Lisa J. States

A new tool for prenatal diagnosis: ultrafast fetal MRI.

The development of ultrafast magnetic resonance imaging scanners and sequences provides a new tool for the diagnosis of fetal anomalies. Magnetic resonance imaging is a valuable adjunct to prenatal ultrasound especially for the evaluation of suspected fetal brain anomalies, chest masses, abdominal masses, and renal diseases.

Clinical Features of Three Girls With Mosaic Genome-Wide Paternal Uniparental Isodisomy

Here we describe three subjects with mosaic genome‐wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live‐born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non‐metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near‐normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5–95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha‐fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients.

Imaging of metabolic bone disease and marrow disorders in children.

There are a wide variety of metabolic and infiltrative diseases that involve the bones. Conventional radiography is the primary imaging examination for the initial evaluation of most of these disorders. MR imaging, however, provides detailed information about the bone marrow and is gaining an increasingly important role in the management of disorders of bone marrow infiltration.

The surgical management of insulinomas in children.

PURPOSE Insulinomas are rare pediatric tumors for which optimal localization studies and management remain undetermined. We present our experience with surgical management of insulinomas during childhood. METHODS A retrospective review was performed of patients who underwent surgical management for an insulinoma from 1999 to 2012. RESULTS The study included eight patients. Preoperative localization was successful with abdominal ultrasound, abdominal CT, endoscopic ultrasound, or MRI in only 20%, 28.6%, 40%, and 50% of patients, respectively. Octreotide scan was non-diagnostic in 4 patients. For diagnostic failure, selective utilization of 18-Fluoro-DOPA PET/CT scanning, arterial stimulation/venous sampling, or transhepatic portal venous sampling were successful in insulinoma localization. Intraoperatively, all lesions were identified by palpation or with the assistance of intraoperative ultrasound. Surgical resection using pancreas sparing techniques (enucleation or distal pancreatectomy) resulted in a cure in all patients. Postoperative complications included a pancreatic fistula in two patients and an additional missed insulinoma in a patient with MEN-1 requiring successful reoperation. CONCLUSIONS Preoperative tumor localization may require many imaging modalities to avoid unsuccessful blind pancreatectomy. Intraoperative palpation with the assistance of ultrasound offers a reliable method to precisely locate the insulinoma. Complete surgical resection results in a cure. Recurrent symptoms warrant evaluation for additional lesions.

Fetal magnetic resonance imaging.

Ultrafast magnetic resonance imaging (MRI) sequences have changed the use of MRI to evaluate fetal abnormalities. Currently, the best application is the evaluation of suspected brain abnormalities found on ultrasound. MRI differentiates the various types of fetal ventriculomegaly. Superior posterior fossa visualization allows differentiation of Dandy-Walker malformation from a large cisterna magna. Anomalies of the corpus callosum can be seen. MRI also is valuable in the evaluation of fetal giant neck masses for planning delivery of the baby and surgery for life-threatening airway obstruction. In the chest, MRI differentiates masses such as diaphragmatic hernia, cystic adenomatoid malformation, and sequestration, and it aids in planning fetal surgery because MRI directly visualizes the position of the lung, liver, and bowel.

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li–Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. Clin Cancer Res; 23(13); e98–e106. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Von Hippel–Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Von Hippel–Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors. Clin Cancer Res; 23(12); e68–e75. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations. Clin Cancer Res; 23(13); e115–e22. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI

The American Association for Cancer Research convened a meeting of international pediatric oncologists, geneticists, genetic counselors, and radiologists expert in childhood cancer predisposition syndromes (CPS) in October 2016 to propose consensus surveillance guidelines. Imaging plays a central role in surveillance for most, though not all, syndromes discussed. While encompassing the full gamut of modalities, there is increasing emphasis on use of nonionizing radiation imaging options such as magnetic resonance imaging (MRI) in children and adolescents, especially in the pediatric CPS population. In view of rapid evolution and widespread adoption of whole-body MRI (WBMRI), the purpose of our review is to address WBMRI in detail. We discuss its place in the surveillance of a range of pediatric CPS, the technical and logistical aspects of acquiring and interpreting these studies, and the inherent limitations of WBMRI. We also address issues associated with sedation and use of gadolinium-based contrast agents in MRI in children. Clin Cancer Res; 23(11); e6–e13. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Pancreatic surgery in infants with Beckwith-Wiedemann syndrome and hyperinsulinism.

PURPOSE To present our experience in the care of infants with Beckwith-Wiedemann syndrome (BWS) who required pancreatectomy for the management of severe Congenital Hyperinsulinism (HI). METHODS We did a retrospective chart review of patients with BWS who underwent pancreatectomy between 2009 and 2012. RESULTS Four patients with BWS and severe HI underwent pancreatectomy, 3 females and one male. Eight other BWS patients with HI could be managed medically. The diagnosis of BWS was established by the presence of mosaic 11p15 loss of heterozygosity and uniparental disomy in peripheral blood and/or pancreatic tissue. All patients had hypoglycemia since birth that did not respond to medical management with diazoxide or octreotide, and required glucose infusion rates of up to 30 mg/kg/min. Preoperative 18-F-DOPA PET/CT scans showed diffuse uptake of the radiotracer throughout an enlarged pancreas in three patients and a normal sized pancreas with a large area of focal uptake in the pancreatic body in one patient. None of the patients had mutations in the ABCC8 or KCNJ1 genes that are typically associated with diazoxide-resistant HI. Age at surgery was 1, 2, 4, and 12 months and the procedures were 85%, 95%, 90%, and 75% pancreatectomy, respectively, with the pancreatectomy extent tailored to HI severity. Pathologic analysis revealed marked diffuse endocrine proliferation throughout the pancreas that occupied up to 80% of the parenchyma with scattered islet cell nucleomegaly. One patient had a small pancreatoblastoma in the pancreatectomy specimen. The HI improved in all cases after the pancreatectomy, with patients being able to fast safely for more than 8 h. All patients are under close surveillance for embryonal tumors. One patient developed a hepatoblastoma at age 2. CONCLUSION The pathophysiology of HI in BWS patients is likely multifactorial and is associated with a dramatic increase in pancreatic endocrine tissue. Severe cases of HI that do not respond to medical therapy improve when the mass of endocrine tissue is reduced by subtotal or near-total pancreatectomy.