International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848

PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE

PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 843
Pathological Pattern of Atypical Meningioma: Diagnostic
Criteria and Tumor Recurrence Predictors
Mohamed A.R Arbab
(1, 2)
, Sawsan A Aldeaf
(2)
, Lamyaa A M El Hassan
(3)
Beshir M Beshir
2,
Alsadeg F.B. Gassoum
2
and Ahmed M El Hassan
(4)
.

1. Department of surgery, Faculty of Medicine, University of Khartoum, Sudan.
2. National Center for Neurological Sciences, Khartoum.
3. Department of Pathology, Ahfad Women University, Omdurman, Sudan.
4. Institute for Endemic Diseases, University of Khartoum
Consultant Neurosurgeon, E mail: [email protected]
[email protected]
Abstract
Purpose
This study aimed to verify the pathological
pattern of atypical meningioma according to
the WHO 2007 grading criteria and to
identify possible predictors of tumor
recurrence.
Patients and methods
This is a hospital based study conducted at
the National Center of Neurological
Sciences- Khartoum during 2007-2012. All
patients operated upon and verified
histologically as cranial atypical
meningioma were considered. Histologic
diagnosis supplemented with
immunohistochemistry using epithelial
membrane and progesterone markers were
used. Review of cellular changes according
to WHO 2007 diagnostic criteria was
adopted in all cases. Patients with recurrent
atypical meningioma plus a control group of
non-recurrent atypical meningioma were
further processed to immunostaining for
detection of Ki67 antigen.
Results
Forty four patients were diagnosed having
atypical meningioma, of which twelve
patients were recurrent cases. The histologic
and immunohistochemical verification of the
cells study showed increased mitosis, high
small cell components with high nuclear
cytoplasmic ratio and tumor necrosis as
predominant histological features of atypical
meningioma. Association of high nuclear
cytoplasmic ratio, mitosis and hyper
cellularity with increased Li Ki67 as strong
predictors of tumor recurrence.
Conclusions
Small cell components with high nuclear
cytoplasmic ratio, increased mitotic figure
and areas of necrosis are strong histological
criteria for diagnosis of atypical meningioma
while coexistence of Li Ki 67 is a predictor
for tumor recurrence
Key words:
Atypical meningioma, Li Ki67, WHO 2007
histological criteria, tumor recurrence.









International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 844
Introduction

Meningiomas are common tumors of the
CNS that originate from the meningeal
coverings of the brain and spinal cord; it
derives from the arachnoid cap cells. It
accounts for about 30% of all primary brain
tumors. The annual incidence of meningioma
is estimated at 5 per 100 000 individuals.
There is distinct gender preponderance
towards women with a female to male ratio
of about 2:1.Although most meningioma are
benign, however, they have a broad spectrum
of clinical characteristics and histologically
distinct subtypes that are associated with high
risk of recurrence, even after microscopic
complete resection
(1,2)
.In rare instances,
meningioma are malignant. The WHO
classification aims to better predict the
divergent clinical characteristics of
meningioma with a histological grading
system based on statistically significant
clinicopathological correlations.
There are three types of meningioma
according to WHO 2000 grading
classification grade1 which is considered
benign, grade 11 that are intermediate and
grade 111 which is malignant. This
classification has set certain morphological
criteria to classify the pathological
characteristics of meningioma
(3)
. The
current version of WHO classification was
updated in 2007; it divided meningioma into
three groups based on morphological criteria
which have important implications on
patients management
(4)
.
In spite of the adopted WHO 2007 scale, still
prediction of the biological behavior of
meningioma remains a challenge.
Immunohistochemical studies using Ki 67
have been done to outline the predictive
correlation of Ki 67 with histological grading
and tumor recurrence
(5, 6).
In Sudan cranial
meningioma is the most encountered cerebral
neoplasm. The atypical variant amounts to
30% of all meningioma and poses a clinical
challenge since it is associated with relatively
high risk of tumor recurrence.
eneral ob!ecti"e:
To identify the immunostaining reactivity of
ki67 antigen in atypical (grade 11)
meningioma among Sudanese patients.
#pecific ob!ecti"es:
1/ to identify the atypical histological criteria
of meningioma among Sudanese patients
according to WHO criteria 2007.

2/ to verify ki67 antigen labeling index, in
atypical meningioma among Sudanese
patients.
3/ to correlate the atypical features according
to WHO criteria 2007 and ki67 antigen
labeling index.
Clinical Material and methods
This is a prospective study done at the
National Center of Neurological Sciences
(NCNS) - Khartoum during the period 2007-
2012. All patients operated upon for cranial
tumors and the histopathology confirmed the
diagnoses of atypical meningioma were
considered in the study. Tumor specimens
were processed for histologic diagnosis of
meningioma. Immunohistochemistry using
epithelial membrane antigen (EMA) and
progesterone markers were used to confirm
diagnosis of atypical meningioma.




International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 845
The diagnosis of atypical meningioma was
made according to 2007 WHO criteria, which
are defined as:
The tumor contains 4 or more mitotic
figures per 10 high power fields (0.16
mm).
The tumor exhibiting at least three of the
following features:
A/ Hyper- cellularity.
B/ Pattern less sheet- like growth.
C/ Macronuclei.
D/ Small cell components with high
nuclear cytoplasmic/ratio.
E/ Zones of necrosis.
In another setting all recurrent atypical
tumors (12 cases) plus 16 random non
recurrent atypical cases were selected. The
atypical features for each case were studied
using immunostaining for ki67 antigen
according to Dako standard protocol. Paraffin
embedded blocks were sectioned 4 m thick.
These were then mounted onto special
immunostaining slides and then incubated in
the oven at 65

C for overnight. The slices
were then treated with xylene, absolute
ethanol, 90% ethanol, 70% ethanol
respectively, and then washed in tap water.
The sections were placed in target retrieval
solution high pH (50 xs) at 95

C in water
path for 30 minutes (Dako Denmark A/S,
productionsvej 42 DK-2600 Glostrup,
Denmark). Dako pen was used for drawing a
circle around the reaction area on the slides.
The slides were then placed in washing buffer
for 10 minutes, followed by hydrogen
peroxide for peroxidase blocking, and then
washed in washing buffer for 15 minutes. ,
The primary antibody was added to all
sections for 30 minutes, then washed in
buffer for 15 minutes, followed by link
solution (HRP) for 25 minutes, and washed in
buffer for 15 minutes, and then diluted DAB
solution was added for 10 minutes, and
washed twice in water and washing buffer
respectively. Mayers heamatoxyline was
used as a counter stain and the slides were
cover slipped using DPX mounting medium.
All sections were examined under the light
microscope. The MIB-1 LI is calculated as
the percentage of tumor cell nuclei that stain
positive out of the total number of tumor cell
nuclei counted, as ( >5%, <5% and ve ).
Data processing and statistical analysis
Data were analyzed using SPSS 13 software
with reference P.value of 0.05 was
considered statistically significant.

Results
During the period from 2007 to 2012 a total
of 44 cases were operated upon for cranial
tumor and diagnosed as atypical meningioma
according to WHO 2007 criteria, accounting
to 12% of the total number of cranial
meningioma operated upon during the same
period. Males constituted 38.9% and females
61 %. Parietal and frontal falx locations were
the most common anatomical locations
constituting 30.6% and 25.0% respectively.
According to the WHO 2007 criteria, high
nucleus to cytoplasmic ratio and increase
mitotic figures were seen in 29 patients each
(65.9%), followed by necrosis in 54.5% of
the patients. Brain invasion was identified in
3 patients and bone invasion in 6 other
patients and in other two patients
inflammatory cells with lymphocytes
infiltrate were identified (Table 1).
In the recurrent group (12 cases) and the
random non-recurrent (16 cases) which was




International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 846
processed for Ki 67 immunostaining, positive
immunostaining for Ki 67 antigen was
identified in 27 cases (96.4%), and only one
case was negative. The Li of Ki 67 antigen
was calculated as (>5% and <5%) of positive
cells nuclei out of the total number of tumor
cells. Seventeen of the cases showed Li Ki 67
of >5% constituting (62.9%). and 10 of the
cases were <5% (Table 2).
Positive immunostaining for Ki 67 was
identified in 14 cases (66.6%) with sections
showing high nuclear cytoplasmic ratio, 13
patients (61.9%) with increased mitotic
figure and in 11 patients (52.3%) with tumor
necrosis (Fig. 1).
Within the twelve patients (42.8%) with
tumor recurrence, the dominant WHO 2007
criteria, were high nuclear cytoplasmic ratio
(75%), increased mitotic figures (66.7%) and
hyper cellularity in (58.3%) (Table 2).
Discussion
Meningioma has been recognized as a tumor
entity for nearly 200 years. It accounts for 24-
30% of intracranial tumors and they are
considered mostly as benign
(3)
. A significant
minority are atypical (WHO Grade II).
Whole older series put the proportion of
atypical meningioma at 5-7%; the actual
proportion using the current WHO
definitions is probably 15-20%.
Before the 2000 WHO classification
scheme, several subjective classification
systems existed. The (2000 WHO) grading
system reclassified meningioma, creating
standard diagnostic criteria, including WHO
Grade II (atypical) meningioma, that is
composed of ; 4 mitotic cells per 10 hpf
and/or 3 or more of the following: hyper
cellularity, small cells, necrosis, prominent
nucleoli, and sheeting.
Further revision of the WHO scheme in 2007
included brain invasion in an otherwise
Grade I tumor as an additional criterion for a
WHO Grade II lesion
(4)
. This recent WHO
2007 classification provides broad criteria for
differentiating benign and atypical
meningioma, with hyper cellularity and
increased mitotic index as possible predictors
for recurrence. Necrosis and focal necrosis
have also been regarded as indicators of
recurrence. Some studies has reported on the
histological features of meningioma and the
genetic predisposition to the disease
(7,8,9)
.Numbers of macrophages and T and
CD8 lymphocytes in meningioma have been
related to atypical histology
(10)
.
In the present study, we adopted the above
WHO 2007 grading criteria. The
histopathological criteria for the accurate
interpretation of atypical meningioma have
been well adopted as defined in this study.
This scoring system clearly distinguished
benign and atypical variants of meningioma.
It is being emphasized that neuro pathologists
should be familiar with these criteria and the
scoring system. In addition, an accurate
interpretation of the atypical meningioma is
essential since these tumors are likely to recur
much earlier than benign and may necessitate
adjuvant radiotherapy as treatment modality.
Results of this study have shown that the
atypical meningioma (WHO Grade II)
constituted 9.4% of all meningioma that were
seen during a five year period 2007-2012 at
the NCNS. They were diagnosed using the
WHO 2007 morphological criteria. In the
present series, small cell components with




International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 847
high nuclear to cytoplasmic ratio and
increased mitotic figures were the most
common features seen, followed by necrosis
and to less extent the other remaining criteria.
The histological criteria in the recurrent
specimens are observed in order of
frequency, high nuclear to cytoplasmic ratio
in 75%, increased mitotic figures in 66.7%
and hypercellurarity in 58%. The other
criteria are less frequent. Furthermore the
histological patterns of the recurrent tumors
and the Ki67 Li have distinct association.
While small cell components with high
nuclear to cytoplasmic ratio, increased
mitotic figures and tumor necrosis seem to be
strong histological indicators of atypical
meningioma, co-existence of Ki 67 Li and/or
small cell components with high nuclear
cytoplasmic ratio, increased mitosis and
hyper cellularity are strong predictors of
tumor recurrence. Accurate histopathological
diagnosis of atypical meningioma is essential
for predicting the recurrence and biological
behavior as well as for planning post-
operative treatment modalities. Large scale
series is needed to consolidate the results of
this study. The frontal and falx areas were the
most common sites affected followed by the
temporal area, CPA and sellar regions. The
anatomic location does not seem to influence
the biological behavior of the tumor.
Conclusion
In conclusion the present study suggests that
small cell components with high nuclear
cytoplasmic ratio, increased mitotic figure
and areas of necrosis are strong histological
criteria for diagnosis of atypical meningioma
while coexistence of Li Ki 67 is a predictor
for tumor recurrence.

References

1. Jaaskelainen, J., et al. "The growth rate of
intracranial meningiomas and its relation
to histology. An analysis of 43 patients."
Surg.Neurol. 24.2 (1985): 165-72.
2. Jaaskelainen, J., M. Haltia, and A. Servo.
"Atypical and anaplastic meningiomas:
radiology, surgery, radiotherapy, and
outcome." Surg.Neurol. 25.3 (1986):
233-
3. Kleihues, P., et al. "The WHO
classification of tumors of the nervous
system." J.Neuropathol.Exp.Neurol. 61.3
(2002): 215-25.
4. Louis, D. N., et al. "The 2007 WHO
classification of tumours of the central
nervous system." Acta Neuropathol. 114.2
(2007): 97-109.

5. Babu S, Uppin SG, Uppin MS, Panigrahi
MK, et al. Meningiomas: correlation of Ki67
with histological grade. Neurol India. 2011
Mar-Apr; 59(2):204-7.

6. Bruna J, Brell M, Ferrer I et al. Ki-67
proliferative index predicts clinical outcome
in patients with atypical or anaplastic
meningioma. Neuropathology. 2007 Apr;
27(2):114-20.
7. Perry, A. and L. P. Dehner. "Meningeal
tumors of childhood and infancy. An update




International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 848
and literature review." Brain Pathol. 13.3
(2003): 386-408.
8. Perry, A., et al. "Aggressive phenotypic and
genotypic features in pediatric and NF2-
associated meningiomas: a clinicopathologic
study of 53 cases."
J.Neuropathol.Exp.Neurol. 60.10 (2001):
994-1003.
9. Su, C. F., et al. "Malignant meningiomas--
clinical and pathological study of 10 cases."
Taiwan.Yi.Xue.Hui.Za Zhi. 85.6 (1986):
608-23.
10. Crompton, M. R. and P. C. Gautier-Smith.
"The prediction of recurrence in
meningiomas."
J.Neurol.Neurosurg.Psychiatry 33.1
(1970): 80-87









International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 849
$igures and Tables
Fig. 1 Positive immune staining for Ki 67 showing Li Ki67 >5% (A) and <5% (B).
(X40)).
A B

Table 1 WHO 2007 histological criteria of 44 patients with atypical meningioma
=====================================================================================
Histologic criterion N!"er o# c$ses %
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Incre$se' !itosis () *+,)
H-.er celll$rit- /* 0*,1
M$cronclei (/ 12,2
Hig3 ncle$r to c-to.l$s!ic r$tio () *+,)
Necrosis (1 +1,+
H-.erc3ro!$si$ /0 (),+
Ncleoli 0 *,4
5r$in in6$sion 0 *,4
5one in6$sion * /0,*
In#l$!!$tor- cells ( 1,+
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Tot$l 11 /77




International Journal of Research (IJR) Vol-1, Issue-7, August 2014 ISSN 2348-6848
PATHOLOGICAL PATTERN OF ATYPICAL MENINGIOMA: DIAGNOSTIC CRITERIA AND TUMOR RECURRENCE
PREDICTORS Mohamed A.R Arbab , Sawsan A Aldeaf, Lamyaa A M El Hassan, Beshir M Beshir ,
Alsadeg F.B. Gassoum & Ahmed M El Hassan

P a g e | 850
Table 2. WHO 2007 histologic criteria and Li Ki67 of 12 patients with recurrent atypical
meningioma.
=====================================================================================
Histologic criterion N!"er o# c$ses 8it3 .ositi6e Li 9i*2 Tot$l %
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
:+% ;+%
&&&&&&&&&&&&&&&&&&&&&&&&&&&
Incre$se' !itosis * ( 4 **,2
H-.er celll$rit- 1 0 2 +4,0
M$cronclei 1 / + 1/,2
Hig3 ncle$r c-to.l$s!ic r$tio 2 ( ) 2+,7
Necrosis 1 / + 1/,2
H-.erc3ro!$si$ / 7 / 4,0
Ncleoli / / ( /*,*
5r$in in6$sion 7 7 7 7
5one in6$sion 7 7 7 7
In#l$!!$tor- cells 7 7 7 )
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Tot$l (2 /7
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&