Clinical updates and surveillance recommendations for DNA replication-repair deficiency syndromes in children and young adults.

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2 or MLH1 genes, and/ or in the polymerase-proofreading genes, POLE and POLD1. RRD predisposition syndromes [constitutional MMR deficiency (CMMRD), Lynch, polymerase-proofreading associated polyposis (PPAP)] share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with CMMRD, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations, helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/ genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and PPAP syndromes harbouring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations regarding genetic counselling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance, develop prevention strategies, and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.

Langerhans Cell Histiocytosis With Thyroid Involvement on 18 F-FDG PET/MR.

ABSTRACT: An 18-month-old otherwise healthy girl presented with 1 month of neck swelling. Based on ultrasonography that showed diffusely enlarged heterogeneous thyroid gland, a presumed diagnosis of thyroid cancer was made. Subsequent core needle biopsy revealed Langerhans cell histiocytosis extensively involving the thyroid. 18 F-FDG PET/MR was performed for staging and to evaluate the local extent of the disease in the neck. PET/MR demonstrated a hypermetabolic neck mass inseparable from the thyroid gland. The mass encased the major vessels, trachea, and esophagus without compression or invasion. Osseous involvement was excluded by both skeletal survey and PET/MR.

Rates of Intervention and Cancer Detection on Initial versus Subsequent Whole-body MRI Screening in Li-Fraumeni Syndrome.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WB-MRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult patients with LFS (n = 182) were reviewed, including instances of WB-MRI screening and interventions based on screening results. For each WB-MRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WB-MRI. Of the total cohort (n = 182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WB-MRI screenings, with a mean of 3.8 ± 1.9 (adults) and 4.0 ± 2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, P = 0.0026) and stable for children (19%, P = NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WB-MRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3%-4% initial, 6%-10% subsequent) for both children and adults. These findings provide important data for counseling patients with LFS about screening outcomes. PREVENTION RELEVANCE: The cancer detection rate, burden of recommended interventions, and rate of false-positive findings found on subsequent WB-MRI screenings in patients with LFS are not well understood. Our findings suggest that annual WB-MRI screening has clinical utility and likely does not result in an unnecessary invasive intervention burden for patients.

Neuroblastic Tumor Recurrence Associated With Opsoclonus Myoclonus Ataxia Syndrome Relapse a Decade After Initial Resection and Treatments.

Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare disorder that causes significant neurodevelopmental sequelae in children. Approximately half of pediatric OMAS cases are paraneoplastic, typically associated with localized neuroblastic tumors. Since early persistence or relapse of OMAS symptoms is common even after tumor resection, OMAS relapses may not routinely prompt reevaluation for recurrent tumors. We report a 12-year-old girl with neuroblastic tumor recurrence associated with OMAS relapse a decade after initial treatment. Providers should be aware of tumor recurrence as a trigger for distant OMAS relapse, raising intriguing questions about the role of immune surveillance and control of neuroblastic tumors.

Imaging of pediatric extragonadal pelvic soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

The most common pediatric extragonadal pelvic cancers include germ cell tumors, sacrococcygeal teratomas, and rhabdomyosarcomas (arising from the urinary bladder, prostate, paratesticular tissues, vagina, uterus, and perineum). This paper describes the radiological and nuclear medicine features of these entities and provides consensus-based recommendations for the assessment at diagnosis, during, and after treatment.

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

Primary pancreatic tumors in children are rare with an overall age-adjusted incidence of 0.018 new cases per 100,000 pediatric patients. The most prevalent histologic type is the solid pseudopapillary neoplasm, followed by pancreatoblastoma. This paper describes relevant imaging modalities and presents consensus-based recommendations for imaging at diagnosis and follow-up.

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

Pediatric pulmonary malignancy can be primary or metastatic, with the latter being by far the more common. With a few exceptions, there are no well-established evidence-based guidelines for imaging pediatric pulmonary malignancies, although computed tomography (CT) is used in almost all cases. The aim of this article is to provide general imaging guidelines for pediatric pulmonary malignancies, including minimum standards for cross-sectional imaging techniques and specific imaging recommendations for select entities.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Objective: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. Design: The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. Methods: We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Results: Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. Conclusion: These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

Intrascrotal Lipoblastoma: A Rare Cause of Paratesticular Mass in a Pediatric Patient.

There is a broad differential diagnosis for a pre-pubertal child presenting with a scrotal mass including both benign and malignant etiologies. Lipoblastomas are rare benign neoplasms originating from fat cells that occur most commonly on the trunk or extremities of young children. There have been less than 20 cases of scrotal lipoblastomas reported in the literature, with the majority occurring in children less than 3 years of age. Here we present a unique case of an 18-month male presenting with a paratesticular mass found to be a lipoblastoma on final pathology.

Deep learning-based automatic tumor burden assessment of pediatric high-grade gliomas, medulloblastomas, and other leptomeningeal seeding tumors.

BACKGROUND: Longitudinal measurement of tumor burden with magnetic resonance imaging (MRI) is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors. METHODS: The preoperative and postoperative cohorts were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO (Response Assessment in Pediatric Neuro-Oncology) criteria (AutoRAPNO) was determined. Performance was compared to that of 2 expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared. RESULTS: A total of 794 preoperative MRIs from 794 patients and 1003 postoperative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with intraclass correlation coefficients (ICCs) of 0.912 and 0.960 for the 2 preoperative and 0.947 and 0.896 for the 2 postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC = 0.909; Rater 3 ICC = 0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions. CONCLUSIONS: Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.

Congenital hyperinsulinism: localization of a focal lesion with 18F-FDOPA positron emission tomography.

Hyperinsulinemic hypoglycemia of infancy, also known as congenital hyperinsulinism, is a group of disorders characterized by dysregulated insulin release. Neonates with severe, persistent hyperinsulinemic hypoglycemia who are unresponsive to medical therapy require pancreatectomy to prevent brain damage from hypoglycemia. To date, multiple genetic mutations and syndromes and several unique histopathological entities have been identified in children with hyperinsulinism. Histopathology is characterized as diffuse, focal or atypical. Surgical resection of a focal lesion results in a cure in up to 97% of these children. Imaging with 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) is the test of choice for identifying and localizing a focal lesion and has proved to be an invaluable guide for surgical resection. Genetic evaluation is essential for determining who will benefit from PET imaging. This article provides an approach to determine who should be imaged, how to set up a protocol and how to interpret the imaging findings. The diagnosis and management of this disorder require a multidisciplinary approach to prevent brain damage from hypoglycemia.

18F-6-Fluoro-l-Dopa PET/CT Imaging of Congenital Hyperinsulinism.

Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. 18F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of 18F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.

Neuroblastoma Shown on 18F-DOPA PET/CT Performed to Evaluate Congenital Hyperinsulinism.

ABSTRACT: 18F-DOPA PET/CT was performed to evaluate congenital hyperinsulinism in a 55-day-old boy with hypoglycemia. The images revealed not only a focal 18F-DOPA-avid lesion in the pancreas but also in a left thoracic paraspinal neuroblastoma.

Pediatric Lung MRI: Currently Available and Emerging Techniques.

OBJECTIVE. The purpose of this article is to review currently available and emerging techniques for pediatric lung MRI for general radiologists. CONCLUSION. MRI is a radiation-free alternative to CT, and clearly understanding the strengths and limitations of established and emerging techniques of pediatric lung MRI can allow practitioners to select and combine the optimal techniques, apply them in clinical practice, and potentially improve early diagnostic accuracy and patient management.

Deep learning-based classification of primary bone tumors on radiographs: A preliminary study.

BACKGROUND: To develop a deep learning model to classify primary bone tumors from preoperative radiographs and compare performance with radiologists. METHODS: A total of 1356 patients (2899 images) with histologically confirmed primary bone tumors and pre-operative radiographs were identified from five institutions' pathology databases. Manual cropping was performed by radiologists to label the lesions. Binary discriminatory capacity (benign versus not-benign and malignant versus not-malignant) and three-way classification (benign versus intermediate versus malignant) performance of our model were evaluated. The generalizability of our model was investigated on data from external test set. Final model performance was compared with interpretation from five radiologists of varying level of experience using the Permutations tests. FINDINGS: For benign vs. not benign, model achieved area under curve (AUC) of 0•894 and 0•877 on cross-validation and external testing, respectively. For malignant vs. not malignant, model achieved AUC of 0•907 and 0•916 on cross-validation and external testing, respectively. For three-way classification, model achieved 72•1% accuracy vs. 74•6% and 72•1% for the two subspecialists on cross-validation (p = 0•03 and p = 0•52, respectively). On external testing, model achieved 73•4% accuracy vs. 69•3%, 73•4%, 73•1%, 67•9%, and 63•4% for the two subspecialists and three junior radiologists (p = 0•14, p = 0•89, p = 0•93, p = 0•02, p < 0•01 for radiologists 1-5, respectively). INTERPRETATION: Deep learning can classify primary bone tumors using conventional radiographs in a multi-institutional dataset with similar accuracy compared to subspecialists, and better performance than junior radiologists. FUNDING: The project described was supported by RSNA Research & Education Foundation, through grant number RSCH2004 to Harrison X. Bai.

Whole-Body PET/MRI Applications in Pediatric Oncology.

OBJECTIVE. Fluorine-18-labeled FDG PET/CT and MRI are current imaging standards for staging and assessing tumor response and recurrence of pediatric extracranial solid tumors. PET/MRI combines anatomic and physiologic imaging in a single session with reduced radiation compared with CT. Pediatric protocols are primarily whole-body protocols because of the behavior and type of cancers unique to children. This article will focus on the practice and utility of whole-body PET/MRI for pediatric oncologic imaging. CONCLUSION. The strengths of PET/MRI over PET/CT are compelling and include decreased radiation exposure, decreased number of sedation and general anesthesia events, single-day one-stop visits, and simultaneous imaging with two stand-alone advanced imaging techniques essential to staging and assessing treatment response in pediatric oncology.

Pediatric applications of Dotatate: early diagnostic and therapeutic experience.

In recent years, new somatostatin receptor agents (SSTRs) have become available for diagnostic imaging and therapy in neuroendocrine tumors. The novel SSTR ligand DOTA-DPhel-Tyr3-octreotate (Dotatate) in particular can be linked with 68Gallium for diagnostic imaging purposes, and with the ß-emitter 177Lutetium for radiotherapy in the setting of neuroendocrine tumors. Dotatate imaging offers distinct advantages in the evaluation of neuroendocrine tumors compared to standard techniques, including greater target-to-background ratio and lesion conspicuity, high sensitivity/specificity, improved spatial resolution with positron emission tomography (PET)/CT or PET/MR, and decreased radiation exposure. Although currently off-label in pediatrics, Dotatate theranostics in children are being explored, most notably in the setting of neuroblastoma and hereditary neuroendocrine syndromes. This article provides a multicenter case series of Dotatate imaging and therapy in pediatric patients in order to highlight the spectrum of potential clinical applications.