Skip to main content
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging 3/2018

17.10.2017 | Original Article

Immunohistochemical evaluation of molecular radiotherapy target expression in neuroblastoma tissue

verfasst von: Jennifer E. Gains, Neil J. Sebire, Veronica Moroz, Keith Wheatley, Mark N. Gaze

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Neuroblastoma may be treated with molecular radiotherapy, 131I meta-Iodobenzylguanidine and 177Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy.

Methods

Tissue bank samples of formalin fixed paraffin embedded neuroblastoma tissue from patients for whom clinical outcome data were available were sectioned and stained with haematoxylin and eosin, and monoclonal antibodies directed against NAT and SSTR2. Sections were examined blinded to clinical information and scored for the percentage and intensity of tumour cells stained. These data were analysed in conjunction with clinical data.

Results

Tissue from 75 patients was examined. Target expression scores varied widely between patients: NAT median 45%, inter-quartile range 25% - 65%; and SSTR2 median 55%, interquartile range 30% – 80%; and in some cases heterogeneity of expression between different parts of a tumour was observed. A weak positive correlation was observed between the expression scores of the different targets: correlation coefficient = 0.23, p = 0.05. MYCN amplified tumours had lower SSTR2 scores: mean difference 23% confidence interval 8% - 39%, p < 0.01. Survival did not differ by scores.

Conclusions

As expression of both targets is variable and heterogeneous, imaging assessment of both may yield more clinical information than either alone. The clinical value of immunohistochemical assessment of target expression requires prospective evaluation. Variable target expression within a patient may contribute to treatment failure.
Literatur
1.
Zurück zum Zitat Gains J, Mandeville H, Cork N, Brock P, Gaze M. Ten challenges in the management of neuroblastoma. Future Oncol. 2012;8:839–58.CrossRefPubMed Gains J, Mandeville H, Cork N, Brock P, Gaze M. Ten challenges in the management of neuroblastoma. Future Oncol. 2012;8:839–58.CrossRefPubMed
2.
Zurück zum Zitat Pearson AD, Pinkerton CR, Lewis IJ, et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: A randomised trial. Lancet Oncol. 2008;9:247–56.CrossRefPubMed Pearson AD, Pinkerton CR, Lewis IJ, et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: A randomised trial. Lancet Oncol. 2008;9:247–56.CrossRefPubMed
3.
Zurück zum Zitat Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: A children's oncology group study. J Clin Oncol. 2009;27:1007–13.CrossRefPubMedPubMedCentral Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: A children's oncology group study. J Clin Oncol. 2009;27:1007–13.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat AL Y, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–34.CrossRef AL Y, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–34.CrossRef
5.
Zurück zum Zitat Ladenstein R, Pötschger U, Pearson AD, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): An international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.CrossRefPubMed Ladenstein R, Pötschger U, Pearson AD, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): An international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.CrossRefPubMed
6.
Zurück zum Zitat Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MNA. Systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer. 2014;50:801–15.CrossRefPubMed Wilson JS, Gains JE, Moroz V, Wheatley K, Gaze MNA. Systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer. 2014;50:801–15.CrossRefPubMed
7.
Zurück zum Zitat Gaze MN, Gains JE, Walker C, Bomanji JB. Optimization of molecular radiotherapy with [131I]-meta Iodobenzylguanidine for high-risk neuroblastoma. Q J Nucl Med Mol Imaging. 2013;57:66–78.PubMed Gaze MN, Gains JE, Walker C, Bomanji JB. Optimization of molecular radiotherapy with [131I]-meta Iodobenzylguanidine for high-risk neuroblastoma. Q J Nucl Med Mol Imaging. 2013;57:66–78.PubMed
8.
Zurück zum Zitat Gains JE, Bomanji JB, Fersht NL, et al. 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med. 2011;52:1041–7.CrossRefPubMed Gains JE, Bomanji JB, Fersht NL, et al. 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. J Nucl Med. 2011;52:1041–7.CrossRefPubMed
9.
Zurück zum Zitat Glowniak JV, Kilty JE, Amara SG, Hoffman BJ, Turner FE. Evaluation of metaiodobenzylguanidine uptake by the norepinephrine, dopamine and serotonin transporters. J Nucl Med. 1993;34:1140–6.PubMed Glowniak JV, Kilty JE, Amara SG, Hoffman BJ, Turner FE. Evaluation of metaiodobenzylguanidine uptake by the norepinephrine, dopamine and serotonin transporters. J Nucl Med. 1993;34:1140–6.PubMed
10.
Zurück zum Zitat Mairs RJ, Gaze MN, Barrett A. The uptake and retention of metaiodobenzyl guanidine by the neuroblastoma cell line NB1-G. Br J Cancer. 1991;64:293–5.CrossRefPubMedPubMedCentral Mairs RJ, Gaze MN, Barrett A. The uptake and retention of metaiodobenzyl guanidine by the neuroblastoma cell line NB1-G. Br J Cancer. 1991;64:293–5.CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Matthay KK, Shulkin B, Ladenstein R, et al. Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: A report for the international Neuroblastoma risk group (INRG) task force. Br J Cancer. 2010;102:1319–26.CrossRefPubMedPubMedCentral Matthay KK, Shulkin B, Ladenstein R, et al. Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: A report for the international Neuroblastoma risk group (INRG) task force. Br J Cancer. 2010;102:1319–26.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Lewington V, Lambert B, Poetschger U, et al. 123I-mIBG scintigraphy in neuroblastoma: Development of a SIOPEN semi-quantitative reporting method by an international panel. Eur J Nucl Med Mol Imaging. 2017;44:234–41.CrossRefPubMed Lewington V, Lambert B, Poetschger U, et al. 123I-mIBG scintigraphy in neuroblastoma: Development of a SIOPEN semi-quantitative reporting method by an international panel. Eur J Nucl Med Mol Imaging. 2017;44:234–41.CrossRefPubMed
13.
Zurück zum Zitat Taniyama Y, Suzuki T, Mikami Y, Moriya T, Satomi S, Sasano H. Systemic distribution of somatostatin receptor subtypes in human: An immunohistochemical study. Endocr J. 2005;52:605–11.CrossRefPubMed Taniyama Y, Suzuki T, Mikami Y, Moriya T, Satomi S, Sasano H. Systemic distribution of somatostatin receptor subtypes in human: An immunohistochemical study. Endocr J. 2005;52:605–11.CrossRefPubMed
14.
Zurück zum Zitat Albers AR, O'Dorisio MS, Balster DA, et al. Somatostatin receptor gene expression in neuroblastoma. Regul Pept. 2000;88:61–73.CrossRefPubMed Albers AR, O'Dorisio MS, Balster DA, et al. Somatostatin receptor gene expression in neuroblastoma. Regul Pept. 2000;88:61–73.CrossRefPubMed
15.
Zurück zum Zitat Georgantzi K, Tsolakis AV, Stridsberg M, Jakobson A, Christofferson R, Janson ET. Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma. Pediatr Blood Cancer. 2011;56:584–9.CrossRefPubMed Georgantzi K, Tsolakis AV, Stridsberg M, Jakobson A, Christofferson R, Janson ET. Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma. Pediatr Blood Cancer. 2011;56:584–9.CrossRefPubMed
16.
Zurück zum Zitat Schilling FH, Bihl H, Jacobsson H, et al. Combined 111In-pentetreotide scintigraphy and 123I-mIBG scintigraphy in neuroblastoma provides prognostic information. Med Pediatr Oncol. 2000;35:688–91.CrossRefPubMed Schilling FH, Bihl H, Jacobsson H, et al. Combined 111In-pentetreotide scintigraphy and 123I-mIBG scintigraphy in neuroblastoma provides prognostic information. Med Pediatr Oncol. 2000;35:688–91.CrossRefPubMed
17.
Zurück zum Zitat Menda Y, O'Dorisio MS, Kao S, et al. Phase I trial of 90Y-DOTATOC therapy in children and young adults with refractory solid tumors that express somatostatin receptors. J Nucl Med. 2010;51:1524–31.CrossRefPubMedPubMedCentral Menda Y, O'Dorisio MS, Kao S, et al. Phase I trial of 90Y-DOTATOC therapy in children and young adults with refractory solid tumors that express somatostatin receptors. J Nucl Med. 2010;51:1524–31.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376:125–35.CrossRefPubMed Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376:125–35.CrossRefPubMed
19.
Zurück zum Zitat Ladenstein R, Weixler S, Baykan B, et al. Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients: A SIOPEN phase 1 study. MAbs. 2013;5:801–9.CrossRefPubMedPubMedCentral Ladenstein R, Weixler S, Baykan B, et al. Ch14.18 antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients: A SIOPEN phase 1 study. MAbs. 2013;5:801–9.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Kramer K, Humm JL, Souweidane MM, et al. Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J Clin Oncol. 2007;25:5465–70.CrossRefPubMed Kramer K, Humm JL, Souweidane MM, et al. Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J Clin Oncol. 2007;25:5465–70.CrossRefPubMed
21.
Zurück zum Zitat Dubois SG, Geier E, Batra V, et al. Evaluation of Norepinephrine transporter expression and Metaiodobenzylguanidine avidity in Neuroblastoma: A report from the Children's oncology group. Int J Mol Imaging. 2012;250834:2012. Dubois SG, Geier E, Batra V, et al. Evaluation of Norepinephrine transporter expression and Metaiodobenzylguanidine avidity in Neuroblastoma: A report from the Children's oncology group. Int J Mol Imaging. 2012;250834:2012.
22.
Zurück zum Zitat Volante M, Brizzi MP, Faggiano A, et al. Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: A proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol. 2007;20:1172–82.CrossRefPubMed Volante M, Brizzi MP, Faggiano A, et al. Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: A proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol. 2007;20:1172–82.CrossRefPubMed
23.
Zurück zum Zitat Carlin S, Mairs RJ, McCluskey AG, et al. Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[131I]iodobenzylguanidine by neuroblastoma tumors. Clin Cancer Res. 2003;9:3338–44.PubMed Carlin S, Mairs RJ, McCluskey AG, et al. Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[131I]iodobenzylguanidine by neuroblastoma tumors. Clin Cancer Res. 2003;9:3338–44.PubMed
24.
Zurück zum Zitat Lode HN, Bruchelt G, Seitz G, et al. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of monoamine transporters in neuroblastoma cell lines: Correlations to meta-iodobenzylguanidine (MIBG) uptake and tyrosine hydroxylase gene expression. Eur J Cancer. 1995;31A:586–90.CrossRefPubMed Lode HN, Bruchelt G, Seitz G, et al. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of monoamine transporters in neuroblastoma cell lines: Correlations to meta-iodobenzylguanidine (MIBG) uptake and tyrosine hydroxylase gene expression. Eur J Cancer. 1995;31A:586–90.CrossRefPubMed
25.
Zurück zum Zitat Mairs RJ, Livingstone A, Gaze MN, Wheldon TE, Barrett A. Prediction of accumulation of 131I-labelled meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction. Br J Cancer. 1994;70:97–101.CrossRefPubMedPubMedCentral Mairs RJ, Livingstone A, Gaze MN, Wheldon TE, Barrett A. Prediction of accumulation of 131I-labelled meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction. Br J Cancer. 1994;70:97–101.CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Montaldo PG, Raffaghello L, Guarnaccia F, Pistoia V, Garaventa A, Ponzoni M. Increase of metaiodobenzylguanidine uptake and intracellular half-life during differentiation of human neuroblastoma cells. Int J Cancer. 1996;67:95–100.CrossRefPubMed Montaldo PG, Raffaghello L, Guarnaccia F, Pistoia V, Garaventa A, Ponzoni M. Increase of metaiodobenzylguanidine uptake and intracellular half-life during differentiation of human neuroblastoma cells. Int J Cancer. 1996;67:95–100.CrossRefPubMed
27.
Zurück zum Zitat More SS, Itsara M, Yang X, et al. Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. Clin Cancer Res. 2011;17:2339–49.CrossRefPubMedPubMedCentral More SS, Itsara M, Yang X, et al. Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. Clin Cancer Res. 2011;17:2339–49.CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Raggi CC, Maggi M, Renzi D, et al. Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome. J Clin Endocrinol Metab. 2000;85:3866–73.PubMed Raggi CC, Maggi M, Renzi D, et al. Quantitative determination of sst2 gene expression in neuroblastoma tumor predicts patient outcome. J Clin Endocrinol Metab. 2000;85:3866–73.PubMed
29.
Zurück zum Zitat Sestini R, Orlando C, Peri A, et al. Quantitation of somatostatin receptor type 2 gene expression in neuroblastoma cell lines and primary tumors using competitive reverse transcription-polymerase chain reaction. Clin Cancer Res. 1996;2:1757–65.PubMed Sestini R, Orlando C, Peri A, et al. Quantitation of somatostatin receptor type 2 gene expression in neuroblastoma cell lines and primary tumors using competitive reverse transcription-polymerase chain reaction. Clin Cancer Res. 1996;2:1757–65.PubMed
30.
Zurück zum Zitat Briganti V, Sestini R, Orlando C, et al. Imaging of somatostatin receptors by indium-111-pentetreotide correlates with quantitative determination of somatostatin receptor type 2 gene expression in neuroblastoma tumors. Clin Cancer Res. 1997;3:2385–91.PubMed Briganti V, Sestini R, Orlando C, et al. Imaging of somatostatin receptors by indium-111-pentetreotide correlates with quantitative determination of somatostatin receptor type 2 gene expression in neuroblastoma tumors. Clin Cancer Res. 1997;3:2385–91.PubMed
31.
Zurück zum Zitat Kogner P, Borgström P, Bjellerup P, et al. Somatostatin in neuroblastoma and ganglioneuroma. Eur J Cancer. 1997;33:2084–9.CrossRefPubMed Kogner P, Borgström P, Bjellerup P, et al. Somatostatin in neuroblastoma and ganglioneuroma. Eur J Cancer. 1997;33:2084–9.CrossRefPubMed
32.
Zurück zum Zitat Orlando C, Raggi CC, Bagnoni L, et al. Somatostatin receptor type 2 gene expression in neuroblastoma, measured by competitive RT-PCR, is related to patient survival and to somatostatin receptor imaging by indium −111-pentetreotide. Med Pediatr Oncol. 2001;36:224–6.CrossRefPubMed Orlando C, Raggi CC, Bagnoni L, et al. Somatostatin receptor type 2 gene expression in neuroblastoma, measured by competitive RT-PCR, is related to patient survival and to somatostatin receptor imaging by indium −111-pentetreotide. Med Pediatr Oncol. 2001;36:224–6.CrossRefPubMed
33.
Zurück zum Zitat John M, Meyerhof W, Richter D, et al. Positive somatostatin receptor scintigraphy correlates with the presence of somatostatin receptor subtype 2. Gut. 1996;38:33–9.CrossRefPubMedPubMedCentral John M, Meyerhof W, Richter D, et al. Positive somatostatin receptor scintigraphy correlates with the presence of somatostatin receptor subtype 2. Gut. 1996;38:33–9.CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Montaldo PG, Carbone R, Ponzoni M, Cornaglia-Ferraris P. Gamma-interferon increases metaiodobenzylguanidine incorporation and retention in human neuroblastoma cells. Cancer Res. 1992;52:4960–4.PubMed Montaldo PG, Carbone R, Ponzoni M, Cornaglia-Ferraris P. Gamma-interferon increases metaiodobenzylguanidine incorporation and retention in human neuroblastoma cells. Cancer Res. 1992;52:4960–4.PubMed
35.
Zurück zum Zitat Iavarone A, Lasorella A, Servidei T, Riccardi R, Mastrangelo R. Uptake and storage of m-iodobenzylguanidine are frequent neuronal functions of human neuroblastoma cell lines. Cancer Res. 1993;53:304–9.PubMed Iavarone A, Lasorella A, Servidei T, Riccardi R, Mastrangelo R. Uptake and storage of m-iodobenzylguanidine are frequent neuronal functions of human neuroblastoma cell lines. Cancer Res. 1993;53:304–9.PubMed
36.
Zurück zum Zitat Moyes JS, Babich JW, Carter R, Meller ST, Agrawal M, McElwain TJ. Quantitative study of radioiodinated metaiodobenzylguanidine uptake in children with neuroblastoma: Correlation with tumor histopathology. J Nucl Med. 1989;30:474–80.PubMed Moyes JS, Babich JW, Carter R, Meller ST, Agrawal M, McElwain TJ. Quantitative study of radioiodinated metaiodobenzylguanidine uptake in children with neuroblastoma: Correlation with tumor histopathology. J Nucl Med. 1989;30:474–80.PubMed
37.
Zurück zum Zitat Hadj-Djilani NL, Lebtahi NE, Delaloye AB, Laurini R, Beck D. Diagnosis and follow-up of neuroblastoma by means of iodine-123 metaiodobenzylguanidine scintigraphy and bone scan, and the influence of histology. Eur J Nucl Med. 1995;22:322–9.CrossRefPubMed Hadj-Djilani NL, Lebtahi NE, Delaloye AB, Laurini R, Beck D. Diagnosis and follow-up of neuroblastoma by means of iodine-123 metaiodobenzylguanidine scintigraphy and bone scan, and the influence of histology. Eur J Nucl Med. 1995;22:322–9.CrossRefPubMed
38.
Zurück zum Zitat Brans B, Laureys G, Schelfhout V, et al. Activity of iodine-123 metaiodobenzylguanidine in childhood neuroblastoma: Lack of relation to tumour differentiation in vivo. Eur J Nucl Med. 1998;25:144–9.CrossRefPubMed Brans B, Laureys G, Schelfhout V, et al. Activity of iodine-123 metaiodobenzylguanidine in childhood neuroblastoma: Lack of relation to tumour differentiation in vivo. Eur J Nucl Med. 1998;25:144–9.CrossRefPubMed
Metadaten
Titel
Immunohistochemical evaluation of molecular radiotherapy target expression in neuroblastoma tissue
verfasst von
Jennifer E. Gains
Neil J. Sebire
Veronica Moroz
Keith Wheatley
Mark N. Gaze
Publikationsdatum
17.10.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 3/2018
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-017-3856-4

Weitere Artikel der Ausgabe 3/2018

European Journal of Nuclear Medicine and Molecular Imaging 3/2018 Zur Ausgabe