BACKGROUND: To evaluate the value of random urinary vanillylmandelic acid (VMA) as a surrogate marker for monitoring tumor response and predicting outcome in patients with neuroblastoma (NB). METHODS: Medical records of 91 patients newly diagnosed with NB at the Samsung Medical Center between June 2014 and August 2017 were reviewed. Clinical associations and other prognostic factors, including age at diagnosis, stage, pathologic subtype, MYCN amplification, and other cytogenetic aberrations, were analyzed. Furthermore, the significance of random urinary VMA level in predicting outcome and tumor response was also evaluated. RESULTS: The median random urinary VMA level at diagnosis was 27.9 (range: 1.7–600) mg/g creatinine. Abdominal primary site, male sex, advanced stage, less differentiated pathology (poorly differentiated, undifferentiated), 11q deletion, and high-risk tumor were associated with a higher VMA level at diagnosis. The VMA level decreased during chemotherapy (28.4%, 16.9%, and 9.6% of the VMA level at diagnosis after 3, 6, and 9 cycles of chemotherapy, respectively). A higher VMA level at diagnosis tends to be associated with a better overall survival in high-risk patients with borderline significance (58.3±18.6% vs. 76.5±13.4%, P=0.050). However, in the multivariate analysis, the VMA level was not a significant predictor of survival. A slower reduction in VMA level during chemotherapy was not associated with a worse overall survival. However, event free survival was significantly better in the rapid responder group. CONCLUSION: A higher VMA level was associated with high-risk features at diagnosis of NB. Random urinary VMA is a valuable marker for monitoring NB response during chemotherapy.
Biomarkers ; Chromosome Aberrations ; Creatinine ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Humans ; Male ; Medical Records ; Multivariate Analysis ; Neuroblastoma* ; Pathology ; Prognosis ; Vanilmandelic Acid*

PURPOSE: The purpose of this study is to investigate the clinical significance of tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma. MATERIALS AND METHODS: TH mRNA expression in PB was measured by reverse transcription quantitative real-time polymerase chain reaction in 210 patients who were newly diagnosed with neuroblastoma from July 2005 to June 2015 and the clinical significance of TH expression in PB at diagnosis was evaluated. RESULTS: TH expression was positive in 60 patients (28.6%). Fifty of 60 TH-positive patients had metastatic tumors and the remaining 10 had localized tumors. TH expression was associated with high-risk features (i.e., advanced stage, older age, unfavorable pathology, and MYCN amplification) at diagnosis. Among TH-positive patients, higher TH expression level was observed in high-risk patients than in low- or intermediate-risk patients (p=0.035). The probability of 5-year progression-free survival (PFS) was lower in TH-positive patients than in TH-negative patients (63.8±6.9% vs. 94.7±2.1%, p < 0.001). In analysis confined to high-risk patients, the 5-year probability of PFS remained lower in TH-positive patients (55.7±8.2% vs. 89.6±5.8%, p < 0.001). Among TH-positive patients, a higher expression level of TH was associated with a worse outcome. In multivariate analyses, positive TH expression in PB at diagnosis was an independent poor prognostic factor for PFS. CONCLUSION: The treatment intensity should be tailored according to TH expression in PB at diagnosis.
Diagnosis* ; Disease-Free Survival ; Humans ; Multivariate Analysis ; Neuroblastoma* ; Pathology ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; Reverse Transcription ; RNA, Messenger* ; Tyrosine 3-Monooxygenase* ; Tyrosine*

Small round cell tumors (SRCTs) are a heterogeneous group of neoplasms composed of small, primitive, and undifferentiated cells sharing similar histology under light microscopy. SRCTs include Ewing sarcoma/peripheral neuroectodermal tumor family tumors, neuroblastoma, desmoplastic SRCT, rhabdomyosarcoma, poorly differentiated round cell synovial sarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, small cell malignant peripheral nerve sheath tumor, and small cell schwannoma. Non-Hodgkin\'s malignant lymphoma, myeloid sarcoma, malignant melanoma, and gastrointestinal stromal tumor may also present as SRCT. The current shift towards immunohistochemistry and cytogenetic molecular techniques for SRCT may be inappropriate because of antigenic overlapping or inconclusive molecular results due to the lack of differentiation of primitive cells and unavailable genetic service or limited moleculocytogenetic experience. Although usage has declined, electron microscopy (EM) remains very useful and shows salient features for the diagnosis of SRCTs. Although EM is not always required, it provides reliability and validity in the diagnosis of SRCT. Here, the ultrastructural characteristics of SRCTs are reviewed and we suggest that EM would be utilized as one of the reliable modalities for the diagnosis of undifferentiated and poorly differentiated SRCTs.
Chondrosarcoma, Mesenchymal ; Cytogenetics ; Diagnosis ; Gastrointestinal Stromal Tumors ; Genetic Services ; Humans ; Immunohistochemistry ; Lymphoma ; Melanoma ; Microscopy ; Microscopy, Electron ; Microscopy, Electron, Transmission* ; Neurilemmoma ; Neuroblastoma ; Neuroectodermal Tumors ; Osteosarcoma ; Pathology ; Peripheral Nerves ; Reproducibility of Results ; Rhabdomyosarcoma ; Sarcoma, Myeloid ; Sarcoma, Synovial

OBJECTIVETo study clinicopathologic features, immunohistochemical profile, diagnosis and differential diagnosis of childhood central nervous system primitive neuroectodermal tumors (CNS PNETs) with the features of ependymoblastoma and neuroblastoma.

METHODSThe clinical data, morphologic and immunohistochemical features were analyzed in 4 cases of pediatric CNS PNETs with features of ependymoblastoma and neuroblastoma. EnVision method immunohistochemistry was applied.

RESULTSFour patients including three boys and one girl presented at the age from 12 month to 4 years and three tumors located in cerebrum, one in brain stem. All tumors showed typical combined histological patterns of ependymoblastoma and neuroblastoma, demonstrating zones of true rosettes, occasional pseudovascular rosettes, and undifferentiated neuroepithelial cells in a prominent background of mature neuropils. There was focal expression of glial fibrillary acidic protein (GFAP) consistent with glial differentiation and epithelial membrane antigen (EMA) consistent with ependymal differentiation. Necrosis was seen in three cases and calcification was present in one case. Immunohistochemically, the rosettes and undifferentiated neuroepithelial cells were positive for vimentin, partially positive for GFAP and EMA but negative for synaptophysin. The tumor cells were also positive for synaptophysin in neuropils. The Ki-67 label index ranged from 20% to 60%.

CONCLUSIONSCNS PNETs with the features of ependymoblastoma and neuroblastoma is a rare tumor with poor prognosis. The tumor primarily occurs in childhood, especially infant and belongs to the family of embryonal tumors of the CNS. The morphologic, immunohistochemical and genetic features are important in differential diagnosis from other tumors of the CNS.

Antigens, Neoplasm ; metabolism ; Central Nervous System ; pathology ; Child ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Humans ; Immunohistochemistry ; Infant ; Male ; Mucin-1 ; metabolism ; Neuroblastoma ; diagnosis ; pathology ; Neuroectodermal Tumors, Primitive ; diagnosis ; pathology ; Neuroectodermal Tumors, Primitive, Peripheral ; diagnosis ; pathology ; Synaptophysin ; metabolism ; Vimentin ; metabolism

12E7 Antigen ; Adolescent ; Antigens, CD ; metabolism ; Cell Adhesion Molecules ; metabolism ; Diagnosis, Differential ; Humans ; Kidney Neoplasms ; metabolism ; pathology ; surgery ; Lymph Node Excision ; Lymphatic Metastasis ; Lymphoma ; metabolism ; pathology ; Male ; Neoplastic Cells, Circulating ; Nephrectomy ; Neuroblastoma ; metabolism ; pathology ; Neuroectodermal Tumors, Primitive, Peripheral ; metabolism ; pathology ; surgery ; Synaptophysin ; metabolism ; Venae Cavae ; pathology ; Vimentin ; metabolism ; Wilms Tumor ; metabolism ; pathology

BACKGROUND: The prognostic impact of the presence of differentiating neuroblasts in bone marrow (BM) remains unclear in BM metastatic neuroblastoma (NB). We aimed to identify the prognostic impact of differentiating neuroblasts in BM at diagnosis and after chemotherapy. METHODS: A total of 51 patients diagnosed with BM metastatic NB at Asan Medical Center between January 1990 and July 2005 were enrolled. BM histology and laboratory data along with overall survival (OS) were compared with regard to the differentiation status of neuroblasts in BM at diagnosis and after chemotherapy. RESULTS: Among the 51 patients, 13 (25.5%) exhibited differentiating neuroblasts in BM at diagnosis and 17/51 (33.3%) exhibited them after chemotherapy. The only significant difference among patient groups was the improved OS in patients with differentiated neuroblasts in BM at diagnosis (P=0.021). In contrast, the differentiation status of neuroblasts in BM after chemotherapy did not affect OS (P=0.852). CONCLUSIONS: Our study is the first report describing the presence of differentiating neuroblasts in BM. The presence of differentiating neuroblasts in BM at diagnosis may be a favorable prognostic factor for patients with BM metastatic NB; however, the same phenomenon after chemotherapy is irrelevant to prognosis.
Adolescent ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bone Marrow/*pathology ; Bone Marrow Cells/*cytology ; Bone Marrow Neoplasms/*diagnosis/secondary ; Cell Differentiation ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Karyotyping ; Male ; Neoplasm Grading ; Neuroblastoma/*diagnosis/drug therapy/pathology ; Prognosis ; Survival Analysis ; Young Adult

Adolescent ; Bone Marrow ; pathology ; Female ; Humans ; Leukemia ; diagnosis ; Neuroblastoma ; diagnosis

This study was purposed to analyze the relation of N-myc gene copy number with clinical staging, pathological types and tumor biological factors in children with neuroblastoma (NB), and to investigate the influence of chemotherapy on N-myc gene expression and explore the relationship of N-myc gene copies with prognosis of NB children. The newly diagnosed children with NB from 1 March 2007 to 31 January 2011 were enrolled in this study. The treatment was carried out by BCH-NB-2007 based on Hongkong NB-07 protocol, and the patients were follow up to 31 January 2012. The N-myc gene in NB children was detected by FISH. According to number of N-myc gene copies, the NB children were divided into 3 groups. A group (N-myc gene negative) had less than 2 copies, B group (N-myc gene gains) had 3 to 9 copies, and C group (N-myc amplification) had more than 10 copies. The results showed that the N-myc gene expression in 58 cases of NB was observed. There were 36 males and 22 females. NB children aged from 6.5 to 138 months (median age 47.5 months), all patients were followed up for 11 - 57 months with an average of 31.5 months. INSS stages I-IV were 1, 5, 8 and 44 cases, respectively. Twenty-five cases had primary post mediastinal tumor, thirty-three cases had retroperitoneal and pelvic tumor, three of which also companied with post mediastinal tumor. Thirty-five cases had bone metastasis (60.3%), thirty-two cases had bone marrow metastasis (55%). Of the 54 patients with fully known biologic features, seventeen cases had ganglioneuroblastoma, thirty-seven cases had neuroblastoma (15 displayed differentiated, 7 poorly differentiated or undifferentiated, 15 with pathological changes after chemotherapy), four cases had bone marrow metastasis only detected by bone marrow biopsy. Eleven cases had N-myc gene negative, forty-three had N-myc gains, four had N-myc amplification. The average copy number of N-myc gene copies in 58 cases was 5.96 ± 7.81 in which 28 children were non chemotherapy cases, their average copy number was 4.00 ± 1.88, thirty cases out of 58 cases received preoperation chemotherapy (chemotherapy group), and their average copy number was 7.80 ± 10.46, the difference is significant (P = 0.064). The clinic stage, the location of primary tumor, pathological classification, urine VMA and serum neurogenic specific enolase had no effects on the N-myc gene expression, but the serum LDH level had influence (P < 0.01). Single factor Kaplan-Meier analysis showed that the number of N-myc gene copies in NB patients were closely related with the poor prognosis. The more copies of N-myc gene, the more poor prognosis, the difference is statistically significant (P < 0.05). It is concluded that the number of N-myc gene copies correlates with the rapid growth of NB and its poor prognosis, detecting the N-myc amplification can help to estimate the prognosis and decide the program of treatment. Serum LDH, which correlated with the rapid growth of NB, had effect on the N-myc gene expression and is closely related with the poor prognosis of NB.
Child ; Child, Preschool ; Female ; Gene Amplification ; Genes, myc ; Humans ; Infant ; Male ; Neoplasm Staging ; Neuroblastoma ; diagnosis ; genetics ; pathology ; Prognosis

OBJECTIVETo investigate the basic clinical characteristics of paraneoplastic neurological syndrome (PNS) in children.

METHODTo retrospectively analyze the clinical data of 12 PNS children who were hospitalized in neurology department in Beijing Children's Hospital from 2010 to 2011. Some patients were followed up after surgery.

RESULTIn 12 patients with PNS, 11 were male and 1 was female. The mean onset age were (30.5 ± 15.3) months. The mean duration from neurological symptom onset to finding out of tumor was (112.7 ± 154.4) days. The onset of the disease in 2 patients was acute, in 3 was subacute and in the other 7 was chronic (2 of 7 had 2 to 3 relapses). Of 12 patients, 11 had symptoms of ataxia (3 patients also had opsoclonus and myoclonus, OMS), 1 had weakness of limbs at onset and then had ataxia. Nine of 12 patients had surgery, and pathologic diagnosis was neuroblastoma and ganglioneuroma. Six patients were followed-up for 8 to 21 months. One patient had a little improvement and 5 almost recovered.

CONCLUSIONThe PNS children can have neurological symptoms only at the onset and there were no particular evidence of tumor. It is prone to misdiagnosis. The prognosis of PNS in children was poor.

Adrenocorticotropic Hormone ; therapeutic use ; Biomarkers, Tumor ; analysis ; Brain ; diagnostic imaging ; pathology ; Child, Preschool ; Female ; Ganglioneuroma ; diagnosis ; pathology ; therapy ; Humans ; Immunoglobulins, Intravenous ; therapeutic use ; Infant ; Magnetic Resonance Imaging ; Male ; Neuroblastoma ; diagnosis ; pathology ; therapy ; Opsoclonus-Myoclonus Syndrome ; diagnosis ; pathology ; therapy ; Paraneoplastic Syndromes, Nervous System ; diagnosis ; pathology ; therapy ; Prognosis ; Radiography ; Retrospective Studies

Adult ; Diagnosis, Differential ; Follow-Up Studies ; Humans ; Infant ; Keratins ; metabolism ; Male ; Mandibular Neoplasms ; metabolism ; pathology ; surgery ; Melanoma ; metabolism ; pathology ; Neuroblastoma ; metabolism ; pathology ; Neuroectodermal Tumor, Melanotic ; metabolism ; pathology ; surgery ; Rhabdomyosarcoma, Embryonal ; metabolism ; pathology ; Synaptophysin ; metabolism