Advertisement

Diagnosis and Classification of the Small Round-Cell Tumors of Childhood

  • Susan L. Cohn
    Correspondence
    Address reprint requests to Dr. Susan Cohn, Division of Hematology/Oncology, Box 30, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614
    Affiliations
    Department of Pediatrics, Children's Memorial Hospital and Northwestern University, Chicago, Illinois
    Search for articles by this author
      The small-round-cell tumors of childhood include neuroblastoma, the Ewing family of tumors, rhabdomyosarcoma, lymphoma, and desmoplastic small-round-cell tumor. Although classical histological features are generally highly suggestive of tumor type, on occasion these tumors may be indistinguishable by light microscopy, making a definitive diagnosis difficult. Accurate diagnosis of pediatric small-round-cell tumors has become increasingly crucial, as disparate approaches to therapy are used for distinct tumor types. In addition, because for many pediatric cancers, therapy is also tailored according to patient risk, it has become important to further classify tumors biologically, using cytogenetic or molecular studies to identify chromosome translocations, gene amplification, gene expression patterns, and/or mutations.
      In this issue of The American Journal of Pathology, Gilbert and colleagues used a reverse transcriptase polymerase chain reaction (RT-PCR) assay to analyze the expression of two genes involved in the catecholamine biosynthetic pathway, tyrosine hydoxylase and dopa decarboxylase, in 84 pediatric malignancies.
      • Gilbert J
      • Haber M
      • Bordow SB
      • Marshall GM
      • Norris MD
      Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small-round-cell malignancies.
      Their studies demonstrate that the expression of these two genes is highly specific for neuroblastoma. Of the 29 non-neuroblastoma tumor samples examined, only pheochromocytomas expressed clearly detectable levels of the genes. These results suggest that analysis of tyrosine hydoxylase and dopa decarboxylase expression may help distinguish neuroblastoma from other small-round-cell childhood tumors.
      Despite recent advances in immunohistochemistry and molecular pathology, some cases of small-round-cell tumors of childhood remain diagnostically problematic. Thus, additional diagnostic tools, such as the ones described by Gilbert and co-workers, are needed to ensure that every child with a small-round-cell tumor is diagnosed correctly. The value and limitations of current immunohistochemical, cytogenetic, and molecular studies as diagnostic aids for the small-round-cell tumors of childhood are highlighted below.

      Immunohistology

      Immunhistochemistry can be helpful in narrowing the differential diagnosis of small-round-cell tumors. For example, the cell surface glycoprotein p30/32MIC2 is highly expressed in the Ewing family of tumors.
      • Weidner N
      • Tjoe J
      Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma.
      Several monoclonal antibodies have been developed that detect different epitopes of this antigen. Many studies have used HBA71 or O13, and up to 98% of Ewing family tumors have been shown to exhibit immunoreactivity.
      • Fellinger EJ
      • Garin-Chesa P
      • Su SL
      • DeAngelis P
      • Lane JM
      • Rettig WJ
      Biochemical and genetic characterization of the HBA71 Ewing's sarcoma cell surface antigen.
      • Gelin C
      • Aubrit F
      • Phalipon A
      • Raynal B
      • Cole S
      • Kaczorek M
      • Bernard A
      The E2 antigen, a 32 kd glycoprotein involved in T-cell adhesion processes, is the MIC2 gene product.
      However, positive results with HBA71 can also be seen in non-neoplastic tissues and other tumor types, including rhabdomyosarcoma and non-Hodgkin's lymphoma.
      • Winters JL
      • Geil JD
      • O'Connor WN
      Immunohistology, cytogenetics, and molecular studies of small round cell tumors of childhood.
      Antibodies to desmin can be used to distinguish rhabdomyosarcoma from Ewing's sarcoma, neuroblastoma, and lymphoma.
      • Dehner LP
      Primitive neuroectodermal tumor and Ewing's sarcoma.
      • Kodet R
      Rhabdomyosarcoma in childhood: an immunohistological analysis with myoglobin, desmin and vimentin.
      Similarly, antibodies to leukocyte common antigen (LCA) can be used to separate hematolymphoid malignancies from the remainder of small-round-cell tumors.
      • Pilkington GR
      • Pallesen G
      Phenotypic characterization of non-haemopoietic small cell tumours of childhood with monoclonal antibodies to leucocytes, epithelial cells and cytoskeletal proteins.
      Nevertheless, there is no antibody specific for a single tumor type. Overlap of mesenchymal, epithelial, and neural markers are present in a variety of tumors. Furthermore, reactivity to antibodies can vary depending on the preparation of the specimen, the antibody used, and the degree of tumor differentiation.
      The immunohistochemical markers used for neuroblastoma have significant limitations. Neuron-specific enolase (NSE) is seen in neuroblastomas as well as tumors from the Ewing's family. In addition, NSE is present in a wide variety of non-neural cells, such as smooth muscle cells, and is present in some rhabdomyosarcomas.
      • Dehner LP
      Primitive neuroectodermal tumor and Ewing's sarcoma.
      • Triche TJ
      • Tsokos M
      • Linnoila RI
      • Marangos PJ
      • Chandra R
      NSE in neuroblastoma and other round cell tumors of childhood.
      • Haimoto H
      • Takahashi Y
      • Koshikawa T
      • Nagura H
      • Kato K
      Immunohistochemical localization of γ-enolase in normal human tissues other than nervous and neuroendocrine tissues.
      Ganglioside 2 antibodies identify neuroblastomas but may also react in osteosarcoma and rhabdomyosarcoma.
      • Sariola H
      • Terava H
      • Rapola J
      • Saarinen UM
      Cell-surface ganglioside GD2 in the immunohistochemical detection and differential diagnosis of neuroblastoma.
      Similarly, synaptophysin and neurofilament proteins are not specific for neuroblastoma.

      Cytogenetic and Molecular Studies

      Cytogenetics are routinely performed in hematolymphoid malignancies, and in some cases the diagnosis is dependent on the presence of specific cytogenetic abnormalities. Similarly, many small-round-cell tumors of childhood also exhibit highly characteristic cytogenetic abnormalities. However, accurate karyotyping of solid tumors is technically difficult, and successful cytogenetic analysis can be performed in only a subset of cases. Despite the technical limitations, detection of a cytogenetic abnormality can be an important diagnostic aid in some childhood cancers. For example, the t(11;22)(q24;q12) translocation is frequently seen in the Ewing family of tumors, which includes Ewing's sarcoma, peripheral neuroectodermal tumors (PNET), and Askin's tumor.
      • Douglass EC
      Chromosomal rearrangements in Ewing's sarcoma and peripheral neuroectodermal tumor (PNET).
      However, this translocation is not specific for the Ewing's family of tumors. Recent studies have demonstrated that the t(11;22)(q24;q12) translocation can be identified in some cases of neuroblastoma
      • Burchill SA
      • Wheeldon J
      • Cullinane C
      • Lewis IJ
      EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma.
      and rhabdomyosarcoma.
      • Thorner P
      • Squire J
      • Chilton-MacNeil S
      • Marrano P
      • Bayani J
      • Malkin D
      • Greenberg M
      • Lorenzana A
      • Zielenska M
      Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor?.
      Molecular approaches, including fluorescence in situ. hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR), have facilitated the detection of chromosome translocations and have provided the methodology necessary for fully characterizing the involved genes. The t(11;22)(q24;q12) translocation has been shown to result in the production of a chimeric gene between EWS, which codes for a novel putative RNA-binding protein, and FLI1, a member of the ETS family of transcription factors.
      • Delattre O
      • Zucman J
      • Plougastel B
      • Desmaze C
      • Melot T
      • Peter M
      • Kovar H
      • Joubert I
      • de Jong P
      • Rouleau G
      Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.
      Two other variant translocations have been described that involve other members of the ETS. gene family. The t(21;22)(q12;q12) translocation involves the gene ERG, which is located on chromosome 21, and t(7;22)(p22;q12. translocation involves a gene known as ETV1 at 7p22. Although several subtly different EWS/FLI1 and EWS/ERG fusion transcripts have been identified,
      • Zucman J
      • Melot T
      • Desmaze C
      • Ghysdael J
      • Plougastel B
      • Peter M
      • Zucker JM
      • Triche TJ
      • Sheer D
      • Turc-Carel C
      Combinatorial generation of variable fusion proteins in the Ewing family of tumours.
      to date, significant correlations between the different chimeric EWS transcripts and clinical parameters have not been identified.
      • Zoubek A
      • Pfleiderer C
      • Salzer-Kuntschik M
      • Amann G
      • Windhager R
      • Fink FM
      • Koscielniak E
      • Delattre O
      • Strehl S
      • Ambros PF
      Variability of EWS chimaeric transcripts in Ewing tumours: a comparison of clinical and molecular data.
      • Delattre O
      • Zucman J
      • Melot T
      • Garau XS
      • Zucker JM
      • Lenoir GM
      • Ambros PF
      • Sheer D
      • Turc-Carel C
      • Triche TJ
      The Ewing family of tumors: a subgroup of small-round-cell tumors defined by specific chimeric transcripts.
      Specific cytogenetic abnormalities have also been used in the diagnosis and classification of rhabdomyosarcomas.
      • Scrable H
      • Witte D
      • Shimada H
      • Seemayer T
      • Sheng WW
      • Soukup S
      • Koufos A
      • Houghton P
      • Lampkin B
      • Cavenee W
      Molecular differential pathology of rhabdomyosarcoma.
      The translocation t(2;13)(q35;q14) is consistently found in the alveolar form of rhabdomyosarcoma.
      • Turc-Carel C
      • Lizard-Nacol S
      • Justrabo E
      • Favrot M
      • Philip T
      • Tabone E
      Consistent chromosomal translocation in alveolar rhabdomyosarcoma.
      This translocation results in the fusion of 5′ sequences of the PAX3 gene to 3′ sequences of the gene FKHR. PAX3 codes for a developmentally regulated transcription factor involved in muscle development
      • Barr FG
      • Galili N
      • Holick J
      • Biegel JA
      • Rovera G
      • Emanuel BS
      Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma.
      and FKHR is a member of the fork head family of transcription factors.
      • Galili N
      • Davis RJ
      • Fredericks WJ
      • Mukhopadhyay S
      • Rauscher FJ
      • Emanuel BS
      • Rovera G
      • Barr FG
      Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma.
      The PAX3-FKHR fusion protein has been shown to be a more potent transcriptional activator than PAX3 protein alone.
      • Fredericks WJ
      • Galili N
      • Mukhopadhyay S
      • Rovera G
      • Bennicelli J
      • Barr FG
      • Rauscher FJ
      The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3.
      A variant t(1;13)(p36;q14) translocation has also been described in alveolar rhabdomyosarcoma, involving the PAX7 gene located on chromosome 1.
      • Davis RJ
      • D'Cruz CM
      • Lovell MA
      • Biegel JA
      • Barr FG
      Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma.
      Although the more common embryonal form of rhabdomyosarcoma does not exhibit a consistent cytogenetic profile, in many cases loss of heterozygosity on the short arm of chromosome 11, at 11p15.5, is found.
      • Scrable H
      • Witte D
      • Shimada H
      • Seemayer T
      • Sheng WW
      • Soukup S
      • Koufos A
      • Houghton P
      • Lampkin B
      • Cavenee W
      Molecular differential pathology of rhabdomyosarcoma.
      Intra-abdominal desmoplastic small-round-cell tumor is an extremely rare, highly aggressive neoplasm that exhibits a nesting growth pattern.
      • Gerald WL
      • Miller HK
      • Battifora H
      • Miettinen M
      • Silva EG
      • Rosai J
      Intra-abdominal desmoplastic small round-cell tumor: report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals.
      Although only a few karyotypic studies have been performed on desmoplastic small-round-cell tumors, the reciprocal translocation t(11;22)(p13;q12) has consistently been described.
      • Rodriguez E
      • Sreekantaiah C
      • Gerald W
      • Reuter VE
      • Motzer RJ
      • Chaganti RS
      A recurring translocation, t(11;22)(p13;q11.2), characterizes intra-abdominal desmoplastic small round-cell tumors.
      • Sawyer JR
      • Tryka AF
      • Lewis JM
      A novel reciprocal chromosome translocation t(11;22)(p13;q12) in an intraabdominal desmoplastic small round-cell tumor.
      This translocation results in the creation of a fusion gene between the EWS gene and the Wilms tumor 1 gene (WT1).
      • Ladanyi M
      • Gerald W
      Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor.
      There are no consistent molecular genetic abnormalities in neuroblastoma tumors. However, cytogenetic abnormalities have been identified in subsets of neuroblastomas and found to be prognostically significant. For example, poor outcome is associated with deletion of the short arm of chromosome 1, 17q gain, and amplification of the MYCN oncogene.
      • Brodeur GM
      • Castleberry RP
      Neuroblastoma.
      Chromosome number or ploidy has also been shown to be clinically important in neuroblastoma. Hyperdiploidy is correlated with favorable outcome in patients with neuroblastoma, whereas resistance to chemotherapeutic agents has been observed in infants with diploid tumors.
      • Look AT
      • Hayes FA
      • Nitschke R
      • McWilliams NB
      • Green AA
      Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma.
      • Look AT
      • Hayes FA
      • Shuster JJ
      • Douglass EC
      • Castleberry RP
      • Bowman LC
      • Smith EI
      • Brodeur GM
      Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.
      • Bourhis J
      • DeVathaire F
      • Wilson GD
      • Hartmann O
      • Terrier-Lacombe MJ
      • Boccon-Gibod L
      • McNally NJ
      • Lemerle J
      • Riou G
      • Benard J
      Combined analysis of DNA ploidy index and N-myc genomic content in neuroblastoma.
      • Cohn SL
      • Rademaker AW
      • Salwen HR
      • Franklin WA
      • Gonzales-Crussi F
      • Rosen ST
      • Bauer KD
      Analysis of DNA ploidy and proliferative activity in relation to histology and N-myc amplification in neuroblastoma.
      • Oppedal BR
      • Oien O
      • Jahnsen T
      • Brandtzaeg P
      N-myc amplification in neuroblastomas: histopathological, DNA ploidy, and clinical variables.
      In an effort to tailor therapy according to patient risk, Bowman and colleagues recently conducted a prospective nonrandomized Pediatric Oncology Group (POG) study using ploidy as the sole guide for treatment selection in infants with unresectable or metastatic neuroblastoma.
      • Bowman LC
      • Castleberry RP
      • Cantor A
      • Joshi V
      • Cohn SL
      • Smith EI
      • Yu A
      • Brodeur GM
      • Hayes FA
      • Look AT
      Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group Study.
      Patients with hyperdiploid tumors were treated with a less intensive chemotherapeutic regimen than those with diploid neuroblastomas. The 3-year survival estimate for 127 assessable infants with hyperdiploid tumors was 94%, whereas the overall 3-year survival estimate for the 41 infants with diploid disease was 55%. Although the outcome for patients with diploid tumors improved in this clinical trial compared with a previous study in which infants were treated with cyclophosphamide and adriamycin,
      • Look AT
      • Hayes FA
      • Shuster JJ
      • Douglass EC
      • Castleberry RP
      • Bowman LC
      • Smith EI
      • Brodeur GM
      Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.
      better therapy is still needed for this subset of patients.
      Gene amplification generally is detectable by cytogenetic analysis either as extrachromosomal double minute chromatid bodies (DMs) or as chromosomally integrated homogeneously staining regions (HSRs).
      • Schimke RT
      Methotrexate resistance and gene amplification: mechanisms and implications.
      DMs or HSRs are present in most neuroblastoma cell lines as well as some neuroblastoma primary tumors.
      • Kaneko Y
      • Kanda N
      • Maseki N
      • Sakurai M
      • Tsuchida Y
      • Takeda T
      • Okabe I
      Different karyotypic patterns in early and advanced stage neuroblastomas.
      • Brodeur GM
      • Green AA
      • Hayes FA
      • Williams KJ
      • Williams DL
      • Tsiatis AA
      Cytogenetic features of human neuroblastomas and cell lines.
      • Gilbert F
      • Feder M
      • Balaban G
      • Brangman D
      • Lurie DK
      • Podolsky R
      • Rinaldt V
      • Vinikoor N
      • Weisband J
      Human neuroblastomas and abnormalities of chromosomes 1 and 17.
      In situ hybridization studies have demonstrated that the normal single copy of MYCN is located on chromosome 2p24 and that in neuroblastoma MYCN. amplification is present in the majority of DMs and HSRs.
      • Schwab M
      • Alitalo K
      • Klempnauer KH
      • Varmus HE
      • Bishop JM
      • Gilbert F
      • Brodeur G
      • Goldstein M
      • Trent J
      Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.
      • Kohl NE
      • Kanda N
      • Schreck RR
      • Bruns G
      • Latt SA
      • Gilbert F
      • Alt FW
      Transposition and amplification of oncogene-related sequences in human neuroblastomas.
      However, MYCN amplification is not unique to neuroblastoma. Amplification of the oncogene has also been reported in some cases of rhabdomyosarcoma
      • Garson JA
      • Clayton J
      • McIntyre P
      • Kemshead JT
      N-myc oncogene amplification in rhabdomyosarcoma at release.
      and retinoblastoma.
      • Godbout R
      • Squire J
      Amplification of a DEAD box protein gene in retinoblastoma cell lines.
      Furthermore, high levels of MYCN expression have been detected in Wilms tumor and hepatoblastoma.
      • Nisen PD
      • Zimmerman KA
      • Cotter SV
      • Gilbert F
      • Alt FW
      Enhanced expression of the N-myc gene in Wilms' tumors.
      MYCN amplification is seen in 30% to 50% of patients with advanced-stage neuroblastoma. In this subset of patients, MYCN amplification is strongly correlated with rapid tumor progression and poor outcome.
      • Seeger RC
      • Brodeur GM
      • Sather H
      • Dalton A
      • Siegel SE
      • Wong KY
      • Hammond D
      Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas.
      • Brodeur GM
      • Seeger RC
      • Schwab M
      • Varmus HE
      • Bishop JM
      Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.
      Only 5% to 10% of patients with localized disease or stage 4s neuroblastoma have tumors with MYCN amplification,
      • Seeger RC
      • Brodeur GM
      • Sather H
      • Dalton A
      • Siegel SE
      • Wong KY
      • Hammond D
      Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas.
      • Cohn SL
      • Look AT
      • Joshi VV
      • Holbrook T
      • Salwen H
      • Chagnovich D
      • Chesler L
      • Rowe ST
      • Valentine MB
      • Komuro H
      • Castleberry RP
      • Bowman LC
      • Rao PV
      • Seeger RC
      • Brodeur GM
      Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study.
      and the clinical relevance of MYCN amplification in favorable stage disease remains controversial.
      • Cohn SL
      • Look AT
      • Joshi VV
      • Holbrook T
      • Salwen H
      • Chagnovich D
      • Chesler L
      • Rowe ST
      • Valentine MB
      • Komuro H
      • Castleberry RP
      • Bowman LC
      • Rao PV
      • Seeger RC
      • Brodeur GM
      Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study.
      • Fabbretti G
      • Valenti C
      • Loda M
      • Brisigotti M
      • Cozzutto C
      • Paolo T
      • Callea F
      N-myc gene amplification/expression in localized stroma-rich neuroblastoma (ganglioneuroblastoma).
      • Rubie H
      • Hartmann O
      • Michon J
      • Frappaz D
      • Coze C
      • Chastagner P
      • Baranzelli MC
      • Plantaz D
      • Avet-Loiseau H
      • Benard J
      • Delattre O
      • Favrot M
      • Peyroulet MC
      • Thyss A
      • Perel Y
      • Bergeron C
      • Courbon-Collet B
      • Vannier JP
      • Lemerle J
      • Sommelet D
      • for the Societe Francaise d'Oncologie Pediatrique
      N-myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL 90 Study.
      There are reports of small numbers of patients with localized MYCN-amplified tumors treated with either surgery alone or surgery and low-dose chemotherapy that have been cured of their disease.
      • Cohn SL
      • Look AT
      • Joshi VV
      • Holbrook T
      • Salwen H
      • Chagnovich D
      • Chesler L
      • Rowe ST
      • Valentine MB
      • Komuro H
      • Castleberry RP
      • Bowman LC
      • Rao PV
      • Seeger RC
      • Brodeur GM
      Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study.
      • Fabbretti G
      • Valenti C
      • Loda M
      • Brisigotti M
      • Cozzutto C
      • Paolo T
      • Callea F
      N-myc gene amplification/expression in localized stroma-rich neuroblastoma (ganglioneuroblastoma).
      Furthermore, in a large Italian study, Tonini and colleagues recently reported that MYCN amplification was not associated with a worse outcome in infants with stage 4s disease.
      • Tonini GP
      • Boni L
      • Pession A
      • Rogers D
      • Iolascon A
      • Basso G
      • Cordero di Montezemolo L
      • Casale F
      • Perri P
      • Mazzocco K
      • Scaruffi P
      • Lo Cunsolo C
      • Marchese N
      • Milanaccio C
      • Conte M
      • Bruzzi P
      • De Bernardi B
      MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children.
      In contrast, poor outcome was seen in stage 4s infants with MYCN amplification in a study conducted by the POG.
      • Katzenstein HM
      • Bowman LC
      • Brodeur GM
      • Thorner PS
      • Joshi VV
      • Smith EI
      • Look AT
      • Rowe ST
      • Nash MB
      • Holbrook T
      • Alvarado C
      • Rao PV
      • Castleberry RP
      • Cohn SL
      Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the Pediatric Oncology Group experience–a Pediatric Oncology Group study.
      The conflicting results highlight the biological heterogeneity of neuroblastoma, and suggest that multiple factors are likely to contribute to tumor phenotype.
      Deletion of the short arm of chromosome 1 is found in ∼30% of primary human neuroblastomas resulting from simple terminal deletions, interstitial deletions, and unbalanced translocations with known or unknown chromosome fragments to the short arm of chromosome 1.
      • Kaneko Y
      • Kanda N
      • Maseki N
      • Sakurai M
      • Tsuchida Y
      • Takeda T
      • Okabe I
      Different karyotypic patterns in early and advanced stage neuroblastomas.
      • Brodeur GM
      • Green AA
      • Hayes FA
      • Williams KJ
      • Williams DL
      • Tsiatis AA
      Cytogenetic features of human neuroblastomas and cell lines.
      • Brodeur GM
      • Fong CT
      Molecular biology and genetics of human neuroblastoma.
      • Hayashi Y
      • Kanda N
      • Inaba T
      • Hanada R
      • Nahgahara R
      • Muchi H
      • Yamamoto K
      Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1.
      It has been hypothesized that a neuroblastoma suppressor gene is located at 1p36, and this hypothesis is supported by the observation that neuroblastoma has developed in children with constitutional 1p abnormalities.
      • Laureys G
      • Speleman F
      • Opdenakker G
      • Benoit Y
      • Leroy J
      Constitutional translocation t(1;17)(p36;q12–21) in a patient with neuroblastoma.
      • Biegel JA
      • White PS
      • Marshall HN
      • Fujimori M
      • Zackai EH
      • Scher CD
      • Brodeur GM
      • Emanuel BS
      Constitutional 1p36 deletion in a child with neuroblastoma.
      However, Maris and colleagues were unable to detect loss of heterozygosity at 1p36 in 13 patients with familial neuroblastoma, suggesting that there may be more than one NB suppressor gene.
      • Maris JM
      • Kyemba SM
      • Rebbeck TR
      • White PS
      • Sulman EP
      • Jensen SJ
      • Allen C
      • Biegel JA
      • Yanofsky RA
      • Feldman GL
      • Brodeur GM
      Familial predisposition to neuroblastoma does not map to chromosome band 1p36.
      Chromosome 1p deletions are most often seen in tumors that are near-diploid and MYCN. amplified.
      • Kaneko Y
      • Kanda N
      • Maseki N
      • Sakurai M
      • Tsuchida Y
      • Takeda T
      • Okabe I
      Different karyotypic patterns in early and advanced stage neuroblastomas.
      • Hayashi Y
      • Kanda N
      • Inaba T
      • Hanada R
      • Nahgahara R
      • Muchi H
      • Yamamoto K
      Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1.
      • Fong CT
      • Dracopoli NC
      • White PS
      • Merrill PT
      • Griffith RC
      • Housman DE
      • Brodeur GM
      Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastomas: correlation with N-myc amplification.
      • Maris JM
      • White PS
      • Beltinger CP
      • Sulman EP
      • Castleberry RP
      • Shuster JJ
      • Look AT
      • Brodeur GM
      Significance of chromosome 1p loss of heterozygosity in neuroblastoma.
      • Kaneko Y
      • Kanda N
      • Maseki N
      • Nakachi K
      • Takeda T
      • Okabe I
      • Sakurai M
      Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study.
      • Caron H
      • van Sluis P
      • de Kraker J
      • Bokkerink J
      • Egeler M
      • Laureys G
      • Slater R
      • Westerveld A
      • Voute PA
      • Versteeg R
      Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.
      Two large independent studies have shown that while deletion of 1p is associated with unfavorable outcome in univariate analysis, this factor is not prognostic after adjusting for MYCN copy number.
      • Maris JM
      • White PS
      • Beltinger CP
      • Sulman EP
      • Castleberry RP
      • Shuster JJ
      • Look AT
      • Brodeur GM
      Significance of chromosome 1p loss of heterozygosity in neuroblastoma.
      • Gehring M
      • Berthold F
      • Edler L
      • Schwab M
      • Amler LC
      The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma.
      In contrast, Caron and colleagues recently reported that loss of 1p was predictive of unfavorable outcome, independent of MYCN. amplification.
      • Caron H
      • van Sluis P
      • de Kraker J
      • Bokkerink J
      • Egeler M
      • Laureys G
      • Slater R
      • Westerveld A
      • Voute PA
      • Versteeg R
      Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.
      Studies to identify the putative neuroblastoma suppressor gene (or genes) are ongoing.
      Chromosome 17q abnormalities are also found in a subset of neuroblastoma tumors. Gilbert and co-workers found 17q gains in 8 of 35 (23%) neuroblastomas by classical cytogenetic technique.
      • Gilbert F
      • Feder M
      • Balaban G
      • Brangman D
      • Lurie DK
      • Podolsky R
      • Rinaldt V
      • Vinikoor N
      • Weisband J
      Human neuroblastomas and abnormalities of chromosomes 1 and 17.
      Chromosome 17q abnormalities were subsequently detected by FISH and allelic imbalance studies by other investigators.
      • Caron H
      • van Sluis P
      • de Kraker J
      • Bokkerink J
      • Egeler M
      • Laureys G
      • Slater R
      • Westerveld A
      • Voute PA
      • Versteeg R
      Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.
      • Van Roy N
      • Laureys G
      • Cheng NC
      • Willem P
      • Opdenakker G
      • Versteeg R
      • Speleman F
      1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines.
      • Meddeb M
      • Danglot G
      • Chudoba I
      • Venuat AM
      • Benard J
      • Avet-Loiseau H
      • Vasseur B
      • Le Paslier D
      • Terrier-Lacombe MJ
      • Hartmann O
      • Bernheim A
      Additional copies of a 25 Mb chromosomal region originating from 17q23.1–17qter are present in 90% of high-grade neuroblastomas.
      These studies demonstrated 17q gains in more than 90% of high-risk patients with neuroblastoma.
      • Meddeb M
      • Danglot G
      • Chudoba I
      • Venuat AM
      • Benard J
      • Avet-Loiseau H
      • Vasseur B
      • Le Paslier D
      • Terrier-Lacombe MJ
      • Hartmann O
      • Bernheim A
      Additional copies of a 25 Mb chromosomal region originating from 17q23.1–17qter are present in 90% of high-grade neuroblastomas.
      Clinical studies have demonstrated that favorable outcome is associated with whole chromosome 17 gains, whereas poor outcome is seen in the subset of neuroblastoma patients with 17q gains.
      • Plantaz D
      • Mohapatra G
      • Matthay KK
      • Pellarin M
      • Seeger RC
      • Feuerstein BG
      Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization.
      The Trk family of neurotropin receptors are important regulators of survival, growth, and differentiation of normal and neoplastic cells, and there is increasing evidence that these genes also play an important role in the biology and clinical behavior of neuroblastoma tumors. Several independent retrospective studies have demonstrated that high levels of TrkA expression in neuroblastoma are associated with favorable outcome.
      • Nakagawara A
      • Arima-Nakagawara M
      • Scavarda NJ
      • Azar CG
      • Cantor AB
      • Brodeur GM
      Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma.
      • Kogner P
      • Barbany G
      • Dominici C
      • Castello MA
      • Raschella G
      • Persson H
      Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis.
      • Borrello MG
      • Bongarzone I
      • Pierotti MA
      • Luksch R
      • Gasparini M
      • Collini P
      • Pilotti S
      • Rizzetti MG
      • Mondellini P
      • DeBernardi B
      • DiMartino D
      • Garaventa A
      • Brisigotti M
      • Tonini GP
      TRK and RET protooncogene expression in human neuroblastoma specimens: high-frequency of TRK expression in non-advanced stages.
      • Suzuki T
      • Bogenmann E
      • Shimada H
      • Stram D
      • Seeger RC
      Lack of high-affinity nerve growth factor receptors in aggressive neuroblastomas.
      • Brodeur GM
      • Nakagawara A
      • Yamashiro DJ
      • Ikegaki N
      • Liu XG
      • Azar CG
      • Lee CP
      • Evans AE
      Expression of TrkA, TrkB and TrkC in human neuroblastomas.
      High levels of TrkA mRNA are present in tumors from patients with favorable stage disease, whereas low to undetectable levels are observed in MYCN-amplified tumors. Recently, high levels of expression of TrkC have also been shown to correlate with favorable prognosis in neuroblastoma patients.
      • Ryden M
      • Sehgal R
      • Dominici C
      • Schilling FH
      • Ibanez CF
      • Kogner P
      Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis.
      • Yamashiro DJ
      • Nakagawara A
      • Ikegaki N
      • Liu XG
      • Brodeur GM
      Expression of TrkC in favorable human neuroblastomas.
      Truncated TrkB is predominantly expressed in differentiated tumors, whereas co-expression of full-length TrkB and brain-derived neurotrophic factor (BDNF) is associated with MYCN. amplification and may represent an autocrine survival pathway.
      • Brodeur GM
      • Nakagawara A
      • Yamashiro DJ
      • Ikegaki N
      • Liu XG
      • Azar CG
      • Lee CP
      • Evans AE
      Expression of TrkA, TrkB and TrkC in human neuroblastomas.
      • Nakagawara A
      • Azar CG
      • Scavarda NJ
      • Brodeur GM
      Expression and function of TRK-B and BDNF in human neuroblastomas.

      Summary

      Accurate diagnosis and classification of small-round-cell tumors of childhood has become increasingly important as modern therapy is not only disease specific but is also tailored according to patient risk. Despite advances in immunohistochemistry, cytogenetics, and molecular techniques, in some cases of small-round-cell tumors of childhood the correct diagnosis can remain elusive. Antibodies used in immunocytochemistry studies have limitations in sensitivity and specificity. Furthermore, although chromosomal abnormalities have proven to be useful in the characterization of certain pediatric cancers, other tumors lack a consistent genetic profile. It has also become evident that many genetic abnormalities are not tumor specific. Thus, although individual molecular tests can aid in delineating the entities of small-round-cell tumors of childhood, the diagnosis should not be based solely on the result of a molecular study. Rather, standard clinical and laboratory diagnostic modalities should be combined with immunohistochemistry, cytogenetics, and molecular studies. Studies similar to the one reported by Gilbert and colleagues,
      • Gilbert J
      • Haber M
      • Bordow SB
      • Marshall GM
      • Norris MD
      Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small-round-cell malignancies.
      analyzing the expression of patterns of genes specific to certain tumor types, are likely to result in the identification of additional molecular tools that will ensure that each child with a small-round-cell tumor is diagnosed correctly. The identification of additional molecular markers may also lead to a further refinement of risk-group classification and thereby provide the biological information needed to determine optimal treatment for every affected child.

      References

        • Gilbert J
        • Haber M
        • Bordow SB
        • Marshall GM
        • Norris MD
        Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small-round-cell malignancies.
        Am J Pathol. 1999; 155: 17-21
        • Weidner N
        • Tjoe J
        Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma.
        Am J Surg Pathol. 1994; 18: 486-494
        • Fellinger EJ
        • Garin-Chesa P
        • Su SL
        • DeAngelis P
        • Lane JM
        • Rettig WJ
        Biochemical and genetic characterization of the HBA71 Ewing's sarcoma cell surface antigen.
        Cancer Res. 1991; 51: 336-340
        • Gelin C
        • Aubrit F
        • Phalipon A
        • Raynal B
        • Cole S
        • Kaczorek M
        • Bernard A
        The E2 antigen, a 32 kd glycoprotein involved in T-cell adhesion processes, is the MIC2 gene product.
        EMBO J. 1989; 8: 3253-3259
        • Winters JL
        • Geil JD
        • O'Connor WN
        Immunohistology, cytogenetics, and molecular studies of small round cell tumors of childhood.
        Ann Clin Lab Sci. 1995; 25: 66-78
        • Dehner LP
        Primitive neuroectodermal tumor and Ewing's sarcoma.
        Am J Surg Pathol. 1993; 17: 1-13
        • Kodet R
        Rhabdomyosarcoma in childhood: an immunohistological analysis with myoglobin, desmin and vimentin.
        Pathol Res Pract. 1989; 185: 207-213
        • Pilkington GR
        • Pallesen G
        Phenotypic characterization of non-haemopoietic small cell tumours of childhood with monoclonal antibodies to leucocytes, epithelial cells and cytoskeletal proteins.
        Histopathology. 1989; 14: 347-357
        • Triche TJ
        • Tsokos M
        • Linnoila RI
        • Marangos PJ
        • Chandra R
        NSE in neuroblastoma and other round cell tumors of childhood.
        Prog Clin Biol Res. 1985; 175: 295-317
        • Haimoto H
        • Takahashi Y
        • Koshikawa T
        • Nagura H
        • Kato K
        Immunohistochemical localization of γ-enolase in normal human tissues other than nervous and neuroendocrine tissues.
        Lab Invest. 1985; 52: 257-263
        • Sariola H
        • Terava H
        • Rapola J
        • Saarinen UM
        Cell-surface ganglioside GD2 in the immunohistochemical detection and differential diagnosis of neuroblastoma.
        Am J Clin Pathol. 1991; 96: 248-252
        • Douglass EC
        Chromosomal rearrangements in Ewing's sarcoma and peripheral neuroectodermal tumor (PNET).
        Semin Dev Biol. 1990; 1: 393-396
        • Burchill SA
        • Wheeldon J
        • Cullinane C
        • Lewis IJ
        EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma.
        Eur J Cancer. 1997; 33: 239-243
        • Thorner P
        • Squire J
        • Chilton-MacNeil S
        • Marrano P
        • Bayani J
        • Malkin D
        • Greenberg M
        • Lorenzana A
        • Zielenska M
        Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor?.
        Am J Pathol. 1996; 148: 1125-1138
        • Delattre O
        • Zucman J
        • Plougastel B
        • Desmaze C
        • Melot T
        • Peter M
        • Kovar H
        • Joubert I
        • de Jong P
        • Rouleau G
        Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.
        Nature. 1992; 359: 162-165
        • Zucman J
        • Melot T
        • Desmaze C
        • Ghysdael J
        • Plougastel B
        • Peter M
        • Zucker JM
        • Triche TJ
        • Sheer D
        • Turc-Carel C
        Combinatorial generation of variable fusion proteins in the Ewing family of tumours.
        EMBO J. 1993; 12: 4481-4487
        • Zoubek A
        • Pfleiderer C
        • Salzer-Kuntschik M
        • Amann G
        • Windhager R
        • Fink FM
        • Koscielniak E
        • Delattre O
        • Strehl S
        • Ambros PF
        Variability of EWS chimaeric transcripts in Ewing tumours: a comparison of clinical and molecular data.
        Br J Cancer. 1994; 70: 908-913
        • Delattre O
        • Zucman J
        • Melot T
        • Garau XS
        • Zucker JM
        • Lenoir GM
        • Ambros PF
        • Sheer D
        • Turc-Carel C
        • Triche TJ
        The Ewing family of tumors: a subgroup of small-round-cell tumors defined by specific chimeric transcripts.
        N Engl J Med. 1994; 331: 294-299
        • Scrable H
        • Witte D
        • Shimada H
        • Seemayer T
        • Sheng WW
        • Soukup S
        • Koufos A
        • Houghton P
        • Lampkin B
        • Cavenee W
        Molecular differential pathology of rhabdomyosarcoma.
        Genes Chromosomes & Cancer. 1989; 1: 23-35
        • Turc-Carel C
        • Lizard-Nacol S
        • Justrabo E
        • Favrot M
        • Philip T
        • Tabone E
        Consistent chromosomal translocation in alveolar rhabdomyosarcoma.
        Cancer Genet Cytogenet. 1986; 19: 361-362
        • Barr FG
        • Galili N
        • Holick J
        • Biegel JA
        • Rovera G
        • Emanuel BS
        Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma.
        Nature Genet. 1993; 3: 113-117
        • Galili N
        • Davis RJ
        • Fredericks WJ
        • Mukhopadhyay S
        • Rauscher FJ
        • Emanuel BS
        • Rovera G
        • Barr FG
        Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma.
        Nature Genet. 1993; 5: 230-235
        • Fredericks WJ
        • Galili N
        • Mukhopadhyay S
        • Rovera G
        • Bennicelli J
        • Barr FG
        • Rauscher FJ
        The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3.
        Mol Cell Biol. 1995; 15: 1522-1535
        • Davis RJ
        • D'Cruz CM
        • Lovell MA
        • Biegel JA
        • Barr FG
        Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma.
        Cancer Res. 1994; 54: 2869-2872
        • Gerald WL
        • Miller HK
        • Battifora H
        • Miettinen M
        • Silva EG
        • Rosai J
        Intra-abdominal desmoplastic small round-cell tumor: report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals.
        Am J Surg Pathol. 1991; 15: 499-513
        • Rodriguez E
        • Sreekantaiah C
        • Gerald W
        • Reuter VE
        • Motzer RJ
        • Chaganti RS
        A recurring translocation, t(11;22)(p13;q11.2), characterizes intra-abdominal desmoplastic small round-cell tumors.
        Cancer Genet Cytogenet. 1993; 69: 17-21
        • Sawyer JR
        • Tryka AF
        • Lewis JM
        A novel reciprocal chromosome translocation t(11;22)(p13;q12) in an intraabdominal desmoplastic small round-cell tumor.
        Am J Surg Pathol. 1992; 16: 411-416
        • Ladanyi M
        • Gerald W
        Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor.
        Cancer Res. 1994; 54: 2837-2840
        • Brodeur GM
        • Castleberry RP
        Neuroblastoma.
        in: Pizzo PA Poplack DG Principles and Practice of Pediatric Oncology. ed 2. JB Lippincott, Philadelphia1997: 761-797
        • Look AT
        • Hayes FA
        • Nitschke R
        • McWilliams NB
        • Green AA
        Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma.
        N Engl J Med. 1984; 311: 231-235
        • Look AT
        • Hayes FA
        • Shuster JJ
        • Douglass EC
        • Castleberry RP
        • Bowman LC
        • Smith EI
        • Brodeur GM
        Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.
        J Clin Oncol. 1991; 9: 581-591
        • Bourhis J
        • DeVathaire F
        • Wilson GD
        • Hartmann O
        • Terrier-Lacombe MJ
        • Boccon-Gibod L
        • McNally NJ
        • Lemerle J
        • Riou G
        • Benard J
        Combined analysis of DNA ploidy index and N-myc genomic content in neuroblastoma.
        Cancer Res. 1991; 51: 33-36
        • Cohn SL
        • Rademaker AW
        • Salwen HR
        • Franklin WA
        • Gonzales-Crussi F
        • Rosen ST
        • Bauer KD
        Analysis of DNA ploidy and proliferative activity in relation to histology and N-myc amplification in neuroblastoma.
        Am J Pathol. 1990; 136: 1043-1052
        • Oppedal BR
        • Oien O
        • Jahnsen T
        • Brandtzaeg P
        N-myc amplification in neuroblastomas: histopathological, DNA ploidy, and clinical variables.
        J Clin Pathol. 1989; 42: 1148-1152
        • Bowman LC
        • Castleberry RP
        • Cantor A
        • Joshi V
        • Cohn SL
        • Smith EI
        • Yu A
        • Brodeur GM
        • Hayes FA
        • Look AT
        Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group Study.
        J Natl Cancer Inst. 1997; 89: 373-380
        • Schimke RT
        Methotrexate resistance and gene amplification: mechanisms and implications.
        Cancer. 1986; 57: 1912-1917
        • Kaneko Y
        • Kanda N
        • Maseki N
        • Sakurai M
        • Tsuchida Y
        • Takeda T
        • Okabe I
        Different karyotypic patterns in early and advanced stage neuroblastomas.
        Cancer Res. 1987; 47: 311-318
        • Brodeur GM
        • Green AA
        • Hayes FA
        • Williams KJ
        • Williams DL
        • Tsiatis AA
        Cytogenetic features of human neuroblastomas and cell lines.
        Cancer Res. 1981; 41: 4678-4686
        • Gilbert F
        • Feder M
        • Balaban G
        • Brangman D
        • Lurie DK
        • Podolsky R
        • Rinaldt V
        • Vinikoor N
        • Weisband J
        Human neuroblastomas and abnormalities of chromosomes 1 and 17.
        Cancer Res. 1984; 44: 5444-5449
        • Schwab M
        • Alitalo K
        • Klempnauer KH
        • Varmus HE
        • Bishop JM
        • Gilbert F
        • Brodeur G
        • Goldstein M
        • Trent J
        Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.
        Nature. 1983; 305: 245-248
        • Kohl NE
        • Kanda N
        • Schreck RR
        • Bruns G
        • Latt SA
        • Gilbert F
        • Alt FW
        Transposition and amplification of oncogene-related sequences in human neuroblastomas.
        Cell. 1983; 35: 359-367
        • Garson JA
        • Clayton J
        • McIntyre P
        • Kemshead JT
        N-myc oncogene amplification in rhabdomyosarcoma at release.
        Lancet. 1986; 1: 1496
        • Godbout R
        • Squire J
        Amplification of a DEAD box protein gene in retinoblastoma cell lines.
        Proc Natl Acad Sci USA. 1993; 90: 7578-7582
        • Nisen PD
        • Zimmerman KA
        • Cotter SV
        • Gilbert F
        • Alt FW
        Enhanced expression of the N-myc gene in Wilms' tumors.
        Cancer Res. 1986; 46: 6217-6222
        • Seeger RC
        • Brodeur GM
        • Sather H
        • Dalton A
        • Siegel SE
        • Wong KY
        • Hammond D
        Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas.
        N Engl J Med. 1985; 313: 1111-1116
        • Brodeur GM
        • Seeger RC
        • Schwab M
        • Varmus HE
        • Bishop JM
        Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.
        Science. 1984; 224: 1121-1124
        • Cohn SL
        • Look AT
        • Joshi VV
        • Holbrook T
        • Salwen H
        • Chagnovich D
        • Chesler L
        • Rowe ST
        • Valentine MB
        • Komuro H
        • Castleberry RP
        • Bowman LC
        • Rao PV
        • Seeger RC
        • Brodeur GM
        Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study.
        Cancer Res. 1995; 55: 721-726
        • Fabbretti G
        • Valenti C
        • Loda M
        • Brisigotti M
        • Cozzutto C
        • Paolo T
        • Callea F
        N-myc gene amplification/expression in localized stroma-rich neuroblastoma (ganglioneuroblastoma).
        Hum Pathol. 1993; 24: 294-297
        • Rubie H
        • Hartmann O
        • Michon J
        • Frappaz D
        • Coze C
        • Chastagner P
        • Baranzelli MC
        • Plantaz D
        • Avet-Loiseau H
        • Benard J
        • Delattre O
        • Favrot M
        • Peyroulet MC
        • Thyss A
        • Perel Y
        • Bergeron C
        • Courbon-Collet B
        • Vannier JP
        • Lemerle J
        • Sommelet D
        • for the Societe Francaise d'Oncologie Pediatrique
        N-myc gene amplification is a major prognostic factor in localized neuroblastoma: results of the French NBL 90 Study.
        J Clin Oncol. 1997; 15: 1171-1182
        • Tonini GP
        • Boni L
        • Pession A
        • Rogers D
        • Iolascon A
        • Basso G
        • Cordero di Montezemolo L
        • Casale F
        • Perri P
        • Mazzocco K
        • Scaruffi P
        • Lo Cunsolo C
        • Marchese N
        • Milanaccio C
        • Conte M
        • Bruzzi P
        • De Bernardi B
        MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children.
        J Clin Oncol. 1997; 15: 85-93
        • Katzenstein HM
        • Bowman LC
        • Brodeur GM
        • Thorner PS
        • Joshi VV
        • Smith EI
        • Look AT
        • Rowe ST
        • Nash MB
        • Holbrook T
        • Alvarado C
        • Rao PV
        • Castleberry RP
        • Cohn SL
        Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the Pediatric Oncology Group experience–a Pediatric Oncology Group study.
        J Clin Oncol. 1998; 16: 2007-2017
        • Brodeur GM
        • Fong CT
        Molecular biology and genetics of human neuroblastoma.
        Cancer Genet Cytogenet. 1989; 41: 153-174
        • Hayashi Y
        • Kanda N
        • Inaba T
        • Hanada R
        • Nahgahara R
        • Muchi H
        • Yamamoto K
        Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1.
        Cancer. 1989; 63: 126-132
        • Laureys G
        • Speleman F
        • Opdenakker G
        • Benoit Y
        • Leroy J
        Constitutional translocation t(1;17)(p36;q12–21) in a patient with neuroblastoma.
        Genes Chromosomes & Cancer. 1990; 2: 252-254
        • Biegel JA
        • White PS
        • Marshall HN
        • Fujimori M
        • Zackai EH
        • Scher CD
        • Brodeur GM
        • Emanuel BS
        Constitutional 1p36 deletion in a child with neuroblastoma.
        Am J Hum Genet. 1993; 52: 176-182
        • Maris JM
        • Kyemba SM
        • Rebbeck TR
        • White PS
        • Sulman EP
        • Jensen SJ
        • Allen C
        • Biegel JA
        • Yanofsky RA
        • Feldman GL
        • Brodeur GM
        Familial predisposition to neuroblastoma does not map to chromosome band 1p36.
        Cancer Res. 1996; 56: 3421-3425
        • Fong CT
        • Dracopoli NC
        • White PS
        • Merrill PT
        • Griffith RC
        • Housman DE
        • Brodeur GM
        Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastomas: correlation with N-myc amplification.
        Proc Natl Acad Sci USA. 1989; 86: 3753-3757
        • Maris JM
        • White PS
        • Beltinger CP
        • Sulman EP
        • Castleberry RP
        • Shuster JJ
        • Look AT
        • Brodeur GM
        Significance of chromosome 1p loss of heterozygosity in neuroblastoma.
        Cancer Res. 1995; 55: 4664-4669
        • Kaneko Y
        • Kanda N
        • Maseki N
        • Nakachi K
        • Takeda T
        • Okabe I
        • Sakurai M
        Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study.
        J Clin Oncol. 1990; 8: 2005-2013
        • Caron H
        • van Sluis P
        • de Kraker J
        • Bokkerink J
        • Egeler M
        • Laureys G
        • Slater R
        • Westerveld A
        • Voute PA
        • Versteeg R
        Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.
        N Engl J Med. 1996; 334: 225-230
        • Gehring M
        • Berthold F
        • Edler L
        • Schwab M
        • Amler LC
        The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma.
        Cancer Res. 1995; 55: 5366-5369
        • Van Roy N
        • Laureys G
        • Cheng NC
        • Willem P
        • Opdenakker G
        • Versteeg R
        • Speleman F
        1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines.
        Genes Chromosomes & Cancer. 1994; 10: 103-114
        • Meddeb M
        • Danglot G
        • Chudoba I
        • Venuat AM
        • Benard J
        • Avet-Loiseau H
        • Vasseur B
        • Le Paslier D
        • Terrier-Lacombe MJ
        • Hartmann O
        • Bernheim A
        Additional copies of a 25 Mb chromosomal region originating from 17q23.1–17qter are present in 90% of high-grade neuroblastomas.
        Genes Chromosomes & Cancer. 1996; 17: 156-165
        • Plantaz D
        • Mohapatra G
        • Matthay KK
        • Pellarin M
        • Seeger RC
        • Feuerstein BG
        Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization.
        Am J Pathol. 1997; 150: 81-89
        • Nakagawara A
        • Arima-Nakagawara M
        • Scavarda NJ
        • Azar CG
        • Cantor AB
        • Brodeur GM
        Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma.
        N Engl J Med. 1993; 328: 847-854
        • Kogner P
        • Barbany G
        • Dominici C
        • Castello MA
        • Raschella G
        • Persson H
        Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis.
        Cancer Res. 1993; 53: 2044-2050
        • Borrello MG
        • Bongarzone I
        • Pierotti MA
        • Luksch R
        • Gasparini M
        • Collini P
        • Pilotti S
        • Rizzetti MG
        • Mondellini P
        • DeBernardi B
        • DiMartino D
        • Garaventa A
        • Brisigotti M
        • Tonini GP
        TRK and RET protooncogene expression in human neuroblastoma specimens: high-frequency of TRK expression in non-advanced stages.
        Int J Cancer. 1993; 54: 540-545
        • Suzuki T
        • Bogenmann E
        • Shimada H
        • Stram D
        • Seeger RC
        Lack of high-affinity nerve growth factor receptors in aggressive neuroblastomas.
        J Natl Cancer Inst. 1993; 85: 337-384
        • Brodeur GM
        • Nakagawara A
        • Yamashiro DJ
        • Ikegaki N
        • Liu XG
        • Azar CG
        • Lee CP
        • Evans AE
        Expression of TrkA, TrkB and TrkC in human neuroblastomas.
        J Neurol Oncol. 1997; 31: 49-55
        • Ryden M
        • Sehgal R
        • Dominici C
        • Schilling FH
        • Ibanez CF
        • Kogner P
        Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis.
        Br J Cancer. 1996; 74: 773-779
        • Yamashiro DJ
        • Nakagawara A
        • Ikegaki N
        • Liu XG
        • Brodeur GM
        Expression of TrkC in favorable human neuroblastomas.
        Oncogene. 1996; 12: 37-41
        • Nakagawara A
        • Azar CG
        • Scavarda NJ
        • Brodeur GM
        Expression and function of TRK-B and BDNF in human neuroblastomas.
        Mol Cell Biol. 1994; 14: 759-767