–1740.

53. Boubaker A, Bischof Delaloye A. Nuclear medicine procedures and neuroblastoma in childhood. Their value in the diagnosis, staging and assessment of response to therapy. Q J Nucl Med. 2003;47(1):31–40.

54. Gordon I, Peters AM, Gutman A, et al. Skeletal assessment in neuroblastoma—the pitfalls of iodine-123-MIBG scans. J Nucl Med. 1990;31(2):129–134.

55. McHugh K, Pritchard J. Problems in the imaging of three common paediatric solid tumours. Eur J Radiol. 2001;37(2):72–78.

56. Osmanagaoglu K, Lippens M, Benoit Y, et al. A comparison of iodine-123 meta-iodobenzylguanidine scintigraphy and single bone marrow aspiration biopsy in the diagnosis and follow-up of 26 children with neuroblastoma. Eur J Nucl Med. 1993;20(12):1154–1160.

57. Suc A, Lumbroso J, Rubie H, et al. Metastatic neuroblastoma in children older than one year: Prognostic significance of the initial metaiodobenzylguanidine scan and proposal for a scoring system. Cancer. 1996;77(4):805–811.

58. Ady N, Zucker JM, Asselain B, et al. A new 123I-MIBG whole body scan scoring method—application to the prediction of the response of metastases to induction chemotherapy in stage IV neuroblastoma. Eur J Cancer. 1995;31A(2): 256–261.

59. Matthay KK, Edeline V, Lumbroso J, et al. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol. 2003;21(13): 2486–2491.

60. Messina JA, Cheng SC, Franc BL, et al. Evaluation of semi-quantitative scoring system for metaiodobenzylguanidine (mIBG) scans in patients with relapsed neuroblastoma. Pediatr Blood Cancer. 2006;47(7):865–874.

61. Philip T, Zucker JM, Bernard JL, et al. Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: Is cure possible in a small subgroup? J Clin Oncol. 1991;9(6):1037–1044.

62. Dorr U, Sautter-Bihl ML, Schilling FH, et al. Somatostatin receptor scintigraphy (SRS): A new diagnostic tool in neuroblastoma (NB)? Prog Clin Biol Res. 1994;385:355–361.

63. Pashankar FD, O’Dorisio MS, Menda Y. MIBG and somatostatin receptor analogs in children: Current concepts on diagnostic and therapeutic use. J Nucl Med. 2005;46(suppl 1):55S–61S.

64. Schilling FH, Bihl H, Jacobsson H, et al. Combined (111)In-pentetreotide scintigraphy and (123)I-mIBG scintigraphy in neuroblastoma provides prognostic information. Med Pediatr Oncol. 2000;35(6):688–691.

65. Kropp J, Hofmann M, Bihl H. Comparison of MIBG and pentetreotide scintigraphy in children with neuroblastoma. Is the expression of somatostatin receptors a prognostic factor? Anticancer Res. 1997;17(3B):1583–1588.

66. O’Dorisio MS, Chen F, O’Dorisio TM, et al. Characterization of somatostatin receptors on human neuroblastoma tumors. Cell Growth Differ. 1994;5(1):1–8.

67. Srirajaskanthan R, Kayani I, Quigley AM, et al. The role of 68Ga-DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-DTPA-octreotide scintigraphy. J Nucl Med. 2010;51(6):875–882.

68. Kroiss A, Putzer D, Uprimny C, et al. Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr 3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine. Eur J Nucl Med Mol Imaging. 2011;38(5):865–873.

69. Sharp SE, Shulkin BL, Gelfand MJ, et al. 123I-MIBG scintigraphy and 18F-FDG PET in neuroblastoma. J Nucl Med. 2009;50(8):1237–1243.

70. Kushner BH, Yeung HW, Larson SM, et al. Extending positron emission tomography scan utility to high-risk neuroblastoma: Fluorine-18 fluorodeoxyglucose positron emission tomography as sole imaging modality in follow-up of patients. J Clin Oncol. 2001;19(14):3397–3405.

71. Taggart DR, Han MM, Quach A, et al. Comparison of iodine-123 metaiodobenzylguanidine (MIBG) scan and [18F]fluorodeoxyglucose positron emission tomography to evaluate response after iodine-131 MIBG therapy for relapsed neuroblastoma. J Clin Oncol.2009;27(32):5343–5349.

72. Shulkin BL, Wieland DM, Baro ME, et al. PET hydroxyephedrine imaging of neuroblastoma. J Nucl Med. 1996;37(1):16–21.

73. Piccardo A, Lopci E, Conte M, et al. Comparison of 18F-dopa PET/CT and 123I-MIBG scintigraphy in stage 3 and 4 neuroblastoma: A pilot study. Eur J Nucl Med Mol Imaging. 2012;39(1):57–71.

74. Lopci E, Piccardo A, Nanni C, et al. 18F-DOPA PET/CT in neuroblastoma: Comparison of conventional imaging with CT/MR. Clin Nucl Med. 2012;37(4): e73–e78.

75. Tepmongkol S, Heyman S. 131I MIBG therapy in neuroblastoma: Mechanisms, rationale, and current status. Med Pediatr Oncol. 1999;32(6):427–431; discussion 32.

76. Hoefnagel CA, Voute PA, De Kraker J, et al. [131I]metaiodobenzylguanidine therapy after conventional therapy for neuroblastoma. J Nucl Biol Med. 1991; 35(4):202–206.

77. Troncone L, Rufini V, Montemaggi P, et al. The diagnostic and therapeutic utility of radioiodinated metaiodobenzylguanidine (MIBG). 5 years of experience. Eur J Nucl Med. 1990;16(4–6):325–335.

78. Klingebiel T, Berthold F, Treuner J, et al. Metaiodobenzylguanidine (mIBG) in treatment of 47 patients with neuroblastoma: Results of the German neuroblastoma trial. Med Pediatr Oncol. 1991;19(2):84–88.

79. Voute PA, van der Kleij AJ, De Kraker J, et al. Clinical experience with radiation enhancement by hyperbaric oxygen in children with recurrent neuroblastoma stage IV. Eur J Cancer. 1995;31A(4):596–600.

80. Mastrangelo R, Tornesello A, Mastrangelo S. Role of 131I-metaiodobenzylguanidine in the treatment of neuroblastoma. Med Pediatr Oncol. 1998;31(1):22–26.

81. Yanik GA, Levine JE, Matthay KK, et al. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. J Clin Oncol. 2002;20(8):2142–2149.

82. Rutgers M, Tytgat GA, Verwijs-Janssen M, et al. Uptake of the neuron-blocking agent meta-iodobenzylguanidine and serotonin by human platelets and neuro-adrenergic tumour cells. Int J Cancer. 1993;54(2):290–295.

83. De Krijger RR, Petri BJ, Van Nederveen FH, et al. Frequent genetic changes in childhood pheochromocytomas. Ann N Y Acad Sci. 2006;1073:166–176.

84. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: Recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007;3(2):92–102.

85. Havekes B, Romijn JA, Eisenhofer G, et al. Update on pediatric pheochromocytoma. Pediatr Nephrol. 2009;24(5):943–950.

86. Sisson JC, Frager MS, Valk TW, et al. Scintigraphic localization of pheochromocytoma. N Engl J Med. 1981;305(1):12–17.

87. Gurney JG. Topical topics: Brain cancer incidence in children: Time to look beyond the trends. Med Pediatr Oncol. 1999;33(2):110–112.

88. Oriuchi N, Tamura M, Shibazaki T, et al. Clinical evaluation of thallium-201 SPECT in supratentorial gliomas: Relationship to histologic grade, prognosis and proliferative activities. J Nucl Med. 1993;34(12):2085–2089.

89. Dierckx RA, Martin JJ, Dobbeleir A, et al. Sensitivity and specificity of thallium-201 single-photon emission tomography in the functional detection and differential diagnosis of brain tumours. Eur J Nucl Med. 1994;21(7):621–633.

90. Glantz MJ, Hoffman JM, Coleman RE, et al. Identification of early recurrence of primary central nervous system tumors by [18F]fluorodeoxyglucose positron emission tomography. Ann Neurol. 1991;29(4):347–355.

91. Hoffman JM, Hanson MW, Friedman HS, et al. FDG-PET in pediatric posterior fossa brain tumors. J Comput Assist Tomogr. 1992;16(1):62–68.

92. Borgwardt L, Hojgaard L, Carstensen H, et al. Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade: A study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion. J Clin Oncol.2005;23(13): 3030–3037.

93. Hipp SJ, Steffen-Smith EA, Patronas N, et al. Molecular imaging of pediatric brain tumors: Comparison of tumor metabolism using (18)F-FDG-PET and MRSI. J Neurooncol. 2012;109(3):521–527.

94. Zukotynski KA, Fahey FH, Kocak M, et al. Evaluation of 18F-FDG PET and MRI associations in pediatric diffuse intrinsic brain stem glioma: A report from the Pediatric Brain Tumor Consortium. J Nucl Med. 2011;52(2):188–195.

95. Di Chiro G, Oldfield E, Wright DC, et al. Cerebral necrosis after radiotherapy and/or intraarterial chemotherapy for brain tumors: PET and neuropathologic studies. AJR Am J Roentgenol. 1988;150(1):189–197.

96. Torii K, Tsuyuguchi N, Kawabe J. Correlation of amino-acid uptake using methionine PET and histological classifications in various gliomas. Ann Nucl Med. 2005;19(8):677–683.

97. Kumar R, Shandal V, Shamim SA, et al. Clinical applications of PET and PET/CT in pediatric malignancies. Expert Rev Anticancer Ther. 2010;10(5):755–768.

98. Ceyssens S, Van Laere K, de Groot T, et al. [11C]methionine PET, histopathology, and survival in primary brain tumors and recurrence. AJNR Am J Neuroradiol. 2006;27(7):1432–1437.

99. Van Laere K, Ceyssens S, Van Calenbergh F, et al. Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: Sensitivity, inter-observer variability and prognostic value. Eur J Nucl Med Mol Imaging. 2005;32(1):39–51.

100. Constance L, Percy MAS, Linet M, et al. Lymphomas and Reticuloendothelial Neoplasms. 2009.

101. Sty JR, Kun LE, Starshak RJ. Pediatric applications in nuclear oncology. Semin Nucl Med. 1985;15(2):171–200.

102. Howman-Giles R, Stevens M, Bergin M. Role of gallium-67 in management of paediatric solid tumours. Aust Paediatr J. 1982;18(2):120–125.

103. Janicek M, Kaplan W, Neuberg D, et al. Early restaging gallium scans predict outcome in poor-prognosis patients with aggressive non-Hodgkin’s lymphoma treated with high-dose CHOP chemotherapy. J Clin Oncol. 1997;15(4):1631–1637.

104. Even-Sapir E, Bar-Shalom R, Israel O, et al. Single-photon emission computed tomography quantitation of gallium citrate uptake for the differentiation of lymphoma from benign hilar uptake. J Clin Oncol. 1995;13(4):942–946.

105. Simmonds P, Silberstein M, McKendrick J. Thymic hyperplasia in adults following chemotherapy for malignancy. Aust N Z J Med. 1993;23(3):264–267.

106. Waxman AD, Eller D, Ashook G, et al. Comparison of gallium-67-citrate and thallium-201 scintigraphy in peripheral and intrathoracic lymphoma. J Nucl Med. 1996;37(1):46–50.

107. Martin DJ, Ash JM. Diagnostic radiology in non-Hodgkin’s lymphoma. Semin Oncol. 1977;4(3):297–309.

108. Bar-Shalom R, Israel O, Epelbaum R, et al. Gallium-67 scintigraphy in lymphoma with bone involvement. J Nucl Med. 1995;36(3):446–450.

109. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–586.

110. Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood. 2007;110(10):3507–3516.

111. Buchmann I, Reinhardt M, Elsner K, et al. 2-(fluorine-18)fluoro-2-deoxy-D-glucose positron emission tomography in the detection and staging of malignant lymphoma. A bicenter trial. Cancer. 2001;91(5):889–899.

112. Depas G, De Barsy C, Jerusalem G, et al. 18F-FDG PET in children with lymphomas. Eur J Nucl Med Mol Imaging. 2005;32(1):31–38.

113. Kabickova E, Sumerauer D, Cumlivska E, et al. Comparison of 18F-FDG-PET and standard procedures for the pretreatment staging of children and adolescents with Hodgkin’s disease. Eur J Nucl Med Mol Imaging. 2006;33(9):1025–1031.

114. Hermann S, Wormanns D, Pixberg M, et al. Staging in childhood lymphoma: Differences between FDG-PET and CT. Nuklearmedizin. 2005;44(1):1–7.

115. Bodet-Milin C, Eugene T, Gastinne T, et al. FDG-PET in follicular lymphoma management. J Oncol. 2012;2012:370272.

116. Stumpe KD, Urbinelli M, Steinert HC, et al. Whole-body positron emission tomography using fluorodeoxyglucose for staging of lymphoma: Effectiveness and comparison with computed tomography. Eur J Nucl Med. 1998;25(7): 721–728.

117. Okada J, Oonishi H, Yoshikawa K, et al. FDG-PET for predicting the prognosis of malignant lymphoma. Ann Nucl Med. 1994;8(3):187–191.

118. Rhodes MM, Delbeke D, Whitlock JA, et al. Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol. 2006;28(5):300–306.

119. Lavely WC, Delbeke D, Greer JP, et al. FDG PET in the follow-up management of patients with newly diagnosed Hodgkin and non-Hodgkin lymphoma after first-line chemotherapy. Int J Radiat Oncol Biol Phys. 2003;57(2):307–315.

120. Jadvar H, Connolly LP, Fahey FH, et al. PET and PET/CT in pediatric oncology. Semin Nucl Med. 2007;37(5):316–331.

121. Lugtenburg PJ, Krenning EP, Valkema R, et al. Somatostatin receptor scintigraphy useful in stage I–II Hodgkin’s disease: More extended disease identified. Br J Haematol. 2001;112(4):936–944.

122. Gasparini M, Bombardieri E, Tondini C, et al. Clinical utility of radioimmunoscintigraphy of non-Hodgkin’s lymphoma with radiolabelled LL2 monoclonal antibody, LymphoSCAN: Preliminary results. Tumori. 1995;81(3):173–178.

123. Kapucu LO, Akyuz C, Vural G, et al. Evaluation of therapy response in children with untreated malignant lymphomas using technetium-99m-sestamibi. J Nucl Med. 1997;38(2):243–247.

124. Ramanna L, Waxman A, Binney G, et al. Thallium-201 scintigraphy in bone sarcoma: Comparison with gallium-67 and technetium-MDP in the evaluation of chemotherapeutic response. J Nucl Med. 1990;31(5):567–572.

125. Rosen G, Loren GJ, Brien EW, et al. Serial thallium-201 scintigraphy in osteosarcoma. Correlation with tumor necrosis after preoperative chemotherapy. Clin Orthop Relat Res. 1993(293):302–306.

126. Soderlund V, Larsson SA, Bauer HC, et al. Use of 99mTc-MIBI scintigraphy in the evaluation of the response of osteosarcoma to chemotherapy. Eur J Nucl Med. 1997;24(5):511–515.

127. Volker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of pediatric sarcoma patients: Results of a prospective multicenter trial. J Clin Oncol. 2007;25(34):5435–5441.

128. Hawkins DS, Rajendran JG, Conrad EU 3rd, et al. Evaluation of chemotherapy response in pediatric bone sarcomas by [F-18]-fluorodeoxy-D-glucose positron emission tomography. Cancer. 2002;94(12):3277–3284.

129. Huang TL, Liu RS, Chen TH, et al. Comparison between F-18-FDG positron emission tomography and histology for the assessment of tumor necrosis rates in primary osteosarcoma. J Chin Med Assoc. 2006;69(8):372–376.

130. Goldstein H, McNeil BJ, Zufall E, et al. Is there still a place for bone scanning in Ewing’s sarcoma? Concise communication. J Nucl Med. 1980;21(1): 10–12.

131. Elison B, Murray IP. Aspects of paediatric oncology. Ann Acad Med Singapore. 1986;15(4):581–589.

132. Erlemann R, Sciuk J, Bosse A, et al. Response of osteosarcoma and Ewing sarcoma to preoperative chemotherapy: Assessment with dynamic and static MR imaging and skeletal scintigraphy. Radiology. 1990;175(3): 791–796.

133. Estes DN, Magill HL, Thompson EI, et al. Primary Ewing sarcoma: Follow-up with Ga-67 scintigraphy. Radiology. 1990;177(2):449–453.

134. Kostakoglu L, Panicek DM, Divgi CR, et al. Correlation of the findings of thallium-201 chloride scans with those of other imaging modalities and histology following therapy in patients with bone and soft tissue sarcomas. Eur J Nucl Med. 1995;22(11):1232–1237.

135. Arush MW, Israel O, Postovsky S, et al. Positron emission tomography/computed tomography with 18fluoro-deoxyglucose in the detection of local recurrence and distant metastases of pediatric sarcoma. Pediatr Blood Cancer. 2007;49(7):901–905.

136. Cogswell A, Howman-Giles R, Bergin M. Bone and gallium scintigraphy in children with rhabdomyosarcoma: A 10-year review. Med Pediatr Oncol. 1994; 22(1):15–21.

137. De Corti F, Dall’Igna P, Bisogno G, et al. Sentinel node biopsy in pediatric soft tissue sarcomas of extremities. Pediatr Blood Cancer. 2009;52(1):51–54.

138. Kayton ML, Delgado R, Busam K, et al. Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer. 2008;112(9):2052–2059.

139. Parida L, Morrisson GT, Shammas A, et al. Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int. 2012;28(6):571–578.

140. Cohade C, Wahl RL. Applications of positron emission tomography/computed tomography image fusion in clinical positron emission tomography-clinical use, interpretation methods, diagnostic improvements. Semin Nucl Med. 2003; 33(3):228–237.

141. Adler LP, Blair HF, Makley JT, et al. Noninvasive grading of musculoskeletal tumors using PET. J Nucl Med. 1991;32(8):1508–1512.

142. Tateishi U, Hosono A, Makimoto A, et al. Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med. 2009;23(2):155–161.

143. Ricard F, Cimarelli S, Deshayes E, et al. Additional benefit of F-18 FDG PET/CT in the staging and follow-up of pediatric rhabdomyosarcoma. Clin Nucl Med. 2011;36(8):672–677.

144. Klem ML, Grewal RK, Wexler LH, et al. PET for staging in rhabdomyosarcoma: An evaluation of PET as an adjunct to current staging tools. J Pediatr Hematol Oncol. 2007;29(1):9–14.

145. Morrison SC, Adler LP. Photopenic areas on bone scanning associated with childhood leukemia. Clin Nucl Med. 1991;16(1):24–26.

146. Wong KK, Lan LC, Lin SC, et al. The use of positron emission tomography in detecting hepatoblastoma recurrence—a cautionary tale. J Pediatr Surg. 2004;39(12):1779–1781.

147. Mody RJ, Pohlen JA, Malde S, et al. FDG PET for the study of primary hepatic malignancies in children. Pediatr Blood Cancer. 2006;47(1):51–55.

148. Thyroid cancer, National Cancer Institute at the National Institute of Health. <http://seer.cancer.gov/statfacts/html/thyro.html,2013>.

149. Chaukar DA, Rangarajan V, Nair N, et al. Pediatric thyroid cancer. J Surg Oncol. 2005;92(2):130–133.

150. Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer. 1998;83(12):2638–2648.

151. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998;338(5):297–306.

152. Degrossi OJ, Rozados IB, Damilano S, et al. Serum thyroglobulin and whole-body scanning as markers in the follow-up of differentiated thyroid carcinomas. Medicina. 1991;51(4):291–295.

153. Parisi MT, Mankoff D. Differentiated pediatric thyroid cancer: Correlates with adult disease, controversies in treatment. Semin Nucl Med. 2007;37(5):340–356.

154. Verkooijen RB, Rietbergen D, Smit JW, et al. A new functional parameter measured at the time of ablation that can be used to predict differentiated thyroid cancer recurrence during follow-up. Eur J Endocrinol. 2007;156(1):41–47.

155. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167–1214.

156. Menendez Torre E, Lopez Carballo MT, Rodriguez Erdozain RM, et al. Prognostic value of thyroglobulin serum levels and 131I whole-body scan after initial treatment of low-risk differentiated thyroid cancer. Thyroid. 2004; 14(4):301–306.

157. Pacini F, Schlumberger M, Dralle H, et al. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol. 2006;154(6):787–803.

158. Cailleux AF, Baudin E, Travagli JP, et al. Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab. 2000;85(1):175–178.

159. Park EK, Chung JK, Lim IH, et al. Recurrent/metastatic thyroid carcinomas false negative for serum thyroglobulin but positive by posttherapy I-131 whole body scans. Eur J Nucl Med Mol Imaging. 2009;36(2):172–179.

160. Thomas CC, Cowan RJ, Albertson DA, et al. Detection of medullary carcinoma of the thyroid with I-131 MIBG. Clin Nucl Med. 1994;19(12):1066–1068.

161. Beheshti M, Pocher S, Vali R, et al. The value of 18F-DOPA PET-CT in patients with medullary thyroid carcinoma: Comparison with 18F-FDG PET-CT. Eur Radiol. 2009;19(6):1425–1434.

162. Howe TC, Padhy AK, Loke K, et al. Role of Tc-99m DMSA (V) scanning and serum calcitonin monitoring in the management of medullary thyroid carcinoma. Singapore Med J. 2008;49(1):19–22.

163. Hoe FM, Charron M, Moshang T Jr. Use of the recombinant human TSH stimulated thyroglobulin level and diagnostic whole body scan in children with differentiated thyroid carcinoma. J Pediatr Endocrinol Metab. 2006;19(1):25–30.

164. Juweid M, Sharkey RM, Behr T, et al. Radioimmunotherapy of medullary thyroid cancer with iodine-131-labeled anti-CEA antibodies. J Nucl Med. 1996;37(6):905–911.

165. Cheuk DK, Sabin ND, Hossain M, et al. PET/CT for staging and follow-up of pediatric nasopharyngeal carcinoma. Eur J Nucl Med Mol Imaging. 2012; 39(7):1097–1106.

166. von Falck C, Maecker B, Schirg E, et al. Post transplant lymphoproliferative disease in pediatric solid organ transplant patients: A possible role for [18F]-FDG-PET(/CT) in initial staging and therapy monitoring. Eur J Radiol. 2007; 63(3):427–435.

167. Otonkoski T, Nanto-Salonen K, Seppanen M, et al. Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes. 2006;55(1):13–18.

168. Ribeiro MJ, De Lonlay P, Delzescaux T, et al. Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-L-DOPA. J Nucl Med. 2005; 46(4):560–566.

169. Portwine C, Marriott C, Barr RD. PET imaging for pediatric oncology: An assessment of the evidence. Pediatr Blood Cancer. 2010;55(6):1048–1061.

170. Kaste SC, Rodriguez-Galindo C, McCarville ME, et al. PET-CT in pediatric Langerhans cell histiocytosis. Pediatr Radiol. 2007;37(7):615–622.

171. Phillips M, Allen C, Gerson P, et al. Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer. 2009;52(1):97–101.

172. Daldrup-Link HE, Hawkins RA, Meier R, et al. Receptor imaging of pediatric tumors: Clinical practice and new developments. Pediatr Radiol. 2008; 38(11):1154–1161.