Diagnostic Discrepancies Between Intraoperative Frozen Section and Permanent Histopathological Diagnosis of Brain Tumors
Maher KURDI1, Saleh BAEESA2, Yazid MAGHRABI3, Anas BARDEESI3, Rothaina SAEEDI41, Taghreed AL-SINANI5, Alaa SAMKARI6, Ahmed LARY7, Sahar HAKAMY8
1Department of Pathology, King Abdulaziz University, Faculty of Medicine in Rabigh, RABIGH, KINGDOM OF SAUDI ARABIA
2Division of Neurosurgery, King Abdulaziz University, Faculty of Medicine, JEDDAH, KINGDOM OF SAUDI ARABIA3Department of Neuroscience, King Faisal Specialist Hospital and Research Center, JEDDAH, KINGDOM OF SAUDI ARABIA
4Division of Neurosurgery, Department of Surgery, King Abdulaziz University Hospital, JEDDAH, KINGDOM OF SAUDI ARABIA
5King Fahad General Hospital, JEDDAH, KINGDOM OF SAUDI ARABIA
6Department of Pathology and Laboratory Medicine, King Saud Bin Abdulaziz University for Health Science, JEDDAH, KINGDOM OF SAUDI ARABIA
7Division of Neurosurgery, Department of Surgery, King Abdulaziz Medical City, JEDDAH, KINGDOM OF SAUDI ARABIA
8Center of Excellence in Genomic Medicine Research, King Abdulaziz University, JEDDAH, KINGDOM OF SAUDI ARABIA
Keywords: Brain tumor, Histopathology, Frozen section, Diagnostic compatibility
Intraoperative frozen section (IOFS) diagnosis of brain tumors plays an important role in assessing the adequacy of the sample and
determining the treatment plan. The aim of this study was to investigate the diagnostic accuracy between IOFS and permanent sections.
Material and Method: The authors reviewed the histopathological results of 383 brain tumors, including IOFS and permanent histological
diagnosis. The cases were classified into three diagnostic compatibilities (i) Perfect fit; the diagnosis of IOFS was identical to the permanent
diagnosis, (ii) Partial compatibility; IOFS diagnosis was not incorrect but was too broad to be considered full compatibility, (iii) Conflict; IOFS
diagnosis is completely different from the permanent diagnosis. The permanent diagnosis was used as a primary criterion and was compared to
IOFS diagnosis and recurrence rate using different statistical methods.
Results: 84% of the patients underwent craniotomy and tumor resection, while 15% only underwent tumor biopsy. Approximately, 53.8 %
of the cases revealed perfect matching in the diagnosis between IOFSs and permanent sections, while 16.2% of the cases revealed complete
mismatching in the diagnosis between the sections. The remaining 30% of the cases showed partial compatibility in the diagnosis between the
two diagnostic methods. There was no significant difference in recurrence rate among all cases of different diagnostic compatibility (p=0.54).
Conclusion: There is a diagnostic discrepancy between IOFSs and permanent sections. However, cases that revealed no consensus in the
diagnoses showed no negative effect on the patient outcome. Further studies should be conducted to explore the reasons of this conflict in the
two diagnostic methods.
Brain tumors, known as intracranial tumors, are abnormal
masses of tissue with cells that continuously grow and
multiply. More than 150 types of brain tumors have been
documented by the World Health Organization (WHO) (1).
They can be categorized as primary and metastatic tumors.
Primary tumors arise from brain tissue or surrounding
structures, which include neuroglial cells, meninges, or
the ependymal layer. They can be benign (low-grade) or
malignant (high-grade). Secondary metastatic brain tumors
include any organ cancer that hematogenously spreads to
the brain. To distinguish primary from secondary brain
tumors, a detailed clinical history and body imaging are important to identify the origin of the tumor but not the
exact histological subtype. Furthermore, intraoperative
examination of tumor tissue is the gold diagnostic tool to
differentiate the two types and to determine the surgical
Intraoperative frozen section (IOFS) diagnosis of brain
tumors plays an important role in assessing the adequacy
of the specimen, determining the surgical treatment
plan, improving surgical procedures, and facilitating
postoperative follow-up. In certain cases, when unexpected
lesions cannot be identified by radiological imaging, the
surgeon can determine the best procedure and endpoint
of the operation (2,3). This can reduce the incidence of surgical complications and avoid unnecessary second
surgical procedures. The key criteria and indications for
requesting an intraoperative diagnosis by the surgeon are as
follows: (a) intraoperative surgery would be affected by the
diagnosis, (b) an unexpected lesion appears during surgery
that is different from what was clinically suspected, (c) the
primary goal is to obtain a biopsy diagnosis, and (d) the
necessity to assess the margins if a total resection is planned
(4-6). The distinction between primary tumor, lymphoma,
metastatic tumor, or unusual lesions are considered the
main reasons for requesting intraoperative diagnosis of
brain tumors. Sometimes, the tumor is not accessible
by surgery, and thus a stereotactic biopsy with IOFS is
recommended. The assessment of brain tumors through
IOFS is commonly used in clinical practice to verify the
origin and type of tumor; however, the final diagnosis
should be reported later after the permanent section (4,6).
Several studies have discussed the diagnostic accuracy
of IOFS in assessing brain tumor type and grading, and
inconsistencies were found between IOFS diagnosis and
permanent diagnosis. Nevertheless, permanent paraffinembedded
examination remains the gold standard in
diagnosing brain tumors. In Saudi Arabia, no publications
have discussed the diagnostic accuracy between IOFS and
permanent tissue diagnosis of brain tumors. In this study,
we aimed to assess the compatibility between the results
of frozen sections and permanent sections in patients
diagnosed with brain tumors. We also discussed the reasons
attributed to the lack of diagnostic accuracy between the
two diagnostic methods.
In this retrospective study, we reviewed the histopathological
reports of 383 primary and secondary brain tumors
between 2013 and 2019 from two medical institutions in
Saudi Arabia. The study was ethically approved by the National
Biomedical Ethics Committee at King Abdulaziz
University (HA-02-J-008) under general ethical approval.
Patient age, gender, intraoperative and permanent histological
diagnosis and grading, and recurrence rate were
used as statistical factors. The permanent section result was
used as a primary criterion, and the frozen section diagnosis
was compared with the final diagnosis.
The histopathological report of IOFS and permanent
paraffin-embedded section of each patient with a brain
tumor was examined. The diagnostic compatibility between the two diagnostic methods was determined on the basis
of tumor type and grading. The cases were classified into
three degrees of diagnostic compatibility as follows: 1)
the diagnosis of IOFS was identical to the final diagnosis
(perfect fit); 2) the diagnosis of IOFS was not incorrect but
was too broad to be considered fully compatible (partial
compatibility); and 3) the diagnosis of IOFS were incorrect
and differs from the final diagnosis (conflict).
Statistical analysis was performed using SPSS software
(version 20). To describe the data, we used means,
frequencies, and percentages. To assess the diagnostic
compatibility of different methods, we used the linear
model, ANOVA and people’s Chi-square test. The number
and types of discrepancies were identified.
The mean age of the 383 patients was 37.6 + 23.1 years
(females: 212 (55.4%); males: 171 (44.6%)). 84.86% of the
patients underwent craniotomy and tumor resection, while
15.14% only underwent tumor biopsy (open or stereotactic
biopsy). Most of the tumors were grade IV (n=177, 46.2%),
followed by grade II (n=105, 27.4%) (Table I
locations were summarized in (Figure 1
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|Figure 1: Tumor locations of all cases enrolled in this study. There
is 0.25% of cases did not have specific location or the location was
not mentioned in the report.
Diagnostic Compatibility Between IOFS and Permanent
The diagnostic compatibility between IOFS and permanent
section showed comprehensive variability, as 53.8%
(n=206) of the cases showed perfect match between IOFS
and permanent section diagnosis, while 16.2% (n=62)
of the cases showed complete mismatch. Furthermore,
30% (n=115) of the cases showed partial compatibility
between the two diagnostic methods (Table I; Figure 2).
For example, the cases diagnosed as glioblastoma with
IOFS were also diagnosed as glioblastoma with permanent
section; however, these cases represented 13% perfect
compatibility among all investigated brain tumors (Table
II). In a few cases, glioblastomas were misdiagnosed with
IOFS as low-grade gliomas, necrotic cells, or glioneuronal
tumors (Table III).
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|Table II: Diagnostic compatibilities of the probabilities of all frozen sections compared with permanent final diagnosis in brain lesions.
This table compares the diagnostic compatibility of each tumor through the total number of all cases.
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|Figure 2: Diagnostic compatibility between intraoperative frozen
sections and permanent paraffin-embedded sections in all brain
tumors enrolled in this study.
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|Table III: List of brain tumors with their misdiagnosis with
intraoperative frozen sections (IOFS).
Diagnostic Compatibility of Low-Grade and High-
Approximately 9% of the cases diagnosed as low-grade
gliomas with IOFS were diagnosed as high-grade gliomas
with permanent sections, and one case was found to be
a meningioma (Table II). Conversely, 17% of the cases
diagnosed as high-grade gliomas with IOFS were diagnosed
on permanent sections as either low-grade gliomas or a different histological subtype such as medulloblastoma or
metastasis. Furthermore, 19% of the cases diagnosed with
infiltrating glioma with IOFS showed partial compatibility
on permanent sections. The final diagnosis was grade II,
such as cases of oligodendrogliomas (Table II).
Diagnostic Compatibility Between Atypical, Reactive,
and Necrotic Cells
From the 22 cases diagnosed as atypical glial cells with
IOFS, two of them were permanently diagnosed as mature
teratoma and hemangioblastoma. The remaining 20
cases of atypical glial cells were compatible with the same
glioma histogenesis, regardless of the grading. These cases
were considered partially compatible. The cases that were
showing reactive cells in IOFS (n=6, 9.6%) were diagnosed
differently from permanent sections (Table II). These
cases included teratoma, hemangioblastoma, germinoma,
ganglioglioma, pilocytic astrocytoma, and pituitary
adenoma. Cases for which IOFS revealed necrotic cells
were diagnostically deferred at the time of surgery. Their
permanent sections revealed malignant tumors except one
case (pilocytic astrocytoma in the brainstem), which was
rediagnosed as diffuse midline glioma.
Relationship Between Recurrence Status and Diagnostic
There was no statistically significant relationship between
the recurrence rates and the diagnostic compatibilities
of different brain tumors (p=0.54) (Table IV). Cases that
showed conflicts in diagnostic compatibility showed no
significant differences in recurrence rates compared to
cases with perfect diagnosis matches. This clarifies that
conflict in the diagnostic compatibility between IOFS,
and permanent histological sections may not affect tumor
Click Here to Zoom
|Table IV: Relationship between recurrence rate and diagnostic compatibilities of intraoperative frozen sections and permanent sections.
Various types of brain tumors have been documented by
the 2016 WHO-Central Nervous System 1
. They are
categorized as primary and metastatic tumors. Primary
tumors arise from brain tissue or surrounding structures
and are benign (low-grade) or malignant (high-grade).
Secondary metastatic brain tumors arise from any systemic
organ cancer. To distinguish primary from secondary brain
tumors, body imaging and intraoperative examination of
tumor tissue are considered the best diagnostic methods,
which can also determine the surgical treatment plan. Our
current study included 369 primary brain tumors and 14
metastatic tumors to the brain.
The IOFS analysis was first introduced in 1891 by a
pathologist at Johns Hopkins Hospital, and is currently
used worldwide. The application of this method became
much easier through improvements in cryostat devices 7.
IOFS is mainly useful for solid and stretchy tumors such as
meningiomas, schwannoma, and most metastases in which
cell smears are difficult to prepare 8,9. It also provides good architectural detail of the lesion, and better reveals
histological patterns and cell morphology 10,11. IOFS
is commonly used to verify the competence, and origin of
brain tumors 4,6.
There are two methods to assess the diagnostic compatibility
between IOFS and permanent sections. The first method
is to determine whether the IOFS diagnosis matches the
permanent diagnosis, e.g., glioblastoma diagnosed with
IOFS is also diagnosed as glioblastoma with permanent
section. The second method is to determine whether the
permanent diagnosis is histologically close to the IOFS
diagnosis, e.g., glioblastoma diagnosed on permanent
section is observed as atypical glial cells in frozen sections.
In our current study, both methods were used; however,
we focused more on the first method as it represents the
foundation of the general diagnostic accuracy of brain
The compatibility between IOFS and permanent section
in clinical practice always shows diagnostic diversity. In
our study, 53% of the lesions diagnosed on permanent
histological sections matched the IOFS diagnosis, while
16% showed complete mismatching (Figure 2). This
variation is considered clinically significant as it reveals
that IOFS itself should not be solely used as a definitive
diagnostic method. Most of the discordances between IOFS
and permanent histological sections were observed in highgrade
gliomas. This might be attributed to the difficulty in
the microscopic interpretation, and the lack of experience.
It is sometimes quite hard to identify the cytoplasmic
processes in the frozen section, which makes it difficult to
differentiate glial background from other types of tumors,
particularly metastasis. For example, glioblastomas may
be misdiagnosed as low-grade gliomas during the IOFS.
This is because the peripheral edges of glioblastoma may
contain reactive or atypical glial cells without necrosis or
endothelial proliferation. Furthermore, the distinction
between high-grade gliomas and metastasis is also difficult
unless the malignant glial cells with gliotic background
are clearly seen. In diffusely astrocytic cases, missing IOFS
diagnosis of astrocytomas could be due to the thickness of the sections and technical problems with staining,
which disrupts the cellular morphology. The difficulties
in diagnosing hemangioblastoma with IOFS were because
most hemangioblastomas are bloody and vascular, which
may mask the cellular features of the tumors. Cases that
showed reactive or necrotic cells with IOFS revealed
different diagnostic results on permanent sections. For
example, most of the cases diagnosed as necrotic cells with
IOFS had a permanent section diagnosis of glioblastoma,
while IOFS diagnosis of reactive cells had a permanent
section diagnosis of teratoma, germinoma, ganglioglioma,
pilocytic astrocytoma, or pituitary adenoma. These findings
depend on the biopsy location, and the size of the necrotic
component in the tumor.
The diagnostic accuracy in our study was 53%. In other
studies, the diagnostic accuracy was 92.4% in Talan-
Hranilović et al. 12, and 95% in Roessler et al. 13
with 89% complete concordance among 4,172 patients.
The most accurate IOFS diagnoses in Roessler’s study
were made in cases of meningioma (97.9%), metastasis
(96.3%), and glioblastoma (95.7%) 13. Although the
high-grade gliomas showed high discordance between
IOFS and permanent histological section, the diagnostic
compatibility was still acceptable. Plesec et al., had almost
3% discordancy among 2,156 cases. Approximately 80%
of these cases were spindle cell lesions, astrocytoma versus
oligodendroglioma, lymphoma, reactive versus neoplastic
process, and tumor overgrading 14. We also have found
that 97% of meningioma cases showed perfect matching
between the IOFS and permanent section diagnoses. One
case turned out to be a schwannoma.
Several reasons might be attributed to this mismatching.
Theoretically, the reasons can either be related to the
quality of surgical procedure or the quality beyond the
laboratory diagnostic techniques. If the neurosurgeon takes
the biopsy from the necrotic part of the tumor or from the
surrounding reactive area, the tissue may be fragmented,
nonviable, or nondiagnostic. An experienced neurosurgeon
should navigate the tumor using a brain imaging navigator
before taking the biopsy. However, multiple punch biopsies are recommended in cases where the necrotic parts are
deeply seated in the tumour center. Freezing processes
may also mask the tissue diagnosis. Calcification, autolysis,
improper hematoxylin and eosin staining, or inappropriate
usage of hemostatic agents all can contribute to incorrect
As we mentioned before, one of the common reasons for
diagnostic disagreements between IOFS, and permanent
paraffin-embedded section is the microscopic interpretation.
Most pathologists who see the brain tumors during
IOFS are non-neuropathologists with limited experience
in the brain. Pathologists, who see brain tumors during
IOFS, must have enough knowledge to correlate between
brain imaging and histology. This would help pathologists
minimize the differential diagnoses, and approximate the
diagnostic probabilities with neurosurgeons. This problem
is more common in developing countries where health care
systems have shortage of neuropathologists. A fully certified
neuropathologist with a minimum two-year training
in neuropathology will have better diagnostic outcome
than a non-neuropathologist.
The role of frozen sections during intraoperative
consultation is important. Our results showed some
diagnostic discrepancies between the intraoperative
diagnosis of brain tumors, and permanent final diagnosis.
Appropriate knowledge of pathologists regarding
radiological findings and microscopic interpretation with
proper communication with neurosurgeons are required
to minimize IOFS misdiagnosis. Further studies should be
conducted to determine the reasons for this discrepancy
and to solve the problems related to this incompatibility.
CONFLICT of INTEREST
The authors declare no conflicts of interest.
Concept: MK, Design: MK, Data collection or processing:
YM, AB, RS, AL, TS, AS, Analysis or Interpretation: MK,
SB, SH, Literature search: MK, SB, RS, Writing: MK, SB,
YM, RS, AS, Approval: MK,SB, AL.
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