Abstract
The most common childhood malignancy is leukemia (30%), followed by brain tumors (20%), lymphomas, both Hodgkin’s (HL) and non-Hodgkin’s lymphoma (NHL) (14%), neuroblastoma (7%), soft tissue sarcoma (7%), Wilms’ tumor (6%), bone tumors (5%), germ cell tumors (3%), melanoma (3%), and hepatic tumors (1%). Their incidence varies according to patient age. Less common pediatric malignancies include head and neck cancer, Langerhans cell histiocytosis (LCH), germ cell tumors, neurofibromatosis type 1 with suspected malignant transformation, adrenocortical carcinoma, gastrointestinal stromal tumor (GIST), hepatoblastoma, hepatocellular carcinoma, carcinoid, insulinoma, and pheochromocytoma (Steliarova-Foucher et al., Lancet Oncol 18(6):719–731, 2017; Institute, NC. https://nccrexplorer.ccdi.cancer.gov/). Neuroblastoma is the second most common solid tumor in young children. It is a NET derived from the primitive neural crest. Although currently MIBG is embedded and required by international therapy protocols for patients with neuroblastoma and has a large body of evidence proving its validity and usefulness, PET tracers such as FDOPA, FDG, and 68Ga-peptides are increasingly used in imaging of neuroblastoma (Pai Panandiker et al., Clin Nucl Med 40(9):737–739, 2015). Additional pediatric NETs include ganglioneuroma, bronchial carcinoid (most common primary malignant pulmonary tumor in children), abdominal carcinoid (rare), pheochromocytoma, and PPGL. Approximately 75% of juvenile nasopharyngeal carcinomas also express surface membrane SSTRs. FDG-PET/CT is the scintigraphic study of choice for the assessment of lymphoma and sarcoma.
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12.1 General Tracer-Related Parameters
12.1.1 Radiopharmaceutical and Administered Activity
The EANM pediatric dosage card and to the North American consensus guidelines on radiopharmaceutical administration in children in the respective EANM and SNMMI and image gently web sites should be followed [1, 2].
Reference to national regulation guidelines, if available, should be considered.
Box 12.1 FDG Imaging Protocol [3,4,5,6]
Patient Preparation
-
Fast: 4 h before tracer injection and during the uptake.
-
Good hydration with plain, unflavored water is allowed and encouraged.
-
Measure and record patient’s height and weight on the day of the exam.
-
Avoid strenuous exercise 24 h prior to scan.
-
Discontinue glucose-containing IV fluids and parenteral nutrition from midnight before test or minimum of 6 h.
-
Blood glucose level must be measured before radiotracer administration and should be below 200 mg/dL (11.1 mmol/L), preferably below 120 mg/dL (6.66 mmol/L).
-
Date of last dose of potentially interfering medications that may cause false positive and false negative altered biodistribution should be recorded in technologist/ study notes (see below in study interpretation).
-
Brown fat reduction techniques include:
-
Early arrival (30–45 min prior to planned radiotracer injection time) to settle patient, establish IV line, and warm the patient in a temperature-controlled room with the addition of warm regular or electric blankets.
-
Avoid cold and air-conditioned spaces in transportation prior to study.
-
Premedication such as benzodiazepines and beta-adrenergic blockers (oral propranolol, IV fentanyl, oral diazepam in moderate dose) may be carefully used as a second option in consultation with referring physicians and pediatric anesthetists.
-
Radioisotope:
-
[18F]-Fluorodeoxyglucose (FDG)
Activity:
-
3.7–5.2 MBq/kg (0.10–0.14 mCi/kg), minimum dose 26 MBq (0.7 mCi).
Refer to the EANM pediatric dosage card and to the North American consensus guidelines on radiopharmaceutical administration in children in the respective EANM and SNMMI and image gently web sites.
Reference to national regulation guidelines, if available, should be considered.
-
FDG activity can be reduced when using modern PET technology, to 0.06–0.08 mCi/ kg 2.46–2.96 MBq/kg [7].
Acquisition Protocol
-
Uptake time: 60 min (±10%) between injection and scanning.
-
Patients should not talk, text, play video games, chew gum, or suck candies during the uptake phase.
-
Diapers should be changed in infants before the scan.
-
Acquisition parameters: 2–4 min/bed position (depending on equipment).
12.1.2 Study Interpretation for FDG Imaging [8,9,10]
-
Standardized elements to include in the PET/CT report can be found at the SNMMI website http://interactive.snm.org/docs/PET_PROS/ElementsofPETCTReporting.pdf
-
Abnormally increased FDG uptake should be described with respect to:
-
Intensity: mild, moderate, or severe, or compared to the blood pool and liver activity.
-
Pattern: focal, diffuse, linear.
-
Localization: based on CT or MRI.
-
-
Physiological tracer distribution, including specific patterns in children: brain, salivary glands, lymphatic tissue of the Waldeyer’s ring, muscles, brown fat, myocardium, mediastinum, thymus, liver, kidneys and bladder, gastrointestinal tract, testis, uterus, and ovaries.
-
False positives, including specific patterns in children:
-
Infant mouth with feeding or sucking during the uptake phase.
-
Thymus: uptake decreases with age but may increase after chemotherapy, thymic rebound.
-
Brown fat: usually bilateral in the neck, supraclavicular regions, axillae, mediastinum, paravertebral regions, and perinephric areas. Infradiaphragmatic activity considered to be brown fat is seen, as a rule, in conjunction with supradiaphragmatic brown fat.
-
Diffuse uptake in bone marrow following hematopoietic stimulating drugs such as G-CSF.
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Increased uptake in infectious and inflammatory processes, and in other benign entities.
-
Uptake in post-surgical scars.
-
Uptake in growth plate.
-
-
False negatives:
-
Hyperinsulinemia and hyperglycemia.
-
Small lesions, with limited tracer avidity.
-
Low metabolic tumors are rare in children but may occur with differentiated thyroid cancer and well-differentiated NETs.
-
Tumor necrosis.
-
Recent radiation or chemotherapy.
-
Recent treatments such as high-dose corticosteroid therapy and anti-retroviral medication.
-
Box 12.2 Radioiodinated Meta-Iodobenzylguanidine (MIBG) Imaging Protocol [11, 12]
Patient Preparation
-
Administer thyroid-blocking medication.
-
LUGOL solution:
-
Starting 2 days prior to and continued for 3 days after injection.
-
Dose: 0.6 mL of 5 % solution/day, single dose or split into 2 × 0.3 mL doses.
-
Delivery: diluted in any drink such as milk or juice as may cause a burn in the throat if undiluted.
-
-
Supersaturated potassium iodide (SSKI):
-
Starting 30–60 min prior to tracer administration, on day 0 and continued for a week.
-
Dose: <1 month—one drop orally/day; 1 month—3 years: 2 drops orally/twice a day; 3–18 years of age: 3 drops orally/three times a day; ≥70 kg—adult: 6 drops orally (2 drops/3 times a day).
-
-
Potassium iodate (in individuals sensitive to iodine and if no other thyroid blockade is available).
-
Starting 1 h prior to tracer injection, up to 5 times within the next 36 h.
-
Dose: 10 mg/kg, maximum 500 mg, minimum 50 mg.
-
Delivery: 200 mg tablet can be crushed, dissolved in 2 mL of sterile water, and administered by syringe or placed on a sugar lump.
-
Radiopharmaceuticals
-
[123I]-MIBG—the current standard SPECT tracer.
-
[131I]-MIBG—should only be used if 123I-MIBG or an alternative PET tracer is not available.
Activity
-
123I-MIBG: North American consensus guidelines recommend a dose of 5.2 MBq/kg (0.14 mCi/kg), minimum dose of 37 MBq (1 mCi), and maximum dose of 370 MBq (10 mCi). The EANM pediatric dosage card recommends a slightly higher activity, minimum dose of 37 MBq (1 mCi), and maximum dose of 400 MBq (10.8 mCi).
-
131I-MIBG: minimum injected dose of 35 MBq (0.95 mCi) and maximum dose of 78 MBq (2.11 mCi).
Acquisition Protocols
123 I-MIBG:
-
Time of scan: 24 h post-injection. Rare images at 48 h are added to clarify sites with low-grade uptake.
-
Collimator: medium energy is preferred, reduces scatter and septal penetration of high-energy photons; low energy can be also used.
-
Planar scans:
-
In older children: whole-body anterior and posterior projections, 5 cm/min, minimum 30 min, matrix 1024 × 512 or 1024 × 256.
-
In young children: multiple spot views of the entire body are preferred, matrix 256 × 256, trunk: 10 min/500 Kcounts. Limbs and skull 100 Kcounts, skull (anterior, posterior, left and right lateral views).
-
SPECT: 120 projections, 25–35 s/step, matrix 128 × 128, iterative reconstruction.
-
-
SPECT/CT, when available, is recommended.
131 I-MIBG:
-
Time of scan: 48 h post-injection, possible supplements at 72 h.
-
Collimator: high energy or medium energy.
-
Planar scans: whole body, anterior and posterior images, scan speed 4 cm/min, or multiple spot views of the entire body (150 Kcounts/view).
-
SPECT and SPECT/CT as indicated.
Box 12.3 [18F] Fluoro-Dihydroxyphenylalanine (FDOPA) Imaging Protocol [11, 15]
Patient Preparation
-
Fast: 4 h
-
Adequate hydration
-
Drug withdrawal (48 h prior to tracer administration): aromatic L-amino acid decarboxylase (AADC), catechol-o-methyl transferase (COMT), and monoamine oxidase (MAO) inhibitors.
-
Premedication with carbidopa: if used in children a dose of 2 mg/Kg is administered 1 h before FDOPA injection.
Activity
-
3 MBq/Kg (0.08 mCi/Kg), minimum dose is 26 MBq (0.7 mCi).
Acquisition Protocol
-
Uptake time: 60–90 min.
-
Acquisition parameters: 3 min/bed position.
12.1.3 Study Interpretation for MIBG Imaging [11, 13, 14]
-
Physiological biodistribution: myocardium, salivary and lacrimal glands, liver, lungs (blood pool on early images), bowel, renal collecting system, uterus (during menstrual period).
-
Adrenal glands: symmetric, mild (≤to the liver), normal size on CT.
-
Brown fat.
-
Thyroid (uptake of free iodine in case of poor blockade).
-
-
False positives:
-
Lung atelectasis, pneumonia.
-
Heterogeneous liver uptake (including focal uptake in the left lobe).
-
Kidneys and/or dilated ureters.
-
Rare-vascular malformations, accessory spleen, ectopic kidneys, foregut duplication, hemorrhagic cysts, ovarian torsion, and hernia.
-
-
False negatives:
-
MIBG-negative neuroblastoma (10% of cases)
-
MIBG-negative metastases
-
Small lesions, below the camera resolution
-
12.1.4 Study Interpretation for FDOPA Imaging [16, 17]
-
Physiologic biodistribution:
-
High: basal ganglia, liver, adrenals, pancreas (variable).
-
Moderate: myocardium, skeletal muscles, growth plate.
-
Faint: breasts, oral cavity, esophagus, bowel.
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Excretion: biliary (gallbladder and biliary tract) and urinary (kidneys, ureters, urinary bladder).
-
-
False positives:
-
Physiologically intense, variable uptake in uncinate process of pancreas.
-
Stasis in small intrahepatic bile ducts and/or in the urinary system.
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Growth plate fractures.
-
-
False negative:
-
Lesions adjacent to sites with high physiologic uptake.
-
Small lesions.
-
Lesions with low tracer avidity.
-
Box 12.4 [68Ga]-Peptides Imaging Protocol [15]
Patient Preparation
-
No fasting requiring.
-
Drug withdrawal: therapy with short-/long-acting somatostatin analogues (rare in children)—to avoid possible somatostatin receptor (SSTR) blockade.
-
Short-acting: 1–2 days discontinuation.
-
Long-acting: 4–6 weeks discontinuation.
Radiopharmaceuticals
-
68Ga-DOTA-TATE, -TOC, -NOC.
Activity
-
2 MBq/kg (0.054 mCi/kg), minimum dose is 14 MBq (0.3 mCi).
Acquisition Protocol
-
Uptake time: 60 min (range 45–90 min)
-
Field-of-view (FOV): true vertex-to-toe
-
Acquisition parameters: 2–4 min/bed position
12.1.5 Study Interpretation for 68Ga-Peptide Imaging [18, 19]
-
Physiologic biodistribution:
-
High uptake: pancreas (uncinate process), spleen, kidneys, pituitary gland.
-
Moderate uptake: liver, salivary glands, thyroid, bowel.
-
Faint uptake: adrenals, prostate, breast.
-
-
False positives:
-
Physiologic uptake in uncinate process, accessory spleens, splenosis, epiphyseal growth plates.
-
Meningiomas.
-
Skeletal lesions such as fractures, vertebral hemangioma, fibrous dysplasia.
-
Inflammatory processes such as reactive lymph nodes, post-radiation therapy changes.
-
Urine contamination.
-
-
False negatives:
-
Small lesions.
-
Lesions adjacent to sites with high physiologic uptake.
-
Tumors with low or variable SSTR expression.
-
Lesion dedifferentiation.
-
Box 12.5 Bone Imaging Protocols [20,21,22,23,24]
Patient Preparation
-
No need to fast.
-
No need for medication withdrawal.
-
Good hydration.
-
Frequent bladder emptying between injection and delayed imaging, and immediately before scanning.
-
Change diapers immediately before scanning.
Radiopharmaceuticals
-
[99mTc]Tc-methylene diphosphonate (MDP) or similar diphosphates.
-
[18F]sodium fluoride (NaF)
Activity
-
MDP: 9.3 MBq/kg (0.25 mCi/Kg), minimum dose 37 MBq (1.0 mCi).
-
NaF 2.22 MBq/kg (0.06 mCi/kg), minimum dose 14 MBq (0.4 mCi).
Refer to the EANM pediatric dosage card and to the North American consensus guidelines on radiopharmaceutical administration in children in the respective EANM and SNMMI and image gently web sites.
Reference to national regulation guidelines, if available, should be considered.
Acquisition Protocols
Bone scintigraphy
-
Position: supine, comfortably secured to the bed.
-
Collimators: high- or ultrahigh low energy, parallel hole collimator.
-
Time of scanning: at 2–4 h post-injection.
-
Acquisition parameters:
-
Whole body sweeps with bed speed adjusted to the child’s age.
-
8 cm/min for ages 4–8 years.
-
10 cm/min for ages 8–12 years.
-
12 cm/min for ages 12–16 years.
-
15 cm/min over 16 years of age.
-
-
Alternative: multiple spot views over entire skeleton, anterior and posterior projections, matrix 256 × 256, counts: torso 500 Kcounts, skull 300 Kcounts, knees 100–200 Kcounts, hands and feet 50–100 Kcounts.
-
SPECT 120 projections, 15–30 s/view, matrix 128 × 128 should be included:
-
To areas of localized symptoms.
-
If an abnormality is detected on planar imaging.
-
-
SPECT/CT, if available should replace SPECT [25].
-
For the CT component of SPECT/CT—tube setting will depend on whether the CT is intended to be low dose or fully diagnostic.
-
-
Delayed 24-h scan can be performed:
-
In cases of uncertain findings on routine 3-h scintigraphy.
-
When residual bladder activity overlies the pelvis and the child refuses to urinate or when bladder emptying is incomplete.
-
Bone NaF PET/CT:
-
Time of imaging: at 30–45 min after tracer injection.
-
Position: supine; arms by the sides for whole-body imaging, elevated when only the axial skeleton is scanned.
-
Acquisition parameters: 2–5 min /bed position, varies depending on injected amount, BMI, and camera.
12.1.6 Study Interpretation for Bone Imaging
-
Physiologic tracer biodistribution:
-
Homogeneous throughout the entire skeleton.
-
Visualization of kidneys, ureters, bladder.
-
Increased uptake in metaphyses of children and adolescents.
-
-
Abnormally increased skeletal uptake should be described with respect to:
-
Intensity higher or lower than in adjacent or in corresponding contralateral bone.
-
Pattern: focal or diffuse.
-
Location and number of foci.
-
Patterns of ST uptake:
-
Diffuse decreased: due to increased heterogeneous uptake in bone.
-
Diffuse increased: renal failure, short uptake time, of significant tracer extravasation at the injection site.
-
Focal increased: infection/inflammation, trauma, (calcified) ST metastasis.
-
-
-
Pitfalls
-
Urinary contamination or diversion reservoirs
-
Injection artifacts
-
Patient motion
-
Faulty energy window for image acquisition
-
12.2 Lymphoma and Sarcoma
12.2.1 Clinical Indications—Imaging with FDG (see also Box 12.1) [22, 26,27,28,29]
-
Staging/restaging
-
Metastatic workup in sarcoma
-
Response assessment
-
End of therapy baseline
-
Biopsy site planning
-
Confirmation of equivocal or discrepant findings on other imaging studies
12.2.2 Specific Study Interpretation Criteria
Lymphoma [30]
-
The (Deauville) five-point scale can be used in the assessment of treatment response in HL and NHL.
-
Score 1: No uptake above the background.
-
Score 2: Uptake ≤ mediastinum.
-
Score 3: Uptake > mediastinum but ≤ liver.
-
Score 4: Uptake moderately increased compared to the liver at any site.
-
Score 5: Uptake markedly increased compared to the liver at any site.
-
Score X: New areas of uptake unlikely to be related to lymphoma.
-
-
Reduction in standard uptake values (SUV) max from baseline of greater than 50% has been associated with overall improved progression-free survival.
12.2.3 Correlative Imaging [34]
-
Chest radiograph may be the first examination in a child presenting with chest/ mediastinal symptoms and can identify mediastinal mass and possible tracheal compression.
-
US of the abdomen and pelvis may identify lymphadenopathy but is not adequate for staging purposes. Cross-sectional imaging with contrast-enhanced CT and or MRI will be the next cross-sectional imaging study.
-
PET/CT and/or PET/MRI may be performed as next cross-sectional imaging in some institutions without intermediate stand-alone CT or MRI study.
-
In suspected sarcoma radiographs will be the first study in a child presenting with focal pain. Cross-sectional imaging with contrast-enhanced CT and dedicated high-resolution MRI will follow.
12.2.4 Red Flags
-
Good hydration prior to tracer administration will accelerate and increase excretion of the excess radiotracer.
-
If blood glucose levels are above 200 mg/dL (11.1 mmol/L), the study should be rescheduled, if possible. In diabetic patients, consultation with treating endocrinologist can be helpful in case of complex diabetic or insulin requirements.
-
Check the quality of images and of factors that may influence the SUV before reporting.
-
Study scheduling: in patients after treatment the study should be ideally scheduled at least 14 days after the last course of chemotherapy, and 2 months after surgery and 3 months after radiotherapy.
-
Semiquantitative analysis, in particular, SUV measurements, should be used with caution.
-
PERCIST criteria have not been validated in children.
-
FDG-PET is recommended in surveillance of lymphoma only in selected cases, determined by clinical situation [30].
-
Base of the skull to mid-thigh examination has been found sufficient in patients with lymphoma [35].
-
Staging scans performed after the initiation of treatment may result in false-negative studies [36].
12.2.5 Take Home Messages
-
FDG is taken up by malignant cells via glucose membrane transporters and phosphorylated by hexokinase into FDG-6-Phosphate, which does not follow further enzymatic pathways and accumulates proportionally to the glycolytic cellular rate.
-
Fasting decreases serum glucose levels and maintains a low insulin level.
-
The 60 min uptake time is needed for absorption and clearance of the radiotracer.
-
Patients should not talk, text, play video games, chew gum, or suck candies during the uptake phase to avoid FDG uptake in tense muscles.
-
PET imaging for staging in pediatric lymphoma should be given high priority for scheduling pre-therapy, especially in patients with critical condition.
-
Whole-body PET studies, from vertex to toes, should be performed in sarcoma and most of the pediatric solid cancers since the diseases can often occur distal to elbows and knees.
12.2.6 Representative Case Examples
Case 12.1 Diffuse Large B-cell Non-Hodgkin’s Lymphoma (NHL), Staging (Fig. 12.1)
Case 12.2 Burkitt’s Non-Hodgkin’s Lymphoma (NHL)—Staging (Fig. 12.2)
Case 12.3 Hodgkin Lymphoma (HL), Staging, Monitoring Treatment Response and Follow-Up (Fig. 12.3)
Case 12.4 Post-transplant Lymphoproliferative Disorder (PTLD), Transformation to Non-Hodgkin’s Lymphoma (NHL)–PET/MRI (Fig. 12.4)
Case 12.5 Osteosarcoma, Metastatic to Bone, Staging (Fig. 12.5)
Case 12.6 Metastatic Rhabdomyosarcoma (Fig. 12.6)
12.3 Neuroblastoma
12.3.1 Clinical Indications [11]
-
Staging.
-
Prognostic information based on scoring methods measuring disease extent.
-
Assessment of response to treatment.
-
Restaging of recurrence.
-
Long-term surveillance.
-
Imaging prior to treatment with radiolabelled tracers: 123I-MIBG scan will determine whether a neuroblastoma is tracer-avid and treatment with 131I- MIBG can be considered.
12.3.2 Correlative Imaging [37, 38]
-
Neuroblastoma will often present as an abdominal mass and the US will be the initial imaging study. Characteristic calcification and location of disease may suggest the likelihood of neuroblastoma diagnosis.
-
Bone scintigraphy is not routinely performed in a child presenting with suspected neuroblastoma since MIBG scintigraphy and PET imaging have replaced this test. However, a child presenting with bone pain or limp may have initial imaging with a bone scan.
-
Bone scintigraphy in a patient with suspected neuroblastoma can show typical abnormal, often symmetrical metaphyseal activity, focal bony lesions in the axial and appendicular skeleton as well as soft tissue uptake in a, mainly abdominal, mass (see Case 12.14. and Fig. 12.15).
-
Plain radiographs can show no abnormalities in cases with skeletal involvement of neuroblastoma.
-
MRI is the most common study performed to evaluate a mass in the chest, abdomen, and/or pelvis, in a child with neuroblastoma. It is mandatory when epidural and intracranial disease is suspected.
-
CT scans may also be used for imaging evaluation of chest, abdomen, and pelvic disease suspected to be neuroblastoma. It is not adequate as the single cross-sectional anatomic imaging modality when epidural or intracranial disease is suspected.
MIBG Scintigraphy of Neuroblastoma
12.3.3 Specific Study Interpretation Criteria (See also Box 12.2—Imaging with MIBG)
-
Pathological tracer uptake is found in the primary tumor and in metastases in lymph nodes, liver, bone, bone marrow, and rarely, skin, lungs, and brain.
MIBG Scoring Systems [39]
-
Provides a semiquantitative assessment of initial disease burden and response to therapy.
-
It is used for treatment tailoring and for prognosis.
-
Two validated scoring systems are in use:
-
The Curie Score (Children’s Oncology Group—COG) divides the skeleton into 9 compartments and a 10th compartment for the soft tissues. The uptake score for each compartment ranges from 0 to 3 [40].
-
The SIOPEN score (International Society of Paediatric Oncology Europe Neuroblastoma), only scores skeletal disease. The skeleton is divided into 12 segments. The uptake score for each segment reflects the disease extent in that segment and ranges from 0 to 6 [41].
-
12.3.4 Red Flags [14]
-
Careful drug history should be obtained before imaging. Numerous drugs interfere with the uptake or retention of MIBG and should be discontinued for approximately 4 biological half-lives. A detailed list of interfering drugs, most of them rarely used in children, can be found in Appendix 1 of the EANM guidelines [11]. The main drugs to be withdrawn in children are those used for symptomatic treatment of asthma and of upper respiratory tract infections (decongestants), and occasional antihypertensive drugs.
-
Thyroid blockage medication is required to prevent unnecessary irradiation of the thyroid gland by free radioiodine. Sedation, especially important for SPECT/CT, may be required because most children undergoing MIBG scintigraphy are young, and acquisition takes 60–90 min. In some occasions, feeding and bundling the infant prior to scan is all that is required to keep the child immobile.
-
Slow administration of the tracer reduces the likelihood of adverse reactions such as hypertension, nausea, vomiting, and pallor that may occasionally occur.
-
Children should be monitored during, and for a short time after, MIBG injection.
-
The most appropriate collimator type for 123I-MIBG imaging varies among different manufacturers and should be decided based on the equipment available in each department.
-
In young children, multiple spot views should be used because of higher count density and improved spatial resolution. Multiple views obtained for the skull (anterior, posterior, left, and right lateral views) improve detection of orbital and skull base lesions.
-
A full bladder can conceal pelvic lesions. Post-void images, SPECT, and/or SPECT/CT of the pelvis and less commonly, bladder catheterization can be employed.
12.3.5 Take Home Messages [14]
-
Primary tumors most commonly originate from the adrenal gland or from the sympathetic ganglia, along the abdominal, thoracic, and rarely cervical spine.
-
MIBG is an iodinated analogue of guanidine, structurally similar to norepinephrine (NE). It shares the same transport pathway as NE via the cell membrane NE transporter system. In the cytoplasmic compartment, MIBG is stored in the neurosecretory granules.
-
For functional imaging assessment of neuroblastoma, 123I-MIBG is considered a first-line test. It is the current standard due to appropriate physical characteristics for the best image quality and dosimetry.
-
131I-MIBG should not be used for diagnostic purposes due to poor image quality and higher radiation exposure.
-
About 10% of neuroblastomas do not accumulate MIBG.
-
Any MIBG uptake in the skeleton indicates metastatic disease.
-
SPECT/CT is of particular value for:
-
Differential diagnosis of heterogeneous hepatic tracer uptake, a known physiologic pattern vs. metastatic involvement.
-
To distinguish intracranial from skull lesions. Lesions involving the calvarium are on rare occasions due to cerebral metastases.
-
Distinction between cortical bone and bone marrow metastases.
-
Discrepancy in MIBG uptake between the primary tumor and metastases may be due to:
-
Biological heterogeneity in populations of tumor cells can alter their MIBG avidity.
-
Changes occur during the course of the disease course.
-
MIBG avidity of relapsed disease might differ from the initial disease.
-
After treatment, uptake in residual tumor deposits may persist due to differentiation of the tumor to mature MIBG-avid ganglioneuroma.
-
MIBG imaging plays a theranostic role in the assessment of neuroblastoma.
-
Alternative imaging of neuroblastoma with PET tracers can be considered.
-
PET Imaging of Neuroblastoma (see also Box 12.1, Box 12.3, and Box 12.4)
12.3.6 Clinical Indications [42, 43]
-
Alternative metabolic imaging in cases of MIBG-negative or weakly positive tumor.
-
When radiologic imaging modalities show more disease than MIBG scintigraphy.
-
Advantages of PET imaging of neuroblastoma include:
-
One-day appointment
-
No need for iodine blockage
-
Faster scan
-
Lesser need for anesthesia
-
Improved lesion detectability
-
Quantitation of tracer uptake
-
FDOPA [44,45,46] (See also Box 12.3)
-
FDOPA uptake is relatively specific for NETs including neuroblastoma. When available, it is considered the preferred PET alternative to 123I-MIBG.
12.3.7 Red Flags
-
In adults, carbidopa reduces physiologic uptake in peripancreatic region and increases uptake in lesions. However, there is no consensus regarding the use of carbidopa in children.
-
Avoid misinterpretations by performing late imaging after ambulation/hydration/diuretic administration.
12.3.8 Take Home Messages [47]
-
DOPA is present in the nervous system as a precursor of dopamine and FDOPA PET imaging tracks the metabolism of catecholamines.
-
Neuroblastoma FDOPA PET imaging provides a sensitive and specific assessment of the disease status. While being a relatively specific tracer for NETs other indications are also known.
-
Small-scale studies comparing FDOPA with 123I-MIBG in children show a higher sensitivity of the former tracer and superior detectability of small metastases in bones, soft tissues, and bone marrow.
-
Advantages:
-
Uptake is proportional to the degree of malignancy.
-
Prognostic value with higher FDG uptake at diagnosis is associated with poorer prognosis.
-
It can differentiate between residual active tumor and benign ganglioneuromas which maintain MIBG avidity but are typically FDG negative.
-
-
Limitations:
-
Lack of specificity, mainly for assessing the presence of bone marrow involvement, a very common location for neuroblastoma metastases and also a site of physiologic FDG uptake.
-
Cranial vault lesions may be difficult to detect on FDG imaging due to the adjacent high brain activity.
-
68GA-PEPTIDES [15, 48, 49] (see also Box 12.4)
12.3.9 Clinical Indication
-
68Ga-peptides target SSTR which are commonly expressed in neuroblastoma cells.
-
To select suitable patients for theranostics using peptide receptor radionuclide therapy (PPRT).
12.3.10 Red Flags
-
Poorly differentiated tumors have a low affinity for the tracer.
-
Inflammatory processes such as reactive lymph nodes or post-radiotherapy changes may show some degree of tracer activity, usually of mild intensity, due to the expression of SSTRs in activated lymphocytes.
-
Further validation is required prior to increasing the utilization of this modality in routine clinical practice.
-
SSTR imaging to determine whether a NET is receptor positive. Peptide receptor radionuclide therapy (PRRT) such a 177Lu-DOTA- octreotate is, in pediatric patients, still investigational.
12.3.11 Take Home Messages
-
Pathological uptake in neuroblastoma is typically intense SUVs.
-
Somatostatin receptor imaging of neuroblastoma is a sensitive, second-line PET alternative to 123I-MIBG with a potential for theranostic application.
-
All these tracers target SSTRs.
-
They have rapid clearance from the blood and renal excretion. Maximum tumor activity is reached at 70 ± 20 min.
12.3.12 Relevant Case Examples
Case 12.7 Metastatic Neuroblastoma—MIBG Scintigraphy (Fig. 12.7)
Case 12.8 Metastatic Neuroblastoma, Response to Treatment—MIBG Scintigraphy (Figs. 12.8 and 12.9)
Case 12.9 Metastatic Neuroblastoma, Heterogeneous Uptake on MIBG Scintigraphy (Fig. 12.10)
Case 12.10 Neuroblastoma, Tumor Progression, PET/CT with FDOPA (Fig. 12.11)
Case 12.11 Metastatic Neuroblastoma, PET/CT with 68Ga-DOTATATE PET/CT (Fig. 12.12)
12.4 Other Neuroendocrine Tumors
68GA-PEPTIDE IMAGING OF NETS (see also Box 12.4—Imaging with 68Ga-peptides)
12.4.1 Clinical Indications [15]
-
Localization and characterization of NETs with the expression of high density of SSTR such as succinate dehydrogenase (SDHx)-mutated NETs and head and neck PGL when 18F-FDG-PET is negative.
-
Detection of occult NETs in cases of metastatic tumors with unknown primary or if high serum tumor markers are found.
-
Characterization of a bronchial tumor mass.
-
In the theranostic setting, when PRRT is considered.
12.4.2 Red Flags [50]
-
Brown fat visualization is not a common problem in 68Ga-peptide imaging in NETs.
12.4.3 Take Home Message
-
In well-differentiated NETs, 68Ga-peptides PET imaging has a higher detection rate as compared to FDG imaging which may play a complementary role, especially in cases of poorly differentiated tumors known to show high FDG avidity.
-
68Ga-peptides PET may evolve as a preferred imaging modality for disease surveillance in certain cancer predisposition or premalignancy syndromes (e.g., von Hippel Lindau disease).
FDOPA IMAGING OF NETS (See also Box 12.3—Imaging with FDOPA)
12.4.4 Clinical Indications [51, 52]
-
NETs with absent SSTR expression, for (re)staging and monitoring response to treatment.
-
Adrenal pheochromocytoma, sporadic or related to cancer predisposition syndromes.
-
Congenital hyperinsulinism, to identify focal forms in the pancreas that can be resected [53].
12.4.5 Red Flags
-
Inflammatory processes such as reactive lymph nodes or post-radiotherapy changes may show tracer activity.
-
SSTR imaging to determine whether a NET is receptor positive. Peptide receptor radionuclide therapy (PRRT) such as 177Lu-DOTA-octreotate is, in pediatric patients, still investigational.
12.4.6 Take Home Message
-
FDOPA PET imaging is more specific in cases of neuroblastoma and insulinoma as compared with FDG and 68Ga-peptides.
-
Advantages of NET PET imaging (over NET SPECT imaging):
-
Earlier and shorter acquisition time
-
Improved patient comfort
-
Improved spatial resolution
-
Less radiation exposure
-
12.4.7 Representative Case Examples
Case 12.12 Paraganglioma (PGL), 68Ga-DOTATE PET/CT (Fig. 12.13)
Case 12.13 Pheochromocytoma—FDG-PET/CT (Fig. 12.14)
12.5 Musculo-Skeletal Malignancies (see also Box 12.5)
12.5.1 Clinical Indications [21, 23, 54,55,56]
-
To identify and localize bone and bone marrow metastases in order to determine the extent of disease in patients with known malignancies.
-
To assess primary bone and ST tumors such as osteosarcoma, Ewing sarcoma, and rhabdosarcoma.
12.5.2 Correlative Imaging
-
In the presence of specific symptoms, plain radiographs are followed as a rule by MRI, the first choice investigation in most children with bone tumors.
12.5.3 Red Flags
-
If MRI is not readily available or the child needs sedation or general anesthesia, bone scintigraphy and, recently in some centers, bone PET/CT are the next choice.
-
For multiple spot views of the whole body start with the pelvis when the bladder is empty.
-
It is still debated whether SPECT should be routinely performed even if planar scan is unremarkable or only for better characterization of an abnormality detected on planar imaging.
-
When performing SPECT/CT the FOV of the CT should be shortened to include only the region of the abnormality seen on SPECT to reduce radiation exposure.
-
The CT component of a bone SPECT/CT can be acquired as a pediatric low-dose CT for localization and attenuation correction or as a diagnostic CT. Many skeletal lesions are adequately evaluated even with low-dose CT parameters.
12.5.4 Take Home Messages
-
Increased tracer uptake, due to locally increased blood flow or calcium depositions, indicates an alteration in bone metabolism caused by increased new bone formation (osteoid) due to higher availability of binding sites, but also related to local or regional hyperemia.
-
Bone marrow lesions tend to have a more diffuse pattern along a portion of a bone whereas cortical bone lesions are typically focal.
-
With the dissemination of FDG-PET imaging which is the method of choice in oncology, most centers use this modality as the main scintigraphic study for malignancies even when they are limited to bone. Skeletal scintigraphy is used only occasionally and thus the significant decrease in its use in children with cancer.
-
NaF PET imaging is becoming the preferred alternative for imaging of the skeleton due to the tracer’s rapid localization and rapid clearance from the blood.
12.5.5 Representative Case Examples
Case 12.14 Metastatic Neuroblastoma, Bone Scintigraphy
Case 12.15 Ewing Sarcoma, Staging, Bone Scintigraphy (Fig. 12.16)
Case 12.16 Metastatic Osteosarcoma, Bone Scintigraphy (Fig. 12.17)
Case 12.17 Osteosarcoma, NaF PET/CT (Fig. 12.18)
Case 12.18 Langerhans Cell Histiocytosis, NaF PET/CT (Fig. 12.19)
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Nadel, H., Shulkin, B., Bar-Sever, Z., Giammarile, F. (2023). Pediatric Malignancies. In: Bar-Sever, Z., Giammarile, F., Israel, O., Nadel, H. (eds) A Practical Guide for Pediatric Nuclear Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-67631-8_12
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