Nuclear Medicine in Pediatric and Adolescent Tumors

Nuclear Medicine in Pediatric and Adolescent Tumors Pınar Özgen Kiratli, MD,* Murat Tuncel, MD,* and Zvi Bar-Sever, MD† Nuclear medicine has an important role in the management of many cancers in pediatric age group with multiple imaging modalities and radiopharmaceuticals targeting various biological uptake mechanisms. 18-Flourodeoxyglucose is the radiotracer of choice especially in patients with sarcoma and lymphoma. 18FDG-PET, for sarcoma and lymphomas, is proved to be superior to conventional imaging in staging and therapy response. Although studies are limited in pediatric population, 18FDG-PET/CT has found its way through international guidelines. Limitations and strengths of PET imaging must be noticed before adapting PET imaging in clinical protocols. Established new response criteria using multiple parameters derived from 18 FDG-PET would increase the accuracy and repeatability of response evaluation. Current data suggest that I-123 metaiodobenzylguanidine (MIBG) remains the tracer of choice in the evaluation of neuroblastoma (NB) because of its high sensitivity, specificity, diagnostic accuracy, and prognostic value. It is valuable in determining the response to therapy, surveillance for disease recurrence, and in selecting patients for I-131 therapy. SPECT/CT improves the diagnostic accuracy and the interpretation confidence of MIBG scans. 18FDG-PET/CT is an important complementary to MIBG imaging despite its lack of specificity to NB. It is valuable in cases of negative or inconclusive MIBG scans and when MIBG findings underestimate the disease status as determined from clinical and radiological findings. F-18 DOPA is promising tracer that reflects catecholamine metabolism and is both sensitive and specific. F-18 DOPA scintigraphy provides the advantages of PET/CT imaging with early and short imaging times, high spatial resolution, inherent morphologic correlation with CT, and quantitation. Regulatory and production issues currently limit the tracer’s availability. PET/CT with Ga-68 DOTA appears to be useful in NB imaging and may have a unique role in selecting patients for peptide receptor radionuclide therapy with somatostatin analogues. C-11 hydroxyephedrine PET/CT is a specific PET tracer for NB, but the C-11 label that requires an on-site cyclotron production and the high physiologic uptake in the liver and kidneys limit its use. I-124 MIBG is useful for I-131 MIBG pretherapeutic dosimetry planning. Its use for diagnostic imaging as well as the use of F-18 labeled MIBG analogues is currently experimental. PET/MR imaging is emerging and is likely to become an important tool in the evaluation. It provides metabolic and superior morphological data in one imaging session, expediting the diagnosis and lowering the radiation exposure. Radioactive iodines not only detect residual tissue and metastatic disease but also are used in the treatment of differentiated thyroid cancer. However, these are not well documented in pediatric age group like adult patients. Use of radioactivity in pediatric population is very important and strictly controlled because of the possibility of secondary malignities; therefore, management of oncological cases requires detailed literature knowledge. This article aims to review the literature on the use of radionuclide imaging and therapy in pediatric population with thyroid cancer, sarcomas, lymphoma, and NB. Semin Nucl Med 46:308-323 C 2016 Elsevier Inc. All rights reserved.

*Department of Nuclear Medicine, Hacettepe University Medical Center, Ankara, Turkey. †Department of Nuclear Medicine, Schneider Children’s Medical Center, Petah Tikva, Israel. Address reprint requests to Pınar Özgen Kiratli, MD, Department of Nuclear Medicine, Hacettepe University Medical School, Sıhhiye 06100, Ankara, Turkey. E-mail: [email protected]

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http://dx.doi.org/10.1053/j.semnuclmed.2016.01.004 0001-2998/& 2016 Elsevier Inc. All rights reserved.

Thyroid Cancers in Pediatric and Adolescent Patients Incidence

T

he incidence of differentiated thyroid cancer (DTC) has increased over the past decades and became 0.5-0.7/

Pediatric and adolescent tumors million among pediatric patients.1 Although it is less common compared to the adult population, it has increased gradually and became the fifth most common cancer in children aged between 0 and 14 years.2-4 Geographic region and iodine insufficiency are considered the most possible reasons for this increase, as well as the availability of the screening tests.5

Risk Factors Previous history of thyroid disease is a risk factor for DTC. Papillary thyroid carcinoma (PTC) has been reported in 9.6% of the patients with thyroid nodules associated with autoimmune thyroiditis.6 On the contrary congenital hypothyroidism caused by dyshormonogenesis or iodine transporter defect increases the risk of nodules in children which may turn to follicular thyroid cancer.7 Thyroid cancers originating from follicular cells have a familial association of 5% and 25% for parafollicular cell–originated cancers in children. Radioactive accidents have been considered the primary reason responsible for the increase in DTC incidence8,9 and the most well known is the Chernobyl accident, where there has been an increased rate of thyroid cancer among the survivors younger than 15.10 However, the main responsible radiation exposure is caused by imaging procedures using radioactivity and radiotherapy. External radiation therapy used for the treatment of some benign disorders in the past, as well as in some malign diseases, results in an increased rate of DTC.11 Children, younger than 5 years, are the most sensitive group to radiation. Patients with DTC due to radiation exposure have higher rates of lymph node involvement and distant metastases, with short latency period and worse clinical outcome.12

Presentation DTC in pediatric age group presents with a relatively advanced stage at the time of diagnosis and shows higher rate of recurrence.13 Mazzaferri and Kloos14 reported that cervical lymph node metastases were seen as high as 79%, and distant organ metastases in 15% of these patients. The recurrence rate was reported in 37% of the pediatric patients, but fortunately the mortality rate is lower (1%) compared to adults.12 The reasons for this better prognosis and overall survival in pediatrics still remain unclear.15 Gene rearrangement is common, and point mutations are rare in pediatric PTC. Besides, studies have shown that BRAF mutations are rare, but RET/PTC relocations are common in children with DTC. Point mutations of RAS and BRAF lead to genomic instability and dedifferentiation causing diminished expression of the sodium iodide symporter, but RET/PTC relocations do not cause genomic instability.16,17 Sodium iodide symporter expression is a strong marker for differentiation, and it is higher in both primary tumor and metastases.18 These molecular differences might be the reason for better response to radioiodine in children and may explain low mortality and low progression rate. The incidence of DTC is lower in prepubertal children, but the course is more aggressive.15 Extrathyroidal extension and lung metastases are commonly seen in prepubertal period

309 compared to pubertal period (80% and 70% vs 35.5% and 23.5%, respectively).15,19

Histopathology PTC is the most common DTC in pediatric age group including Turkey.20 The size of the tumor is generally more than 1 cm, multifocal and bilateral, and presents with metastases to the lungs in approximately 25% of cases generally with substantial local lymph node metastases.19 It was hypothesized that invasion of the thyroid capsule and adjacent tissues is due to the smaller size of the thyroid gland in children.15 Histologic subtypes of PTC in pediatrics are classic, solid, follicular, and diffuse sclerosing. On the contrary, follicular type DTC is frequently seen in pubertal children.21 It is often unifocal and shows hematogenous metastases to the lungs and bones. Hurtle cell (oncocytic), clear cell, and insular (poorly differentiated) carcinoma are histologic variants of follicular type DTC. Medullary thyroid cancer (MTC) is seen in 5% of childhood thyroid carcinoma. It arises from parafollicular C cells of the thyroid gland2 and is often associated with multiple endocrine neoplasia type 2, where sporadic MTC and anaplastic thyroid cancer are almost only seen in adults. In patients with hereditary MTC, RET proto-oncogene mutation is always seen. RET mutation screening is more sensitive than traditional biochemical markers. As MTC is a functional neuroendocrine tumor, it secretes calcitonin, carcinoembriogenic antigen, and other peptides.22 Calcitonin level is correlated with the tumor volume, recurrence, and carcinoembriogenic antigen is correlated with the lymph node involvement and distant metastases.23 Prophylactic thyroidectomy is suggested once this mutation is detected.

Diagnosis Patients generally present with palpable thyroid nodule or mass. Ultrasonography (US) is very valuable in the assessment of thyroid nodules. Signs of benign course are cystic or hyperechoic nodules with good demarcation and external vascularization,24 whereas solid hypoechoic nodules, irregular borders, internal vascularization, and the presence of microcalcification are associated with malignancy. Thyroid scintigraphy has a role in the evaluation of the nodules’ function. Nonfunctional thyroid nodules with suspicious US findings have higher risk for malignancy.24 Once a nodule is found, it should be evaluated with fine-needle aspiration biopsy. Although fine-needle aspiration biopsy has a high sensitivity and specificity for the diagnosis of malignancy, the relatively low rate for positive predictive value (PPV) for benign diagnosis made surgery a preferable method for children younger than 10 years.25 Surgery is the primary treatment for thyroid cancer. Near-total or total thyroidectomy is the preferred operation for DTC. If the surgery is performed by experienced hands, children with DTC have lower rates of complications. The multifocal nature of PTC and better disease-free survival in children, made surgeons favor total thyroidectomy or near-

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310 total thyroidectomy in recent years.26-28 Recurrent surgery for lymph node metastasis is not uncommon and increases the risk of complications.29,30 Although some authors recommend routine central neck dissection (CND) for small children and male sex,31 others suggest lymph node dissection wherever evidence for metastatic disease is present.29 CND should be performed in patients with suspicion of neck metastasis.32 These are also the patients with an increased risk of pulmonary metastases. Therefore, a good preoperative evaluation with neck US is very important. CND decreases risk of persistent or recurrent regional disease as well as helps to increase the efficacy of I-131. Type of lymph node dissection is also important, compartment-based lymph node dissection is better than berry picking type of lymph node dissection.32 Postoperative imaging procedures aim to find out thyroid remnant and regional involvement as well as distant metastasis. Postoperative neck US is used for the evaluation of residual thyroid tissue and neck lymph nodes. However, it is not uncommon to see residual thyroid cells concentrating iodine despite a negative US. Hence, radionuclide imaging is used for patients with any possible remaining tissue. Thyroid scintigraphy with Tc-99m pertechnetate, radioiodine I-123, or I-131 is the main radionuclide imaging procedures. Thyroid scintigraphy using radioiodine not only evaluates residual thyroid tissue, but finds out functional lung and bone metastasis. Radioiodine I-123 is a beta emitter with gamma photon energy as well. It can be used for therapeutic dose planning without the risk of stunning.33 Radioiodine I-124 is used in PET studies, with better resolution using CT, and it enables better dosimetry and detailed information.33 Radioiodine I-131 is available in many centers, but its potential risk for stunning is a major disadvantage. For this reason, decreasing the dose (1874 MBq) and application of therapy after 72 hours is recommended. Low-dose I-131 decreases the risk of stunning, but this time detectable number of metastatic foci is being lost. High thyroglobulin (Tg) value postoperatively should warn the clinician for possible lung metastases, which is not rare in pediatric patients, unless there is detected residual tissue or metastatic lymph node left behind after surgery. A lung CT without intravenous iodinated contrast can be carried out even if it is not unusual to miss metastases due to its miliary nature.34 Pediatric staging systems are derived from extrapolations from adults’ systems, but as the postoperative staging systems are based on mortality, the different behavior of the pediatric DTC tumor made its use not effective. A staging system, MACIS, based on distant metastases, age, completeness of resection, local invasion, and tumor size has been introduced by Powers et al36 as it is presumed to be a better predictor for prognosis,35 but data on this subject are limited. Recently, American Thyroid Association (ATA) recommended grouping pediatric DTC patients as low risk, intermediate risk, and high risk.32 For patients in low-risk category, the disease is limited in the thyroid with none or microscopic metastasis to the central neck lymph nodes. They have the slightest risk for distant metastasis if they had proper surgery with CND. In intermediate-risk group, patients have extensive lymph node metastases. They have a low risk for distant metastasis, but they

have an increased risk for persistent cervical disease. Patients in high-risk group have an extensive local disease or invasive disease, with or without distant metastases. These patients have the highest risk for persistent disease and distant metastasis.

Treatment The goal of radioactive iodine (RAI) therapy in pediatric DTC is to decrease the possibility of recurrence and to improve survival. In 1946, Seidlin et al37 proposed RAI as a specific treatment for DTC after an elder patient with functional metastases responded to radioiodine treatments, and since then I-131 has been in the treatment protocols for both adults and children. Residual thyroid tissue is often seen even after total thyroidectomy. To destroy this residual tissue or microscopic disease, radioiodine ablation therapy is performed. This allows clinicians to follow-up with Tg level. Pediatric patients with gross tumor, lymphovascular invasion, lymph node, or distant metastasis undergo RAI therapy. A posttherapy whole-body RAI scintigraphy reveals the extent of disease so that restaging can be done. Hay et al38 found no difference in local recurrence or lymph node metastasis between surgery alone and surgery combined with radioiodine ablation therapy and concluded that initial surgical approach has the greatest effect on recurrence. This is true if patients are not from iodine-deficient areas, tumor is diagnosed in early stage, and the patients had adequate surgery. The International Atomic Energy Agency recommends RAI therapy in patients with DTC if the tumor is invasive, unresectable, or there are distant metastases.39 RAI ablation therapy is performed 3-6 weeks after surgery. It is advised that serum thyroid-stimulating hormone (TSH) should be more than 30 IU/mL for effective I-131 uptake of the tumor. For this reason, patients undergo an iodine-poor diet to decrease iodine pool and discontinue thyroid hormone replacement to induce uptake of radioiodine in residual thyroid tissue.40 (Fig. 1). RAI doses are decided as either empirically fixed doses (30-100 mCi [3.7 GBq] for ablation, 150 mCi [5.5 GBq] for lymph node involvement, and 200 mCi [7.4 GBq] for distant metastasis to the lung and bone) or individualized doses derived from diagnostic whole-body imaging.39 Empiric fixeddose approach is widely used, because it is safe, effective, and easily performed. Of course, the doses are corrected for body surface area or weight for the pediatric patients. There are mainly two dosimetric approaches for individualized RAI therapy.41 (1) Bone marrow dose-limited approach; less than 2 Gy of radiation-absorbed dose to the bone marrow is given, as it is accepted by the critical organ.42 It allows higher activities and fractionated therapy is avoided. Also, it is possible to give the safest dose limits in distant metastasis.43 (2) Lesion-based dosimetry; it aims to increase the effectiveness of RAI treatment. Radiation-absorbed doses for

Pediatric and adolescent tumors

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Figure 1 (A) A 10-years-old girl with a diagnosis of papillary thyroid cancer with lymph node metastases was referred for I-131 therapy. Tc-99m pertechnetate scintigraphy showed residual thyroid tissue in pyramidal lobe (black arrow a), left upper juguler lymph node (White arrow, b), and lung metastases (black arrow heads a and c). Her stimulated Tg level was 670 ng/mL. (B) Patient received 5.5 GBq of I-131 therapy. Posttherapy scans showed increased uptake in lung metastases, which is completely resolved in the follow-up scans with stimulated Tg levels of Tg o 0.2 ng/mL.

Both approaches are not suitable for pediatric patients, as they require repetitive blood sampling and imaging, to find effective half time of I-131. Thyroid hormone replacement is started after RAI treatment. The aim is to suppress serum TSH levels and ensure subclinical hyperthyroidism so that the risk of recurrence can be lessened. In pediatric patients with high-risk DTC, TSH suppression under 0.1 mU/mL is recommended,45 but long-term suppression is not preferred due to its complications, mainly growth retardation and cardiac complications. External radiotherapy has no role in the routine management of DTC. It is used in a palliative manner for extensive local invasion in neck region, painful bone metastasis, or brain metastasis where surgery is not possible.

2.2%, and leukemia 2.5% in a group of patients receiving cumulative dose of 6 GBq. Children with DTC have low mortality rate and increased life expectancy; therefore, less aggressive treatment modalities (lower doses) can be aimed to reduce complications of therapy. Response to therapy can be evaluated with RAI diagnostic scintigraphy along with neck US, serum Tg, and anti-Tg antibody levels 12 months later. The aim of surgery accompanied with RAI therapy is to decrease Tg level below 5 ng/mL, negative RAI scintigraphy, and a negative neck US. If this is achieved, the child can be evaluated with annual follow-ups. 18-Floro-deoxy-glucose (FDG) PET is not vital in DTC, unless patients have elevated Tg levels with negative I-131 scintigraphy findings. Uptake on an FDG-PET scan is a sign for dedifferentiation that is a predictor of poor outcome. Then alternative therapies should be planned.

Complications of RAI

18

remnant ablation is 300 Gy, and lymph node metastasis is 80 Gy.44

Gastrointestinal symptoms are commonly seen immediately or the following day of therapy. Nausea and vomiting are seen (36%-67%), which is controlled by antiemetics.46 Bitter taste and tenderness of salivary glands are other side effects and usually resolve in a few days to months. Transient neck pain, edema, and hoarseness can be seen if the patient has residual thyroid tissue or locally invasive tumor. In the follow-up, the most common problem is impaired salivary gland function. A few months after the therapy, transient bone marrow suppression can be seen that is generally self-limiting and does not require transfusion. In children, risk of pulmonary fibrosis with high cumulative doses can be seen.47,48 During RAI treatment, gonads receive radiation as well. Females in their reproductive ages have temporary amenorrhea. Young male spermatogonia are sensitive to radiation-absorbed doses over 50 cGy.49 Secondary cancer development can be another complication of RAI in children. Rubino et al50 found that the relative risk of bone and soft tissue tumors were 4%, female genital organ tumors 2.2%, central nervous system tumors

FDG-PET/CT in Childhood Sarcomas Childhood sarcomas constitute rare, wide range, heterogeneous group of neoplasms with mesenchymal origin. Tumors may arise in bone or soft tissues anywhere in the body. They account for only 1% of all malignancies, and although the incidence of malignancy is higher in adults, sarcomas occur with higher frequency in children. These tumors have different histopathological subtypes, mainly osteosarcoma (OS), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), and non-RMSs.51-53 Several factors affect prognosis, including age and sex of the patient, site, subtype, grade, stage, or volume of tumor. A 5-year survival rate for all bone and soft tissue sarcomas is approximately 65% and decreases to 20%-30% for recurrent and metastatic patients despite aggressive surgery, multiagent chemotherapy, and radiation therapy.54 Diagnostic workup and staging is critical for the optimal therapy decision. Detection of lymph node or distant metastases may avoid surgery as an initial treatment and may guide

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312 radiation therapy planning after chemotherapy. Initial evaluation of a child or adolescent with a suspected bone or soft tissue mass often begins with radiography, then primary tumor evaluation for bone or soft tissue sarcoma includes MRI or CT or both. For extremity lesions, the imaging should include the entire long bone involved and adjacent joints. Imaging for metastatic disease includes a bone scan (BS) and CT of the chest for patients with any bone or soft tissue sarcoma.55-57 Although several radiotracers were used, 18FDG is the most commonly used radiotracer in patients with sarcoma and has gained worldwide acceptance. The usefulness and suggestions for 18FDG-PET/CT depend on different sarcoma types. National Cancer Center Network (NCCN) guidelines states that 18FDG-PET/CT must be considered for the initial diagnostic workup, restaging, and surveillance of ES and OS. For soft tissue sarcomas, 18FDG-PET/CT was found to be useful under certain circumstances such as prognostication, grading, and determining response to chemotherapy.58,59

Initial Staging or Restaging Studies evaluating the additional value of 18FDG-PET/CT for staging and restaging of childhood bone and soft tissue carcinoma are heterogeneous. Most of these have small number of patients with different sarcoma subtypes. Early studies included 18FDG-PET only, whereas later studies had used PET/CT which is particularly a concern in detection of pulmonary metastases which is supposed to be a limitation of PET-only images. The use of intravenous contrast in PET/CT is not well studied and has the potential to further improve the accuracy of 18FDG-PET. The staging or restaging of sarcomas includes primary tumor, lymph nodes, lung, and bone metastases. Although rare, other sites such as brain and liver may also be affected. Evaluation of primary tumor site is achieved by radiological imaging mainly by MRI. MRI provides superior soft tissue contrast resolution images of the primary tumor and detects the relation of the primary with vital organs that are crucial for surgical planning. 18FDG-PET in primary tumor may help to improve the diagnosis and may guide biopsy site in heterogeneous soft tissue tumors. 18FDG-PET scan in biopsy setting helps to identify most malignant site on the whole mass histology when compared to MRI.60 Although in few studies, 18 FDG-PET, by using different techniques such as “delayed imaging,” is found to be able to identify benign and malignant soft or bone lesions; however, there is a marked overlap that limits the clinical effect. As reported by Shin et al, there was a significant difference between standardized uptake values (SUV)max of benign and malignant musculoskeletal tumors both in soft tissue tumors and bone tumors. When the SUVmax threshold of 3.8 was used, sensitivity, specificity, and diagnostic accuracy of 18FDG-PET/CT was found to be 80%, 65.2%, and 73%, respectively.61,62 In the primary diagnosis, 18FDG-PET may also help in the identification of disease grade. Charest et al in a group of patients with sarcomas found that 18FDG-PET/CT has high sensitivity (94% when SUVmax Z 2.5 was considered positive) for detection of bone and soft tissue sarcomas. In the initial staging group,

18

FDG-PET could reliably identify low-grade and high-grade sarcoma groups (area under the receiver operating characteristic [ROC] curve of 94%), and all sarcomatous lesions with SUVmax Z 6.5 were of high-grade histology.63 Although there was a potential of 18FDG-PET for grading, availability of advanced biopsy-pathology and radiological techniques reduces the need for 18FDG-PET for that application. 18 FDG-PET was found to be most useful in the detection of lymph node and distant metastases. Tateishi et al compared the diagnostic accuracy of 18FDG-PET/CT and conventional imaging (CI; BS, chest radiograph, whole-body CT, and MRI of the primary site) for the staging and restaging of 35 patients suffering from RMS. 18FDG-PET/CT was found not to be superior to CI for the T and N stages. However, 18FDG-PET/ CT could determine the M stage correctly in 31 patients (89%), whereas the accuracy of CI in M stage was 63%.64 Similarly, Völker et al in a multicenter study of 46 pediatric patients with sarcoma (ES, n ¼ 23; OS, n ¼ 11; RMS, n ¼ 12) found that 18 FDG-PET and CI were equally effective in primary tumor detection (accuracy of 100%). 18FDG-PET was superior to CI for the detection of lymph node (sensitivity, 95% vs 25%) and bone involvement (sensitivity, 90% vs 57%), whereas CT was more reliable than 18FDG-PET in detecting pulmonary metastases (sensitivity, 100% vs 25%).65 In another study, London et al compared 18FDG-PET/CT with CI in detecting malignant lesions. Excluding pulmonary lesions, 18FDG-PET/CT had higher sensitivity and specificity than CI (83%, 98% vs 78%, 97%); however, in pulmonary lesions, PET/CT had higher specificity than CI (96% vs 87%) but lower sensitivity (80% vs 93%).66 Accurate detection of pulmonary nodules in patients with sarcoma is important, and oligo-metastases of lung may undergo resection or local ablative therapies that may improve patients’ survival.67 Recently, all PET devices were used as hybrid PET/CT, and accurate evaluation of CT portion of studies is crucial in the pulmonary lesions. CT portion increases the sensitivity of test with compromise from specificity. PET part of the study may be improved in suspicious cases by respiratory gating,68 and CT part may also be improved by breath-hold images used after whole-body images. In selected patients, inspiratory CT added to conventional PET/CT significantly improves the detection of small nodules (10.6%), especially in those lesions located in the lower lobes, due to respiratory movements and may have an effect on patient management.69 Bone metastases detection is also a debatable issue in patients with sarcomas. The most cited study in this subject was by Franzius et al, who compared 18 FDG-PET and BS for the detection of osseous metastases from primary malignant osseous tumors. In 70 patients (32 OS and 38 ES), 18FDG-PET had a sensitivity of 90%, a specificity of 96%, and an accuracy of 95% on an examination-based analysis. The corresponding values for BS were 71%, 92%, and 88%. In only ES patients, the sensitivity, specificity, and accuracy of 18FDG-PET and BS were 100%, 96%, 97% and 68%, 87%, 82%, respectively. 18FDG-PET could not detect the five osseous metastases from OS, but all of them were accurately detected by BS. Authors concluded that 18 FDG-PET is superior to BS for detection of osseous

Pediatric and adolescent tumors metastases from ES. However, in patients with OS, 18 FDG-PET seems to be less sensitive than BS.70 The addition of CT to PET as hybrid PET/CT changed this results by the detection of sclerotic lesions in the CT part in the thin slice bone window images. The studies also reported that compared to 18FDG-PET/CT, BS has difficulty in detection of metastases near the growth plate because of physiological activity.71,72

Therapy Response Evaluation of success of chemotherapy or radiotherapy or both is important. Early detection of nonresponding tumor may lead to a change in chemotherapy that prevents continuation of an already ineffective therapy. In different cases, therapy response may also affect the radiation field and even may prevent aggressive therapy such as surgery. 18FDG-PET was found to be useful and superior to anatomic imaging modalities in therapy response evaluation. There are several studies which used 18FDG-PET/CT as a marker for chemotherapy response detection. Some studies used 18FDG-PET dynamic data (MRGlu of K(1), k(2), k(3), k(4), fractional blood volume, and influx according to Patlak) and others used static imaging analysis (SUVmax, total lesion glycolysis [TLG], SUVmax/ SUVliver, metabolic tumor volume [MTV], anatomic tumor volume, etc). Dimitrakopoulou-Strauss et al performed dynamic PET studies with 18FDG in patients with soft tissue sarcomas who received neoadjuvant chemotherapy. 18 FDG-PET/CT was performed pretherapy and after two cycles of chemotherapy. For the evaluation of therapy response, the ΔSUVmax led to an accuracy of 58%. The combined use of SUVmax and influx according to Patlak of each study led to the highest accuracy of 83%. The combined use was found to be useful for the prediction of responders (PPV, 92%).73 Byun et al compared 18FDG-PET/CT with MRI after neoadjuvant chemotherapy to predict a poor histologic response in OS. Among the parameters studied (SUVmax, MTV, TLG, and

313 tumor volume based on MRI [MRV]) either MTV Z 47 mL or TLG Z 190 g after one cycle of chemotherapy was significantly associated with a poor histologic response (OR ¼ 8.98).74 Therapeutic response among different histological sarcoma subtypes is also different. Gaston et al reviewed the patients with ES and OS after neoadjuvant chemotherapy and showed that ΔSUVmax between baseline and posttherapy was associated with histologic response for ES or OS. A 50% reduction in MTV was found to be significantly associated with favorable histologic response in OS. The same criteria for ES could not predict good responders accurately. Increasing the threshold for ES to a 90% reduction in MTV resulted in high correlation with favorable histologic response. Authors concluded that response to neoadjuvant chemotherapy evaluated by PET findings should be interpreted differently for ES and OS.75 (Fig. 2). 18 FDG-PET also has a prognostic value, in addition to studies showing 18FDG-PET as a good response predictor of therapy response. In a group of patients suffering from OS, high SUVmax or TLG before and after chemotherapy was found to be associated with worse progression-free and overall survival. The cut point for SUVmax-lean was greater than 15 g/mL before chemotherapy, and it was greater than 5 g/mL after chemotherapy.76 The superiority of 18FDG-PET/CT over CI in staging and therapy response evaluation, as described briefly, has proved to have major clinical effect. In our preliminary study in a group of patients with RMS, we have found that 18FDG-PET changed clinical management in 37.5% of patients’ referrals when 18 FDG-PET/CT evaluated side by side with pediatric oncologist.77 In conclusion, 18FDG-PET/CT has found important application in pediatric patients with sarcoma. Staging and response to therapy are the most validated applications. Prospective trials with 18FDG-PET/CT as a surrogate marker for therapy response may further increase the clinical utility.

Figure 2 (A) A 9-year-old girl with a diagnosis of Ewing sarcoma originating from left illac bone. FDG-PET/CT images show destructive mass in left illiac bone (black and white arrows a and b) with extensive bone marrow metastases (black arrow heads, c) with no abnormality on CT. (B) After two cycles of chemotherapy, FDG-PET/CT images showed complete resolution of metabolic activity of primary tumor and metastases (d) with partial decrease of size of primary in the left illiac bone (white arrows e).

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involvement. In several studies, 18FDG-PET/CT had led to a stage change in 10%-50% of patients.78,90,91 Montravers et al evaluated the utility of 18FDG-PET in childhood lymphomas compared with CT and clinical data. 18FDG-PET was found to be very sensitive for staging and restaging of lymphoma, showing more lesions than CT, with 50% of the patients upstaged. In this study, standardized questionnaire for evaluation of the clinical effect of 18FDG was answered by referring physicians, which showed that clinical management was modified based on the 18FDG-PET results in 23% of patients.90 Paulino et al searched the effect of 18FDG-PET/CT over CI in patients with HL who underwent chemotherapy followed by involved-field radiotherapy (IFRT). In 19 of 53 patients (35.8%), there was discordance between CT and PET/CT findings. Spleen and lymph nodes in neck, mediastinum, and inguinal region were the most common locations for the discordance. A change in stage occurred by PET/CT imaging in five patients (9.4%) and a change in IFRT fields occurred in nine patients (17%); eight were more extensive while one was less extensive.92 Extranodal sites, especially bone marrow and spleen, is critical in the staging. In patients with pediatric lymphoma, 18 FDG-PET/CT has been found as effective as BMB and predict BMB results with high accuracy. The sensitivity and negative predictive value (NPV) of 18FDG-PET/CT was 87.5% and 96%, respectively, for bone marrow involvement.93 In focal bone marrow involvement of the disease, 18FDG-PET/CT outperformed BMB. The overall sensitivity of detecting focal bone marrow involvement by lymphoma was 92% and 54% for 18FDG-PET/CT and BMB, respectively. BMB obtains information from a limited area, typically the iliac crest; however, 18FDG-PET/CT provides information about the entire bone marrow and may guide biopsy site.94 Spleen enlargement in patients with lymphoma is a rather nonspecific finding, and approximately 30% of patients with marked splenic enlargement do not have malignant involvement. 18 FDG-PET/CT could detect spleen involvement better than CT in diffuse involvement uptake higher than liver (spleen/ liver ratio 4 1.4), or in focal lesions, SUV 4 2,3 was found to be highly accurate predictors of lymphomatous involvement.95,96 CT part of PET/CT is more sensitive than PET in the evaluation of pulmonary involvement: limited spatial resolution of PET and continuous breathing during PET data acquisition impair the detection of small pulmonary nodules especially in lower lobes. Although rare in HL, thoracic CT was reported to be more sensitive than 18FDG-PET in the detection of pulmonary involvement of HL (70% vs 100%).85,89

FDG-PET/CT in Childhood Lymphomas Lymphomas are the third most common malignancy in the pediatric population and constitute approximately 15% of all malignancies in childhood. Non-Hodgkin lymphoma (NHL) is more common than Hodgkin lymphoma (HL) (60% vs 40%) and contributes to the most deaths from lymphoma.78,79 As defined by World Health Organization classification, there are two major subclasses of HL, namely classical HL and nodular lymphocyte predominant HL. Classical HL is subdivided into nodular sclerosing, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types. Nodular sclerosing HL accounts for nearly 60% of all newly diagnosed cases in the developed countries, whereas mixed cellularity disease is more common in poor countries.80 Almost all NHL in children is high grade, and there are three major subtypes: Burkitt lymphoma 45%, lymphoblastic lymphoma 35%, and anaplastic large cell lymphoma 10%. In contrary, in adults there are several subtypes of NHL, most of which are rarely seen in children and may have low-grade indolent course.81 The treatment of lymphoma includes chemotherapy alone or combined with radiotherapy, and in patients with refractory disease, high-dose multi-agent chemotherapy with stem cell transplantation support is also considered. There are several prognostic factors for lymphomas; age, sex of the patient, stage, site of disease, tumor biology, and response to therapy.82 Diagnostic evaluation of the patients includes history, physical examination, bone marrow biopsy (BMB) and aspiration, total-body imaging, and laboratory tests. Previously, total-body imaging was performed with the radiological imaging methods such as CT, MRI, or US. Nowadays, 18 FDG-PET/CT has been accepted as the method of choice as a whole-body imaging, especially for HL with sensitivity over 90%. The sensitivity of 18FDG is a concern in NHL in adults in whom low-grade lymphomas with low 18FDG uptake such as small lymphocytic lymphoma is more common; however, this is not the case in children with NHL that are mostly high grade with high 18FDG avidity.83,84

Initial Staging and Restaging 18

FDG-PET/CT was proved to be superior for staging malignant lymphomas when compared with conventional, scintigraphic, and radiological imaging modalities, including BS, 67 Ga-scintigraphy, US, contrast-enhanced CT, and MRI.85,86 Although its specificity is decreased because of nonspecific inflammatory uptakes in lymph nodes or physiologic 18 FDG uptake in brown fat, thymus, muscles, or tonsils, CT part of the PET/CT and pattern recognition may avoid falsepositive interpretations.87 The sensitivities and specificities of 18 FDG-PET/CT or 18FDG-PET for initial staging of malignant lymphomas are 93%-99% and 95%-100%, respectively.85,88,89 Overall, PET/CT may demonstrate more nodal and extranodal lesions compared to CT, resulting in upstage of their disease. Especially in the restaging, 18FDG-PET/CT may also downstage the patient by excluding malignant

Therapy Response Standard therapy of pediatric lymphoma typically involves chemotherapy, which may be followed by IFRT in selected cases. Patients with early-stage HL often do not receive radiotherapy, whereas those with intermediate and advanced stages, especially with bulky disease, have demonstrated improved progression-free survival with the addition of radiotherapy. Optimal detection of tumor response to chemotherapy is essential to determine the need for radiotherapy and

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Figure 3 (A) A 13-year-old male patient with diagnosis of HL mixed cellularity type. Initial staging FDG-PET/CT imaging shows disease in lower servikal, mediastinal, left axillary, abdominal lymph nodes with spleen involvement (black arrows on PET images [a] and white arrows on fusion images [b]). (B) Interim FDG-PET shows incomplete resolution of disease with Deauville score ¼ 4 and no significant change in SUVmax, and end-of-therapy images showed complete resolution of disease. Further, 6 months after end-of-therapy, patient had relapse in parasternal, abdominal lymph nodes, spleen, and also in the previously noninvolved areas like in left illac bone which shows sign of invovement on CT images.

the radiation dose. NHL represents a heterogeneous group of tumors, which is typically treated with chemotherapy. The use of radiotherapy is limited in pediatric NHL.97,98 (Fig. 3). Therapy response is best evaluated by 18FDG-PET/CT, and reported sensitivities and specificities of 18FDG-PET/CT for therapy response assessment of HL and NHL at interim or after completion of therapy were 75%-100% and 75%-90.9%, respectively.91,99 Several response criteria for 18FDG-PET, such as International Harmonization Project, Gallamini, London, and Deauville score were reported.91,99 Among these, Deauville criteria were accepted as a therapy response criteria in patients with HL by National Cancer Center Network guideline.83 In addition to these criteria, there are several semiquantitative parameters used for the evaluation of therapy response such as change in individualized SUV, PET-derived MTV, and TLG. The best parameter or criteria for response evaluation and best timing for response assessment are still under debate. Using the semiquantitative parameters defined above, Hussien et al evaluated 18FDG-PET for early therapy response prediction in pediatric HLs. All semiquantitative SUV estimates obtained from interim PET were significantly superior to the visual analysis. However, ΔSUVmax revealed the best results (area under the curve [AUC], 0.92; sensitivity, 100%; specificity, 85.4%; PPV, 46.2%; NPV, 100%; and accuracy, 87.0%) but was not significantly superior to SUVmax-estimation at interim PET and ΔTLGmax. Authors concluded that sophisticated semiquantitative PET measures in early response assessment of patients with HL do not perform significantly better than the previously proposed ΔSUVmax.100 In another study, Bhojwani et al used London criteria to compare CT and 18FDG-PET/CT findings with biopsy results in patients with NHL. The sensitivity and NPV of 18 FDG-PET/CT were 100%, but specificity and the PPV were low (25% and 60%, respectively).101 As seen with several studies, PPV of PET is relatively low owing to nonspecific inflammation after therapy, mimicking residual disease. Because false-positive 18FDG-PET/CT findings are common,

for accurate determination of residual disease, biopsy or close monitoring or both are required.83 Furth et al in a prospective multicenter trial, evaluated the results of 18FDG-PET in 40 pediatric patients with HL in different time intervals (before polychemotherapy [PET-1], after two cycles of polychemotherapy [PET-2], and at the end of polychemotherapy [PET-3]). At early and late response assessment, the proportion of PET-negative patients was significantly higher than patients with negative findings in CI. Sensitivity and NPV were 100% for early and late therapy response assessment by PET. Patients with relapse during follow-up were detected by PET-2/3, whereas one of these patients was not detected by CI-3. PET was superior to CI with regard to specificity in early and late response assessment (68% vs 3%, and 78% vs 11%, respectively). Specificity of early response assessment by PET was improved to 97% by quantitative analysis of SUVmax reduction using a cutoff value of 58%.102 18FDG-PET not only detected therapy response, but it also has a prognostic value and helps in the estimation of progression-free or overall survival. Bailly et al in 19 children with Burkitt lymphoma compared 18FDG-PET and CT after induction chemotherapy. 18FDG-PET showed no evidence of residual disease in 15 cases, in agreement with CT in 9 of 15 cases. The six discordant cases negative by histology and 18 FDG-PET was true negative for these cases. The 5-year progression-free survival was significantly higher in patients with negative 18FDG-PET than those with positive 18FDGPET.103 Our group observed the high NPV of 18FDG-PET and found that progression-free survival in disease-free patients with Deauville score of 1-3 was better than in patients with Deauville 4-5. Similarly, patients with values interim SUVmax o 2.7, end-of-therapy SUVmax o 2.2, and end-of-therapy tumor diameter o10.5 mm had longer progression free survival (PFS) than patients with higher values.104 18 FDG-PET/CT is a well-established imaging method for staging and restaging of pediatric patients with lymphoma and superior to CI. High NPV is the definite superiority of 18FDG-

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Figure 4 I-123 MIBG whole-body images, (A) no evidence of disease in a 9-year-old girl with high-risk neuroblastoma in remission. A routine I-123 MIBG follow-up scan (B) 6 months later, while the patient was asymptomatic, showed unexpected, extensive disease relapse in the skeleton.

PET; however, low PPV warrants further follow-up or biopsy. Optimal response criteria in different patient groups of lymphoma need to be determined with more prospective studies.

Advances in Radionuclide Imaging of Neuroblastoma Neuroblastoma (NB) is the second most common solid tumor in young children accounting for 8% of the pediatric malignancies and 15% of the pediatric cancer deaths.105,106 Functional and morphological imaging modalities have complimentary roles at various stages of disease assessment. Imaging findings are embedded in the International Neuroblastoma Risk Group Staging System (INRGSS) that includes presurgical image-defined risk factors.107 CT and MRI are the most commonly employed morphological imaging modalities and are essential for the initial staging and for planning surgical procedures. Functional modalities are included in all parts of disease evaluation. They are especially important, and considered superior to morphologic modalities, in assessing response to therapy and in surveillance for disease recurrence because they demonstrate tumor viability. Metaiodobenzylguanidine (MIBG) scintigraphy is the leading functional modality in NB evaluation.108 This article presents advances in established nuclear medicine studies as well as novel studies and radiopharmaceuticals in the diagnostic workup of NB.

MIBG Scintigraphy MIBG, a noradrenaline analogue, localizes in tumor cells originating from the primitive neural crest (NB, ganglio-NB, ganglioneuroma, and pheochormocytoma) using the norepinephrine transporter system via the type I catecholamine

reuptake system.109,110 It is, therefore, highly specific for these tumor types. It is labeled with iodine 123 (I-123) that replaced the original I-131 label. Few centers may still be using I-131MIBG due to limited availability of I-123. Compared to I-131, I-123 has a shorter half-life, lacks beta particle emission, allows injection of higher tracer activities, and is better suited for SPECT because of higher count densities. These differences result in superior image quality at a lower patient radiation dose.111 MIBG scintigraphy is the best established and most widely used scintigraphic technique in the evaluation of NB because of its high sensitivity (97%) and specificity (83%-92%).112 It is indicated for initial staging, assessment of response to therapy, and surveillance for disease relapse.107 It is also required to determine eligibility for I-131 MIBG therapy by documenting MIBG avid disease. It is superior to MRI and 18FDG-PET/CT in assessing response of bone marrow disease to therapy because unlike these modalities its interpretation is not limited by posttherapy changes.113 It is superior to BSs and CT in evaluating response of cortical bone metastases to therapy because interpretation of BSs and CT may be complicated by healing changes.114 At the primary tumor site, it can distinguish between residual tumor and posttherapy changes that are often seen on CT and MRI.115 MIBG scintigraphy is highly valuable in long-term surveillance after completion of therapy. It was shown to have a 94% detection rate for skeletal relapse compared to 43% for 18 FDG.115 It was more sensitive than BSs and bone marrow biopsies in detecting relapses as well116 (Fig. 4). MIBG studies are technically demanding. Several guidelines describe the procedure.115,117 The weight appropriate radiopharmaceutical dose is available from the latest version of the European Association of Nuclear Medicine pediatric dosage card118 or from the North American Consensus guidelines for radiopharmaceutical administration in children.119 SPECT is an

Pediatric and adolescent tumors important element of the study. It is important in the assessment of the primary tumor, detection of residual disease postsurgery, and detection of lymph node metastases that may be difficult to identify on planar images when they are adjacent to areas with high uptake such as the liver, bladder, or the primary tumor. It allows meaningful correlation, as well as the option to co-register the study with other cross-sectional modalities such as CT or MRI and can improve the certainty in interpretations over planar images.120,121 SPECT/CT can improve interpretation of MIBG scans. The type of CT in the study may vary from a low-dose scanner used for anatomical localization and attenuation correction to a fully diagnostic CT with or without contrast enhancement. The choice is dependent on the scanner capabilities, the imaging routines of individual centers, and the use of other modalities such as MRI or stand-alone CT. In any case, the CT settings in MIBG SPECT/CT studies should be optimized for pediatric imaging to reduce the dose. Nadel122 reported that MIBG SPECT/CT performed with diagnostic pediatric settings resulted in complete staging or restaging of 27 out of 44 children with NB and added additional valuable information in 29% of the cases. Rozovsky et al123 reported that SPECT/CT with a lowdose scanner provided additional diagnostic information compared to stand-alone diagnostic CT in more than half of the cases. In another study, a low-dose SPECT/CT improved lesion localization in 77% of sites compared to stand-alone SPECT, improved the diagnostic confidence and reduced the number of equivocal results. The main incremental value over SPECT was in excluding malignancy in sites of physiologic and benign uptake in the soft tissues.124 Traditionally, low-energy collimators are used in I-123 MIBG scans because of the 159 keV principle photon energy of I-123. In recent years, it was noted that medium-energy collimators may improve image quality of MIBG scans. Approximately 3% of the total I-123 photon emissions have energies above 400 keV. Medium-energy collimation reduces septal penetration of these high-energy photons resulting in improved image quality with less scatter.125 Interpretations of MIBG studies are sometimes hindered by low tracer uptake by the tumor and by physiologic uptake in normal tissues that may be confused with disease. Most of the NBs show high avidity for MIBG; however, approximately 10% of tumors are MIBG negative.126 Furthermore, some medications may alter the MIBG biodistribution, and prevent or decrease the localization in the tumor.127 Some of these medications such as phenyleprhrine, labetalol, and tricyclic antidepressants may be encountered in children.128 In certain cases, both MIBG avid and nonavid disease may be present concomitantly.126,129 In some unusual cases, large abdominal tumors may be MIBG negative while their metastases avidly localize the tracer. MIBG has a physiologic heterogeneous pattern of uptake in the liver. Jacobsson et al130 showed that MIBG uptake in the left liver lobe is often higher than in the right lobe. Bar-Sever et al reported that the heterogeneity of MIBG distribution in the liver includes both diffuse and focal patterns mainly affecting the left lobe. Focal patterns typically involve segments two and four of the left lobe.131 Owing to these complex patterns of normal tracer distribution in the liver, MIBG scintigraphy cannot reliably

317 determine the presence of liver metastases, especially of small metastases, and correlation with other imaging modalities is essential. The ability of MIBG to demonstrate disease sites can be dose dependent. It has been shown that immediate posttherapy I-131 MIBG scans often show more disease sites than pretherapy diagnostic I-123 MIBG scans.132,133 Another limitation, which should be considered, is that tumors that mature into ganglioneuromas may continue to show MIBG avidity.134 The major effect of MIBG results on disease management dictated a need for more objective and standardized reporting. Semiquantitative scoring systems were developed to achieve this goal. These scoring systems provide more accurate and standardized assessment of disease extent at diagnosis and following therapy and are an important instrument for objective evaluations in large multicenter clinical trials. They are also used for prognostication purposes.135,136 The most widely used systems in large clinical trials are the Curie score in North America and the SIOPEN score in Europe. The Curie score divides the skeleton into nine segments to assess bone and bone marrow disease, and a 10th sector that counts any soft tissue involvement. The cumulative Curie score can range from 0-30.137 The SIOPEN score divides the skeleton into 12 anatomical segments. The extent and pattern of MIBG uptake in each segment is scored using a 0-6 scale. The SIOPEN score ranges from 0-72 and does not include soft tissues. Both systems have been validated in large patient cohorts with low interobserver and intraobserver variability.137-139 The scoring systems can be used for prognostication purposes facilitating the identification of patients with the highest risk. Yanik et al showed that Curie scoring carries prognostic significance in the management of patients with high-risk NB. In particular, patients with scores 42 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies.140 Ladenstein et al139 reported that a SIOPEN total score greater than 45 indicates a poor outcome. Decarolis et al compared both systems on 58 children with grade four NB, from the German Neuroblastoma Trial NB97, preinduction and postinduction chemotherapy. Their results show a good agreement between the scoring methods. A Curie score equal or less than two and a SIOPEN score equal or smaller than four at diagnosis and negative MIBG scores after four cycles of chemotherapy were associated with favorable outcome compared to the outcome of patients with higher scores.141

Skeletal Scintigraphy Bone scans can depict skeletal metastases and often the primary tumor as well that appears as faint uptake in an ill-defined region in the soft tissues due to tracer deposition in tumor calcifications commonly seen in NB. Bone scans can occasionally suggest the presence of marrow disease. Diffuse tracer activity, often symmetrical, in metaphyseal regions around the knees, in the proximal femurs, and in the iliac bones, although nonspecific may indicate bone marrow involvement. A pattern of multiple focal or diffuse bone lesions seen concomitantly with a region of diffuse soft tissue uptake (commonly in the abdomen) is suspicious for metastatic NB and warrants further investigation without delay. This concerning pattern may be encountered

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318 every once in a while in the investigation of limping children with no history of previous disease. Bone scans are sensitive in depicting sites with abnormal bone metabolism, but their specificity is low.142 MIBG scintigraphy often shows more skeletal lesions than BSs143-145 and, unlike BSs, can be used to evaluate their response to therapy. Bone metastases in NB may have a symmetrical distribution adjacent to growth plates of long bones. These metastases may be difficult to identify and require meticulous imaging technique and patient positioning.146 Skeletal scintigraphy can complement MIBG scans at diagnosis, because even with MIBG avid disease there may be a lesion without MIBG uptake that would be positive on skeletal scintigraphy.147 The effect of skeletal scintigraphy in demonstrating metastatic disease is significantly higher in cases of MIBG-negative disease. Bone scans are not routinely indicated in the follow-up of children with NB because of their low specificity and limitations in assessing response to therapy. 18

FDG-PET/CT

18

FDG is transported into the cells by glucose transporters, entrapped and accumulates in metabolically active tissues. It is a highly sensitive tumor imaging probe but is limited in specificity. Most NBs show 18FDG avidity both in the skeleton and in the soft tissues, and PET/CT imaging with 18FDG can be used at diagnosis as well as during and after therapy.148,149 18 FDG-PET/CT offers high-resolution images, CT correlation, and a relatively short and widely available diagnostic study for the evaluation of children with NB. Physiologic or enhanced 18 FDG activity in the marrow during chemotherapy and granulocytes stimulating factor treatment can result in both false-positive and false-negative results (Fig. 5). Physiologic intense 18FDG activity in the brain can limit its sensitivity in

identifying adjacent skull metastases.149-152 18FDG activity in unsuspected sites of infection, trauma, or in incidental benign bone lesions may also complicate image interpretation.87,149,151,153 Most studies comparing MIBG scintigraphy to 18FDG-PET/CT in NB concluded that owing to the low specificity of 18FDG, it should be considered as a complimentary study to MIBG that may be especially important in cases of MIBG-negative tumors or when MIBG scintigraphy reveals less disease than suggested by other CI modalities or by clinical symptoms.148 A large comparison between I-123 MIBG and 18 FDG-PET/CT consisting of 113 paired studies was conducted by Sharp et al They concluded that I-123 MIBG was superior to 18FDG-PET/CT in stage four NB, mainly due to better delineation of bone and bone marrow disease (the most common sites of disease progression). 18FDG-PET/CT was superior to MIBG in the less commonly encountered stages one and two. 18FDG provided important information in tumors that weakly accumulated MIBG and at major decision points during therapy.148 Papathanasiou et al152 reported that I-123 MIBG imaging was superior to 18FDG-PET/CT in high-risk NB, but the intensity of 18FDG tumor uptake and extent of uptake in the bone and bone marrow may have significant prognostic implications.

C-11 Hydroxyephedrine PET/CT C-11 hydroxyephedrine (HED) is a norepinephrine analogue that was developed to visualize the sympathetic nervous system to evaluate neuroendocrine tumors and the myocardial sympathetic innervations.154 Advantages of HED PET over I-123 MIBG scintigraphy include high spatial resolution, rapid tumor accumulation (minutes) as compared to 24 hours that are required in MIBG scans to achieve optimal tumor to

Figure 5 A MIP image (A) from a FDG-PET/CT scan performed on a 15-year-old girl with a right suprarenal intermixed ganglioneuroblastoma shows patchy and intense tracer uptake in the bones and marrow indicating extensive skeletal involvement (A). Selected PET and CT transaxial slices, (B) tracer uptake in part of the suprarenal tumor. Following chemotherapy and granulocytes stimulating factor treatment before surgery, a FDG-PET/CT MIP image (C) extensive homogeneous, diffuse tracer uptake in the bone marrow, a pattern more typical of reactive bone marrow changes than metastatic disease. Persistent tracer uptake is noted on selected transaxial slices in the abdominal mass suggesting viable tumor. MIP, maximum intensity projection. (Courtesy: Dr Elinor Goshen and Dr Dalia Valdman, Shiba Medical Center, Israel.)

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background contrast and lower effective doses. Disadvantages include the short C-11 half-life requiring an on-site cyclotron, limited availability, price, and high physiologic uptake in the liver, that may limit detection of hepatic metastases. High physiologic uptake in the kidneys (parenchyma and collecting systems) may also be a limitation.155,156 One study reported excellent sensitivity and specificity157 for this tracer but in a very small patient cohort. Additional studies with more patients are required to evaluate the role of C-11 HED in NB.

Gallium 68 DOTA TOC/TATE PET/CT Somatostatin receptor scintigraphy (SRS) is feasible in NB because tumor cells over express somatostatin receptors (SS types one and two). Indium-111 pentetreotide SPECT imaging has been largely replaced by Ga-68 DOTA TATE/TOC PET/CT with the benefit of a shorter imaging procedure, high spatial resolution, and CT correlation. In a small patient cohort, Ga-68 DOTA TOC was shown to have superior sensitivity in comparison to I-123 MIBG.158 Larger patient cohorts are required to support this observation. SRS can be useful in cases of MIBG-negative or weakly positive tumors or in cases where clinical and morphological imaging findings are more prominent than MIBG findings. An attractive feature of SRS imaging is that it can be used to select patients for peptide receptor radionuclide therapy by replacing the positron emitter, Gallium 68, with a beta emitter such as Lu-177 or Y-90. Gains et al159 treated eight patients with relapsed or refractory NB who were positive on Ga-68 DOTA-TATE diagnostic PET imaging with Lu-177 DOTA-TATE and demonstrated the feasibility of this approach and the safety of the treatment. Kong et al160 reported on peptide receptor radionuclide therapy with either Lu-177 or Y-90 DOTA TATE in six patients with NB based on Ga-68 DOTA TATE findings.

Figure 6 F-18 DOPA PET/CT of a 13-year-old boy with relapsed neuroblastoma. The MIP image (A) and sagittal fused image (B) show extensive bone and marrow disease. MIP, maximum intensity projection. The images were kindly provided by Dr Arnoldo Piccardo, Galliera Hospital, Genova, Italy.

load in the skeleton and soft tissues for both modalities. Their results showed good agreement between the MIBG and F-18 DOPA findings. Higher scores were independently and significantly associated with disease progression.165 F-18 DOPA PET/CT shows significant promise in NB imaging (Fig. 6) but currently is not widely available worldwide because of high costs and regulatory issues.

I-124 MIBG PET F-18 DOPA PET/CT F-18-dihydroxyphenylalanine (F-18 DOPA) is a PET radiopharmaceutical consisting of dihydroxyphenylalanine radiolabeled with fluorine-18. It is a PET imaging probe that demonstrates cathecholamine metabolism resulting in high specificity for neuroendocrine tumors such as MIBG.156 It has been successfully used in adult neuroendocrine tumors showing superiority over other CI modalities.161,162 In a pilot study, comparing F-18 DOPA PET/CT with I-123 MIBG in 19 children with NB, F-DOPA had a superior sensitivity and overall accuracy compared to MIBG.163 F-DOPA studies offer faster imaging times, superior resolution, and improved lesion detectability compared to MIBG studies (Fig. 6). In another study, F-18 DOPA had a higher overall diagnostic accuracy compared to CT and MRI. It was superior to MRI/CT in bone or bone marrow, nodal, and soft tissue disease. CT and MRI were superior to F-18 DOPA in liver lesions.164 The prognostic value of F-18 DOPA PET/CT and I-123 MIBG scans, at the time of suspected or documented recurrence of NB, was investigated by Piccardo et al in a cohort of 24 patients. They employed semiquantitation techniques to measure the disease

Iodine 124 is a positron emitter with a long half-life of 4.2 days and a complex decay scheme that includes high-energy gamma rays, 50% of which are emitted simultaneously with the positron. The long biological half-life is advantageous for following up changes in biological processes but is a disadvantage from a dosimetric perspective.166 The unfavorable dosimetry (10-fold higher mSv/MBq compared to I-123 MIBG) is a major limitation in the employment of I-124 MIBG for diagnostic imaging, especially in children.166,167 Low administered doses and presence of high-energy photons that are emitted simultaneously with the positrons creating false coincidence events with the annihilation photons adversely affect image quality.166,167 I-124 MIBG has been mainly used in animal studies and in human dosimetric studies in adults.168,169 The possibility of using this tracer for diagnostic imaging in children with NB requires further investigation.

Other Experimental Tracers Fluorine-18 labeled MIBG analogues are being developed in an attempt to combine the superior MIBG targeting

320 qualities with the superb image resolution, early imaging, and quantification capabilities of an F-18 labeled PET tracer. The two F-18 labeled MIBG analogues, MFBG and PFBG, were studied in animals in comparison to I-123 MIBG.170 Further evaluation is needed to determine the applicability of these tracers in clinical imaging.

PET/MR Hybrid Imaging in NB MRI is the best morphological imaging modality in NB. It shows high sensitivity in detecting bone marrow metastases, high intrinsic soft tissue contrast resolution, precise definition of intraspinal tumor extension, good delineation of diaphragmatic involvement of thoracic tumors, and lack of ionizing radiation.106,108 A combination of MRI and MIBG scintigraphy has been shown to achieve the best sensitivity and specificity in NB imaging.171 Hybrid PET/MR imaging offers a one-stop shop with reduced radiation doses and has been shown to compare favorably with PET/CT in pediatric malignancies.172,173 Currently, there are insufficient data to define the role of PET/MRI imaging in NB. Nevertheless, it appears that with the ongoing development of tumor-specific PET tracers, the future holds a promising role for this advanced imaging technology in NB.

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