Imaging of pediatric bone tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Malignant primary bone tumors are uncommon in the pediatric population, accounting for 3%-5% of all pediatric malignancies. Osteosarcoma and Ewing sarcoma comprise 90% of malignant primary bone tumors in children and adolescents. This paper provides consensus-based recommendations for imaging in children with osteosarcoma and Ewing sarcoma at diagnosis, during therapy, and after therapy.

Non-Hodgkin Lymphoma Imaging Spectrum in Children, Adolescents, and Young Adults.

In children, adolescents, and young adults (CAYA), non-Hodgkin lymphoma (NHL) is characterized by various age-related dissimilarities in tumor aggressiveness, prevailing pathologic subtypes, and imaging features, as well as potentially different treatment outcomes. Understanding the imaging spectrum of NHL in CAYA with particular attention to children and adolescents is critical for radiologists to support the clinical decision making by the treating physicians and other health care practitioners. The authors discuss the currently performed imaging modalities including radiography, US, CT, MRI, and PET in the diagnosis, staging, and assessment of the treatment response. Familiarity with diagnostic imaging challenges during image acquisition, processing, and interpretation is required when managing patients with NHL. The authors describe potentially problematic and life-threatening scenarios that require prompt management. Moreover, the authors address the unprecedented urge to understand the imaging patterns of possible treatment-related complications of the therapeutic agents used in NHL clinical trials and in practice. Online supplemental material is available for this article. ©RSNA, 2022.

Pediatric Nephro-Urology: Overview and Updates in Diuretic Renal Scans and Renal Cortical Scintigraphy.

Nuclear medicine offers several diagnostic scans for the evaluation of congenital and acquired conditions of the kidneys and urinary track in children. Tc-99m-MAG 3 diuretic renal scans are most commonly used in the evaluation and follow up of urinary track dilatations. They provide functional information on the differential renal function and on drainage quality which is allows distinction between obstructed and non-obstructed kidneys and the need for surgical correction vs conservative management in kidneys with impaired drainage. Standardized imaging and processing protocols are essential for correct interpretation and for meaningful comparisons between follow up scans. Different approaches and conceptions led to some contradicting recommendations between SNMMI and EANM guidelines on diuretic renography in children which caused confusion and to the emergence of self-made institutional protocols. In Late 2018 the two societies published joint procedural guidelines on diuretic renography in infants and children which hopefully will end the confusion. Tc-99m DMSA scans provide important information about the function of the renal cortex allowing detection of acute pyelonephritis, renal scars dysplasia and ectopy as well as accurate determination of the differential renal function. They are commonly used in the evaluation of children with urinary tract infections and affect clinical management. A standardized imaging and processing protocol improves the diagnostic accuracy of these studies. SPECT or pinhole images should be a routine part of the imaging protocol. This is one of the recommendations in the new EANM and SNMMI procedural guidelines for renal cortical scintigraphy in children available online on the SNMMI website and is under publication. This article provides an overview on the clinical role of diuretic renography and cortical scintigraphy in children and describes the imaging protocols focusing on the new recommendations in the procedural guidelines.

Residual meta-iodobenzyl guanidine (MIBG) positivity following therapy for metastatic neuroblastoma: Patient characteristics, imaging, and outcome.

BACKGROUND: Meta-iodobenzylguanidine(MIBG) scans are used to detect neuroblastoma metastatic lesions at diagnosis and during posttreatment surveillance. MIBG positivity following induction chemotherapy correlates with poor outcome; however, there are reports of patients with progression-free survival despite MIBG positivity at the end of therapy. The factors distinguishing these survivors from patients who progress or relapse are unclear. FDG-positron-emission tomography (PET) scans can also detect metastatic lesions at diagnosis; however, their role in posttherapy surveillance is less well studied. METHODS: We performed a retrospective analysis of International Neuroblastoma Staging System (INSS) stage 4 patients to identify those with residual MIBG-avid metastatic lesions on end-of-therapy scans without prior progression. Data collected included age, disease sites, histopathology, biomarkers, treatment, imaging studies, and response. RESULTS: Eleven of 265 patients met inclusion criteria. At diagnosis three of 11 patients were classified as intermediate and eight of 11 high risk; nine of 11 had documented marrow involvement. Histologic classification was favorable for four of 10 and MYCN amplification was detected in zero of 11 cases. The median time with persistent MIBG positivity following treatment was 1.5 years. Seven patients had at least one PET scan with low or background activity. Biopsies of three of three MIBG-avid residual lesions showed differentiation. All patients remain alive with no disease progression at a median of 4.0 years since end of therapy. CONCLUSION: Persistently MIBG-avid metastatic lesions in subsets of patients following completion of therapy may not represent active disease that will progress. Further studies are needed to determine whether MYCN status or other biomarkers, and/or PET scans, may help identify patients with residual inactive MIBG lesions who require no further therapy.

Theranostics in Neuroblastoma.

Theranostics combines diagnosis and targeted therapy, achieved by the use of the same or similar molecules labeled with different radiopharmaceuticals or identical with different dosages. One of the best examples is the use of metaiodobenzylguanidine (MIBG). In the management of neuroblastoma-the most common extracranial solid tumor in children. MIBG has utility not only for diagnosis, risk-stratification, and response monitoring but also for cancer therapy, particularly in the setting of relapsed/refractory disease. Improved techniques and new emerging radiopharmaceuticals likely will strengthen the role of nuclear medicine in the management of neuroblastoma.

Artificial intelligence and radiomics in pediatric molecular imaging.

In the past decade, a new approach for quantitative analysis of medical images and prognostic modelling has emerged. Defined as the extraction and analysis of a large number of quantitative parameters from medical images, radiomics is an evolving field in precision medicine with the ultimate goal of the discovery of new imaging biomarkers for disease. Radiomics has already shown promising results in extracting diagnostic, prognostic, and molecular information latent in medical images. After acquisition of the medical images as part of the standard of care, a region of interest is defined often via a manual or semi-automatic approach. An algorithm then extracts and computes quantitative radiomics parameters from the region of interest. Whereas radiomics captures quantitative values of shape and texture based on predefined mathematical terms, neural networks have recently been used to directly learn and identify predictive features from medical images. Thereby, neural networks largely forego the need for so called "hand-engineered" features, which appears to result in significantly improved performance and reliability. Opportunities for radiomics and neural networks in pediatric nuclear medicine/radiology/molecular imaging are broad and can be thought of in three categories: automating well-defined administrative or clinical tasks, augmenting broader administrative or clinical tasks, and unlocking new methods of generating value. Specific applications include intelligent order sets, automated protocoling, improved image acquisition, computer aided triage and detection of abnormalities, next generation voice dictation systems, biomarker development, and therapy planning.

Severe Primary Hyperparathyroidism Caused by Parathyroid Carcinoma in a 13-Year-Old Child; Novel Findings From HRpQCT.

Primary hyperparathyroidism is a condition that occurs infrequently in children. Parathyroid carcinoma, as the underlying cause of hyperparathyroidism in this age group, is extraordinarily rare, with only a few cases reported in the literature. We present a 13-year-old boy with musculoskeletal pain who was found to have brown tumors from primary hyperparathyroidism caused by parafibromin-immunodeficient parathyroid carcinoma. Our patient had no clinical, biochemical, or radiographic evidence of pituitary adenomas, pancreatic tumors, thyroid tumors, pheochromocytoma, jaw tumors, renal abnormalities, or testicular lesions. Germline testing for AP2S1, CASR, CDC73/HRPT2, CDKN1B, GNA11, MEN1, PTH1R, RET, and the GCM2 gene showed no pathological variants, and a microarray of CDC73/HRPT2 did not reveal deletion or duplication. He was managed with i.v. fluids, calcitonin, pamidronate, and denosumab prior to surgery to stabilize hypercalcemia. After removal of a single parathyroid tumor, he developed severe hungry bone syndrome and required 3 weeks of continuous i.v. calcium infusion, in addition to oral calcium and activated vitamin D. Histopathological examination identified an angioinvasive parathyroid carcinoma with global loss of parafibromin (protein encoded by CDC73/HRPT2).HRpQCT and DXA studies were obtained prior to surgery and 18-months postsurgery. HRpQCT showed a resolution of osteolytic lesions combined with structural improvement of cortical porosity and an increase in both cortical thickness and density compared with levels prior to treatment. These findings highlight the added value of HRpQCT in primary hyperparathyroidism. In addition to our case, we have provided a review of the published cases of parathyroid cancer in children. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Posttransplant Lymphoproliferative Disorder in Children: A 360-degree Perspective.

An earlier incorrect version of this article appeared online. This article was corrected on December 17, 2019.

The impact of 18F-FDG PET on initial staging and therapy planning of pediatric soft-tissue sarcoma patients.

BACKGROUND: Soft-tissue sarcomas in children are a histologically heterogenous group of malignant tumors accounting for approximately 7% of childhood cancers. There is a paucity of data on the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for initial staging and whether PET influenced management of these patients. OBJECTIVE: The aim of this analysis is to assess the use of 18F-FDG PET exclusively, and as a supplement to cross-sectional imaging in comparison to typical imaging protocols (CT and magnetic resonance imaging [MRI]) for initial staging as well as therapy planning in pediatric soft-tissue sarcoma patients. MATERIALS AND METHODS: The list of 18F-FDG PET/CT performed for soft-tissue sarcoma between March 2007 and October 2017 was obtained from the Hospital Information System database. Twenty-six patients who had received 18F-FDG PET, MRI and/or CT at initial diagnosis were included in the study. 18F-FDG PET and concurrent diagnostic CT and MRI at initial staging were independently reviewed to note the number of primary and metastatic lesions detected by each modality. A chart review was conducted to collect information on final diagnosis, staging and treatment plan. RESULTS: During the study period, 26 patients (15 females) ages 1.3-17.9 years (median age: 6 years) had received 18F-FDG PET/CT at initial diagnosis of soft-tissue sarcoma. Diagnostic CT was available for comparison in all 26 patients and MRI was available in 18 patients. The mean interval between cross-sectional imaging and 18F-FDG PET was 5.9 days (range: 0-30 days). All 26 primary lesions were equally detected by 18F-FDG PET compared to CT and MRI. From 84 metastatic lesions, 16 were detected by PET as well as CT and MRI, 12 by 18F-FDG PET only (included mainly lymph node metastases) and 56 by CT and MRI only (included mainly lung metastases). 18F-FDG PET changed therapy planning in 5 patients out of 26 (19%) by showing additional lesions not detected by CT and MRI. CONCLUSION: 18F-FDG PET proved to be a valuable tool for precise initial staging of pediatric soft-tissue sarcoma patients, especially in detecting lymph node metastasis, and could be included in their initial work-up. Given the relative rarity and heterogeneity of this group of tumors, additional investigations are required to definitely establish a role for 18F-FDG PET in the initial staging and therapy planning of soft-tissue sarcoma in the pediatric population.

Unusual lymphoid malignancy and treatment response in two children with Down syndrome.

BACKGROUND: Lymphoid malignancies other than acute lymphoblastic leukemia (ALL) are rare in children with Down syndrome (DS). Information about the toxicity of chemotherapy and prognosis is largely derived from the experience of children with DS and ALL or children without DS. PROCEDURE: We describe the treatment and outcome of two unusual lymphoid malignancies in children with DS. One patient was diagnosed with Burkitt lymphoma (BL) and the second, after treatment for B precursor ALL, with T-cell EBV-positive proliferative disorder (LPD). RESULTS: BL was treated with standard doses of LMB group B therapy subsequently intensified to group C therapy, including high-dose methotrexate (HD-MTX, 3-8 g/m2 ). The patient did not experience excessive toxicity and remains in complete remission 13 months later. Despite presentation with disseminated disease the patient with T-cell EBV-positive LPD after treatment for B precursor ALL responded to dexamethasone and rituximab and remains in complete remission two years later. CONCLUSIONS: Upfront reduction of the high treatment intensity, which is associated with excellent survival outcomes in BL, may not be warranted in all children with DS. Response to therapy and prognosis of T-cell EBV-positive LPD in a patient with DS was not predicted by reported experience in the absence of DS.

Correction to: FDG uptake in cervical lymph nodes in children without head and neck cancer.

The original version of this article unfortunately contained a mistake. Author name Alaa Bakkari was incorrect. The correct spelling is given above.

Review: The Role of Radiolabeled DOTA-Conjugated Peptides for Imaging and Treatment of Childhood Neuroblastoma.

BACKGROUND: Childhood neuroblastoma is a heterogenous disease with varied clinical presentation and biology requiring different approaches to investigation and management. Metaiodobenzylguanidine (MIBG) is an essential component of metastatic staging for neuroblastoma and has been used as a treatment strategy for relapsed and refractory neuroblastoma. However, as 10% of children with neuroblastoma will have 123I-MIBG non-avid imaging and up to 60% with relapsed and refractory neuroblastoma will require further treatment with 131I-MIBG, alternative radioisotopes have been investigated for imaging and treatment. Neuroblastoma tumors express mostly somatostatin receptor- 2 (SSTR2) that can be targeted by somatostatin analogues including DOTA-conjugated peptides e.g. DOTATATE, DOTATOC. OBJECTIVES: This review summarizes the rationale, utility and experience of DOTA-conjugated peptides in imaging and treatment of childhood neuroblastoma. RESULTS AND CONCLUSIONS: Radiolabeled DOTA-peptides are used routinely in adults to image neuroendocrine tumors and have potential to be used to image and treat neuroblastoma. 68Ga-DOTATATE PET/CT has been shown to have better sensitivity, quicker clearance and administration times, reduced radiation exposure and limited toxicity compared to 123I-MIBG. Therapeutic studies of peptide receptor radionuclides e.g. 177Lu-DOTATATE in patients with relapsed neuroblastoma have used 68Ga- DOTATATE PET/CT to determine eligibility for therapy. Further studies would need to investigate appropriate indications, timings, scoring and clinical significance of radiolabeled DOTA-peptide conjugated PET/CT imaging in childhood neuroblastoma.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

The clinical impact of 18F-FDG PET/CT in extracranial pediatric germ cell tumors.

BACKGROUND: Extracranial germ cell tumors are an uncommon pediatric malignancy with limited information on the clinical impact of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the literature. OBJECTIVE: The purpose of this study was to evaluate and compare the clinical impact on management of 18F-FDG PET/CT with diagnostic computed tomography (CT) in pediatric extracranial germ cell tumor. MATERIALS AND METHODS: The list of 18F-FDG PET/CT performed for extracranial germ cell tumor between May 2007 and November 2015 was obtained from the nuclear medicine database. 18F-FDG PET/CT and concurrent diagnostic CT were obtained and independently reviewed. Additionally, the patients' charts were reviewed for duration of follow-up and biopsy when available. The impact of 18F-FDG PET/CT compared with diagnostic CT on staging and patient management was demonstrated by chart review, imaging findings and follow-up studies. RESULTS: During the study period, 9 children (5 males and 4 females; age range: 1.6-17 years, mode age: 14 years) had 11 18F-FDG PET/CT studies for the evaluation of germ cell tumor. Diagnostic CTs were available for comparison in 8 patients (10 18F-FDG PET/CT studies). The average interval between diagnostic CT and PET/CT was 7.2 days (range: 0-37 days). In total, five lesions concerning for active malignancy were identified on diagnostic CT while seven were identified on PET/CT. Overall, 18F-FDG PET/CT resulted in a change in management in 3 of the 9 patients (33%). CONCLUSION: 18F-FDG PET/CT had a significant impact on the management of pediatric germ cell tumors in this retrospective study. Continued multicenter studies are required secondary to the rarity of this tumor to demonstrate the benefit of 18F-FDG PET/CT in particular clinical scenarios.

FDG uptake in cervical lymph nodes in children without head and neck cancer.

BACKGROUND: Reactive cervical lymphadenopathy is common in children and may demonstrate increased 18F-fluoro-deoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). OBJECTIVE: We sought to evaluate the frequency and significance of 18F-FDG uptake by neck lymph nodes in children with no history of head and neck cancer. MATERIALS AND METHODS: The charts of 244 patients (114 female, mean age: 10.4 years) with a variety of tumors such as lymphoma and post-transplant lymphoproliferative diseases (PTLD), but no head and neck cancers, who had undergone 18F-FDG PET/CT were reviewed retrospectively. Using the maximum standardized uptake value (SUVmax), increased 18F-FDG uptake by neck lymph nodes was recorded and compared with the final diagnosis based on follow-up studies or biopsy results. RESULTS: Neck lymph node uptake was identified in 70/244 (28.6%) of the patients. In 38 patients, the lymph nodes were benign. In eight patients, the lymph nodes were malignant (seven PTLD and one lymphoma). In 24 patients, we were not able to confirm the final diagnosis. Seven out of the eight malignant lymph nodes were positive for PTLD. The mean SUVmax was significantly higher in malignant lesions (4.2) compared with benign lesions (2.1) (P = 0.00049). CONCLUSION: 18F-FDG uptake in neck lymph nodes is common in children and is frequently due to reactive lymph nodes, especially when the SUVmax is <3.2. The frequency of malignant cervical lymph nodes is higher in PTLD patients compared with other groups.

Correlation of PET/CT and Image-Guided Biopsies of Pediatric Malignancies.

OBJECTIVE: The purpose of this study was to evaluate an early experience with correlation of PET/CT findings and image-guided biopsy results in pediatric patients. MATERIALS AND METHODS: In a single-center retrospective case series, the inclusion criterion was performance of image-guided biopsy within 6 weeks of PET/CT, either before or after the biopsy. RESULTS: Forty-five patients (23 boys, 22 girls; age range, 4-17 years; median, 10.5 years; weight range, 14.6-86.2 kg; median, 48 kg) underwent 47 PET/CT examinations and biopsies. Nineteen patients (20 biopsies) had known malignancy, and 26 patients had suspected malignancy. The results were malignant in 24 cases, benign in 16, and inadequate or normal in 7 cases. Thirty-nine of 47 PET/CT examinations had positive results, and eight had negative results. Final analysis of 37 of the 47 cases (confounders excluded) showed concordant results between biopsy and PET in 36 cases and discordant results in one case. CONCLUSION: PET/CT can be used for disease staging and follow-up. In the future PET/CT can play a valuable role in directing image-guided biopsies of children.

Variants and pitfalls on radioiodine scans in pediatric patients with differentiated thyroid carcinoma.

BACKGROUND: Potentially false-positive findings on radioiodine scans in children with differentiated thyroid carcinoma can mimic functioning thyroid tissue and functioning thyroid carcinomatous tissue. Such false-positive findings comprise variants and pitfalls that can vary slightly in children as compared with adults. OBJECTIVE: To determine the patterns and frequency of these potential false-positive findings on radioiodine scans in children with differentiated thyroid carcinoma. MATERIALS AND METHODS: We reviewed a total of 223 radioiodine scans from 53 pediatric patients (mean age 13.3 years, 37 girls) with differentiated thyroid carcinoma. Focal or regional activity that likely did not represent functioning thyroid tissue or functioning thyroid carcinomatous tissue were categorized as variants or pitfalls. The final diagnosis was confirmed by reviewing the concurrent and follow-up clinical data, correlative ultrasonography, CT scanning, serum thyroglobulin and antithyroglobulin antibody levels. We calculated the frequency of these variants and pitfalls from diagnostic and post-therapy radioiodine scans. RESULTS: The most common variant on the radioiodine scans was the thymic activity (24/223, 10.8%) followed by the cardiac activity (8/223, 3.6%). Salivary contamination and star artifact, caused by prominent thyroid remnant, were the most important observed pitfalls. CONCLUSION: Variants and pitfalls that mimic functioning thyroid tissue or functioning thyroid carcinomatous tissue on radioiodine scan in children with differentiated thyroid carcinoma are not infrequent, but they decrease in frequency on successive radioiodine scans. Potential false-positive findings can be minimized with proper knowledge of the common variants and pitfalls in children and correlation with clinical, laboratory and imaging data.

A Pilot Study of 18F-FLT PET/CT in Pediatric Lymphoma.

We performed an observational pilot study of 18F-FLT PET/CT in pediatric lymphoma. Eight patients with equivocal 18F-FDG PET/CT underwent imaging with 18F-FLT PET/CT. No immediate adverse reactions to 18F-FLT were observed. Compared to 18F-FDG, 18F-FLT uptake was significantly higher in bone marrow and liver (18F-FLT SUV 8.6 ± 0.6 and 5.0 ± 0.3, versus 18F-FDG SUV 1.9 ± 0.1 and 3.4 ± 0.7, resp., p < 0.05). In total, 15 lesions were evaluated with average 18F-FDG and 18F-FLT SUVs of 2.6 ± 0.1 and 2.0 ± 0.4, respectively. Nonspecific uptake in reactive lymph nodes and thymus was observed. Future studies to assess the clinical utility of 18F-FLT PET/CT in pediatric lymphoma are planned.