This study investigated the relationship between tumor characteristics and somatostatin receptor 2 (SSTR2) expression in 81 patients with meningioma. Univariate and multivariate analyses found that older age (>65), larger tumor size (>3 cm), and female sex were associated with poorer overall survival. However, there was no association found between SSTR2 expression levels (negative, weakly positive, strongly positive) and overall survival or other tumor characteristics. Therefore, further research is needed to understand the role of SSTR2 receptor expression in meningiomas beyond its diagnostic value.

1. 189
OBJECTIVE: Numerous studies have been conducted
on risk factors for meningioma, mostly investigating the
relationship between meningioma tumor somatostatin
receptor 2 status (SSTR2), tumor size, age at diagnosis,
and tumor grade. This single-center study performed
in patients undergoing meningioma resection was per-
formed to investigate the relationships between tumor
characteristics.
STUDY DESIGN: This study involved a retrospective
analysis of patients undergoing meningioma resection
at our hospital. Univariate and multivariate logistic re-
gression models were used to investigate the relation-
ships between tumor SSTR2 expression status, proges-
terone receptor status, Ki-67 proliferation index, grade,
and size, as well as to identify factors.
RESULTS: A total of 81 patients had a median age at
diagnosis of 50 (21–80) years. The overall survival (OS)
periods in female and male patients were 100.2 and 56.4
months, respectively (p=0.02). There was a significant
difference in OS rates between the patients ≤65 years of
age and those >65 (99.1 and 58.8 months, respectively)
(p=0.008). The patients with tumors >3 cm had poorer
OS than patients with tumors ≤3 cm (p=0.004). There
was no association between tumor SSTR2 expression
status and OS; i.e., the OS periods were 75 months in
patients with SSTR2-negative tumors, 100.2 months
in those with weakly SSTR2-positive tumors, and 89
months in those with strongly SSTR2-positive tumors
(p=0.472).
CONCLUSION: Interestingly, despite the high positive
expression rate of SSTR2, there was no relation between
SSTR2 expression status and characteristic features of
meningiomas. Therefore, further investigations of the
role of SSTR2 receptor expression in meningiomas other
than its diagnostic value are required. (Anal Quant
Cytopathol Histpathol 2020;42:189–196)
Keywords: biomarkers, tumor; central nervous
system neoplasms; diagnosis; immunohistochemis-
try; meningeal neoplasms; meningioma; receptors,
progesterone; somatostatin receptor; tumor grade;
tumor proliferation.
Meningioma is the most common primary central
nervous system (CNS) tumor originating from
arachnoid cells. Meningiomas constitute approxi-
Analytical and Quantitative Cytopathology and Histopathology®
0884-6812/20/4206-0189/$18.00/0 © Science Printers and Publishers, Inc.
Analytical and Quantitative Cytopathology and Histopathology®
Importance of Clinical and Pathological
Characteristics of Meningiomas and Their
Relationship with Somatostatin Receptor-2
Positivity
Nilgün Söğütçü, M.D., Şahin Laçin, M.D., and Abdurrahman Çetin, M.D.
From the Departments of Pathology and of Neurosurgery, University of Health Sciences, Diyarbakır Gazi Yaşargil Training and Research
Hospital, Diyarbakır; the Department of Medical Oncology, Yeditepe University, Faculty of Medicine, I
∙
stanbul, Turkey.
Nilgün Söğütçü is Physician, Department of Pathology, University of Health Sciences, Diyarbakır Gazi Yaşargil Training and Research
Hospital.
Şahin Laçin is Assistant Professor, Department of Medical Oncology, Yeditepe University, Faculty of Medicine.
Abdurrahman Çetin is Associate Professor, Department of Neurosurgery, University of Health Sciences, Diyarbakır Gazi Yaşargil Train-
ing and Research Hospital.
Address correspondence to: Nilgün Söğütçü, M.D., Department of Pathology, University of Health Sciences, Diyarbakır Gazi Yaşargil
Training and Research Hospital, Sur, 21200, Diyarbakır, Turkey (nilgunsogutcu@gmail.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

2. mately 13–30% of primary CNS and 25% of intra-
spinal tumors; these lesions are observed pre-
dominantly in females and generally after age
65.1 Histologically, meningiomas have been classi-
fied into 3 grades of malignancy according to the
World Health Organization (WHO) criteria.2 Grade
I meningiomas are the most common, slowly grow-
ing, and benign tumors, representing almost 80%
of meningiomas. Grade II meningiomas are less
frequent and have a higher proportion of recur-
rence. Grade III anaplastic meningiomas are un-
common and are related to aggressive growth pat-
terns and poor overall survival.3 Hematoxylin and
eosin staining of sections is routinely used for the
diagnosis of meningioma, and immunohistochem-
istry (IHC) is generally not necessary. However,
several immunohistochemical markers have been
used for the diagnosis of meningioma, including
epithelial membrane antigen, progesterone recep-
tor (PR), and newer markers, such as somatostatin
receptors.4,5 A diverse range of human tumor tis-
sues, including meningiomas, express somatosta-
tin receptors. However, meningiomas exhibit a
high density of somatostatin receptors that can be
detected by somatostatin receptor scintigraphy.6
The expression level of specific somatostatin recep-
tor types in meningioma has not been studied in
sufficient detail to conclusively indicate its role in
the disease. To date, the number of somatostatin
receptors that have been defined is 5, which have
been shown to bind natural somatostatin with dif-
ferent binding characteristics.7,8 Analysis of soma-
tostatin receptors, especially somatostatin receptor
2 (SSTR2), has been reported as a valuable means
of evaluating meningiomas.9-11 We aim to analyze
the expression of SSTR2 immunohistochemically
in meningiomas and its relation with clinical and
pathological features of the disease, and to com-
pare these results with those of previous studies.
Materials and Methods
Patients
Patients undergoing surgical resection for intracra-
nial meningioma at the Diyarbakır Gazi Yaşargil
Training and Research Hospital, Division of Neu-
rosurgery, between June 2006 and April 2019 were
enrolled in this study. The patients’ medical rec-
ords were retrospectively reviewed for data collec-
tion, and 81 patients were deemed to be eligible for
inclusion in the study according to the following
criteria: pathological diagnosis of meningioma at
age ≥18 years. The exclusion criterion was patho-
logical diagnosis of an intracranial tumor other
than meningioma. The resected tumor tissues of
patients were evaluated, reviewed, and confirmed
by a qualified pathologist according to the WHO
Classification of Tumors of the Central Nervous
System, and tumors were classified as WHO grades
I, II, or III. Approval for the study was obtained
from the local ethics committee. The study was
performed in accordance with the ethical guidelines
for trials described in the Declaration of Helsinki.
Histopathology
All resected tumor tissues were fixed in 10% for-
malin solution for 24 hours and embedded in par-
affin blocks. Tissue sections used for staining were
4 mm thick. The histological diagnosis of menin-
giomas was determined by hematoxylin and eosin
staining. A single pathologist used the current
WHO Classification of Tumors of the Central Ner-
vous System to determine tumor grades, and tu-
mor mitotic index was also determined by count-
ing the percentage of cells with mitotic figures
found in 10 high power fields (HPFs).
Immunohistochemical Analysis
Immunohistochemical analysis was performed
with tumor tissue sections that had been fixed in
10% buffered formalin and embedded in paraffin.
The patient tissue blocks were cut into sections
4 mm thick, deparaffinized, and rehydrated. The
labeled streptavidin-biotin method (LSAB kit+Per-
oxidase; Epitomics, Burlingame, California, USA)
was used for detection of SSTR using a concen­
trated rabbit monoclonal anti-human SSTR2 pri-
mary antibody specific for SSTR2 (clone EP149,
Cat. No. AC-0162RUO, 1:100 dilution; Epitomics).
Tissue from a neuroendocrine tumor of the ap-
pendix was used as a positive control, and the
primary antibodies were replaced with saline as
a negative control. Immunostained samples were
evaluated under a light microscope by a patholo-
gist blinded to the clinicopathological data. SSTR2
expression was determined according to the pres-
ence of cell staining in the membrane. The immu-
nohistochemical reaction for SSTR2 was assessed
and classified by immunostaining intensity (IS) as
0 (negative), 1 (weak), 2 (moderate), or 3 (strong).
The staining areas of cells (ASP) recorded as the
percentages of staining were classified as follows:
0 (<5%), 1 (5–25%), 2 (26–50%), 3 (51–75%), or 4
(76–100%). IS and ASP values were multiplied to
obtain a density distribution (ID) score for each
190 Analytical and Quantitative Cytopathology and Histopathology®
Söğütçü et al

3. case. Patients with an ID score <1 were classified
as negative, patients with a score of 1–6 were
classified as weakly positive, and those with an
ID score of 6–12 were classified as positive. How-
ever, statistical analysis was done according to 3
classes, which were negative, weakly positive, and
positive SSTR2 expression level (Figures 1–3). Im­
munohistochemical assessments of PR and Ki-67
were performed using primary monoclonal rab-
bit antibodies against human PR (PR 1E2) and
Ki-67 (30-9) obtained from Ventana (Tucson, Ari-
zona, USA) in accordance with the manufactur-
er’s instructions. The nuclear staining pattern was
used for Ki-67 evaluation, and classification was
performed according to the percentage of tumor
cells showing positive nuclear staining; tumors
with no nuclear staining were scored as negative.
For PR evaluation, tumors were divided into sub-
groups and were considered PR-positive if >10%
of tumor cell nuclei were stained, weakly positive
if 1–9% of nuclei were stained, and negative if
there was no nuclear staining. A breast cancer
specimen was used as a positive control for PR
immunostaining.
Statistical Analysis
Descriptive statistics were used to summarize
the clinical data. The relationship between tumor
grade and PR, SSTR2, and Ki-67 expression were
evaluated. Tumor tissue PR expression, SSTR2
expression, and proliferative index (Ki-67) results
were compared and analyzed separately by linear
regression in all meningioma groups. The con­
tinuous variables of the patients characterized
Volume 42, Number 6/December 2020 191
Meningiomas and SSTR2 Positivity
Figure 1 Kaplan-Meier survival curve showing general overall
survival time of patients by all histological and regardless of
gender subtypes. The median overall survival was 91.6 months.
Figure 3 Kaplan-Meier survival curve showing overall survival
of patients by age group (group A, ≤65 years old and group B,
>65 years old). The median overall survival of groups A and B
were 99.1 and 58.8, respectively (p=0.008).
Figure 2 Kaplan-Meier survival curve showing overall survival
of patients by gender. The median overall survival of female and
male patients was 100.2 and 56 months, respectively (p=0.002).

4. according to distribution pattern were compared
using Student’s t test, Mann-Whitney U test, or
χ2 test as appropriate. Overall survival was de-
fined as the time from initial surgery to death or
to the last follow-up date. Survival graphs were
created using the Kaplan-Meier method, and the
Cox proportional hazards test was used to ana-
lyze prognostic factors. Receiver operating char-
acteristic (ROC) curve analysis was used to deter-
mine the cutoff value of variables. Statistical anal-
yses were performed using IBM SPSS Statistics
for Windows, Version 20.0 (IBM Corp., Armonk,
New York, USA). In each analysis of the study,
statistical significance was determined as p<0.05
value.
Results
A total of 81 patients were registered in our pa-
tient population. Patient demographic character-
istics and tumor subtype distribution patterns are
presented in Table I. There were no statistically
significant differences in the allocation of these
patients according to gender. The study popula-
tion consisted of 65 female patients (80.2%) and
16 male patients (19.8%). The median age at diag-
nosis was 50 (21–80), and by gender: 50 (25–80)
years for females and 49 (21–74) years for males.
The median overall survival of the total patient
population was 91.6 months (Figure 1) and dif-
fered significantly according to gender, with fe-
male and male patients showing overall survival
of 100.2 and 56.4 months, respectively (p=0.02)
(Figure 2). Two groups were created according to
patient age, and a significant difference was ob-
served in overall survival rates between those
aged ≤65 years (Group A) and those >65 years
(Group B) (99.1 and 58.8 months, respectively, p=
0.008) (Figure 3). According to the WHO grading
scheme, 70 (86.4%) meningiomas were classified
as grade I, 10 (12.3%) were grade II, and 1 (1.2%)
was grade III. The total patient population was
divided into 3 groups according to tumor tissue
SSTR2 expression score: 11 (13.6%) patients were
SSTR2-negative, 18 (22.2%) patients were weakly
positive, and 52 (64.2%) were positive. SSTR2 pos-
itivity was detected in 56 of 65 tumors in female
patients and in 14 of 16 tumors in male patients.
There was a statistically significant relationship
between SSTR2 expression and tumor grade in
male patients (p=0.012), but the relationship was
not statistically significant in females (p=0.11).
There was no significant association of overall
survival determined from survival analysis with
tumor tissue SSTR2 expression status—overall
survival was 75 months in patients with SSTR2-
negative tumors, 100.2 months in those with weak-
ly SSTR2-positive tumors, and 89 months in those
with positive tumors (p=0.472) (Figure 4). Tumor
tissue was PR-negative in 8 (9.9%) patients, weak­
ly positive in 17 (21%) patients, and positive in 56
(69.1%) patients, and there were statistically sig-
nificant differences in overall survival between PR
expression groups (p=0.008). However, we could
not find any relationship between PR expression
status and SSTR2 expression status (p=0.43). His­
192 Analytical and Quantitative Cytopathology and Histopathology®
Söğütçü et al
Table I Demographic and Clinical Characteristics of the Patients
at Baseline
No. or Per-
median age centage
Total patients (N) 81 100.0
Median age of all patients 50 (21–80) 100.0
Median age
Male 50 (25–80) 80.2
Female 49 (21–74) 19.8
Gender
Male 65 80.2
Female 16 19.8
Tumor size
≤3 cm 28 34.6
>3 cm 53 65.4
Patient age group
≤65 64 79.0
>65 17 21.0
Tumor tissue SSTR2 expres-
sion status
Negative 11 13.6
Weakly positive 18 22.2
Positive 52 64.2
Tumor histological subtype
Benign
Transitional 31 38.3
Meningothelial 23 28.4
Fibroblastic 9 11.1
Psammomatous 6 7.4
Microcystic 1 1.2
Atypical or malignant
Atypical 9 11.1
Chordoid 1 1.2
Anaplastic 1 1.2
WHO grade
I 70 86.4
II 10 12.3
III 1 1.2
Ki-67 proliferation index
1+ 64 79.0
2+ 12 14.8
3+ 5 6.2

5. topathologically, among all meningioma patients,
the majority of patients (n=69, 85.2%) had the
common types of meningiomas, such as transi-
tional (n=31, 38.3%), meningothelial (n=23, 28.4%),
fibroblastic (n=9, 11.1%), psammomatous (n=6,
7.4%), and microcystic (n=1, 1.2%). However,
14.8% (n=12) of the patients had uncommon types
of meningiomas; i.e., atypical (n=9, 11.1%), chor-
doid (n=1, 1.2%), and anaplastic meningiomas (n=
1, 1.2%). PR expression was detected as weakly
positive or positive in 73 patients (90.1%), while
the rest of the patients were negative. The ROC
analysis was used to determine the cutoff value
of tumor diameter, which was a diameter of 3 cm,
with 88% sensitivity and 42% specificity (Figure
5). There was a significant difference in overall
survival between patients according to the 2 dif-
ferent tumor diameter cutoff values; the median
overall survival of patients with tumors ≤3 cm
and >3 cm in diameter were 119 and 74.5 months,
respectively (p=0.004) (Figure 6). There were no
statistically significant relationships between tu-
mor tissue SSTR2 expression and tumor Ki-67
index, gender, tumor diameter, or age group. On
the other hand, the relationship between Ki-67
index and tumor grade was statistically significant
(p=0.048). The difference between the mean tumor
diameters of patient groups according to tumor
tissue SSTR2 expression status was not signifi-
Volume 42, Number 6/December 2020 193
Meningiomas and SSTR2 Positivity
Figure 4 Kaplan-Meier survival curve showing overall survival
of patients according to somatostatin receptor 2 status (3
subgroups: negative, weakly positive, and positive). The median
overall survival of negative SSTR2, weakly positive SSTR2, and
strongly positive SSTR2 were 75, 100.2, and 88 months,
respectively (p=0.47).
Figure 5 ROC analysis to detect the cutoff value of tumor
diameter in all patients with meningioma. The cutoff value was
3 cm with 88% sensitivity and 42% specificity.
Figure 6 Kaplan-Meier survival curve showing overall survival
of patients by tumor cutoff diameter groups (patients with tumor
size ≤3 cm or >3 cm). The median overall survival times of
patients with tumors ≤3 cm and >3 cm were 119 and 74.5
months, respectively (p=0.004).

6. cant; the mean tumor diameters in SSTR2-negative,
weakly positive, and positive groups were 4.5±
2.05, 3.7±2.04, and 4.1±1.94 cm, respectively (p=
0.52). Although higher-grade tumors tended to
have larger mean tumor size, there were no signif-
icant differences between groups. We performed
univariate Cox regression analysis to determine
whether age, gender, and tumor size were signifi-
cantly associated with overall survival (Table II).
Discussion
In this study we analyzed SSTR2 expression sta-
tus using immunohistochemistry in 7 different his-
tological subtypes of meningiomas in 81 patients
and determined the patterns of SSTR2 protein
expression. Among the 5 somatostatin receptors,
SSTR2 is the most sensitive and specific marker
for diagnosis of meningioma,9 and in our patient
population 86.4% of patients were positive for
SSTR2 staining. In our series, SSTR2 expression
was detected in grades I, II, and III meningiomas,
and there was no significant correlation between
tumor grade and receptor expression status. Our
findings were consistent with a previous trial by
Arena et al, who reported no correlations between
these parameters.9 Although Durand et al detect­
ed higher levels of SSTR2 expression in meningo­
thelial meningiomas than in other histological sub-
types, we found no significant differences in SSTR2
expression between histological subtypes,12 similar
to the findings of other trials.
The role of the PR in meningioma and its value
as a prognostic marker have been investigated.13 A
decrease in PR expression from low-grade to high-
grade meningiomas has been reported.14 There­fore,
an increase in PR expression may indicate a less
aggressive tumor, and PR has been reported as a
positive prognostic factor in one previous trial.15
Gender was reported previously to be a prog-
nostic factor in meningioma.16 In that study, male
patients showed a higher frequency of atypical
or malignant meningiomas than benign meningi-
omas, which have poorer survival rates. Our find-
ings showed that male patients had higher rates
of grade II and grade III tumors, and the survival
rate was poorer for males than for females.
The most common type of meningioma report­
ed in the literature is benign, and atypical or ma-
lignant meningiomas are rare. In a previous trial,
the rate of benign meningioma was 92%, while
the rate of atypical or malignant meningioma was
reported as 8%.17 Similarly, the majority of our
patients (86.4%) had grade I meningiomas that
were classified as benign, and other patients with
grade II and III meningiomas (13.6%) constituted
the minority in our trial. On the other hand, the
most common histological subtypes of meningio-
ma are meningotheliomatous, transitional, fibrous,
and psammomatous, whereas atypical, chordoid,
and anaplastic histological types of meningiomas
are less common. Our patient histological subtype
distribution was consistent with that reported in
the literature.
Meningiomas are usually diagnosed between
the ages of 35 and 55 years, with diagnosis being
uncommon before 14 and after 74 years of age. In
addition, 55 years of age is the most commonly
reported average age at diagnosis of meningio-
ma. Therefore, age is a prognostic factor; age >65
years was reported as a negative prognostic fac-
tor in a large population study.18 In this study,
patient age at diagnosis was a significant predic-
tor of survival for patients with benign, atypical,
and malignant meningiomas, and patients >65
years old had significantly poorer overall survival
than did younger patients.
Tumor size is another important factor deter­
mining survival, with larger tumors associated
194 Analytical and Quantitative Cytopathology and Histopathology®
Söğütçü et al
Table II Cox Regression Analysis of the Factors Which May
Have Effects on Survival
Hazard
Factor ratio ¥ 95% CI p Value
Age >65 vs. age ≤65 2.88 1.26–6.54 0.011*
Male vs. female 3.53 1.5–8.3 0.004*
Tumor diameter >3 cm
vs. ≤3 cm 4.99 1.49–16.7 0.009*
Progesterone receptor
status
0.036*
PR negative 1.000
PR weakly positive 0.20 0.05–0.802 0.023*
PR positive 0.274 0.11–0.71 0.007*
SSTR2 expression status
0.44
Negative 1.000
Weakly positive 0.464 0.11–1.87 0.28
Positive 0.85 0.28–2.55 0.78
Ki-67 index
0.48
+ 1.000
++ 0.45 0.11–1.93 0.28
+++ 0.84 0.11–6.53 0.87
Grade
0.46
1 1.000
2 1.07 0.32–3.6 0.91
3 4.80 0.63–37.1 0.12
*Indicates significance (p<0.05).

7. with higher recurrence rates and greater likeli-
hood of being grade II than grade I tumors.18 How­
ever, the relationship between tumor size and
survival has not been clearly explained. This is the
first trial showing a significant association between
larger tumor size and poorer overall survival.
This study had some limitations, including its
retrospective nature. Second, the largest tumor
diameter was used as a representation of overall
tumor size, which may not be sufficient to rep­
resent the exact size of meningioma. Third, the
sample size in the study was small, with a limited
number of patients, so the distribution of patients
was not balanced between groups. Finally, SSTR2
expression was assessed according to staining
localization because membrane rather than cyto-
plasmic SSTR2 immunostaining was shown to be
correlated with the clinical response to somato­
statin analogues in patients with neuroendocrine
tumors; therefore, we have used the membrane
staining score for evaluation.19 The localization of
SSTR2 expression may affect clinical findings and
correlations.
The anti-tumoral activity of somatostatin has
been defined in 2 different ways: a proliferation
inhibition and the neovascularization inhibition
through decreasing the VEGF secretion by tu-
mor.20,21 Therefore, treating patients with signifi-
cant SSTR expression with somatostatin analogues
appears to be a reasonable option. The implica-
tions of immunohistochemical somatostatin recep-
tor determination for the selection of treatment
for meningioma are controversial, and surgical re-
moval of the tumor is still the first option. In this
study, despite the high expression rate of SSTR2
in tumor tissues, we could not find a significant
relationship between SSTR2 expression and tumor
grade, tumor diameter, patient gender, and tumor
histology (Figures 7–9). Our results raise doubts
about the role of somatostatin receptor expres-
sion in treatment as well. Therefore, somatostatin
receptor’s expression level and its predictive role
in the treatment response need to be investigated
in the future.
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