Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis

Clinical article

Restricted access

Object

In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs).

Methods

Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000–August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded).

Results

Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP-positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein–positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40–0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53–0.96; p = 0.02).

Conclusions

Neurofilament protein–positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein–GBM's unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies.

Abbreviations used in this paper:GBM = glioblastoma multiforme; GFAP = glial fibrillary acidic protein; IDH1 = isocitrate dehydrogenase 1; KPS = Karnofsky Performance Scale; NFP = neurofilament protein; PFS = progression-free survival; RPA = recursive partitioning analysis; RTOG = Radiation Therapy Oncology Group; TMZ = temozolomide.

Article Information

Address correspondence to: Johan Pallud, M.D., Service de Neurochirurgie, Hôpital Sainte-Anne, 1 Rue Cabanis, 75674 Paris cedex 14, France. email: johanpallud@hotmail.com.

Please include this information when citing this paper: published online June 22, 2012; DOI: 10.3171/2012.5.JNS111670.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Neuroimages (A and B) and photomicrographs (C–G) of GBMs in the study. A: Axial postcontrast T1-weighted FLAIR sequences showing NFP-negative GBMs. In a left parietal NFP-negative GBM (left column), the contrast-enhanced area invades the subventricular zone but does not involve the cortex. In a right parietal NFP-negative GBM (center column) and in a bifrontal NFP-negative GBM (right column), the contrast-enhanced area invades the subventricular zone and the corpus callosum, but does not involve the cortex. B: Axial T2-weighted FLAIR sequences showing NFP-positive GBMs. In 2 right temporal NFP-positive GBMs (left and center columns), the contrast-enhanced area invades the cortex but does not involve the subventricular zone. Note the contrast-enhanced dura mater surrounding a contrast-enhancing area, corresponding to leptomeningeal tumor infiltration. In a right frontal NFP-positive GBM (right column), the contrast-enhanced area extends from the cortex to the subventricular zone but does not involve the corpus callosum. C–G: Images showing classic histological features of a GBM with pseudopalisading necrosis (C), endothelial proliferation, and densely packed astrocytic tumoral cells (D). This tumor exhibited a double immunophenotype with a strong and diffuse expression of GFAP (E) and a neuronal NFP immunoexpression (F and G). Note that individual NFP-positive, mitotically active neoplastic cells are heterogeneously found within the tumoral tissue. Hemalum-phloxine (C and D), GFAP (E), and NFP (F and G). Original magnification × 400.

  • View in gallery

    Graphs of Kaplan-Meier estimates of overall survival and PFS according to NFP expression status and oncological treatment. A: Overall survival and PFS in the entire series of 302 supratentorial primary GBMs. B: Overall survival and PFS according to NFP expression. The hazard ratio (HR) for death among patients harboring an NFP-positive GBM, as compared with those harboring an NFP-negative GBM, was 0.54 (95% CI 0.40–0.74; p < 0.0001). The HR for death or disease progression among patients harboring an NFP-positive GBM, as compared with those harboring an NFP-negative GBM, was 0.71 (95% CI 0.53–0.96; p = 0.02). C: Overall survival and PFS according to NFP expression in the subgroup of patients (n = 150) treated with radiotherapy combined with chemotherapy (TMZ). The HR for death among patients harboring an NFP-positive GBM, as compared with those harboring an NFP-negative GBM, was 0.510 (95% CI 0.344–0.755; p = 0.001). The HR for death or disease progression among patients harboring an NFP-positive GBM, as compared with those harboring an NFP-negative GBM, was 0.781 (95% CI 0.534–1.142; p = 0.202).

References

1

Bauchet LMathieu-Daudé HFabbro-Peray PRigau VFabbro MChinot O: Oncological patterns of care and out-come for 952 patients with newly diagnosed glioblastoma in 2004. Neuro Oncol 12:7257352010

2

Blümcke IBecker AJNormann SHans VRiederer BMKrajewski S: Distinct expression pattern of microtubule-associated protein-2 in human oligodendrogliomas and glial precursor cells. J Neuropathol Exp Neurol 60:9849932001

3

Donev KScheithauer BWRodriguez FJJenkins S: Expression of diagnostic neuronal markers and outcome in glioblastoma. Neuropathol Appl Neurobiol 36:4114212010

4

Ducray Fde Reyniès AChinot OIdbaih AFigarella-Branger DColin C: An ANOCEF genomic and transcriptomic microarray study of the response to radiotherapy or to alkylating first-line chemotherapy in glioblastoma patients. Mol Cancer 9:2342502010

5

Fontaine DPaquis P: [Glioblastoma: clinical, radiological and biological prognostic factors.]. Neurochirurgie 56:4674762010. (Fr)

6

Hegi MEDiserens ACGorlia THamou MFde Tribolet NWeller M: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:99710032005

7

Hegi MELiu LHerman JGStupp RWick WWeller M: Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26:418941992008

8

Kappadakunnel MEskin ADong JNelson SFMischel PSLiau LM: Stem cell associated gene expression in glioblastoma multiforme: relationship to survival and the subventricular zone. J Neurooncol 96:3593672010

9

Kozak KRMahadevan AMoody JS: Adult gliosarcoma: epidemiology, natural history, and factors associated with out-come. Neuro Oncol 11:1831912009

10

Kozak KRMoody JS: Giant cell glioblastoma: a glioblastoma subtype with distinct epidemiology and superior prognosis. Neuro Oncol 11:8338412009

11

Liang YDiehn MWatson NBollen AWAldape KDNicholas MK: Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci U S A 102:581458192005

12

Lim DACha SMayo MCChen MHKeles EVandenBerg S: Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9:4244292007

13

Louis DNOhgaki HWiestler ODCavenee WKBurger PCJouvet A: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:971092007

14

Nobusawa SWatanabe TKleihues POhgaki H: IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 15:600260072009

15

Park JKHodges TArko LShen MDello Iacono DMcNabb A: Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 28:383838432010

16

Patru CRomao LVarlet PCoulombel LRaponi ECadusseau J: CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors. BMC Cancer 10:66772010

17

Perry AMiller CRGujrati MScheithauer BWZambrano SCJost SC: Malignant gliomas with primitive neuro-ectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases. Brain Pathol 19:81902009

18

Phillips HSKharbanda SChen RForrest WFSoriano RHWu TD: Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:1571732006

19

Prayson RAAbramovich CM: Glioneuronal tumor with neuropil-like islands. Hum Pathol 31:143514382000

20

Rich JNHans CJones BIversen ESMcLendon RERasheed BK: Gene expression profiling and genetic markers in glioblastoma survival. Cancer Res 65:405140582005

21

Rivera ALPelloski CEGilbert MRColman HDe La Cruz CSulman EP: MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:1161212010. (Erratum in Neuro Oncol 12:617 2010)

22

Sanson MMarie YParis SIdbaih ALaffaire JDucray F: Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:415041542009

23

Stupp RMason WPvan den Bent MJWeller MFisher BTaphoorn MJ: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:9879962005

24

Teo JGGultekin SHBilsky MGutin PRosenblum MK: A distinctive glioneuronal tumor of the adult cerebrum with neuropil-like (including “rosetted”) islands: report of 4 cases. Am J Surg Pathol 23:5025101999

25

Varlet PSoni DMiquel CRoux FXMeder JFChneiweiss H: New variants of malignant glioneuronal tumors: a clinicopathological study of 40 cases. Neurosurgery 55:137713922004

26

Verhaak RGHoadley KAPurdom EWang VQi YWilkerson MD: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:981102010

27

Weller MFelsberg JHartmann CBerger HSteinbach JPSchramm J: Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol 27:574357502009

28

Yan HParsons DWJin GMcLendon RRasheed BAYuan W: IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:7657732009

29

Young GSMacklin EASetayesh KLawson JDWen PYNorden AD: Longitudinal MRI evidence for decreased survival among periventricular glioblastoma. J Neurooncol 104:2612692011

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 112 112 27
Full Text Views 98 98 3
PDF Downloads 163 163 3
EPUB Downloads 0 0 0

PubMed

Google Scholar