Next-Generation Sequencing in the Diagnosis of Rare Pediatric Sinonasal Tumors.

The diagnosis of desmoid fibromatosis or other spindle cell tumors in the sinonasal region is very rare in children and needs to be thoroughly confirmed with immunohistochemical and/or molecular tests. We report 2 patients with such rare tumors and describe the use of next-generation sequencing in their evaluation. A 3-year-old female had a 4.4-cm midline nasal cavity mass involving the bony septum and extending into the base of the skull bilaterally. The moderate cellular fibroblastic proliferation revealed areas of thick keloid-like collagen bands and other areas with myxoid edematous stroma. Deep targeted sequencing identified a novel G34V mutation in the CTNNB1 gene consistent with desmoid fibromatosis. An 11-month-old male infant presented with a right nasal mass that extended through the cribriform plate into the anterior cranial fossa and involved the right ethmoid sinus and adjacent right orbit. Histology revealed an infiltrative atypical fibrous proliferation with focal calcifications that was negative for CTNNB1 and GNAS mutations. A novel RET E511K variant was identified in the tumor and later was also found in the germline and hence rendered of unknown significance. Both cases highlight the utility of next-generation sequencing in the evaluation of pediatric sinonasal spindle cell tumors that may have overlapping pathologic features. Reporting of rare or novel variants in tumor-only sequencing should be cautiously evaluated in children and pairing with germline sequencing may be needed to avoid the pitfall of assigning uncommon variants.

The Children's Oncology Group: Organizational Structure, Membership, and Institutional Characteristics.

BACKGROUND: The Children's Oncology Group (COG) is the only organization within the National Cancer Institute's National Clinical Trials Network dedicated exclusively to pediatric cancer research. The purpose of this article is to provide an overview of COG's organizational structure, to characterize its institutional and individual membership, and to summarize enrollments onto COG clinical trials. METHOD: Data from 2013 to 2015 were compiled from sources internal (Network Operations, Statistics and Data Center, Chair's Office) and external (American Hospital Association, American Nurses Credentialing Center) to COG, to present a comprehensive overview of COG's structure, individual and institutional membership, and group operations. RESULTS: In 2016, COG comprised 8,785 individuals from 223 member institutions, across seven countries. An average of 9,661 new patients were registered with COG per year over the most recent (2013-2015) 3-year period. Over the same 3-year time frame, there were an average of 16,836 enrollments onto therapeutic (i.e., treatment) and nontherapeutic (e.g., epidemiology, survivorship, biology) trials per year. CONCLUSIONS: COG institutions have diverse characteristics related to size, geographical location, and infrastructure. Individual membership also reflects diversity with representation from over 28 disciplines and groups. The diversity of COG institutions and individual members allows for unique perspectives and contributions to science unified under a common goal to enroll children/adolescents onto clinical trials. COG's collaborative, multidisciplinary approach to science functions to support the development of research that seeks to continually improve outcomes for children and adolescents with cancer.

Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors.

Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management.

Spitzoid melanoma in a child with Li-Fraumeni syndrome.

Spitzoid melanoma of childhood is a rare malignancy. The histological features are at the upper end of a range encompassing Spitz nevus and atypical Spitz tumor, the unifying features including large oval, fusiform or polygonal melanocytes with abundant homogeneous-appearing cytoplasma and large vesicular nuclei. The presence of a "bottom-heavy" pattern, strikingly enlarged nuclei and nucleoli in both the upper and lower portions of the lesion, and deep mitotic figures are among the findings that distinguish most of the Spitzoid melanomas from Spitz nevi and atypical Spitz tumors. There are no syndromic associations reported for this malignancy. We report the occurrence of choroid plexus carcinoma, Spitzoid melanoma, and myelodysplasia in a child who was found to carry a germline mutation for TP53. While choroid plexus carcinoma and myelodysplasia have relatively frequently been described, melanomas have been very rarely described in Li-Fraumeni syndrome. The association of Spitzoid melanoma with Li-Fraumeni syndrome, especially in a pediatric patient, has not been reported before.

Treatment of chest wall osteosarcoma presenting as second primary after treatment of neuroblastoma.

Only 2 cases of osteosarcoma as a second primary malignancy after neuroblastoma have been reported in the literature. We present a case of chest wall osteosarcoma that developed in a 14-year-old boy 7 years after completion of chemotherapy, autologous peripheral blood stem cell transplantation, radiation, and resection for stage 3, high-risk neuroblastoma. A biopsy of a painful chest wall mass arising from the right third rib diagnosed osteosarcoma. He went on to have preoperative chemotherapy followed by wide local excision and chest wall reconstruction. He then received additional chemotherapy. This case highlights the importance of close observation for second malignancies in this patient population.

Giant ossifying malignant thymoma in a child.

We present the first reported case of an ossifying pediatric thymoma. Our patient was diagnosed with a massive thymoma replacing the whole of the left thoracic cavity. Percutaneous biopsy was attempted 3 times followed by an open incisional biopsy and adjuvant chemotherapy. Complete resection required a median sternotomy and a "trap door" thoracotomy after the tumor failed to respond to chemotherapy. Histology confirmed World Health Organization type B1 lymphocyte-rich thymoma, Masaoka stage I, with extensive osseous metaplasia.

Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside.

BACKGROUND: Central nervous system (CNS) complications of Langerhans cell histiocytosis (LCH) include mass lesions and a neurodegenerative (ND) syndrome with ataxia, dysarthria, dysmetria, learning and behavior difficulties and/or characteristic changes on brain MRIs. Hydrocephalus has rarely been reported in LCH. LCH lesions of the orbit, mastoid and temporal bones ("CNS-Risk" lesions) and diabetes insipidus predispose patients to ND-CNS-LCH. Treatment options have been limited and only a case series using trans-retinoic acid (ATRA) and intravenous immunoglobulin (IVIG) have been published. METHODS: We have used cytosine arabinoside (ARA-C) with or without vincristine to treat eight patients with ND-CNS LCH. PATIENTS: Seven male children and one young adult male with clinical and radiologic ND-CNS-LCH were treated with a regimen of vincristine 1.5 mg/m(2) on day 1 and ARA-C 100 mg/m(2) daily for 5 days or ARA-C alone monthly for 4-19 months. Seven patients were evaluated with an ataxia rating scale (ARS) and all with serial MRIs of the brain. RESULTS: Five of seven patients had decreases in their ARS scores and/or decreased T2 hyperintense lesions on MRI images. Grade 2 neutropenia was the most frequent adverse event. Vincristine-associated neuropathy occurred in two patients. Hydrocephalus caused symptoms and signs that confounded the diagnosis and management of ND-CNS-LCH in all four patients affected with both. CONCLUSIONS: Subtle changes in neurologic function may be complicated by hydrocephalus. Vcr/ARA-C or ARA-C were an effective therapies for some ND-CNS LCH patients. A clinical trial using this and possibly other modalities such as IVIG or ATRA should be done.

Minimal residual disease testing of acute leukemia by flow cytometry immunophenotyping: a retrospective comparison of detection rates with flow cytometry DNA ploidy or FISH-based methods.

The detection and quantification of minimal residual leukemia (MRD) has importance for monitoring continued disease response and detection of early relapse. We retrospectively compared MRD detection rates and percentages of residual leukemia by flow cytometry immunophenotyping (FCIP) with results obtained by either flow cytometry DNA (FCDNA) ploidy (n = 14) and/or fluorescent in situ hybridization (FISH) (n = 33) testing for cases with 1.5% or less residual leukemia. A total of 42 paired results were obtained from 20 pediatric patients, including 16 with B lineage acute lymphocytic leukemia and 4 patients with acute myeloid leukemia during the course of induction and/or relapse. Eighty-one percent of the results were concordant (20 negative and 14 positive). There was reasonable correlation coefficients for quantity of residual disease by FCIP and FCDNA ploidy, and poor correlation coefficients for levels of residual disease between FCIP- and FISH-based results. FCIP MRD sensitivity and specificity was 78% and 83%, respectively. Factors contributing to the 19% discordant rate include low sensitivity of the DNA-based methods as applied and antigenic modulation of immunophenotype during the course of treatment. There is a reasonable agreement between the FCIP and FCDNA or FISH methods for detecting and quantifying MRD. However, the methods are viewed as complementary with their own inherent limitations.

Having a child diagnosed with cancer: an assessment of values from the mother's viewpoint.

The purpose of this qualitative study was to explore the mother's experience of having a child diagnosed with cancer. Semistructured interview questions, focused specifically on values, provided the foundation for the study. Each of the 9 participants was a mother of a child diagnosed with cancer 30 days prior to participation. Subsequent data were collected from each participant 6 months after the original interview. Using a phenomenological approach for data collection and analyses, themes were uncovered from each interview data set. The initial interviews identified 3 themes: (1) problems accessing the health care system, (2) challenges of family dynamics, and (3) support structures. Each theme persisted in the second interview, with an additional theme, (4) future plans, uncovered. Data from this study may provide guidance for health care professionals who provide care to these children and their families. The importance of maintaining communication and keeping promises cannot be overstated.