Keywords
Human epidermal growth factor receptor 2 - immunohistochemistry - meningioma
Introduction
Meningiomas include between 15% and 30% of the primary intracranial tumors with an
annual incidence of 5/100,000.[1]
[2] These tumors develop more in middle and late adulthood.[1] Meningiomas were graded into three groups (Grade I: benign), (Grade II: atypical),
and (Grade III: anaplastic or malignant).[3] Most meningiomas are benign tumors, but up to 15% are atypical, and 2% malignant
according to the World Health Organization histological criteria reported in 2016.[2] Meningiomas more often afflict women than men and are rare but often aggressive
in children.[4]
[5] Despite the molecular mechanisms of meningioma having been described, the curative
effects of current treatments for invasive and malignant meningiomas have been unsatisfactory.[6] Tumor recurrence was observed in 7%–20% of Grade I, 29%–40% of Grade II, and 50%–78%
of Grade III meningiomas, following surgery. Due to high tumor recurrence in Grade
II/III meningiomas, additional treatment protocols with targeted therapy may be required
with the available chemotherapeutic drugs.[1]
[3] The human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a 185-kD
transmembrane glycoprotein with tyrosine kinase activity expressed in meningiomas
and various other tumors.[7] HER2 status is important in the medical management of patients with various human
cancers[8] and can be a therapeutic target with monoclonal antibodies for meningiomas that
interact with HER2 receptors,[1]
[9] but the prognostic value of this receptor protein in meningiomas is ambiguous.[10]
[11] This study aimed to evaluate the HER2 expression in meningiomas and the correlation
between this expression and age, gender, and grade.
Materials and Methods
Specimen selection
In this descriptive-analytic study, paraffin blocks were checked in patients with
meningiomas admitted to the pathology laboratory of Imam Reza Hospital, Kermanshah,
Iran, from 2008 to 2015. After referring to the computer file and the offices in the
pathology laboratory, the samples were selected to reach a sufficient sample size
(117 samples).
Immunohistochemistry
At first, hematoxylin and eosin (H and E)-stained slides were collected from each
sample from the archives and then the paraffin blocks were prepared by 4-μ sections
for the H and E routine staining and immunohistochemistry (IHC) staining with the
HER2 marker. The tissue sections were reexamined by the pathologist and the diagnosis
of meningioma was confirmed. Then, IHC specimens were examined. Primary antihuman
antibody against c-erbB-2 oncoprotein (DAKO Diagnostics, Polyclonal Rabbit Antihuman
c-erbB-2 Oncoprotein, Code A0485) was used for the IHC. According to the pattern of
staining, the specimen was marked as IHC0 (less than 10% of the tumor cells were stained;
negative), IHC1+ (more than 10% of the tumor cells were stained and the membrane of
the cells was incomplete and poorly stained, negative), IHC2+ (more than 10% of the
tumor cells were stained and the cell membrane was full but weak-to-medium staining,
ambiguous, or duplex), and IHC3+ (more than 10% of the tumor cells were stained and
the cell membrane was full and strong staining, positive). Then, the results were
recorded in the data collection form. We considered score 0 and 1+ as negative, while
those with score 2+ and 3+ considered as positive. A ductal carcinoma of the breast
(in which the intense and high percentages of cells were stained for the HER2 marker)
was used as a positive control of IHC and a normal breast sample as a negative control.
[Figure 1] demonstrates IHC staining patterns in meningiomas.
Figure 1: Meningioma: (a) Grade Ӏ, H and E, ×100. (b) Grade ӀӀ, H and E, ×100. (c)
HER2 positivity 3+, immunohistochemistry; ×100 (case A). (d) HER2 positivity 2+, immunohistochemistry;
×100 (case B). HER2 – Human epidermal growth factor receptor 2
Statistical analysis
The data were analyzed by SPSS version 22 (IBM Corp., Armonk, NY, USA) and by binary
logistic regression (odds ratio [OR] and 95% confidence interval [CI]). P < 0.05 was considered to be statistically significant.
Ethical approval
This study was approved by the Ethics Committee of Kermanshah University of Medical
Sciences, Kermanshah, Iran. The names of the patients remained confidential, and no
additional costs were imposed on patients.
Results
The mean age of patients was 53.6 years (range, 1–88 years); 68.4% were males and
59.8% had age >50 years [Table 1]. Of 117 patients, 106 patients (90.6%) had Grade I, 10 (8.5%) had Grade II, and
1 (0.9%) had Grade III. With regard to HER2 expression, 4 (3.4%) had IHC0, 37 (31.6%)
IHC1+, 67 (57.3%) IHC2+, and 9 (7.7%) IHC3+. Totally, 76 (65%) patients were HER2
positivity and 41 (35%) were negativity.
Table 1
The baseline characteristics of the patients
|
Variable
|
Value
|
|
SD – Standard deviation; HER2 – Human epidermal growth factor receptor 2
|
|
Age (years)
|
|
|
Mean±SD
|
53.6±13.4
|
|
Range
|
1–88
|
|
≤50>50 (%)
|
47 (40.2)/70 (59.8)
|
|
Sex (%)
|
|
|
Male
|
80 (68.4)
|
|
Female
|
37 (31.6)
|
|
Grade (%)
|
|
|
І
|
106 (90.6)
|
|
ІІ
|
10 (8.5)
|
|
ІІІ
|
1 (0.9)
|
|
HER2 expression (%)
|
|
|
0
|
4 (3.4)
|
|
1+
|
37 (31.6)
|
|
2+
|
67 (57.3)
|
|
3+
|
9 (7.7)
|
|
HER2 status (%)
|
|
|
Positive
|
76 (65)
|
|
Negative
|
41 (35)
|
A comparison between three variables with HER2 expression status by binary logistic
regression is shown in [Table 2]. The results showed that there was no significant correlation between the mean age
(OR = 1.012; 95% CI: 0.967, 1.060; P = 0.605), age group (OR = 0.552; 95% CI: 0.158, 1.935; P = 0.353), sex (OR = 1.123; 95% CI: 0.482, 2.615; P = 0.788), and grade (OR = 0.655; 95% CI: 0.179, 2.399; P = 0.523) with HER2 expression status.
Table 2
The correlation between the variables with human epidermal growth factor receptor
2 expression status (human epidermal growth factor receptor 2 positive and human epidermal
growth factor receptor 2 negative) based on the binary logistic regression
|
Variable
|
P
|
OR
|
95% CI
|
|
OR – Odds ratio; CI – Confidence interval; SD – Standard deviation
|
|
Age (years)
|
|
|
|
|
Mean±SD
|
0.605
|
1.012
|
0.967, 1.060
|
|
≤50 versus >50
|
0.353
|
0.552
|
0.158, 1.935
|
|
Sex
|
|
|
|
|
Male versus female
|
0.788
|
1.123
|
0.482, 2.615
|
|
Grade
|
|
|
|
|
І and ІІ versus ІІІ
|
0.523
|
0.655
|
0.179, 2.399
|
Discussion
Meningiomas are caused by arachnoid cells, and typically, these tumors are slow-growing
lesions, but the recurrence followed by surgical treatment is a problem with which
they are.[1] Understanding the invasive molecular mechanism may help design appropriate treatments
and increase survival rates.[12] Due to the significant recurrence rate, including Grades I and II, treatment for
meningiomas requires modalities such as existing drugs.[1] Meanwhile, in all cases of meningioma, there is no possibility of complete resection
of the lesion, and the remainder of the tumor may not be controlled by radiotherapy.
Therefore, targeted molecular therapies for the effects on meningiomas can be very
beneficial, especially if you need to reduce neurological interventions.[13]
[14] In this regard, the HER2 family is noteworthy that they are effective tyrosine kinase
receptors in a tumorigenic activity.[13] These receptors play important roles in the direction of the cell signal involved
in cell growth.[15] The family of tyrosine kinase growth factor receptors, in addition to HER2, also
contains HER1, HER3, and HER4.[15]
[16] Excessive expression of the HER2 gene has been found in many different types of human malignancies, including the
breast, lung, ovary, stomach, pancreas, prostate, and colorectal, and cancers of the
female genital tract, with a poor prognosis in at least a few of them.[1]
[16]
[17] Previous studies have shown a different level of HER2 expression in various types
of brain tumors.[1] Some studies have reported the high expression of this receptor in medulloblastoma
and its association with poor prognosis in these tumors.[1]
[16] HER2 protein has also been reported in the pituitary adenoma and vestibular schwannoma.[1] In a study with work on human invasive specimens, expression and excessive activity
of HER2 and HER3 were shown.[14] In fact, only a few studies have done about the association between meningiomas
and HER2 expression, and the results are different.[1]
[8]
[12]
[17]
[18]
Wang et al.[19] using IHC method showed that the expression of HER2 in benign meningiomas (no recurrence/initial),
the benign recurrence group, the atypical group, and malignant group reported as follows:
35%, 30%, 15%, and 50%. It was also suggested in this study that higher tumor grade
was associated with a higher expression of HER2 expression, and the HER2 gene amplification was reported in 7 of 26 samples (26.9%) of HER2 2+ meningiomas.
In a study by Anderson et al., the expression of the HER2 family in relation to various parameters in 44 glioma
and 26 meningioma samples was analyzed using real-time polymerase chain reaction;
the expressions of HER1, HER2, and HER4 in the majority of meningiomas were observed.
However, HER3 was found only in one of the samples. In addition, the immunohistochemical
method showed a high expression of HER2 in meningiomas.[16] In a study by Mahzouni and Movahedipour using immunohistochemical methods and in
a retrospective study,[1] 31 of 72 samples of meningiomas (43%) were HER2 positivity (55% of Grades II or
III and 38.5% of Grade I samples). Although Grade II meningiomas showed a higher HER2
protein immunoreactivity, this difference was not statistically significant. In this
study, HER2 expression was seen in 39% male and 44.9% female samples, but there was
no statistically significant difference between the two genders. In a 2008 study by
Durand et al., on human meningiomas,[20] the association of the expression of HER2 gene with gradient and histologic grade of the tumor was investigated that the levels
of mRNA of this gene did not correlate with histological grade. One study[7] on 100 samples of meningioma (including 80 samples of Grade I, 18 of Grade II, and
2 of Grade III) investigated the association between HER2 expression and sex, location,
grade, and subtypes of meningiomas. According to the results of this study, HER2 positivity
was seen in 73% of the samples (75% of Grade I, 72.2% of Grade II, and 0% of Grade
III samples). There was no significant association between HER2 expression and the
mentioned factors. Another study[21] checked the expression of HER2 in 60 meningioma samples (48 samples with Grade I
and 12 samples with Grades II or III) using IHC and the relationship between the expression
of HER2 and sex, age, tumor grade, and recurrence or regrowth. HER2 positivity was
seen in 88.3% of the samples (31.7% – weak, 38.3% – moderate, and 18.3% – strong).
There was no statistically significant difference between sex, age, tumor grade, and
recurrence and HER2 expression. Of 186 human meningiomas of all malignancy grades
that 163 of these were in tissue microarrays, about 48% and 11% were HER2 positivity
with antibodies against the extracellular domain and against the activated receptor,
respectively, without gene amplification.[8]
Conclusions
In general, the high expression of HER2 in this study was found in 7.7% of meningiomas
(9 of 117 samples). However, there was no significant difference between the expression
of HER2 and sex, age, and tumor grade. Further studies with a higher number of Grade
II and III meningiomas and using the fluorescent in situ hybridization in equivocal cases may be of benefit in this way.
