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The Neuroblastoma and Ganglion Components of Nodular Modern Pathology (2015) 28, 166–176 166 & 2015 USCAP, Inc All rights reserved 0893-3952/15 $32.00 The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins Paola Angelini1, Sylvain Baruchel1,2, Paula Marrano3, Meredith S Irwin1,2 and Paul S Thorner3,4 1Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 2Department of Pediatrics, University of Toronto, University of Toronto, Toronto, ON, Canada; 3Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada and 4Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Nodular ganglioneuroblastoma is characterized by a macroscopic nodule of neuroblastoma within a ganglioneuromatous component. These two components have been considered to originate from separate clones, with the neuroblastoma clone accounting for the clinical behavior of nodular ganglioneuroblastoma. In order to investigate the clonal origin of the cellular components (neuroblasts, ganglion cells, and Schwann cells) of nodular ganglioneuroblastoma, paraffin-embedded tumor samples from eight cases were analyzed by single nucleotide polymorphism array and in situ hybridization. DNA was extracted separately from neuroblastomatous and ganglioneuromatous areas. By in situ hybridization, MYCN gain (4–10 gene copies/ nucleus) was detected in 7/8 neuroblastoma samples. In ganglioneuromatous regions, gains were also detected in ganglion cells but not in Schwann cells. Single-nucleotide polymorphism array studies identified chromosome losses (11q and 14q) and gains (12, 13q, 17q and 18q) in the neuroblastoma component, whereas the ganglioneuromatous component showed fewer or no genetic alterations. There were no unique copy number changes distinguishing nodular ganglioneuroblastoma from other subtypes of neuroblastoma. By in situ hybridization, ganglion cells but not Schwann cells showed the same alterations detected in neuroblasts. Thus, neuroblasts and ganglion cells in nodular ganglioneuroblastoma are genetically related and may arise from the same clone. In contrast, the Schwann cells have a different origin and may be derived from a non- neoplastic neural crest precursor. Our results suggest that the clinical behavior of nodular ganglioneuro- blastoma cannot be explained by the presence of separate clones with distinct genetic signatures. Modern Pathology (2015) 28, 166–176; doi:10.1038/modpathol.2014.90; published online 1 August 2014 Neuroblastoma, a malignancy of neural crest cells of associated with a poor outcome include: age 418 the autonomic nervous system, is the most common months,2 unfavorable histopathology,5 amplification extracranial solid tumor of childhood.1 The incidence of the MYCN oncogene,6–8 diploid DNA content, is B1 in 7000 children, with a median age at pre- and specific segmental chromosomal aberrations sentation of 17 months,2 and accounts for 15% of such as loss of heterozygosity at 1p and 11q, gain cancer-related deaths in childhood.1,3 A feature of 17q.3,9 distinguishing neuroblastoma from most other pedia- Currently, the pathology of neuroblastoma is tric malignancies is the striking heterogeneity of graded according to the International Neuroblastoma histology, biology, and clinical behavior.3,4 Features Pathology Classification10–12 that separates histologic subtypes of neuroblastoma into favorable and unfavorable categories. One uncommon subtype is Correspondence: Dr PS Thorner, MD, PhD, Division of Pathology, nodular ganglioneuroblastoma, which represents The Hospital for Sick Children, 555 University Avenue, Toronto, 5–10% of neuroblastic tumors.12–14 Nodular ganglio- ON, Canada M5G 1X8. E-mail: [email protected] neuroblastoma is a composite tumor, with a predo- Received 31 January 2014; revised 18 April 2014; accepted 19 minance of differentiated Schwannian-type stroma April 2014; published online 1 August 2014 associated with one or more macroscopically visible www.modernpathology.org Genomics of nodular ganglioneuroblastoma P Angelini et al 167 nodules of neuroblastoma showing neuropil forma- distinct. To examine this issue further and specifically tion but lacking this Schwannian stroma (referred to compare the genetic changes in the neuroblasts, as ‘stroma-poor’). Less common variants without ganglion, and Schwann cells, we used a combined visible nodules have more recently been included approach of single-nucleotide polymorphism array under the category of nodular ganglioneurobla- and in situ hybridization. The goal of our study was stoma.15,16 In the original version of this classi- to determine whether the different cellular com- fication system, this subtype was categorized with ponents of nodular ganglioneuroblastoma have the unfavorable histology group, and those patients distinct chromosomal alterations and identify changes had a 46.8% event-free survival and 59.1% overall potentially specific to nodular ganglioneuroblastoma. survival.12 More recently, it was shown that nodular ganglioneuroblastoma can be subcategorized as favorable or unfavorable according to the histo- pathology of the stroma-poor component, using the Materials and methods same criteria as for other stroma-poor neuro- Study Group blastomas.15,16 By this system, unfavorable tumors outnumber favorable ones B2:1, with an event-free Between 1987 and 2008, there were eight patients survival of 29–32% for unfavorable nodular gang- diagnosed with nodular ganglioneuroblastoma at lioneuroblastoma compared with 86% for favorable, the Hospital for Sick Children, Toronto, Ontario, for and overall survival of 33–40% and 90–95%, which tumor tissue was available (Table 1). An respectively.15,16 Subsequent studies have confirmed additional 18 cases were identified but rejected for these clinical differences.13,17–19 one of the following reasons: (1) insufficient tissue Neuroblastoma is characterized by multiple chro- was available for the studies; (2) the diagnosis was mosomal abnormalities (reviewed in refs 1,3), but based solely on a post-treatment histology and whether these are shared by the nodular ganglio- chemotherapy can alter the original histologic neuroblastoma subtype is not known. Genome-wide appearance to resemble nodular ganglioneuroblas- approaches such as array comparative genomic toma; (3) review of the pathology failed to confirm hybridization20–25 and single-nucleotide polymor- the subtype of nodular ganglioneuroblastoma. The phism arrays26,27 have been used to identify whole eight cases included six males and two females, chromosome and segmental gains and losses in ranging in age from 8 months to 7 years. The sites neuroblastoma; however, only two studies specifi- included adrenal gland, posterior mediastinum, and cally mentioned the inclusion of ganglioneuro- abdomen. Using International Neuroblastoma Risk blastoma samples28,29 and results were inconsistent. Group criteria, six patients were categorized as low The neuroblastoma component is thought to have a risk (one stage 1 and five stage 2) and two patients clonal origin distinct from the ganglioneuromatous were high risk (both stage 4). Using the histologic part of the tumor.11,16 However, there is only one grading system of the International Neuroblastoma report in which the neuroblastic and ganglioneuro- Pathology Committee,15,16 four cases were catego- matous components were compared by array rized as favorable and four cases as unfavorable. comparative genomic hybridization.30 In this study Seven of eight patients had at least 4 years of follow- of six tumors, variable copy number alterations were up. Two patients died of disease, one of which had detected in the neuroblastic component but not in stage 4 disease at diagnosis and the other was stage 2 the stroma-rich component, supporting the concept at diagnosis but relapsed with distant metastatic that these two components might be genetically disease. Paraffin-embedded tissue was available for Table 1 Clinical features of nodular ganglioneuroblastoma study group Chemo before Case Age Sex Site Stage Risk Histology biopsy Met Outcome 1 5 Years M Adrenal 2 Lowa Diff, low MKI (unfavorable) þ GNB intermixed Alive 2 10 Months M Thoracic 2 Low Poorly diff, inter MKI (unfavorable) þ GNB intermixed Alive 3 7 Years M Adrenal 4 High Diff, low MKI (unfavorable) þ GN maturing Y Y Alive 4 2 Years M Thoracic 2 Lowa Poorly diff, high MKI (unfavorable) þ GN maturing Y Dead 5 2 Years F Adrenal 1 Low Diff, low MKI (favorable) þ GNB intermixed Alive 6 4 Years M Adrenal 4 High Diff, low MKI (favorable) þ GNB intermixed Y Dead 7 8 Months F Thoracic 2 Low Poorly diff, low MKI (favorable) þ GN maturing Alive 8 16 Months M Abdomen 2 Low Diff, inter MKI (favorable) þ GN maturing Alive Abbreviations: Diff, differentiated; Poorly diff, poorly differentiated; MKI, mitotic-karyorrhectic index; Inter, intermediate; Chemo, chemotherapy; Met, metastasis studied; GN, ganglioneuroma; GNB, ganglioneuroblastoma. Histologic grading was assessed according to published criteria.15,16 aCases 1 and 4 relapsed as stage 4/International Neuroblastoma Risk Group high risk. Modern Pathology (2015) 28, 166–176 Genomics of nodular ganglioneuroblastoma 168 P Angelini et al all eight cases. Six samples were from the time Single-Nucleotide Polymorphism Arrays of diagnosis and two were post-chemotherapy resection samples (the specimens at time of DNA was extracted separately from neuroblastoma- diagnosis were similar in histology to the post- tous and
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