492196

research-article2013
IJSXXX10.1177/1066896913492196International Journal of Surgical Pathology XX(X)Waage et al

Original Article
International Journal of Surgical Pathology

C-erbB2/HER2 in Human Gliomas,

XX(X) 1­–10
© The Author(s) 2013
Reprints and permissions:
Medulloblastomas, and Meningiomas: sagepub.com/journalsPermissions.nav
DOI: 10.1177/1066896913492196

A Minireview ijs.sagepub.com

Ingunn Syversen Waage, MD1, Ingeborg Vreim, MD1

and Sverre Helge Torp, MD, PhD1,2

Abstract
C-erbB2/HER2 serves as an important prognostic and predictive biomarker in various human tumors, especially in breast
cancer, whereas its role in human intracranial tumors is more uncertain. We therefore performed a search in PubMed to
get an update. This literature review comprises immunohistochemical studies on the clinical significance of c-erbB2/HER2
overexpression in gliomas, medulloblastomas, and meningiomas. In general, the findings were discrepant with regard
to correlations between overexpression, tumor grade, and prognosis. Use of various antibodies may be a contributing
factor to these discrepancies. Standardization of the immunohistochemical procedures is a relevant topic for discussion.

Keywords
astrocytomas, brain tumors, diagnosis, growth factor receptors, immunohistochemistry, NEU, prognosis, survival

Introduction through transcriptional deregulation, constitutes the trans-

The histopathological diagnosis of central nervous system
tumors is based on criteria given by the World Health
Organization1 and constitutes the basis for treatment strat-
egies and prognosis. As the current grading scheme is
based on morphologic features and thereby biased by sub-
jective interpretation, supplemental biomarkers that might
assist the diagnostics are highly desired. Molecular data
represent, however, a more objective basis for diagnostic
assessments. Current molecular markers in brain tumors
are for instance 1p and 19q deletions in oligodendroglio-
mas, amplification of the epidermal growth factor recep-
tor (EGFR) gene, IDH mutations, and methylation status
of O-6 methyl-guanine–DNA methyltransferase in
astrocytomas.2,3
In this context, the proto-oncogene c-erbB2/HER2 has
come into focus, especially due to its importance as a prog-
nostic and predictive factor in breast cancer. This oncopro-
tein is a member of the EGFR/HER family, a receptor
tyrosine kinase family including EGFR (c-erbB1/HER1),
c-erbB2/HER2, c-erbB3/HER3, and c-erbB4/HER4. The
c-erbB2/HER2 gene is mapped to chromosome 17q21 and
encodes a 185 kD transmembranous receptor protein
found in a variety of tissues.4,5 It contains a cystein-rich
extracellular ligand binding domain, a transmembrane
lipophilic domain, and an intracellular region with a cata-
lytic tyrosine kinase domain and a carboxy terminal tail.4,5
Overexpression, either through gene amplification or
forming potential of c-erbB2/HER2. On ligand binding,
the erb receptor proteins dimerize and undergo transphos-
phorylation to activate various intracellular signaling path-
ways. C-erbB2/HER2 lacks ligand-binding activity, so its
signaling function is engaged by its ligand-bound het-
erodimeric partners.4,5 All c-erbB2/HER2-containing
dimers possess enhanced signaling functions and trans-
forming activity and are more stable compared with het-
erodimers and homodimers without this oncoprotein.4,5
The c-erbB2/HER2 signaling network comprises at least 3
different pathways including P13K, MAPK, and phospho-
lipase C-γ, and receptor activation leads to an abundance
of gene expression changes including proliferation, migra-
tion, invasion, and evasion from apoptosis with increased
cellular survival.4,5
Use of biological markers in prognostications and man-
agement decisions for cancer patients is highly dependent
on reliable and standardized laboratory methods with
emphasis on standardization of biopsy handling, assay
procedures, and adequate assessment of testing results.
1
Norwegian University of Science and Technology (NTNU),
Trondheim, Norway
2
St Olavs Hospital, University Hospital, Trondheim, Norway
Corresponding Author:
Sverre Helge Torp, Department of Pathology and Medical Genetics, St
Olavs Hospital, Laboratory Centre, NO-7006 Trondheim, Norway.
Email: sverre.torp@ntnu.no

Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015

2 International Journal of Surgical Pathology XX(X)
Current detection systems for c-erbB2/HER2 in tumor tis-
sue specimens comprise evaluation of gene amplification
by means of in situ hybridization analyses (fluorescence/
chromogene in situ hybridization [FISH/CISH]) and pro-
tein overexpression assessed by immunohistochemistry
(IHC).6-9
Overexpression and/or amplification of the c-erbB2/
HER2 gene have been recognized as prognostic or predic-
tive factors in various human tumors.10-12 In most intra-
cranial tumors, however, the clinical implication of
c-erbB2/HER2 is ambiguous. The aim of this study was
therefore to review the literature to get an update on this
topic with emphasis on gliomas, medulloblastomas, and
meningiomas.
Material and Methods
A literature search was performed in PubMed for articles
written in English in the time period 1990 to 2011. The
following key words were used: gliomas, brain tumors,
astrocytomas, glioblastomas, meningiomas, medulloblas-
tomas, PNET, NEU, HER-2, and c-erbB2 (with various
writing formats used). The search in PubMed resulted in
37 articles, listed in Table 1. They consisted of immuno-
histochemical studies for assessment of the c-erbB2/
HER2 status (i.e. overexpression). Recorded data were
number of patients, patient age, type of tumor, antibody
used, cellular localization of immunoreactivity, percent-
age of c-erbB/HER2-positive tumors, and clinical signifi-
cance. No statistical testing was performed on the
collected data.
Results and Discussion
C-erbB2/HER2 Immunohistochemistry
IHC is a feasible method to determine c-erbB2/HER2
expression in formalin-fixed paraffin-embedded tumor tis-
sue.6-8,51 However, several factors may affect the immuno-
reactivity, such as tissue handling, fixation, antigenic
decay, antigen retrieval methods, type of antibody, work-
ing dilution, incubation time and temperature, tumor het-
erogeneity, assessment of the immunostaining, and
interpretation problems.6,8,9,52-55 Many antibodies are com-
mercial available (see Table 2), both monoclonal and poly-
clonal, with reactivity against either the internal or external
domain of the receptor, and they have all proved their
applicability.9,53,54,56 Only in breast cancer is c-erbB2/
HER2 immunohistochemistry established where only
membranous immunostaining is regarded as specific and
with guidelines about staining intensity and fraction of
immunoreactive tumor cells as well.6-9,55 Although cyto-
plasmic staining has been considered unspecific or artifac-
tual, it has been often found in various tumor types and
Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015
even with clinical significance.53,57-61 The mechanism of
the cytoplasmic expression remains unclear, but it seems
not to be linked to gene amplification and can be related to
various intracellular trafficking of the erb-receptors or
transcriptional mechanisms.59,62-64 Accordingly, c-erbB2/
HER2 IHC is encumbered with several sources of error
making reliable immunostaining challenging and compari-
son of laboratory data difficult.
C-erbB2/HER2 overexpression is closely linked to
gene amplification in some human malignancies, includ-
ing breast, ovary, and gastric carcinomas.65-67 This is rarely
encountered in intracranial tumors where only 4 out of 10
meningiomas and 7 out of 74 medulloblastomas have been
reported to harbor this genetic event.15,18,40,50,68 The result-
ing overexpression despite gene amplification may be
caused by transcriptional or posttranscriptional dysregula-
tion.5 In situ hybridization analyses for determination of
c-erbB2/HER2 gene amplification are therefore superflu-
ous in intracranial tumors.
C-erbB2/HER2 in Normal Brain Tissue
C-erbB2/HER2 has been shown to be essential for devel-
opment and maintenance of the peripheral and central ner-
vous system.69-71 In the adult human brain, studies are
diverging with regard to expression in neurons and menin-
geal cells, however, glial cells are in general reported as
negative.14,16,18,31,48,50 Reactive astrocytes in gliotic brain
tissue have been found to be either immunoreactive or
not.14,18,19,72,73 Thus, c-erbB2/HER2 receptor expression is
not applicable to distinguish tumor tissue from nonneo-
plastic proliferative processes such as gliosis versus low-
grade astrocytoma.19
C-erbB2/HER2 in Gliomas
Most studies reported c-erbB2/HER2 immunoreactivity
in astrocytomas, however, the number of positive tumors
varied considerably ranging from none to more than 90%
positivity.13,14,16-19,21-25,28,29 In general, there is increased
expression with increasing malignancy grade, but some
did not find such a correlation. Furthermore, the expres-
sion in primary and secondary glioblastomas also dif-
fers.21,25 These diverging data may be antibody dependent,
as shown in our study on anaplastic astrocytomas where 3
different antibodies revealed different numbers of posi-
tive tumors in the range of 45% to100%.27 Whereas there
is solid evidence of the involvement of EGFR in the
malignant transformation of astrocytomas,74 the above-
mentioned findings point to a more hazy role of c-erbB2/
HER2 in the gliomagenesis, for instance, whether it is
important in the initiation or the progression. An age-
dependent expression pattern may also exist as one study
found patients older than 50 years of age had a
Waage et al 3

Table 1.  Survey of Included Publications and Results.

Number Age (Range, Localization of Number of Positive
Publication of Cases Years) Antibody Immunoreactivity Tumors Comments

Astrocytoma
  Hiesiger et al13 17 3B5 Not specified 17 GMB (3/10 Higher expression levels in
LTS and 5/7 recurrent tumors
STS +) Tumors with poor prognosis
  tend to express high levels of
both c-erbB2 and EGFR
  Torp et al14 34 >18 CB11 Membranous and 1/21 GBM +  
cytoplasmatic 0/7 AA +
0/6 A +
  Schlegel et al15 47 28-74 21N Not specified 24/37 GBM + No prognostic significance
  5/10 A/AA + No gene amplification
  Coexpression with EGFR
 Schwechheimer 125 3B5 Membranous and 9/11 AI + No prognostic significance
et al16 9G6 cytoplasmatic 28/37 AII + Trend toward higher expression
  CB11 6/7 AA + with increasing tumor grade
63/67 GBM + No gene amplification 
  Dietzmann et al17 63 c-erbB2 (Dako) Difficult to 5/9 AI + Significant higher expression with
distinguish between 13/18 AII + increasing tumor grade
membranous and 15/17 AA + Coexpression with EGFR
cytoplasmatic 17/19 GBM +
  Haapasalo et al18 94 3-77 TAB250 Cytoplasmatic 0/11 AI + No prognostic significance
  0/19 AII + No gene amplification
  2/22 AA +  
  1/42 GBM +  
  Kristt et al19 20 5-68 3 antibodies NOS Not specified 3/5 AII+ Significant higher expression with
5/5 AA + increasing tumor grade
  10/10 GBM +  
  Hwang et al20 33 17-69 CB11 Not specified 3/9 All + No prognostic significance
  9/15 AA + Trend toward higher expression
5/9 GBM + with increasing tumor grade
  Forseen et al21 103 49-78 Dako Herceptest Membranous 4/28 AII + No prognostic significance
  1/3 AA + Overexpression was significantly
  14/69 GBM + associated with an increased
  1/3 glioma NOS risk of a second primary
malignant tumor  
  Koka et al22 149 26-79 Dako Herceptest Membranous 23/149 GBM + Overexpression was significantly
associated with poorer
prognosis
  Andersson et al23 44 22-81 Neu F-11 Not specified 1/2 AI + No prognostic significance
  2/6 AII + Trend toward higher expression
14/19 AA/ with increasing tumor grade
  GBM + Higher expression in patients
>50 years of age
  Coexpression of c-erbB1-4
  Haynik et al24 44 20-79 CB11 0/44 GBM + Negative immunostaining
  No gene amplification
  Mineo et al25 62 >16 CB11 Membranous 1/5 AA + Overexpression was significantly
43/49 primary associated with poorer
GBM + prognosis
  4/8 secondary Primary GBMs had higher level
GBM + of expression than secondary
GBMs
  Torp et al26 21 30-79 3B5 Membranous and 9/21 GBM + No prognostic significance
cytoplasmatic Lower intensity of c-erbB2 than
  other erb-proteins

(continued)

Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015

4 International Journal of Surgical Pathology XX(X)

Table 1. (continued)

Number Age (Range, Localization of Number of Positive

Publication of Cases Years) Antibody Immunoreactivity Tumors Comments

  Gulati et al27 31 28-78 CB11 Membranous and CB11: 14/31 AA + Overexpression was significantly
3B5 cytoplasmatic 3B5: 31/31 AA + associated with poorer
5A2 5A2: 16/31 AA + prognosis (only with CB11
antibody)
  Nabika et al28 59 28-94 Not specified Not specified 5/24 AA + No prognostic significance
  12/35 GBM +  
  Reszec´ et al29 65 Mean age c-erbB2-316 Membranous and 15/17 AII + Trend to lower expression with
55.2 cytoplasmatic 22/25 AA + increasing tumor grade
  19/23 GBM + Only secondary GBMs were
positive
Oligoastrocytoma and oligodendroglioma
  Mineo et al25 11 >16 CB11 Membranous 2/11 O + No prognostic significance
 Schwechheimer 8 3B5 Membranous and 0/3 OII + No prognostic significance
et al16 9G6 cytoplasmatic 3/5 OIII +
  CB11 1/3 OA +  
  Torp et al14 3 CB11 0/3 O +  
  0/3 OA +  
  Forseen et al21 4 49-78 Dako Herceptest Membranous 2/4 O + No prognostic significance
  Overexpression was significantly
associated with an increased
risk of a second primary
malignant tumor
Ependymoma
 Schwechheimer 6 3B5 Membranous and 5/6 E + No prognostic significance
et al16 9G6 cytoplasmatic
CB11
  Torp et al14 1 CB11 0/1 E +  
  Gilbertson et al30 59 ≤18 CB11 Not specified 46/59 E + No prognostic significance
  Coexpression with c-erbB4 and
associated with increased
proliferative activity (increased
Ki67/MIB-1 proliferative index)
and poorer prognosis
  No gene amplification
Medulloblastoma
  Torp et al14 2 CB11 Membranous and 1/2 MB +  
cytoplasmatic
 Schwechheimer 12 3B5 Membranous and 3/8 MB + No prognostic significance
et al16 9G6 cytoplasmatic 1/4 PNET +
  CB11  
  Gilbertson et al31 55 0-14 CB11 Membranous and 46/55 MB + Overexpression was significantly
cytoplasmatic associated with poorer
prognosis
  Herms et al32 45 0-14 3B5 Difficult to 6/45 MB + Overexpression was significantly
CB11 distinguish between associated with poorer
9G6 membranous and prognosis (especially in patients
cytoplasmatic <3 years old)
  Gilbertson et al33 70 0-14 CB11 Membranous and 60/70 MB + Overexpression was significantly
cytoplasmatic associated with poorer
prognosis
  Coexpression of c-erbB3/HER4
was significantly associated
with poorer prognosis and
related to the presence of
metastasis
  Korshunov et al34 73 <18 years: 53 A0485 Membranous and 51/73 MB + Coexpression with EGFR
patients cytoplasmatic Overexpression was significantly
  >20 years: 20 associated with recurrence,
patients not survival

(continued)

Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015

Waage et al 5

Table 1. (continued)

Number Age (Range, Localization of Number of Positive

Publication of Cases Years) Antibody Immunoreactivity Tumors Comments

  Nam et al35 20 <15 CB11 Not specified 14/18 MB + No prognostic significance,

however, trend to higher
expression in patients with
poorer outcome
  Ray et al36 117 0-14 c-erbB2 (Dako) Cytoplasmatic 19/117 MB + Overexpression was significantly
associated with poorer
prognosis
  Bodey et al37 22 CB11 Not specified 11/22 MB + Coexpression with c-erbB4
  Overexpression was significantly
associated with poorer
prognosis
  Bal et al38 50 1-55 CB11 Mixed membranous 29/43 CMB + Overexpression was significantly
and cytoplasmatic 6/7 DMB + associated with poorer
prognosis
  Coexpression with c-erbB4 had
significantly poorer prognosis
  Haberler et al39 82 0-21 CB11 Not able to 49/82 MB + No prognostic significance
distinguish between
membranous and
cytoplasmatic
  Min et al40 73 0-15 c-erbB2 (Dako) Membranous and 7/73 MB + Expression was significantly
cytoplasmatic associated with poorer
prognosis in LC/AMB, not in
no-LC/AMB
  3/7 showed gene amplification
 López-Aguilar 26 1-15 c-erbB2 (Dako) Not specified 2/26 MB + No prognostic significance
et al41
  Meurer et al42 40 1-44 CB11 Not specified 23/40 MB + No statistical significance
between histological subtypes,
age, type of tumor resection
and survival
  Das et al43 30 3-55 c-erbB2 pAb Membranous 27/30 MB + No prognostic significance
(Novocastra) Trend toward higher expression
  in patients with recurrence
  Patereli et al44 27 0-14 CB11 Membranous and 17/27 MB + No prognostic significance
cytoplasmatic No correlation of expression
  with histological subtypes,
but increased expression in
undifferentiated areas
  Srikantha et al45 63 2-51 65% of total MB + Overexpression was significantly
associated with recurrence
  Tabori et al46 108 0-15 c-erbB-2 (Dako) Membranous 20/108 MB + No prognostic significance
Meningioma
  Schlegel et al47 59 32-83 FWP51 Majority with 59/59 Men.I. + No relation to grade or subtype
membranous Immunoreactivity in normal
  arachnoid
  No amplification
  Torp et al14 19 CB11 Membranous and 11/16 Men.I + No immunoreactivity in normal
cytoplasmatic 1/3 Men.III + arachnoid
   
 Schwechheimer 16 3B5 Membranous and 10/14 Men.I + No prognostic significance
et al16 9G6 cytoplasmatic 2/2 Men.II +
  CB11 Expression independent of
meningioma subtype and
tumor grade
  Chozick et al48 52 TAB-250 Membranous 35/35 Men.I + Significant higher expression in
17/17 Men.II + Men.I than in Men.II
  Immunoreactivity in normal
arachnoid
  No gene amplification

(continued)

Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015

6 International Journal of Surgical Pathology XX(X)

Table 1. (continued)

Number Age (Range, Localization of Number of Positive

Publication of Cases Years) Antibody Immunoreactivity Tumors Comments

  Andersson et al23 26 43-83 Neu-F11 Not specified 26/26 Men.I + No relation to subtype
  Immunoreactivity also in
endothelium
  Coexpression of c-erbB1-4
  Potti et al49 237 0-93 Dako Herceptest Membranous 6/237 + No prognostic significance
  Loussouarn et al50 35 16-82 CB11 Membranous 5/17 Men.I + Overexpression was significantly
5/18 Men.II/III + associated with recurrence
  Higher proliferation in Men.II/III
than in Men.I
  No immunoreactivity in normal
arachnoid
  4/35 meningiomas showed
amplification

Abbreviations: AI, astrocytoma WHO grade I; AII, diffuse astrocytoma WHO grade II; AA, anaplastic astrocytoma WHO grade III; CMB, classical type of medulloblasto-
ma; DMB, desmoplastic type of medulloblastoma; E, ependymoma; EGFR, epidermal growth factor receptor (c-erbB1); GBM, glioblastoma WHO grade IV; IHC, immuno-
histochemistry; LC/AMB, large cell/anaplastic medulloblastoma; LTS, long-term survivors; MB, medulloblastoma; Men.I, benign meningioma WHO grade I; Men.II, atypical
meningioma WHO grade II; Men.III, anaplastic meningioma WHO grade III; NOS, not otherwise specified; OII, oligodendroglioma WHO grade II; OIII, oligodendroglioma
WHO grade III; OA, oligoastrocytoma; STS, short-term survivor; WHO, World Health Organization.

significantly higher expression of c-erbB2/HER2,23 an
observation that parallels that of EGFR.75 As far as prog-
nosis is concerned, the literature is also conflicting with
some studies appointing this oncoprotein as a biomarker
whereas others do not.13,25,27 These discrepancies may
also be related to which antibody is used, as discussed
above.27 Indeed, in that study a recommended commercial
c-erbB2/HER2 antibody (CB11) provided the most prom-
ising results (Figure 1).53,76
Amplification of the c-erbB2/HER2 gene has so far
not been detected in astrocytomas.15,18,68 Hence, the over-
expression may be related to other mechanisms at the
transcriptional and translational levels. Coexpression of
other members of the EGFR family in astrocytic tumors
occurs13,15,23,27 in accordance with the dimerization pro-
cess on activation of these receptors supporting a collec-
tive drive in the gliomagenesis. Notable is the observation
that heterodimers with c-erbB2/HER2 have the strongest
signaling activity, so these observations point to a use of
multitargeted therapeutic approach when interfering with
the tyrosine kinase pathways.55,77
Only small series of oligodendrogliomas and ependy-
momas have been investigated, and the results are ambigu-
ous, however, an indication of increased number of
immunoreactive tumors with higher malignancy grade
has been noted.14,16,21,25,30 Interesting is the reported asso-
ciation between overexpression of c-erbB2/HER2,
c-erbB4, and Ki67/MIB-1 proliferative activity supporting
the impact of these receptors on cell proliferation.30
Concerning prognosis, no relation has been found in oligo-
dendrogliomas, whereas in ependymomas one study has
reported a clear trend toward worse prognosis in cases
coexpressing c-erbB2/HER2 and c-erbB4.30
The distribution of immunoreactive cells in glioma tis-
sue has been described as diffuse and/or focal, and both
cytoplasmic and membranous staining have been
observed.16,26,27 This is in contrast to breast cancer where
only membranous immunostaining is accepted.9 There are,
however, tumors with cytoplasmic immunoreactivity with
clinical relevance.52,58,60 Thus, the location of c-erbB2/
HER2 immunoreactivity is another parameter of which
clinical significance and biological mechanisms need to be
clarified.
C-erbB2/HER2 in Medulloblastomas
All studies reported c-erbB2/HER2 immunoreactivity in
their medulloblastoma series, though the number of positive
tumors varied.14,16,31-43,45,46 Srikantha et al showed higher
expression in large cell/anaplastic medulloblastomas than in
classical and desmoplastic subtypes.45 They also demon-
strated a positive association with increased proliferative
activity in contrast to others.35,38,45 Additionally, a larger
number of positive tumors have been found among patients
aged 3 years and younger.32 The literature is ambiguous as
far as the relationship to prognosis is concerned, as some
reports find positive associations with recurrence and sur-
vival and others do not.16,20,30-33,35-40,42-44,46,77 Coexpression
of EGFR members seems to be of prognostic significance in
this tumor entity as expression of c-erbB2/HER2 and
c-erbB4/HER2 is significantly associated with the presence
of metastases and worse outcome.33,38 According to age, 2

Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015

Waage et al 7

Table 2. C-erbB2/HER2 Antibodies Used in the Publications.

Antibody Type Epitope

CB11 Monoclonal Internal domain
3AB Monoclonal Internal domain
5A2 Monoclonal Internal domain
pAb21N Polyclonal Internal domain
TAB-250 Monoclonal External domain
Dako Herceptest Polyclonal Internal domain
Neu F11 Monoclonal Internal domain
FWP51 Monoclonal External domain
9G6 Monoclonal External domain
AO485 Polyclonal Internal domain
c-erbB2-316 Monoclonal Internal domain

Figure 1. C-erbB2/HER2 immunostaining in a high-

studies demonstrated poorer prognosis in the youngest age grade astrocytoma with membranous and cytoplasmatic
immunoreactivity (CB11 antibody; 20× objective).
groups if the tumors were receptor positive.32,37 The fraction
of immunoreactive tumor cells has been shown to be influ-
ential on survival as well, because a study reported that Concluding Remarks
patients with >50% positive tumor cells had a significantly
This literature study of c-erbB2/HER2 expression in glio-
shorter survival.31 Even among medulloblastoma variants,
mas, medulloblastomas, and meningiomas is neither meant
such as large cell/anaplastic medulloblastomas, c-erbB2/
as a meta-analysis nor to propose any guidelines for assess-
HER2 expression indicates poorer prognosis.31,40 In a subset
ment of c-erbB2/HER2 status in these tumors, but it is
of medulloblastomas, overexpression of c-erbB2/HER2 is
meant to present a concise update. Whereas c-erbB2/
due to gene amplification.40
HER2 serves as a significant biomarker in various human
malignancies, especially in breast cancer, this review
C-erbB2/HER2 in Meningiomas shows that the clinical role of this oncoprotein is question-
able in the above-mentioned intracranial tumors, and fur-
All the included studies demonstrated c-erbB2/HER2
ther studies are necessary to address this problem. In
immunoreactivity in meningiomas; however, the range
addition, it is essential to establish standardized detection
differed considerably (2% to 100%).14,16,47,48,50,78 Neither
systems for expression of c-erbB2/HER2 in brain tumor
was the relation between expression and tumor grade obvi-
specimens. There is increasing number of studies on
ous.16,47,48,50 Actually, some found that the expression level
trastuzumab treatment in patients with c-erbB2/HER2
was higher in benign than in atypical/anaplastic meningio-
metastatic breast cancer and brain metastasis and circum-
mas,16,48 in contrast to the typical pattern of increased
venting the blood–brain barrier.79,80 Since there are indica-
expression in higher tumor grade. Due to the conflicting
tions of c-erbB2/HER2 overexpression in human
results concerning receptor expression in normal lepto-
intracranial tumors, this oncoprotein has a promising
meninges and meningeal tumors, makes the role of
potentiality in future strategies for diagnostics and targeted
c-erbB2/HER2 in the tumorigenesis of these tumors
therapy for these patients as well.81,82
unclear. According to Schlegel et al, these observations
may rather indicate a cell-type-specific constitutive
Acknowledgments
expression of this receptor.47 Since gene amplification has
been demonstrated in a few cases, this may explain the We thank Dr Johannes Attems, Dr Christina Vogt, and Dr Ivar
overexpression in these cases, however, in most studies Skjåk Nordrum for their critical reading of the manuscript and
this genetic event has not been found.16,47,48,50 As far as constructive feedback.
meningioma variants are concerned, one study found that
meningiomas with epithelial differentiation (i.e. meningo- Declaration of Conflicting Interests
thelial and secretory) were immunoreactive in accordance The author(s) declared no potential conflicts of interest with
with the general overexpression of this receptor protein in respect to the research, authorship, and/or publication of this
epithelial tumors.50 The prognostic significance of article.
c-erbB2/HER2 positive meningiomas is conflicting, with
studies reporting positive correlation to recurrence whereas Funding
others did not.49,50 Gene amplification was, however, not The author(s) received no financial support for the research,
shown to be associated with recurrence.50 authorship, and/or publication of this article.

Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015

8 International Journal of Surgical Pathology XX(X)
References
1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO
Classification of Tumours of the Central Nervous System.
4th ed. Lyon, France: IARC; 2007.
2. Jansen M, Yip S, Louis DN. Molecular pathology in adult
gliomas: diagnostic, prognostic, and predictive markers.
Lancet Neurol. 2010;9:717-726.
3. Brat DJ, Prayson RA, Ryken TC, Olson JJ. Diagnosis of
malignant glioma: role of neuropathology. J Neurooncol.
2008;89:287-311.
4. Moasser MM. The oncogene HER2: its signaling and trans-
forming functions and its role in human cancer pathogenesis.
Oncogene. 2007;26:6469-6487.
5. Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol.
2001;12(suppl 1):S3-S8.
6. Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF.
Guidelines for human epidermal growth factor receptor 2
testing: biologic and methodologic considerations. J Clin
Oncol. 2009;27:1323-1333.
7. Moelans CB, de Weger RA, Van der Wall E, van Diest PJ.
Current technologies for HER2 testing in breast cancer. Crit
Rev Oncol Hematol. 2011;80:380-392.
8. Shah S, Chen B. Testing for HER2 in breast cancer: a con-
tinuing evolution. Patholog Res Int. 2011;2011:903202.
doi:10.4061/2011/903202.
9. Wolff AC, Hammond ME, Schwartz JN, et al. American
Society of Clinical Oncology/College of American
Pathologists guideline recommendations for human epider-
mal growth factor receptor 2 testing in breast cancer. Arch
Pathol Lab Med. 2007;131:18-43.
10. Gorlick R, Huvos AG, Heller G, et al. Expression of HER2/
erbB-2 correlates with survival in osteosarcoma. J Clin
Oncol. 1999;17:2781-2788.
11. Ross JS, McKenna BJ. The HER-2/neu oncogene in tumors of
the gastrointestinal tract. Cancer Invest. 2001;19:554-568.
12. Uberall I, Kolar Z, Trojanec R, Berkovcova J, Hajduch M.
The status and role of ErbB receptors in human cancer. Exp
Mol Pathol. 2008;84:79-89.
13. Hiesiger EM, Hayes RL, Pierz DM, Budzilovich GN.
Prognostic relevance of epidermal growth factor recep-
tor (EGF-R) and c-neu/erbB2 expression in glioblastomas
(GBMs). J Neurooncol. 1993;16:93-104.
14. Torp SH, Helseth E, Unsgaard G, Dalen A. C-erbB-2/
HER-2 protein in human intracranial tumours. Eur J Cancer.
1993;29A:1604-1606.
15. Schlegel J, Stumm G, Brandle K, et al. Amplification and
differential expression of members of the erbB-gene family
in human glioblastoma. J Neurooncol. 1994;22:201-207.
16. Schwechheimer K, Laufle RM, Schmahl W, Knodlseder M,
Fischer H, Hofler H. Expression of neu/c-erbB-2 in human
brain tumors. Hum Pathol. 1994;25:772-780.
17. Dietzmann K, von Bossanyi P. Coexpression of epidermal
growth factor receptor protein and c-erbB-2 oncoprotein in
human astrocytic tumors. An immunohistochemical study.
Zentralbl Pathol. 1994;140:335-341.
18. Haapasalo H, Hyytinen E, Sallinen P, Helin H, Kallioniemi
OP, Isola J. c-erbB-2 in astrocytomas: infrequent overex-
pression by immunohistochemistry and absence of gene
Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015
amplification by fluorescence in situ hybridization. Br J
Cancer. 1996;73:620-623.
19. Kristt DA, Yarden Y. Differences between phosphotyrosine
accumulation and Neu/ErbB-2 receptor expression in astro-
cytic proliferative processes. Implications for glial oncogen-
esis. Cancer. 1996;78:1272-1283.
20. Hwang SL, Chai CY, Lin HJ, Howng SL. Expression of
epidermal growth factor receptors and c-erbB-2 proteins in
human astrocytic tumors. Kaohsiung J Med Sci. 1997;13:
417-424.
21. Forseen SE, Potti A, Koka V, Koch M, Fraiman G, Levitt R.
Identification and relationship of HER-2/neu overexpression
to short-term mortality in primary malignant brain tumors.
Anticancer Res. 2002;22:1599-1602.
22. Koka V, Potti A, Forseen SE, et al. Role of Her-2/neu overex-
pression and clinical determinants of early mortality in glio-
blastoma multiforme. Am J Clin Oncol. 2003;26:332-335.
23. Andersson U, Guo D, Malmer B, et al. Epidermal growth
factor receptor family (EGFR, ErbB2-4) in gliomas and
meningiomas. Acta Neuropathol. 2004;108:135-142.
24. Haynik DM, Roma AA, Prayson RA. HER-2/neu expression
in glioblastoma multiforme. Appl Immunohistochem Mol
Morphol. 2007;15:56-58.
25. Mineo JF, Bordron A, Baroncini M, et al. Low HER2-
expressing glioblastomas are more often secondary to anaplastic
transformation of low-grade glioma. J Neurooncol. 2007;85:
281-287.
26. Torp SH, Gulati S, Johannessen E, Dalen A. Coexpression
of c-erbB 1-4 receptor proteins in human glioblastomas.
An immunohistochemical study. J Exp Clin Cancer Res.
2007;26:353-359.
27. Gulati S, Ytterhus B, Granli US, Gulati M, Lydersen S, Torp
SH. Overexpression of c-erbB2 is a negative prognostic fac-
tor in anaplastic astrocytomas. Diagn Pathol. 2010;5:18.
28. Nabika S, Kiya K, Satoh H, et al. Prognostic significance of
expression patterns of EGFR family, p21 and p27 in high-
grade astrocytoma. Hiroshima J Med Sci. 2010;59:65-70.
29. Reszeć J, Bernaczyk PS, Milewski R, Chyczewski L, Mariak
Z. c-erbB-2 protein expression in astrocytic tumors of the
brain. Med Sci Monit. 2011;17:BR216-BR220.
30. Gilbertson RJ, Bentley L, Hernan R, et al. ERBB receptor
signaling promotes ependymoma cell proliferation and rep-
resents a potential novel therapeutic target for this disease.
Clin Cancer Res. 2002;8:3054-3064.
31. Gilbertson RJ, Pearson AD, Perry RH, Jaros E, Kelly PJ.
Prognostic significance of the c-erbB-2 oncogene product
in childhood medulloblastoma. Br J Cancer. 1995;71:473-
477.
32. Herms JW, Behnke J, Bergmann M, et al. Potential prognos-
tic value of C-erbB-2 expression in medulloblastomas in very
young children. J Pediatr Hematol Oncol. 1997;19:510-515.
33. Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec
J. Prognostic significance of HER2 and HER4 coexpres-
sion in childhood medulloblastoma. Cancer Res. 1997;57:
3272-3280.
34. Korshunov A, Golanov A, Ozerov S, Sycheva R. Prognostic
value of tumor-associated antigens immunoreactivity and
apoptosis in medulloblastomas. An analysis of 73 cases.
Brain Tumor Pathol. 1999;16:37-44.
Waage et al 9
35. Nam DH, Wang KC, Kim YM, Chi JG, Kim SK, Cho BK.
The effect of isochromosome 17q presence, proliferative and
apoptotic indices, expression of c-erbB-2, bcl-2 and p53 pro-
teins on the prognosis of medulloblastoma. J Korean Med
Sci. 2000;15:452-456.
36. Ray A, Ho M, Ma J, et al. A clinicobiological model predict-
ing survival in medulloblastoma. Clin Cancer Res. 2004;10:
7613-7620.
37. Bodey B, Kaiser HE, Siegel SE. Epidermal growth factor
receptor (EGFR) expression in childhood brain tumors. In
Vivo. 2005;19:931-941.
38. Bal MM, Das Radotra B, Srinivasan R, Sharma SC. Does
c-erbB-2 expression have a role in medulloblastoma progno-
sis? Indian J Pathol Microbiol. 2006;49:535-539.
39. Haberler C, Slavc I, Czech T, et al. Histopathological prog-
nostic factors in medulloblastoma: high expression of sur-
vivin is related to unfavourable outcome. Eur J Cancer.
2006;42:2996-3003.
40. Min HS, Lee YJ, Park K, Cho BK, Park SH. Medulloblastoma:
histopathologic and molecular markers of anaplasia and bio-
logic behavior. Acta Neuropathol. 2006;112:13-20.
41. López-Aguilar E, Sepulveda-Vildosola AC, Rivera-Marquez
H, et al. Clinical and molecular parameters for risk stratifica-
tion in Mexican children with medulloblastoma. Arch Med
Res. 2007;38:769-773.
42. Meurer RT, Martins DT, Hilbig A, et al. Immunohistochemical
expression of markers Ki-67, neun, synaptophysin, p53 and
HER2 in medulloblastoma and its correlation with clini-
copathological parameters. Arq Neuropsiquiatr. 2008;66:
385-390.
43. Das P, Puri T, Suri V, Sharma MC, Sharma BS, Sarkar C.
Medulloblastomas: a correlative study of MIB-1 prolifera-
tion index along with expression of c-Myc, ERBB2, and
anti-apoptotic proteins along with histological typing and
clinical outcome. Childs Nerv Syst. 2009;25:825-835.
44. Patereli A, Alexiou GA, Stefanaki K, et al. Expression of epi-
dermal growth factor receptor and HER-2 in pediatric embry-
onal brain tumors. Pediatr Neurosurg. 2010;46:188-192.
45. Srikantha U, Balasubramaniam A, Santosh V, Somanna
S, Bhagavatula ID, Ashwathnarayana CB. Recurrence
in medulloblastoma—influence of clinical, histologi-
cal and immunohistochemical factors. Br J Neurosurg.
2010;24:280-288.
46. Tabori U, Baskin B, Shago M, et al. Universal poor survival
in children with medulloblastoma harboring somatic TP53
mutations. J Clin Oncol. 2010;28:1345-1350.
47. Schlegel J, Ullrich B, Stumm G, et al. Expression of the
c-erbB-2-encoded oncoprotein and progesterone receptor
in human meningiomas. Acta Neuropathol. 1993;86:473-
479.
48. Chozick BS, Benzil DL, Stopa EG, et al. Immunohistochemical
evaluation of erbB-2 and p53 protein expression in benign and
atypical human meningiomas. J Neurooncol. 1996;27:117-126.
49. Potti A, Panwalkar A, Langness E, et al. Role of her-2/
neu overexpression and clinical features at presentation
as predictive factors in meningiomas. Am J Clin Oncol.
2004;27:452-456.
50. Loussouarn D, Brunon J, Avet-Loiseau H, Campone
M, Mosnier JF. Prognostic value of HER2 expression in
Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015
meningiomas: an immunohistochemical and fluorescence in
situ hybridization study. Hum Pathol. 2006;37:415-421.
51. Yaziji H, Goldstein LC, Barry TS, et al. HER-2 testing in
breast cancer using parallel tissue-based methods. JAMA.
2004;291:1972-1977.
52. Kay EW, Walsh CJ, Cassidy M, Curran B, Leader M.
C-erbB-2 immunostaining: problems with interpretation. J
Clin Pathol. 1994;47:816-822.
53. Singleton TP, Niehans GA, Gu F, et al. Detection of
c-erbB-2 activation in paraffin-embedded tissue by immu-
nohistochemistry. Hum Pathol. 1992;23:1141-1150.
54. Busmanis I, Feleppa F, Jones A, et al. Analysis of cerbB2
expression using a panel of 6 commercially available anti-
bodies. Pathology. 1994;26:261-267.
55. Gutierrez C, Schiff R. HER2: biology, detection, and clinical
implications. Arch Pathol Lab Med. 2011;135:55-62.
56. Press MF, Hung G, Godolphin W, Slamon DJ. Sensitivity of
HER-2/neu antibodies in archival tissue samples: potential
source of error in immunohistochemical studies of oncogene
expression. Cancer Res. 1994;54:2771-2777.
57. Kruszewski WJ, Rzepko R, Ciesielski M, et al. Expression
of HER2 in colorectal cancer does not correlate with prog-
nosis. Dis Markers. 2010;29:207-212.
58. Kay EW, Mulcahy H, Walsh CB, Leader M, O’Donoghue
D. Cytoplasmic c-erbB-2 protein expression correlates with
survival in Dukes’ B colorectal carcinoma. Histopathology.
1994;25:455-461.
59. Horiguchi S, Hishima T, Hayashi Y, et al. HER-2/neu
cytoplasmic staining is correlated with neuroendocrine
differentiation in breast carcinoma. J Med Dent Sci.
2010;57:155-163.
60. Cheng CM, Tsuneyama K, Matsui K, Takahashi H,
Ishizawa S, Takano Y. Cytoplasmic expression of c-erbB2
in non-small cell lung cancers. Virchows Arch. 2005;446:
596-603.
61. Keshgegian AA, Cnaan A. erbB-2 oncoprotein expression
in breast carcinoma. Poor prognosis associated with high
degree of cytoplasmic positivity using CB-11 antibody. Am
J Clin Pathol. 1997;108:456-463.
62. Sorkin A, Goh LK. Endocytosis and intracellular trafficking
of ErbBs. Exp Cell Res. 2008;314:3093-3106.
63. Marx C, Held JM, Gibson BW, Benz CC. ErbB2 trafficking
and degradation associated with K48 and K63 polyubiquiti-
nation. Cancer Res. 2010;70:3709-3717.
64. Wang YN, Yamaguchi H, Hsu JM, Hung MC. Nuclear traf-
ficking of the epidermal growth factor receptor family mem-
brane proteins. Oncogene. 2010;29:3997-4006.
65. Pauletti G, Godolphin W, Press MF, Slamon DJ. Detection
and quantitation of HER-2/neu gene amplification in human
breast cancer archival material using fluorescence in situ
hybridization. Oncogene. 1996;13:63-72.
66. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the
HER-2/neu proto-oncogene in human breast and ovarian
cancer. Science. 1989;244:707-712.
67. Hechtman JF, Polydorides AD. HER2/neu gene amplifica-
tion and protein overexpression in gastric and gastroesopha-
geal junction adenocarcinoma: a review of histopathology,
diagnostic testing, and clinical implications. Arch Pathol
Lab Med. 2012;136:691-697.
10 International Journal of Surgical Pathology XX(X)
68. Helseth E, Unsgaard G, Dalen A, et al. Amplification of the
epidermal growth factor receptor gene in biopsy specimens
from human intracranial tumours. Br J Neurosurg. 1988;2:
217-225.
69. Schmid RS, McGrath B, Berechid BE, et al. Neuregulin
1-erbB2 signaling is required for the establishment of radial
glia and their transformation into astrocytes in cerebral cor-
tex. Proc Natl Acad Sci U S A. 2003;100:4251-4256.
70. Garratt AN, Ozcelik C, Birchmeier C. ErbB2 pathways
in heart and neural diseases. Trends Cardiovasc Med.
2003;13:80-86.
71. Burden S, Yarden Y. Neuregulins and their receptors: a ver-
satile signaling module in organogenesis and oncogenesis.
Neuron. 1997;18:847-855.
72. Cannella B, Pitt D, Marchionni M, Raine CS. Neuregulin
and erbB receptor expression in normal and diseased human
white matter. J Neuroimmunol. 1999;100:233-242.
73. Tokita Y, Keino H, Matsui F, et al. Regulation of neuregulin
expression in the injured rat brain and cultured astrocytes. J
Neurosci. 2001;21:1257-1264.
74. Hagen KW, Torp SH. Prognostic significance of
EGFR gene amplification and overexpression in diffuse
astrocytomas—a literature study. Open J Pathol. 2012;2:71-
80.
75. Simmons ML, Lamborn KR, Takahashi M, et al. Analysis of
complex relationships between age, p53, epidermal growth
factor receptor, and survival in glioblastoma patients. Cancer
Res. 2001;61:1122-1128.
Downloaded from ijs.sagepub.com at Apollo Group - UOP on January 28, 2015
76. Egervari K, Szollosi Z, Nemes Z. Immunohistochemical
antibodies in breast cancer HER2 diagnostics. A compara-
tive immunohistochemical and fluorescence in situ hybrid-
ization study. Tumour Biol. 2008;29:18-27.
77. Citri A, Yarden Y. EGF-ERBB signalling: towards the sys-
tems level. Nat Rev Mol Cell Biol. 2006;7:505-516.
78. Potti A, Forseen SE, Koka VK, et al. Determination of
HER-2/neu overexpression and clinical predictors of sur-
vival in a cohort of 347 patients with primary malignant
brain tumors. Cancer Invest. 2004;22:537-544.
79. Mehta AI, Brufsky AM, Sampson JH. Therapeutic
approaches for HER2-positive brain metastases: circum-
venting the blood-brain barrier. Cancer Treat Rev. 2013;39:
261-269.
80. Kinoshita M, McDannold N, Jolesz FA, Hynynen K.
Noninvasive localized delivery of herceptin to the mouse
brain by MRI-guided focused ultrasound-induced blood-
brain barrier disruption. Proc Natl Acad Sci U S A.
2006;103:11719-11723.
81. Reisoli E, Gambini E, Appolloni I, et al. Efficacy of HER2
retargeted herpes simplex virus as therapy for high-grade
glioma in immunocompetent mice. Cancer Gene Ther.
2012;19:788-795.
82. Berezowska S, Diermeier-Daucher S, Brockhoff G, et al.
Effect of additional inhibition of human epidermal growth
factor receptor 2 with the bispecific tyrosine kinase inhibi-
tor AEE788 on the resistance to specific EGFR inhibition in
glioma cells. Int J Mol Med. 2010;26:713-721.