Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

  • William Temple
  • Lori Mendelsohn
  • Grace E. Kim
  • Erin Nekritz
  • W. Clay Gustafson
  • Lawrence Lin
  • Kathy Giacomini
  • Arlene Naranjo
  • Collin Van Ryn
  • Gregory A. Yanik
  • Susan G. Kreissman
  • Michael Hogarty
  • Katherine K. Matthay
  • Steven G. DuBoisEmail author
Original Article



Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features.


We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 – 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests.


Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62 % and 75 % of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity.


VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.


Neuroblastoma Vesicular monoamine transporters VMAT1  VMAT2  MIBG avidity 


Compliance with ethical standards


This work was supported by the Campini Foundation (S.G.D. and K.K.M.), the Dougherty Family Foundation (K.K.M.), Alex’s Lemonade Stand Foundation (W.T., S.G.D., and K.K.M.), U10CA09853, U10CA180899, and U24CA114766. The funding sources did not play a role in study design, conduct, data analysis, or interpretation.

Conflict of interest


Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

For this type of study, formal consent is not required.

Supplementary material

259_2015_3179_MOESM1_ESM.pptx (915 kb)
Supplemental Fig. 1 a–c Representative photomicrographs of tumors with 3+ (a), 2+ (b), and 1+ (c) VMAT1 staining. d–f Representative photomicrographs of tumors with 3+ (d), 2+ (e), and 1+ (f) VMAT2 staining. All photomicrographs are at 200× magnification. (PPTX 915 kb)
259_2015_3179_MOESM2_ESM.pptx (3.6 mb)
Supplemental Fig. 2 Correlation between VMAT1 composite protein expression score and VMAT2 composite protein expression score (r = 0.66, p < 0.001). (PPTX 3648 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • William Temple
    • 1
    • 4
  • Lori Mendelsohn
    • 1
    • 4
  • Grace E. Kim
    • 2
  • Erin Nekritz
    • 1
    • 4
  • W. Clay Gustafson
    • 1
    • 4
  • Lawrence Lin
    • 3
  • Kathy Giacomini
    • 3
  • Arlene Naranjo
    • 5
  • Collin Van Ryn
    • 5
  • Gregory A. Yanik
    • 6
  • Susan G. Kreissman
    • 7
  • Michael Hogarty
    • 8
  • Katherine K. Matthay
    • 1
    • 4
  • Steven G. DuBois
    • 1
    • 4
    • 9
    Email author
  1. 1.Department of PediatricsUCSF School of MedicineSan FranciscoUSA
  2. 2.Department of PathologyUCSF School of MedicineSan FranciscoUSA
  3. 3.Department of Bioengineering and Therapeutic SciencesUCSF School of PharmacySan FranciscoUSA
  4. 4.UCSF Benioff Children’s HospitalSan FranciscoUSA
  5. 5.Children’s Oncology Group Statistics and Data CenterUniversity of FloridaGainesvilleUSA
  6. 6.CS Mott Children’s HospitalUniversity of MichiganAnn ArborUSA
  7. 7.Duke University Medical CenterDurhamUSA
  8. 8.Children’s Hospital of Philadelphia and Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  9. 9.UCSF School of MedicineSan FranciscoUSA

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