title: IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma.
abstract: Neuroblastoma is a childhood tumor of the sympathetic nervous system. Observations in the Beckwith-Wiedemann syndrome suggest that sympathetic embryonal cells with an abundant expression of the insulin-like growth factor 2 gene (IGF2) may be involved in the genesis of low-malignant infant neuroblastomas. We have therefore compared the cell type-specific IGF2 expression of the human sympathetic nervous system during early development with that of neuroblastoma. An abundant expression in normal sympathetic tissue was specific to extra-adrenal chromaffin cells, ie, paraganglia and small intensely fluorescent (SIF) cells, whereas sympathetic neuronal cells were IGF2-negative. A subpopulation of neuroblastomas expressed IGF2, which correlated with an early age at diagnosis, an extra-adrenal tumor origin, and severe hemodynamic signs of catecholamine secretion. Histologically IGF2-expressing tumors displayed a lobular growth pattern, and expression was restricted to the most mature and least proliferative cells. Typically, these cells were morphologically and histochemically similar to paraganglia/SIF cells and formed distinct ring-like zones in the center of the lobules around a core of apoptosis-like tumor cells. The similarities found between IGF2-expressing neuroblastoma cells and paraganglia/SIF cells in terms of histological features, anatomical origin, and age-dependent growth suggest a paraganglionic/SIF cell lineage of most infant tumors and also of extra-adrenal tumors diagnosed after infancy. Furthermore, since paraganglia/SIF cells undergo postnatal involution, the same cellular mechanism may be responsible for spontaneous regression in infant neuroblastoma.
authors.affiliation: Department of Pathology, University Hospital, Uppsala, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Hedborg
authors.forename: R
authors.initials: R
authors.lastname: Ohlsson
authors.forename: B
authors.initials: B
authors.lastname: Sandstedt
authors.forename: L
authors.initials: L
authors.lastname: Grimelius
authors.forename: J C
authors.initials: JC
authors.lastname: Hoehner
authors.forename: S
authors.initials: S
authors.lastname: Pählman
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D053379:Chromogranin A; D002864:Chromogranins / Q000032:analysis; D005314:Embryonic and Fetal Development / Q000235:genetics; D018305:Ganglioneuroblastoma / Q000737:chemistry / Q000235:genetics; D005729:Ganglioneuroma / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007223:Infant; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000032:analysis*; D009447:Neuroblastoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D010233:Paraganglia, Chromaffin / Q000473:pathology*; D013564:Sympathetic Nervous System / Q000196:embryology
chemical_list: D014408:Biomarkers, Tumor; D053379:Chromogranin A; D002864:Chromogranins; D007335:Insulin-Like Growth Factor II