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Established in 1998, the Asociacion de Hemato-Oncologia Pediatrica de Centro America (AHOPCA) is a consortium of pediatric oncology centers from Central American and Caribbean region countries, including Nicaragua, Guatemala, El [...], * Context.--Several countries of the Central America and Caribbean region have been sharing regional neuroblastoma (NB) treatment guidelines. However, there is no standardization in the diagnosis, subclassification, or tumor biology to aid in the risk stratification of these patients. Objective.--To examine the histology and assess the accuracy of the local pathology reports; to evaluate the usefulness of manual MYCN immunohistochemistry (IHC); and to use NB as a model to identify the needs to establish a central pathology review (CPR) program in this region. Design.--A retrospective CPR of specimens derived from patients with a diagnosis of NB and treated under the regional NB guidelines between 2012 and 2017 was conducted, allowing for a comparison between local diagnoses and the CPR diagnoses. Manual MYCN IHC was performed in the confirmed NB specimens and the results compared with known fluorescence in situ hybridization or automated IHC results, when available. Results.--The 156 specimens reviewed included 460 blocks and 183 original slides. Neuroblastoma was confirmed in 138 samples (88.5%), but low concordance rates for Shimada classification (n = 39; 25.0%), mitotic-karyorrhectic index (n = 4; 2.5%), and International Neuroblastoma Pathology Classification (n = 18; 11.5%) were noted. Manual MYCN IHC performed on 120 specimens showed conclusive results in 89.2% (28 positive, 23.4%; 79 negative, 65.8%) and questionable results in 10.8% (n = 13). Conclusions.--This retrospective CPR highlights the need for a CPR program to serve this region, to ensure correct diagnosis and subclassification of NB, and to provide manual MYCN IHC--with reflexing to fluorescence in situ hybridization, if questionable. This approach can further regional collaboration, enhance test utilization, and ultimately improve patients' outcomes. doi: 10.5858/arpa.2019-0570-0A

The article discusses the latest developments and advances that have taken place in neuroblastoma, an embryonal tumor of the autonomic nervous system. The causes, diagnosis, treatment methodologies and management regime for the same are highlighted.

Analysis of chromosomal aberrations is used to determine the prognosis of neuroblastomas (N Bs) and to aid treatment decisions. MYCN amplification (MNA) alone is an incomplete poor prognostic factor, and chromosome 11q status has recently been included in risk classification. We analyzed 165 NB tumors using high-density SNP microarrays and specifically compared the high-risk groups defined by MNA (n = 37) and 11q-deletion (n = 21). Median patient age at diagnosis was 21 months for MNA tumors and 42 months for 11q-deletion tumors, and median survival time after diagnosis was 16 months for MNA and 40 months for 11q deletion. Overall survival (at 8 years) was ~35% in both groups. MNA and 11q deletion were almost mutually exclusive; only one case harbored both aberrations. The numbers of segmental aberrations differed significantly; the MNA group had a median of four aberrations, whereas the 11q-deletion group had 12. The high frequency of chromosomal breaks in the 11q-deletion group is suggestive of a chromosomal instability phenotype gene located in 11q; one such gene, H2AFX, is located in 11q23.3 (within the 11q-deletion region). Furthermore, in the groups with segmental aberrations without MNA or 11q deletion, the tumors with 17q gain have worse prognosis than those with segmental aberrations without 17q gain, which have a favorable outcome. This study has implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment. comparative genomic hybridization/SNP array | chromosomal aberration | H2AFX | MYCN amplification | pediatric tumor doi/10.1073/pnas.0910684107

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement [sup.18]F-FDG. Copper-64 ([sup.64]Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]- eicosane-1,8-diamine) for use in developing a new class of tumor-specific [sup.64]Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with [sup.64]Cu resulted in >95% of the [sup.64]Cu being chelated by the immunoconjugate. Specific activities of at least 10 [micro]Ci/[micro]g (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after [sup.64]Cu labeling. Solid-phase radioimmuno-assays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15-20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5-10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (

Byline: Tadaharu Okazaki (1), Sumio Kohno (1), Jun-ichi Mimaya (2), Shiro Hasegawa (1), Naoto Urushihara (1), Atsushi Yoshida (1), Shinya Kawano (1), Junichi Kusafuka (1), Yasuo Horikoshi (2), Yoshifumi Takashima (2), Katsuhiko Aoki (3), Minoru Hamazaki (4) Keywords: Neuroblastoma; Mass screening; Observation program Abstract: Japan has a nationwide mass-screening program for neuroblastoma in 6-month-old infants. Neuroblastoma can regress spontaneously, and some institutions observe selected cases. We evaluated the management of screened neuroblastoma at our hospital since 1997 when an observation program was introduced. Criteria for the observation program were stage-I, stage-II, or stage-IVs tumors, urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels &lt 40 ug/mg creatinine, tumor &lt 5 cm in diameter, no invasion to the intraspinal canal or great vessels, and parental consent to participate. Patients who did not meet observation criteria underwent surgery or mild chemotherapy according to the location of the tumor. If patients met observation criteria after chemotherapy, surgical intervention was no longer performed. Thirty-six patients attended our hospital for screened neuroblastoma from 1997 to 2002. Thirty-three patients who were managed at our hospital participated in this study. Ten subjects met observation criteria. Tumors regressed in 7 patients (mean follow-up period 36.3 months) with corresponding decreases in VMA and HVA levels (group A). Three underwent surgery (group B) because of increasing VMA and HVA levels, increase in tumor size, or guardian's request. Twenty-three subjects did not meet observation criteria. Four patients underwent primary surgery (group C), and 19 patients had chemotherapy initially. Fourteen patients met observation criteria after chemotherapy and two are still having chemotherapy (group D). Three patients required surgery due to insufficient regression of their tumors (group E). Fourteen subjects in group D had marked decreases in VMA and HVA levels and tumor size (mean follow-up period 29.1 months), and tumors were not detected using imaging techniques in 8 patients. Histological examination of all resected specimens during the study period showed favorable histology and no N-myc amplification. There was no evidence of unfavorable prognosis in any of the 33 subjects, although 1 patient who underwent primary surgery had a vanishing kidney 1 year later and 1 patient had multiple bony metastases after complete resection of tumor, which was treated by chemotherapy. Until the real significance of mass screening for neuroblastoma as a public health measure is confirmed, observation with careful follow-up should be adopted more extensively because it has a favorable outcome in many cases, and is associated with minimal therapeutic complications. Author Affiliation: (1) Department of Pediatric Surgery, Shizuoka Children's Hospital, 860 Urushiyama, 420-8660, Shizuoka, Japan (2) Department of Hematology/Oncology, Shizuoka Children's Hospital, Shizuoka, Japan (3) Department of Radiology, Shizuoka Children's Hospital, Shizuoka, Japan (4) Department of Pathology, Shizuoka Children's Hospital, Shizuoka, Japan Article History: Registration Date: 01/01/2003 Online Date: 19/12/2003

Testing all one-year-old children for neuroblastoma may not reduce the mortality rate from this type of cancer, according to researchers who tested 2,581,188 children and compared their outcome to 2,117,600 children who were not tested. The test measures the amount of catecholamines in urine.

Screening all newborn babies for neuroblastoma does not appear to lower mortality rates, according to a study of 476,654 newborn children in Quebec, Canada, who were tested between 1989 and 1994. The test measures the amount of catecholamines in the urine.

Byline: Harry P.W. Kozakewich (1), Antonio R. Perez-Atayde (1), Michael J. Donovan (1), Jonathan A. Fletcher (2), Judy A. Estroff (3), Robert C. Shamberger (4), Lisa Diller (5) Keywords: Key words: congenital neuroblastoma, cystic neuroblastoma, adrenal cyst, newborn, infant Abstract: Cystic neuroblastoma (CN) is an unusual variant of neuroblastoma characterized by a grossly visible cyst(s) and almost always distinctive microcysts on light microscopy. Rarely, CN will appear solid grossly, but microcystification will be present. We examined the clinical, pathologic, and biologic features of 17 cases of CN. The majority of CN had been detected by prenatal ultrasound. The tumors were favorable stage, stroma-poor, but with low or intermediate mitotic-karyorhectic indices and had favorable biologic markers reflected by aneuploidy and by an absence of N-myc amplification and chromosome 1p deletions. However, the high trk expression typically identified in good risk tumors was absent. Although the complete natural history of CN is not fully defined, our experience suggests that some tumors progress in size, whereas others may spontaneously regress or mature. The clinical outcome is excellent, as is expected in localized and stage 4S neuroblastoma in infancy. Author Affiliation: (1) Department of Pathology, Children's Hospital, and Department of Pathology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA , US (2) Department of Pathology, Brigham and Women's Hospital, and Departments of Pediatrics and Pathology, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA , US (3) Department of Radiology, Children's Hospital, and Department of Radiology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA , US (4) Department of Surgery, Children's Hospital, and Department of Surgery, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA , US (5) Department of Medicine, Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Department of Pediatrics, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA , US Article note: Received June 13, 1996 accepted June 19, 1997

ABBREVIATIONS. NB, neuroblastoma; GNB, ganglioneuroblastoma; GN, ganglioneuroma; MIBG, metaiodobenzylguanidine; CT, computed tomography. Neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganghoneuroma (GN), three neural crest tumors, represent a histologic spectrum ranging from highly [...]

Ultrasound prenatal diagnosis of neuroblastoma usually results in infant survival. Neuroblastoma is a cancer of the nervous system that occurs in embryos. The records of eleven infant patients with neuroblastoma identified by prenatal ultrasound in a hospital between 1982 and 1992 were reviewed. Nine of the patients had adrenal tumors and two had thoracic paraspinal tumors. All patients had their tumors surgically removed. One patient received chemotherapy when the cancer continued to progress after surgery. No patients died during follow-up periods ranging from three months to ten years. Prenatal ultrasound diagnosis, surgery after birth and chemotherapy as a last resort seems the best treatment and has excellent results., Objectives. To assess the relative frequency of, the clinical and pathological correlates in, and the prognosis of the subset of infants with neuroblastoma who were identified initially by prenatal ultrasonography. Design. Retrospective review of all patients with neuroblastoma evaluated between 1982 and 1992. Setting. Large, urban, tertiary care children's hospital in Boston, Massachusetts. Patients. Eleven infants with neuroblastoma initially detected with prenatal sonograms were identified. Results. Nine patients had adrenal tumors; two had thoracic paraspinal tumors. Typical diagnostic evidence for neuroblastoma including a palpable abdominal mass and elevations in urinary catecholamines were not commonly seen postnatally. These patients had multiple favorable prognostic indicators including low stage of disease (10/11), favorable biological markers including cellular DNA content (5/5) and N-myc oncogene copy number (5/5), and histopathology suggestive for neuroblastoma in situ (7/11). All patients were treated by surgical resection. One patient exhibited progression of disease postoperatively, but demonstrated a complete clinical response to multiagent chemotherapy. Overall survival in our population was excellent with no deaths seen at a mean follow-up of 37 months (range 3 to 120 months). Conclusions. Patients with neuroblastoma identified by prenatal ultrasonography generally, although not exclusively, follow a clinically favorable course in which surgical resection is curative. Chemotherapy is not indicated unless substantial progression of disease occurs.

Neuroblastoma (NB) is the most common extracranial tumor of childhood. (1) It has a diverse clinical behavior ranging from metastatic disease with dismal patient outcome to tumor maturation or spontaneous [...], Context.--Neuroblastoma (NB) is the most common extracranial tumor of childhood. Although most cases have a distinctive histology, a subset of primitive cases require immunohistochemical studies to distinguish them from other small round blue cell tumors of childhood. Immunohistochemistry is also used to detect small amounts of tumor metastatic to the bone marrow and in posttreatment samples with obscuring fibrosis, calcification, or inflammation. The transcription factor PHOX2B is essential for the differentiation and survival of sympathetic neurons and chromaffin cells, and therefore is highly specific for the peripheral autonomic nervous system. Objective.--To determine the diagnostic utility of PHOX2B immunohistochemistry as a marker of primary, treated, and metastatic NB. Design.--Neuroblastoma tissue microarrays were stained with PHOX2B, CD57, and synaptophysin. Arrays containing rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor were stained with PHOX2B, and negative bone marrow samples were stained with PHOX2B and CD57. Results.--PHOX2B and CD57 were similar to synaptophysin in their ability to detect NB. PHOX2B and CD57 similarly showed robust staining in posttreatment NB and NB metastatic to the bone marrow. In contrast to the cytoplasmic staining pattern seen with synaptophysin and CD57, clear and strong nuclear PHOX2B permitted identification of individual tumor cells. PHOX2B staining was absent in all cases of rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor, and in the negative bone marrow. Conclusions.--PHOX2B and CD57 are useful markers of NB. PHOX2B is specific for NB in its differential diagnosis with other small round cell tumors, and its nuclear staining may be helpful for accurate bone marrow tumor quantification. (Arch Pathol Lab Med. 2015;139:543-546; doi: 10.5858/arpa.2014-0255-OA)

Neuroblastoma, a congenital tumor arising from nerve-related cells, is one of the most common cancers of early childhood. Long-term survival from advanced disease has not improved in 30 years, in spite of research and new chemotherapy protocols. Metabolites from the tumor can be detected in urine, supporting the hope for early diagnosis (soon after birth) and improved survival. Based on this reasoning, mass screening of six-month-old infants was instituted in Japan, and scientists have called for similar efforts in North America and Europe. However, although the Japanese program was perceived to be fully successful, it was not closely examined by standard epidemiologic methods. The results of standard analysis of these programs are described. Recent research has changed our understanding of the tumor from what was known when the screening programs were first initiated. In the past, the age of the infant at diagnosis and stage of the tumor were strong prognostic indicators. This now seems a rather simplistic view, as it appears there are two types of neuroblastoma. One seems to be a true congenital tumor, probably growing slowly at birth, and has a good prognosis, tending not to metastasize. The other tumor may lie dormant until cancer-related genes are activated at a later age, when it then grows aggressively and metastasizes, usually before detection. Screening programs use one of several methods of varying sensitivity to identify excesses of neurotransmitter (hormones made by nerves) breakdown products. One result of the screening program was that Japanese pediatricians became more aware of the need to examine the abdomen, so that a number of masses were identified by doctors rather than by urine screening. Analysis shows that not enough information was collected by the screening programs to assess their value. Overdiagnosis appeared to occur, as some cases would have been expected to regress spontaneously. The programs appear to have detected cases that would have had a good prognosis even if they were detected later. Further study is needed to understand whether screening for neuroblastoma is beneficial. (Consumer Summary produced by Reliance Medical Information, Inc.)

Neuroblastoma is a malignant, bleeding tumor consisting of neuroblasts, which are cells that produce cells of the sympathetic nervous system. This malignancy is the most common solid cancer in young children, affecting almost 28 million children per year for the first five years of life, in the United States. The outcome and treatment of this cancer depends on the stage of the disease and the age of the patient at diagnosis. One-third of patients are diagnosed at an early stage of the disease, and they have a survival rate of 85 percent. The other two-thirds are patients with advanced disease; those with metastasis (spreading of the cancer to other areas) have a survival rate of less than 20 percent. Thus, early diagnosis of neuroblastoma is associated with improved survival. Age is also a factor; infants diagnosed with widespread disease have a 50 percent or greater survival rate, whereas older children with metastases have a survival rate of less than 10 percent. It remains unclear whether screening for neuroblastoma before the age of one year is effective, medically or economically. The Quebec Neuroblastoma Screening Project is assessing the effectiveness of screening infants for neuroblastoma in reducing the death rate due to this cancer. All infants born in Quebec within a five-year period will be screened at three weeks and six months of age. The methods used to screen for neuroblastoma are described, and are based on the detection of homovanillic acid and vanillylmandelic acid, which are secreted by the tumor. During the first six months of screening at the three-week stage, nine of 41,673 screened infants had positive results and were referred for further evaluation. The tumor was confirmed in four of the nine infants, no tumor was found in another four, and one infant instead had a calcified adrenal gland. Another three infants were diagnosed with neuroblastoma before they reached three weeks of age. There was one confirmed case of neuroblastoma in which the tumor did not secrete homovanillic acid and vanillylmandelic acid, and screening results from this patient were negative. (Consumer Summary produced by Reliance Medical Information, Inc.)