Differential Clinical Significance of Neurotrophin-3 Expression according to MYCN Amplification and TrkC Expression in Neuroblastoma

Abstract

Background: Neurotrophin-3 (NT-3), a member of the NT family, has only been considered an ancillary compound that provides anti-apoptotic benefits by inactivating tropomyosin receptor kinase C (TrkC)-induced apoptotic signals. However, little is known about the clinical relevance of NT-3 expression itself in neuroblastoma. The purpose of this study was to assess NT-3 expression in patients with neuroblastoma and its relevance to clinicopathologic findings and treatment outcomes.

Methods: In this study, expression of NT-3 and TrkC was analyzed using immunohistochemistry in 240 patients with newly diagnosed neuroblastoma.

Results: The results of the study revealed that NT-3 expression was associated with older age at diagnosis, localized tumors, and more differentiated tumors but was not associated with early treatment response (degree of residual tumor volume after three cycles of chemotherapy) and progression-free survival (PFS). However, when analysis was confined to patients with MYCN amplified tumors, NT-3 expression was associated with better early treatment response with borderline significance (P = 0.092) and higher PFS (86.9% vs. 58.2%; P = 0.044). In multivariate analysis in patients with MYCN amplified tumors, NT-3 was independent prognostic factor (hazard ratio, 0.246; 95% confidence interval, 0.061-0.997; P = 0.050). In another subgroup analysis, the early treatment response was better if NT-3 was expressed in patients without TrkC expression (P = 0.053) while it was poorer in patients with TrkC expression (P = 0.023).

Conclusion: This study suggests that NT-3 expression in neuroblastoma has its own clinical significance independent of TrkC expression, and its prognostic significance differs depending on the status of MYCN amplification and/or TrkC expression.

Keywords: MYCN; Neuroblastoma; Neurotrophin-3; TrkC.

Fig. 1. Representative immunostaining of NT-3 and TrkC. (A) A case of neuroblastoma positive for NT-3. Neuroblasts are positive for NT-3 (arrows), in contrast to stroma cells negative for it. (B) A case of neuroblastoma negative for NT-3. (C) A case positive for TrkC. Neuroblasts are positive for TrkC, while non-neoplastic lymphocytes are negative for it (arrow heads). (D) A case negative for TrkC. Neuroblasts are negative for TrkC (arrows), whereas non-neoplastic chromaffin cells in adrenal medulla are positive for TrkC (arrow heads).

NT-3 = neurotrophin-3, TrkC = tropomyosin receptor kinase C.

Fig. 2. Clinical significance of NT-3 expression. NT-3 expression was associated with (A) older age at diagnosis, (B) localized tumors, and (C) more differentiated histology. (D) However, there was no difference in the proportion of MYCN amplification according to NT-3 expression. (E, F) There was no difference in degree of tumor volume reduction or PFS between patients with NT-3 expression and those without.

NT-3 = neurotrophin-3, GNB = ganglioneuroblastoma, D = differentiated, PD = poorly differentiated, UD = undifferentiated, PFS = progression-free survival.

Fig. 3. Clinical significance of NT-3 expression in subgroup analysis according to MYCN amplification.

(A-C vs. F-H) There was similar association between NT-3 expression and clinicopathologic parameters, such as age at diagnosis and stage regardless of MYCN amplification status. However, treatment results differed between the two groups. (D, I) While percent residual tumor volume at early phase of induction chemotherapy tended to be higher if NT-3 was expressed in patients with MYCN non-amplified tumors, it was lower in patients with MYCN amplified tumors with borderline significance. (E, J) Furthermore, while there was no difference in PFS according to NT-3 expression in patients with MYCN non-amplified tumors, patients with MYCN amplified tumors showed better PFS if NT-3 was expressed. NT-3 = neurotrophin-3, GNB = ganglioneuroblastoma, D = differentiated, PD = poorly differentiated, UD = undifferentiated, PFS = progression-free survival.

Fig. 4. Clinical significance of TrkC expression. (A-C) TrkC expression showed similar associations with known prognostic factors as those observed in NT-3 expression. (D) However, MYCN amplification was rarely detected in tumors with TrkC expression. (E, F) In addition, TrkC expression was associated with poorer early treatment response, although there was no difference in PFS.

TrkC = tropomyosin receptor kinase C, GNB = ganglioneuroblastoma, D = differentiated, PD = poorly differentiated, UD = undifferentiated, PFS = progression-free survival, NT-3 = neurotrophin-3.

Fig. 5. Clinical significance of NT-3 expression in subgroup analysis according to TrkC expression. (A-C vs. F-H) NT-3 expression showed similar associations with known prognostic factors irrespective of TrkC expression. However, there was opposite early treatment response according to NT-3 expression between patients with TrkC expression and those without. (D, I) While the percent residual tumor volume at early phase of induction chemotherapy was lower if NT-3 was expressed in patients without TrkC expression with borderline significance, it was higher in patients with TrkC expression. (E, J) However, there was no difference in PFS according to NT-3 expression irrespective of TrkC expression.

TrkC = tropomyosin receptor kinase C, NT-3 = neurotrophin-3, GNB = ganglioneuroblastoma, D = differentiated, PD = poorly differentiated, UD = undifferentiated, PFS = progression-free survival.