Skip to main content
Top
Published in: Diagnostic Pathology 1/2014

Open Access 01-12-2014 | Research

A prognostic analysis of pediatrics central nervous system small cell tumors: evaluation of EGFR family gene amplification and overexpression

Authors: Weidong Liu, Shigang Zhang, Liyong Zhang, Qingke Cui, Jiyue Wang, Ting Gui, Qi Pang

Published in: Diagnostic Pathology | Issue 1/2014

Login to get access

Abstract

Background

Central nervous system (CNS) tumors are the most common solid tumors that occur in children, however there were few big-data follow-up analysis published in China. Overexpression of epidermal growth factor receptor (EGFR) family members was reported on glioblastoma (GBM) and medulloblastoma (MB) before. However, the correlation between EGFR family members expression with prognosis of MB, supratentorial primitive neuroectodermal tumor (PNET) and small cell GBM is unclear in Chinese children.

Methods

A retrospective and survival analysis was performed on children (age ≤ 16 years) diagnosed as CNS primary small cell tumors in the Affiliated Provincial Hospital, Shandong University from 2000 to 2012, including MB (n = 44), PNET (n = 8) and small cell GBM (n = 19). The expression of EGFR, ERBB-2, ERBB-3 and ERBB-4 were detected by immunohistochemistry (IHC). The fluorescence in situ hybridization (FISH) was used to observe the amplification of EGFR and ERBB-2 gene.

Results

Median survival times of MBs, small GBMs and PNETs were 23 ± 6.7 months, 8 ± 4.7 months and 10 ± 1.4 months. Expression and amplification of ERBB-2, ERBB-3 and ERBB-4 were not observed in all tumor samples. The multiply Cox regression suggested the overexpression and amplification of EGFR were negative prognostic factors for MB. Radiotherapy had the positive function for all pediatric patients.

Conclusion

Overexpression of EGFR predicts poor outcomes of MBs, small cell GBMs and PNETs, suggesting those three CNS tumor subtypes can be considered as one group for the potential common mechanism. The current individual treatment and big data analysis of pediatric CNS embryonal tumors and GBM continues to be very challenging in China.

Virtual Slides

Appendix
Available only for authorised users
Literature
1.
go back to reference Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-oncology. 2013, 15 (2): ii1-ii56.PubMedPubMedCentral Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-oncology. 2013, 15 (2): ii1-ii56.PubMedPubMedCentral
2.
go back to reference Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114 (2): 97-109. 10.1007/s00401-007-0243-4.PubMedPubMedCentralCrossRef Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114 (2): 97-109. 10.1007/s00401-007-0243-4.PubMedPubMedCentralCrossRef
3.
go back to reference Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, Wallace D, Lau C, Chintagumpala M, Ashley DM, Kellie SJ, Kun L, Gilbertson RJ: Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol. 2004, 22 (6): 984-993. 10.1200/JCO.2004.06.032.PubMedCrossRef Gajjar A, Hernan R, Kocak M, Fuller C, Lee Y, McKinnon PJ, Wallace D, Lau C, Chintagumpala M, Ashley DM, Kellie SJ, Kun L, Gilbertson RJ: Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol. 2004, 22 (6): 984-993. 10.1200/JCO.2004.06.032.PubMedCrossRef
5.
go back to reference Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels WS, Bhattacharjee MB, Gilbertson RJ, Shine HD, Weiss HL, Rooney CM, Heslop HE, Gottschalk S: Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 2007, 67 (12): 5957-5964. 10.1158/0008-5472.CAN-06-4309.PubMedCrossRef Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels WS, Bhattacharjee MB, Gilbertson RJ, Shine HD, Weiss HL, Rooney CM, Heslop HE, Gottschalk S: Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 2007, 67 (12): 5957-5964. 10.1158/0008-5472.CAN-06-4309.PubMedCrossRef
6.
go back to reference MacDonald TJ, Rood BR, Santi MR, Vezina G, Bingaman K, Cogen PH, Packer RJ: Advances in the diagnosis, molecular genetics, and treatment of pediatric embryonal CNS tumors. Oncologist. 2003, 8 (2): 174-186. 10.1634/theoncologist.8-2-174.PubMedCrossRef MacDonald TJ, Rood BR, Santi MR, Vezina G, Bingaman K, Cogen PH, Packer RJ: Advances in the diagnosis, molecular genetics, and treatment of pediatric embryonal CNS tumors. Oncologist. 2003, 8 (2): 174-186. 10.1634/theoncologist.8-2-174.PubMedCrossRef
7.
go back to reference Perry A, Aldape KD, George DH, Burger PC: Small cell astrocytoma: an aggressive variant that is clinicopathologically and genetically distinct from anaplastic oligodendroglioma. Cancer. 2004, 101 (10): 2318-2326. 10.1002/cncr.20625.PubMedCrossRef Perry A, Aldape KD, George DH, Burger PC: Small cell astrocytoma: an aggressive variant that is clinicopathologically and genetically distinct from anaplastic oligodendroglioma. Cancer. 2004, 101 (10): 2318-2326. 10.1002/cncr.20625.PubMedCrossRef
8.
go back to reference Takahashi K, Tsuda M, Kanno H, Murata J, Mahabir R, Ishida Y, Kimura T, Tanino M, Nishihara H, Nagashima K, Tanaka S: Differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma: a case report of an elderly man. Brain Tumor Pathol. 2014, 31 (2): 118-123. 10.1007/s10014-013-0158-9.PubMedCrossRef Takahashi K, Tsuda M, Kanno H, Murata J, Mahabir R, Ishida Y, Kimura T, Tanino M, Nishihara H, Nagashima K, Tanaka S: Differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma: a case report of an elderly man. Brain Tumor Pathol. 2014, 31 (2): 118-123. 10.1007/s10014-013-0158-9.PubMedCrossRef
9.
go back to reference Hartmann W, Digon-Sontgerath B, Koch A, Waha A, Endl E, Dani I, Denkhaus D, Goodyer CG, Sorensen N, Wiestler OD, Pietsch T: Phosphatidylinositol 3’-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Canc Res. 2006, 12 (10): 3019-3027. 10.1158/1078-0432.CCR-05-2187.CrossRef Hartmann W, Digon-Sontgerath B, Koch A, Waha A, Endl E, Dani I, Denkhaus D, Goodyer CG, Sorensen N, Wiestler OD, Pietsch T: Phosphatidylinositol 3’-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Canc Res. 2006, 12 (10): 3019-3027. 10.1158/1078-0432.CCR-05-2187.CrossRef
10.
go back to reference Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A: Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008, 116 (6): 597-602. 10.1007/s00401-008-0455-2.PubMedCrossRef Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A: Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008, 116 (6): 597-602. 10.1007/s00401-008-0455-2.PubMedCrossRef
11.
go back to reference Bazley LA, Gullick WJ: The epidermal growth factor receptor family. Endocr Relat Canc. 2005, 12 (1): S17-S27.CrossRef Bazley LA, Gullick WJ: The epidermal growth factor receptor family. Endocr Relat Canc. 2005, 12 (1): S17-S27.CrossRef
12.
go back to reference Halatsch ME, Schmidt U, Behnke-Mursch J, Unterberg A, Wirtz CR: Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Canc Treat Rev. 2006, 32 (2): 74-89. 10.1016/j.ctrv.2006.01.003.CrossRef Halatsch ME, Schmidt U, Behnke-Mursch J, Unterberg A, Wirtz CR: Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Canc Treat Rev. 2006, 32 (2): 74-89. 10.1016/j.ctrv.2006.01.003.CrossRef
13.
go back to reference Gulati S, Ytterhus B, Granli US, Gulati M, Lydersen S, Torp SH: Overexpression of c-erbB2 is a negative prognostic factor in anaplastic astrocytomas. Diagn Pathol. 2010, 5: 18-10.1186/1746-1596-5-18.PubMedPubMedCentralCrossRef Gulati S, Ytterhus B, Granli US, Gulati M, Lydersen S, Torp SH: Overexpression of c-erbB2 is a negative prognostic factor in anaplastic astrocytomas. Diagn Pathol. 2010, 5: 18-10.1186/1746-1596-5-18.PubMedPubMedCentralCrossRef
14.
go back to reference Gomori E, Pal J, Kovacs B, Doczi T: Concurrent hypermethylation of DNMT1. MGMT and EGFR genes in progression of gliomas. Diagn Pathol. 2012, 7: 8-10.1186/1746-1596-7-8.PubMedPubMedCentralCrossRef Gomori E, Pal J, Kovacs B, Doczi T: Concurrent hypermethylation of DNMT1. MGMT and EGFR genes in progression of gliomas. Diagn Pathol. 2012, 7: 8-10.1186/1746-1596-7-8.PubMedPubMedCentralCrossRef
15.
go back to reference Torp SH, Gulati S, Johannessen E, Dalen A: Coexpression of c-erbB 1–4 receptor proteins in human glioblastomas. An immunohistochemical study. Clin Cancer Res. 2007, 26 (3): 353-359. Torp SH, Gulati S, Johannessen E, Dalen A: Coexpression of c-erbB 1–4 receptor proteins in human glioblastomas. An immunohistochemical study. Clin Cancer Res. 2007, 26 (3): 353-359.
16.
go back to reference Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005, 6 (5): 279-286. 10.1016/S1470-2045(05)70102-9.PubMedCrossRef Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005, 6 (5): 279-286. 10.1016/S1470-2045(05)70102-9.PubMedCrossRef
17.
go back to reference Press MF, Slamon DJ, Flom KJ, Park J, Zhou JY, Bernstein L: Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol. 2002, 20 (14): 3095-3105.PubMed Press MF, Slamon DJ, Flom KJ, Park J, Zhou JY, Bernstein L: Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol. 2002, 20 (14): 3095-3105.PubMed
18.
go back to reference Quezado M, Ronchetti R, Rapkiewicz A, Santi M, Blumenthal DT, Rushing EJ: Chromogenic in situ hybridization accurately identifies EGFR amplification in small cell glioblastoma multiforme, a common subtype of primary GBM. Clin Neuropathol. 2005, 24 (4): 163-169.PubMed Quezado M, Ronchetti R, Rapkiewicz A, Santi M, Blumenthal DT, Rushing EJ: Chromogenic in situ hybridization accurately identifies EGFR amplification in small cell glioblastoma multiforme, a common subtype of primary GBM. Clin Neuropathol. 2005, 24 (4): 163-169.PubMed
19.
go back to reference Lo HW, Cao X, Zhu H, Ali-Osman F: Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Canc Res. 2008, 14 (19): 6042-6054. 10.1158/1078-0432.CCR-07-4923.CrossRef Lo HW, Cao X, Zhu H, Ali-Osman F: Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Canc Res. 2008, 14 (19): 6042-6054. 10.1158/1078-0432.CCR-07-4923.CrossRef
20.
go back to reference Kraus JA, Felsberg J, Tonn JC, Reifenberger G, Pietsch T: Molecular genetic analysis of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood. Neuropathol Appl Neurobiol. 2002, 28 (4): 325-333. 10.1046/j.1365-2990.2002.00413.x.PubMedCrossRef Kraus JA, Felsberg J, Tonn JC, Reifenberger G, Pietsch T: Molecular genetic analysis of the TP53, PTEN, CDKN2A, EGFR, CDK4 and MDM2 tumour-associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood. Neuropathol Appl Neurobiol. 2002, 28 (4): 325-333. 10.1046/j.1365-2990.2002.00413.x.PubMedCrossRef
21.
go back to reference Matsuo S, Takahashi M, Inoue K, Tamura K, Irie K, Kodama Y, Nishikawa A, Yoshida M: Inhibitory Potential of Postnatal Treatment with Cyclopamine, a Hedgehog Signaling Inhibitor, on Medulloblastoma Development in Ptch1 Heterozygous Mice. Toxicol Pathol. 2014, Epub Matsuo S, Takahashi M, Inoue K, Tamura K, Irie K, Kodama Y, Nishikawa A, Yoshida M: Inhibitory Potential of Postnatal Treatment with Cyclopamine, a Hedgehog Signaling Inhibitor, on Medulloblastoma Development in Ptch1 Heterozygous Mice. Toxicol Pathol. 2014, Epub
22.
go back to reference Gotschel F, Berg D, Gruber W, Bender C, Eberl M, Friedel M, Sonntag J, Rungeler E, Hache H, Wierling C, Nietfeld W, Lehrach H, Frischauf A, Schwartz-Albiez R, Aberger F, Korf U: Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. PloS One. 2013, 8 (6): e65403-10.1371/journal.pone.0065403.PubMedPubMedCentralCrossRef Gotschel F, Berg D, Gruber W, Bender C, Eberl M, Friedel M, Sonntag J, Rungeler E, Hache H, Wierling C, Nietfeld W, Lehrach H, Frischauf A, Schwartz-Albiez R, Aberger F, Korf U: Synergism between Hedgehog-GLI and EGFR signaling in Hedgehog-responsive human medulloblastoma cells induces downregulation of canonical Hedgehog-target genes and stabilized expression of GLI1. PloS One. 2013, 8 (6): e65403-10.1371/journal.pone.0065403.PubMedPubMedCentralCrossRef
23.
go back to reference Meco D, Servidei T, Riccardi A, Ferlini C, Cusano G, Zannoni GF, Giangaspero F, Riccardi R: Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo. Neuro-oncology. 2009, 11 (3): 250-9. 10.1215/15228517-2008-095.PubMedPubMedCentralCrossRef Meco D, Servidei T, Riccardi A, Ferlini C, Cusano G, Zannoni GF, Giangaspero F, Riccardi R: Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo. Neuro-oncology. 2009, 11 (3): 250-9. 10.1215/15228517-2008-095.PubMedPubMedCentralCrossRef
24.
go back to reference Andersson U, Guo D, Malmer B, Bergenheim AT, Brannstrom T, Hedman H, Henriksson R: Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas. Acta Neuropathol. 2004, 108 (2): 135-42.PubMedCrossRef Andersson U, Guo D, Malmer B, Bergenheim AT, Brannstrom T, Hedman H, Henriksson R: Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas. Acta Neuropathol. 2004, 108 (2): 135-42.PubMedCrossRef
25.
go back to reference Fouladi M, Stewart CF, Blaney SM, Onar-Thomas A, Schaiquevich P, Packer RJ, Gajjar A, Kun LE, Boyett JM, Gilbertson RJ: Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study. J Clin Oncol. 2010, 28 (27): 4221-7. 10.1200/JCO.2010.28.4687.PubMedPubMedCentralCrossRef Fouladi M, Stewart CF, Blaney SM, Onar-Thomas A, Schaiquevich P, Packer RJ, Gajjar A, Kun LE, Boyett JM, Gilbertson RJ: Phase I trial of lapatinib in children with refractory CNS malignancies: a Pediatric Brain Tumor Consortium study. J Clin Oncol. 2010, 28 (27): 4221-7. 10.1200/JCO.2010.28.4687.PubMedPubMedCentralCrossRef
26.
go back to reference Ferretti E, Di Marcotullio L, Gessi M, Mattei T, Greco A, Po A, De Smaele E, Giangaspero F, Riccardi R, Di Rocco C, Pazzaglia S, Maroder M, Alimandi M, Screpanti I, Gulino A: Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. Oncogene. 2006, 25 (55): 7267-73. 10.1038/sj.onc.1209716.PubMedCrossRef Ferretti E, Di Marcotullio L, Gessi M, Mattei T, Greco A, Po A, De Smaele E, Giangaspero F, Riccardi R, Di Rocco C, Pazzaglia S, Maroder M, Alimandi M, Screpanti I, Gulino A: Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. Oncogene. 2006, 25 (55): 7267-73. 10.1038/sj.onc.1209716.PubMedCrossRef
27.
go back to reference Northcott PA, Korshunov A, Pfister SM, Taylor MD: The clinical implications of medulloblastoma subgroups. Nature reviews. Neurology. 2012, 8 (6): 340-51.PubMed Northcott PA, Korshunov A, Pfister SM, Taylor MD: The clinical implications of medulloblastoma subgroups. Nature reviews. Neurology. 2012, 8 (6): 340-51.PubMed
28.
go back to reference Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, et al.: Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012, 488 (7409): 49-56. 10.1038/nature11327.PubMedPubMedCentralCrossRef Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, et al.: Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012, 488 (7409): 49-56. 10.1038/nature11327.PubMedPubMedCentralCrossRef
29.
go back to reference Karsy M, Gelbman M, Shah P, Balumbu O, Moy F, Arslan E: Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features. Folia Neuropathol. 2012, 50 (4): 301-321.PubMedCrossRef Karsy M, Gelbman M, Shah P, Balumbu O, Moy F, Arslan E: Established and emerging variants of glioblastoma multiforme: review of morphological and molecular features. Folia Neuropathol. 2012, 50 (4): 301-321.PubMedCrossRef
Metadata
Title
A prognostic analysis of pediatrics central nervous system small cell tumors: evaluation of EGFR family gene amplification and overexpression
Authors
Weidong Liu
Shigang Zhang
Liyong Zhang
Qingke Cui
Jiyue Wang
Ting Gui
Qi Pang
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2014
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-9-132

Other articles of this Issue 1/2014

Diagnostic Pathology 1/2014 Go to the issue