IGF2 EXPRESSION IS A MARKER FOR PARAGANGLIONIC SIF CELL-DIFFERENTIATION IN NEUROBLASTOMA

Neuroblastoma is a childhood tumor of the sympathetic nervous system O bservations in the Beckwith-Wiedemann syndrome suggest that sympatheti c embryonal cells with an abundant expression of the insulin-like grow th factor 2 gene (IGF2) may be involved in the genesis of low malignan t infant neuroblastomas. We have therefore compared the cell type-spec ific IGF2 expression of the human sympathetic nervous system during ea rly development with that of neuroblastoma. An abundant expression in normal sympathetic tissue was specific to extra-adrenal chromaffin cel ls, ie, paraganglia and small intensely fluorescent (SIF) cells, where as sympathetic neuronal cells were IGF2-negative. A subpopulation of n euroblastomas expressed IGF2, which correlated with an early age at di agnosis, an extraadrenal tumor origin, and severe hemodynamic signs of catecholamine secretion. Histologically IGF2-expressing tumors displa yed a lobular growth pattern, and expression was restricted to the mos t mature and least proliferative cells. Typically, these cells were mo rphologically 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 IG F2-expressing neuroblastoma cells and paraganglia/SIF cells in terms o f histological features, anatomical origin, and age-dependent growth s uggest a paraganglionic/SIF cell lineage of most infant tumors and als o 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 neur oblastoma.