The Role of EGFR, Hepatocyte Growth Factor Receptor (c-Met), c-ErbB2 (HER2-neu) and Clinicopathological Parameters in the Pathogenesis and Prognosis of Chordoma
Zeynep TOSUNER1, Süheyla UYAR BOZKURT2, Türker KILIÇ3, Baran YILMAZ3
1Department of Pathology, Bezmialem Vakıf University Faculty of Medicine, İstanbu l, Turkey
2Marmara University School of Medicine, İstanbu l, Turkey
3Department of Neurosurgery, Bahcesehir University Faculty of Medicine, İstanbu l, Turkey
Keywords: Chordoma, EGFR, c-Met, c-Erb B2
Chordoma is a rare malignant bone tumor with a poor outcome. Although radiotherapy and gamma knife surgery have been used for
treatment, providing a cure for the tumor is not easy, because of the frequent recurrences. Molecular targeted therapy against tyrosine kinases
has been effective in the treatment of malignancies such as breast and lung cancers and brain tumors. We aimed to analyse the histopathological
features of chordomas and the immunoexpression profiles of the three receptor tyrosine kinases of EGFR, c-Met and c-Erb-B2 in chordomas.
We have correlated these results with recurrence and overall survival status of the patients.
Material and Method: We studied 49 chordoma patients in order to evaluate the histopathological features and immunohistochemical stainings
by EGFR, c-Met and c-ErbB2 antibodies. Of the 49 patients, follow up data was available for 40 patients. Clinical data of the patients were
correlated with histopathological features and survival analysis was performed.
Results: The immunostaining rate by EGFR and c-Met was 73.5% and 12.2% respectively. None of the cases showed immunoreactivity by
c-ErbB2 (0%). Of the 40 cases, 17 cases showed recurrences. EGFR expression was detected in 14 recurrent (14/17) and 17 non-recurrent cases
(17/23). Four of the 17 recurrent cases (4/17) were positive by c-Met, while none of the non-recurrent cases (0/23) were positive by this antibody.
Significantly, all cases with positive c-Met expression showed recurrences (p<0.05).
Conclusion: Our study indicates that EGFR expression is detected in the majority of chordoma cases. c-Met expression can be used as a prognostic
indicator for chordoma.
Chordoma is a rare malignant bone tumor originating
from notochordal remnants1,2
. The complete resection
of this tumor is usually not available because of its
invasiveness to adjacent structures. Although radiotherapy
and gamma knife surgery have been tried for treatment,
local control cannot be provided in most of the cases due to
the extensive recurrence ability of the tumor3
. There are
few studies investigating the effect of treatment modalities
on the survival and prognosis of chordoma patients3,4
Histopathological properties of this tumor such as mitosis
and necrosis have been analysed in a number of studies in
order to understand their relations with the prognosis and
survival. However limited information is available from
these studies and also the sample sizes are small because of
the rare incidence of chordoma. There are also discordances between the results of different studies. Despite several
proposed prognostic parameters, no evidence-based
parameter has been defined to predict survival5-7
Receptor tyrosine kinases (RTKs), besides being the key
regulators of cell processes including cell growth and
angiogenesis, have critical roles in the development and
progression of tumors.
The epidermal growth factor receptor (EGFR), ErbB2
(HER-2 neu) and c-met are the members of ErbB family
of RTKs. These trans-membrane proteins are activated
by binding with peptide growth factors of the EGFfamily
of proteins. EGFR and its three related proteins
(the ErbB family) play essential roles in both normal
physiological conditions and malignancies. Upon binding
its ligands, dynamic conformational changes occur in both
extracellular and intracellular domains of the receptor tyrosine kinases, resulting in the transphosphorylation of
tyrosine residues in the C-terminal regulatory domain.
These provide docking sites for downstream molecules
and lead to the evasion of apoptosis, and to proliferation,
invasion and metastases. Mutation in the tyrosine kinase
domain of the EGFR gene was found in a subset of lung
ErbB2 activation also occurs in a ligand-independent
manner, particularly when the receptor is found to
be mutated or overexpressed9. Amplification and
overexpression of the proto-oncogene ErbB2 are found in
approximately 15 to 20% of all invasive breast cancers10.
The c-Met proto-oncogene is located on chromosome 7q21-
3111. The ligand for c-Met is hepatocyte growth factor
(HGF), also known as scatter factor (SF)12. HGF acts as
a cytokine, promoting cell proliferation, survival, motility,
scattering, differentiation and morphogenesis13. Recent
studies have revealed that the molecular treatments against
EGFR, ErbB2 and c-met succeed in cases of lung and breast
carcinomas and glioblastomas, respectively14,15. Based
on the molecular biology of chordomas, targeted therapy
alternatives have been developed16-18. However, only a
few case reports are found in the literature regarding this
Chordomas show dual expression of epithelial and
mesenchymal proteins2. EGFR, c-Met and c-ErbB2
overexpressions have been demonstrated in a majority of
malignant tumors14,15,19-21. Receptor tyrosine kinases
are the novel candidate molecular markers to shed light on
the pathogenesis of chordoma.
The aim of this study was the evaluation of histopathological
properties such as tumor, type, mitosis, necrosis
pleomorphism, hyperchromatic nuclei, apoptosis and
presence of mucin, and the immunoexpression patterns of
EGFR, c-Met and c-Erb-B2, in order to understand their
role in the pathogenesis, prognosis, recurrence and survival
rates of chordoma.
Forty-nine skull base and non-skull base chordomas were
included in our study in order to analyze the expressions
of EGFR (c-ErbB1), ErbB2 and c-Met by the streptavidinbiotin
horseradish peroxidase method (Table I
expression levels of these antibodies and their correlations
with the histopathological properties of chordoma such
as pleomorphism, mitosis, necrosis, hyperchromasia,
extracellular mucin deposition and apoptosis (Table II
were evaluated together with the clinical follow-up data
including the patient’s age, sex, recurrences and overall
Clinical information and follow-up data were obtained
from the Neurosurgery Department and telephone
interviews of the patients or family members were
conducted. Recurrence was defined as the relapse of disease
that occurred more than 6 months after the initial surgery.
Overall survival data was dependent on the current status
of the patients as being dead or alive. Since autopsies were
not performed in cases of death, disease-dependent death
interpretation was not available.
All Hematoxylin & Eosin (H&E)-stained slides were
reviewed by two pathologists for the confirmation of the followdiagnoses.
At the time of initial diagnoses of the cases,
immunomarkers such as epithelial membrane antigene
(EMA), cytokeratin, vimentin, S100 and glial fibrillary
acidic protein (GFAP) had been applied as well as the
histological criteria of chordoma for the exclusion of other
malignancies such as adenocarcinomas. PAS-Alcian Blue
stain had been used for extracellular mucin identification.
None of the cases had a concomitant malignancy.
Hyperchromasia was noted when more than 50% of the
nuclei were intensely hyperchromatic.
Pleomorphism was noted when major cellular differences
were detected in more than 50% of the tumor cells.
At least ten representative fields were analysed at high
magnification (x400 objective) for determining mitosis.
All fields were examined to detect necrosis and any ratio of
detectable necrosis was noted when seen.
This study was approved by the Ethics Committee of
the relevant institute with the identifying code MARYC-
2008-0213. An informed consent form regarding
permission for clinical research was obtained from each
Four-micrometer-thick sections were placed on
3-aminopropyletxylene-covered slides and deparaffinized
at 60 ºC for 1 h. The slides were dewaxed in xylene and
dehydrated in 96% alcohol. Sections were then immersed
in 10 mmol⁄ l citrate buffer (pH 6.0) and microwaved for
20 min for antigen retrieval. Slides were cooled to room
temperature and rinsed in phosphate-buffered saline
(PBS). Endogenous peroxidase activity was blocked by
further pretreatment with 3% H2O2 ⁄ distilled water for
20 min at room temperature. After a thorough washing
in PBS, blocking solution (Lab Vision Co., Fremont, CA,
USA) was applied to block nonspecific antibody binding.
The sections were then incubated with EGFR (SPRING, CA
94566, USA M3091: Ready to use), c-Met (Neomarkers,
Fremont, CA 94539 USA RB-10286, 1:20 dilution) and
c-ErbB2 (Neomarkers, Fremont, CA 94539 USA, 1:50
dilution) for 1 h at room temperature.
After a 10-min rinse in PBS, biotinylated goat antipolyvalent
immunoglobulin (Lab Vision Co., Fremont,
CA, 94539) for 20 min, and in the streptavidin–biotin
peroxidase complex for 20 min being applied at RT, 3,3¹
diaminobenzidine chromogen was used for visualization
of antigen-antibody binding. The sections were
counterstained with hematoxylin, dehydrated, cleared in xylene and mounted on Entellan coverslips.
Evaluation of Immunostaining
Interpretation of c-ErbB2 staining was performed using
the ASCO/CAP 2013 HER-2 Test Guideline in which
membranous immunostaining of tumor that amounts
to 10% of contiguous and homogeneous tumor cells was
stated as positive. The EGFR staining was scored based
on membranous staining intensity as 0= no staining; 1+ =
faint membranous staining in >10% of tumor cells; 2+ =
moderate membranous staining; 3+ = strong membranous
staining. The c-Met staining was scored based on both
membranous and cytoplasmic staining intensity as 0= no
staining; 1+ = faint staining in >10% of tumor cells; 2+ =
moderate staining; 3+ = strong staining. The scores were
than categorized into two as (0,1,2+) and (3+). Background
staining and staining in non-tumoral cells were considered
as nonspecific staining and cases with this kind of staining
pattern were interpreted as negative. The initial biopsy
materials of the recurrent cases (cases with more than one
biopsy specimen) were chosen for immunohistochemical
Statistical analysis was performed using the NCSS (Number
Cruncher Statistical System) 2007 (NCSS, LLC Kaysville,
Utah, USA, Hintze, J. (2008) programme.
Quantity statistics (Mean, Standard deviation, frequency)
and qualitative data were analysed. Normally distributed
parameters between groups were analyzed with Student’s t
test; and the parameters that were not normally distributed
between the groups were analyzed using the Mann-Whitney
U test. Quantitative data were assessed with the chi-square
test and Fisher’s Exact chi-square test. Survival analysis was
evaluated with Kaplan-Meier Survival Analysis excluding
those lost to follow up or who died due to postoperative
surgical complications. Log rank (mantel-Cox) analysis
was used to compare the prognostic significance of the
antibodies’ expressions on survival. Results were evaluated
using a 95% confidence interval and significance was
considered when the p value was lower than 0.05.
|Patients and Follow up
We included 49 patients with 31 males and 18 females
in our study. The age of the cases differed between 5 and
83 years and the mean age at the time of diagnosis was
40.90±18.05 years. Data from clinical follow-up of up to
168 months was available for 40 patients. The mean followdiagnoses up was 61.21±39.75 months (range 1-168 months). Among
the 40 patients 17 (42.5%) had one or more recurrences.
One patient had 5 recurrences, 1 patient had 3 recurrences,
2 patients had 2 recurrences while the other 13 patients had
one recurrence. The mortality rate was 50% as 20 patients
died. Among all cases, localization was cranial in 40 and
spinal in 9 patients.
According to the WHO classification; 40 tumors were of the
conventional type (Figure 1), 8 were chondroid (Figure 2)
and 1 was dedifferentiated (Figure 3). The dedifferentiated
histology was present in the initial biopsy of the patient. The
case with dedifferetiated histology had been nonrecurrent
after being followed for 84 months.
Click Here to Zoom
|Figure 1: Conventional chordoma with nodular growth pattern
and physalipherous cells (inset) (H&E; x100, H&E; x400).
On histopathological examination, mitosis was found in
2 cases, necrosis in 6 cases (Figure 4), pleomorphism in 4 cases, and hyperchromatic nuclei in 15 cases.
Two cases showing mitotic activity were dedifferentiated
and conventional chordomas respectively. Mitotic activity
had been 4/10 HPF (High power field) in the dedifferentiated
variant and 2/10 HPF in the conventional variant.
Three of 6 cases with necrosis were conventional chordomas
while two were chondroid and the remaining one was
dedifferentiated chordoma. The highest extension ratio of
necrosis (necrotic area/total tumor area) was 50% while the
lowest ratio was 10%.
Two of the 4 cases showing pleomorphism had chondroid
morphology while the others had been dedifferentiated and
conventional chordomas. The case with dedifferentiated
histology revealed marked pleomorphism and atypical
features such as sarcomatoid areas, high nuclear/
cytoplasmic ratios and irregular nuclear membranes. Mild pleomorphism was present in the other three cases.
Apoptosis was not observed in any of the cases and all cases
showed mucin deposition (Table II).
The only significant statistical correlation among
histopathological parameters was between necrosis and
survival rates (Table III, Figure 5). Survival rates were
lower in cases with necrosis (p<0.01). No correlation
was detected between histological features and prognosis
(recurrence and overall survival).
Click Here to Zoom
|Figure 5: The Kaplan-Meier survival curves of two groups of
cases according to presence of necrosis.
Expression of EGFR, c-Met and c-ErbB2
Immunohisto-chemical evaluation revealed that 77.5%
of the cases (38/49) were intensely positive (3+) by EGFR
(Figure 6) and 12.2% (6/49) by c-Met (Figure 7). Two cases
were negative by EGFR and 34 were negative by c-Met.
None of the cases stained by c-ErbB2. The only significant
correlation was found between c-Met expression and
recurrence. Recurrence rates were higher in c-Met
intensely positive cases (p<0.05) (Table IV). No significant
correlation was found between immunoexpression
profiles and clinicopathological parameters including
age, sex, localization of tumor, histological type and the
histopathological properties of the tumor.
Click Here to Zoom
|Table IV: Correlation of EGFR, c-Met and c-ErbB2 profiles with recurrence
Although studies based on the correlation of prognosis and
histopathological parameters such as mitosis, apoptosis
and extracellular mucin in chordoma are present in the
literature, no definite evidence-based histopathological
adverse prognostic factor predicting recurrence has been
. Chordomas are believed to originate from
mesenchymal tissue; however they have recently been
considered to have dual epithelial and mesenchymal
. Receptor tyrosine kinases such as EGFR,
c-Met ve c-ErbB2 are implicated in the pathogenesis of
various epithelial tumors. The molecular-targeted therapies
have been recently administered to patients whose tumors
have tyrosine kinase activity15,19,21
. In our study, a cranial localization (81.6% of all cases) was the most
frequent site. This finding contradicts the previous studies
in which the sacrococcyx is presented as the most frequent
. The reason of this contradiction may be the
sample size of our study.
Chordoma predominantly affects men aged 40-50 years5,24-26. In our study, the mean age of the patients was 40.9±
18.05 years and 63.3% of the patients were male. In a study
of 51 cases, survival rates were better in patients younger
than 40 years regardless of the tumor’s histopathological
features, and age was defined as an independent factor27. O’Connel et al. proposed female gender as a poor
prognostic indicator in their study of 62 patients28.
The most effective treatment for chordoma is still surgery.
Complete resection or gross total resection chance depends
on the localization of the tumor. Residual chordoma deeply
infiltrating the surrounding tissues mainly account for the
local recurrences. For complete tumor removal, a radical
wide posterior surgical margin should be employed while
dealing with sacrococcygeal cases26. McGirt et al. assessed
67 sacral and 47 mobile spine chordoma patients who had
been surgically treated and revealed that sacral localization
was associated with poor survival in chordoma29. In
another study based on 29 cases, vertebral localization
appeared to be a significant risk factor for recurrence30.
In a study by Fasig et al., no correlation was found between tumor localization and recurrence in 20 chordoma cases16. We have not found a specific correlation between
localization and recurrence in our study.
Eight cases (16.3%) in our study were diagnosed as
chondroid chordoma. This finding is compatible with the
most comprehensive study of chordoma in which 22 of 155
(14%) cases were diagnosed as chondroid chordoma6.
In a study based on chondroid chordoma, survival rates
were found to be better in chondroid chordoma compared
with classical chordoma6. In another study, no specific
correlation was found between the histological type of
chordoma and prognosis28. In our study, we have not
found a statistically significant correlation between the
histological type and prognosis of chordoma.
Necrosis and survival rates have been found to be correlated
with each other. Survival rates are worse in the cases in
which necrosis is reported. This result is consistent with
the two other studies in the chordoma literature28,31.
However, there are other studies claiming that necrosis has
no role in chordoma prognosis22,32.
No statistical correlation was found between the other
parameters (mitosis, pleomorphism, presence of mucin)
In the study of Bjornsson et al. chondroid differentiation
and cellular atypia were investigated and these parameters were not correlated with the biological behaviour of
chordoma32. Histopathological features such as
hypercellularity, pleomorphism, apoptosis, necrosis and
proliferative index by Ki-67 antibody were assessed in
another study. Tumor growth was found to be increased in
cases showing high mitotic ratios and a proliferative index
more than 6%22. Mitosis was reported only in two cases
in our study. No statistically signficant correlation was
shown between cases with mitotic activity and prognosis.
The controversial results of the studies in the literature can
be explained by the low number of the cases due to the
rarity of chordoma.
A limitation of our study is the correlation of survival
and prognosis with the proliferative index shown by
Ki-67 antibody. We have used the residual tissues in the
paraffin blocks of the patients after the routine reporting
process. During the reporting process, almost all of the
cases were evaluated not only by H&E stain but also
immunohistochemical stains such as EMA, S100, GFAP,
vimentin and CK. The majority of cases included in our
study have been intracranial chordoma cases with limited
tissue samples with volumes lower than 1 cm³. After the
preparation of the routine H&E stain, histochemical
PAS-Alcian Blue stain, sections were taken for the
immunohistochemical analysis of three receptor tyrosine
kinases. Immunohistochemical Ki-67 application was
available in 10 cases and the proliferative activities were less
than 1% in 6 cases, 2% in two cases, 3% in one case and 5%
in one case.
Immunohistochemical staining revealed that 77.6% of the
cases were intensely positive (3+) by EGFR and 12.2% by
c-Met. None of the cases stained by c-ErbB2. A statistically
significant correlation was found between c-Met expression
and recurrence. Recurrence rates were higher in patients
with high levels of c-Met expression. A positive correlation
was determined between extension of staining by EGFR
and c-Met. EGFR positive cases showed significant c-Met
Weinberger et al. examined the expression of c-Met,
c-Erb-b2 (HER2/neu), and epidermal growth factor
(EGFR) in a cohort of 12 chordomas and found that all
chordomas had positive expressions of both the hepatocyte
growth factor/scatter factor receptor and EGFR. c-ErbB2
expression was also detected in 7 out of 12 cases. Another
outcome of this study was the positive correlation between
EGFR and c-Met expressions. Chordoma tumors that had
high c-Met expression were also likely to have high EGFR
In a study by Akhavan-Sigari at al. using immunohistochemical
techniques, the authors investigated Plateletderived
growth factor receptor-α (PDGFR α), EGFR and
c-Met expression in 52 primary lesions33. PDGFR-α,
EGFR and c-Met were found to be expressed in 75.0%,
83% and 77% of primary lesions. In the subsequent study
of Akhavan-Sigari et al. positive immunostaining with
EGFR and c-Met was detected in 92% and 100% of 145
tumor specimens34. Fasig et al. studied receptor tyrosine
kinases in 21 chordoma cases and found PDGFR-b, EGFR,
KIT and c-ErbB2 expressions in 100%, 67%, 33% and 0%
of cases, respectively16. Naka et al. investigated HGF/c-
Met expression in 46 primary and 25 recurrent lesions and
found c-Met expression in 70.0% of primary and 88.0% of
recurrent lesions35. EGFR expression has been reported
in 67-100% and c-Met expression varies between 70% and
100% in these corresponding studies. In our study, EGFR
and c-Met expression rates were 77.6% and 12.2%. The
c-Met expression rate is lower than the rates given in the
studies mentioned in the literature. This discrepancy with
the literature could be associated with the clone of the
antibody used in our study which differed from the clone
and brand of c-Met antibody that had been used in the
regarding studies. This discordance could also be explained
by the sample size. Further molecular research as well as
immunohistochemical studies with a larger number of
cases are indicated in order to analyse the expression rate
of c-Met in chordoma. Peghini et al. demonstrated positive
correlation with EGFR and c-Met staining in gastrinomas
and the staining was also related with the aggressive
behaviour of the tumors36.
Pharmacological inhibition of EGFR kinase has no impact
on the blockage of c-Met activity, however this inhibition
abolishes the proliferative effect after HGF binds to its
receptors37. Common downstream pathways between
EGFR, HGF and c-Met may explain this mechanism. A
study of 21 chordoma cases analysing the genes in the
downstream pathways of EGFR including p44/42 MAPK,
Akt, STAT3 has revealed that 67% of the cases were
reactant by EGFR while the phosphorylated forms of
p44/42 MAPK, Akt, STAT3 were expressed in 86%, 76%,
and %67 respectively. The high expression profiles of these
genes strongly indicate a role for thyrosine kinase activity
in the pathogenesis of chordoma16. Microarray studies
analysing multiple genes are required to examine the exact
mechanism of EGFR, cMet and c-ErbB2 in chordoma.
The c-Met protooncogene is located in chromosome
7q31.21. Scheil et al. showed 7q gain in 69% of chordomas38. c-Met expression via 7q amplification may be a boarding step of chordoma progression. c-Met and HGF
are reported to be implicated in chordoma etiology and
Recurrence rates were higher in cases with intensely positive
c-Met staining. All of the 4 cases with high c-Met expression
showed recurrences. One of them showed two recurrences
and three showed a single recurrence. Localization was
cranial in all cases and gross total resection was performed
in each case. Two of the cases died at the 33rd and 45th
months while the others were alive. Follow-up periods for
the latter were 96 and 168 months after surgery. Three of
these cases were conventional while one was chondroid.
Hyperchromatic nuclei were evident in a single case and
the others did not show any atypical histological feature at
the time of initial biopsies.
There are studies in the literature revealing the correlation
of c-Met staining and poor prognosis in glioblastoma,
bladder, cervix, lung and liver neoplasms and multiple
myeloma40. In the study of Akhavan-Sigari et al.,
recurrent chordoma lesions with higher c-Met expression
were found to be associated with significantly better
prognosis than those with lower c-Met expression. Those
patients with lower EGFR expression were found to have
significantly better prognosis than those with higher EGFR
expression33. However, in our study, recurrence rates
were high in intensely c-Met positive cases. This finding
could also be explained by the limited sample size of the
studies. Therefore meta-analysis reports should be prepared
to obtain more reliable data about the correlation between
the histological features and immunostaining profiles of
chordoma and prognosis.
None of our cases showed immunoreactivity by c-ErbB2.
Conflicting results are present comparing the two other
studies investigating c-ErbB2 in chordoma. Weinberger et
al. claim that c-ErbB2 immunoreactivity is seen in 7 cases
out of 1117 while in the study of Fasig et al no reactivity
by c-ErbB2 is demonstrated although two different clones
of this antibody being used16. Our results are consistent
with the study of Fasig et al.
Complementary studies such as flourescence in situ
hybridization and Western Blot analysis with more cases
are needed to argue whether c-ErbB2 has a role in the
pathogenesis of chordoma.
Because of the aggressive potential and poor prognosis
of chordoma, new therapeutical strategies should be
investigated. Hof et al. presented a case of chordoma under
a combination regimen including cetuximab and gefitinib
who showed partial regression in pulmonary metastasis18. c-Met expression could be used as an indicator
of recurrence risk, as a target for therapeutic agents to
decrease recurrence, and for the prediction of prognosis.
In conclusion, although a high percentage of the cases
showed EGFR overexpression, no statistical correlation
was found between EGFR immunoreactivity and survival.
Further studies are required in order to determine the
population of patients with chordoma who are likely to
benefit from EGFR inhibitors. Recurrences were more
common in cases with c-Met overxpression than ones with
lower c-Met expression levels. c-Met inhibitors may play
a role in controlling the disease in the patients with c-Met
CONFLICT of INTEREST
The authors declare that there are no conflicts of interest
and no relevant financial interests in this manuscript.
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