- Medical Faculty, Norwegian University of Science and Techology, Trondheim, Norway
- Department of Laboratory Medicine, Childeren's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway
- Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway
- National Centre for Ultrasound and Image Guided Therapy, St. Olavs University Hospital, Trondheim, Norway
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway
National Centre for Ultrasound and Image Guided Therapy, St. Olavs University Hospital, Trondheim, Norway
DOI:10.4103/2152-7806.146153Copyright: © 2014 Tofte K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Tofte K, Berger C, Torp SH, Solheim O. The diagnostic properties of frozen sections in suspected intracranial tumors: A study of 578 consecutive cases. Surg Neurol Int 03-Dec-2014;5:170
How to cite this URL: Tofte K, Berger C, Torp SH, Solheim O. The diagnostic properties of frozen sections in suspected intracranial tumors: A study of 578 consecutive cases. Surg Neurol Int 03-Dec-2014;5:170. Available from: http://sni.wpengine.com/surgicalint_articles/the-diagnostic-properties-of-frozen-sections-in-suspected-intracranial-tumors-a-study-of-578-consecutive-cases/
Background:Intraoperative frozen section (FS) diagnostics is an important diagnostic tool in neurosurgery, but agreement with final histopathology diagnoses may vary. In the present study we assess the diagnostic properties of intraoperative FSs in suspected intracranial tumors.
Methods:Retrospective single-center review of consecutive patients with suspected intracranial brain tumors from January 2008 to December 2012. We included all cases were both an intraoperative FS and a formalin-fixed paraffin-embedded (FFPE) section had been acquired. Agreement with final diagnosis, sensitivity, specificity, and predictive values were explored. Time between date of surgery and first final diagnosis based on FFPE section, whether the patients had undergone previous brain surgery and/or prior cerebral radiotherapy were also registered.
Results:Agreement between FS diagnoses and final FFPE section diagnoses was seen in 504/558 (90.3%), while there was lack of agreement in 54/558 (9.7%). In 20 cases, agreement was not classifiable. Agreement was lower in low-grade gliomas (82.5%) than in high-grade gliomas (93.2%). Agreement between FS and FFPE was significantly higher in primary operations (92.1%) than in re-do operations (81.5%) (P = 0.001). Sensitivity of FS ranged from 30.8% in lymphomas to 94.6% in meningiomas.
Conclusions:Intraoperative FS diagnoses demonstrate high diagnostic accuracy. However, agreement varies among histopathological entities and is lower in low-grade tumors than in high-grade tumors. Sensitivity for diagnosing CNS lymphomas is low. A variable degree of reservation is always necessary when interpreting and communicating FS diagnoses.
Keywords: Brain tumor, frozen section, histology, sensitivity, specificity
Today's neurosurgeons usually have a good idea about the probable nature of the lesions they are to operate. Magnetic resonance imaging (MRI) may display anatomical involvement, speed and patterns of growth, effect on the blood–brain-barrier (i.e., contrast enhancement), edema, necrosis, and to some extent the density and vascularity of the lesions. Special image sequences such as diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) can also be helpful in the differential diagnostics.[
Patient selection, laboratory routines, and study variables
The patients were included from St. Olavs University Hospital, Trondheim, Norway. We retrospectively reviewed surgical records for consecutive patients operated (diagnostic biopsy or tumor resection) for suspected brain tumor in the period from January 2008 through December 2012. We included all operations were both an FS and a FFPE section had been acquired (n=578). We only assessed the FS diagnoses given intraoperatively; later reviews of FS samples were therefore ignored. For the final histopathological diagnosis, we identified the first final diagnosis. Later histopathological reviews as a part of other studies or quality control were overlooked since these did not form basis for clinical decision making at the time. For diagnostic biopsies navigated biopsy forceps provides were used to obtain tissue samples of approximately 1 mm in diameter. Typically 4–5 biopsies were sent for FFPE diagnostics and 1–2 samples were taken for FS. Larger forceps were used for tissue samples during open resections. Targeted image-guided bipopsies were guided only by conventional MRI sequences and three dimensional (3D) ultrasound, and metabolic hot spots were generally not assessed. All FFPE diagnoses and most FS diagnoses were made by an experienced neuropathologist (SHT), and in accordance to the current WHO classification system.[
Agreement between FS diagnoses and FFPE section diagnoses was classified into four categories, as presented in
The statistical analyses were made using the IBM SPSS statistics program version 20. Statistical significance was defined as P <0.05. The Pearson's Chi-square test was used for determination of statistical significance in contingency tables. All tests are two-sided. Central tendencies are presented as medians with range if skewed. Sensitivity, specificity, positive predictive values, and negative predictive values were calculated using 2×2 tables, as shown in
The study was approved by the medical faculty of the Norwegian University of Science and Technology as a student project. The regional ethics committee signed a waiver for formal ethical review. The Data Protection Official for Research at St. Olavs University Hospital approved the study.
Median age of included patients was 57 years (range 2 months to 91 years); 25 (4.3%) were children (<16 years) and 153 (26.4%) were elderly (>65years). A total of 478 (82.7%) of FSs were from primary operations. A total of 63 (10.9%) of FS were from patients who had undergone cerebral radiotherapy.
Median time between date of surgery and date of final diagnosis based on FFPE sections was 9 days (range 2–54 days).
As seen from
FS and final FFPE sections from the 54 cases with discrepant diagnoses are presented in
As seen in
Tissue samples were from diagnostic biopsies alone in 70/578 (12.1%). There was an overall agreement between FS results and the final histopathology reports in 448/501 (88.2%) of resection cases as compared with 53/70 (75.7%) in cases undergoing biopsies only, a significant difference (P =0.004). However, these two groups are not necessarily comparable since biopsy alone, for example, was an uncommon strategy in meningiomas and far more common in lymphomas. In glioma patients there was agreement between FSs and the final histopathology reports in 233/262 (89.3%) after surgical resections as compared with 29/32 (90.6%) in biopsy cases (P =0.814).
The experienced neuropathologist (SHT) read 280/578 (48%) of all FSs. Overall agreement was 83.6% when FS were read by the experienced neuropathologist, and 89.9% when FS were read by other pathologists. However, gliomas were less common in the samples read by the other pathologists (46%) as compared with the samples read by the experienced neuropathologist (63%). It is nevertheless likely that experience helps. For example, for low grade gliomas, complete agreement with FFPE was seen in 18 (29.5%) of 61 patients where the experienced neuropathologist read FS. For comparison, complete agreement with FFPE was seen in only 4 (14.8%) of 27 low-grade glioma patients where other pathologists read FS. However, since the neuropathologist is usually involved in the more difficult cases, such subgroup analyses are not necessary valid.
As seen in
When the intraoperative FS diagnosis was a high-grade glioma, this was later confirmed as the final diagnosis in 174/190 (91.6%). In 8/190 (4.2%) cases, the final diagnoses were downgraded from high- to low-grade gliomas. Sensitivity for detecting high-grade gliomas with FS was 79.1% while specificity was 95.5%. The positive predictive value was 91.6% while the negative predictive value was 88.1%.
No WHO grade was given of in 30 FS glioma diagnoses (i.e. unspecified glioma). In 13/30 (43.3%) of these, the final WHO grade was a low-grade glioma, and in 16/30 (53.3%) the final diagnosis was a high-grade glioma.
In 89 cases, the FS section diagnosis was meningioma. As may be summed from
In 72 operations, the FS diagnosis was metastasis. This was confirmed as the final diagnosis in 71(98.6%). As may be calculated from
In only four patients the FS diagnosis was lymphoma. As can be calculated from
Primary surgery or previous radiotherapy
Agreement between FS and FFPE was significantly higher in primary operations (92.2%) than in re-do operations (81.4%) (P =0.001). In 42/75 (56.0%) of reoperations the patients had previously undergone radiotherapy. There was a trend toward poorer agreement between FS and final histopathology if patients had undergone radiotherapy (83.6% vs. 91.1%), P =0.06. However, in multiple logistic regression analyses with prior surgery and prior radiotherapy as variables, only prior brain surgery (P =0.007) was significantly associated with poorer agreement between FS and final histopathology. For the 36 high- and low-grade gliomas that had previously undergone surgery and radiotherapy overall sensitivity of FS for was 75%.
In consecutive FS samples from suspected intracranial tumors we found 90.3% overall agreement with the final FFPE section diagnosis. Agreement varied between histopathological entities and was lower in low-grade tumors than in high-grade tumors. Agreement was significantly higher in primary operations than in re-do operations. Sensitivity and specificity varies among entities, but does not reach 100%, even for meningiomas. A variable degree of reservation is therefore always necessary when interpreting and communicating FS diagnoses.
The present study is the first study in this topic after the new WHO classification system from 2007. The newest version of the WHO classification includes several changes, including grading changes for anaplastic oligoastrocytoma, meningioma, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytoma. Results from our study are nevertheless much in line with previous reports. Plesec and Prayson included 2156 cases with a CNS tumor diagnosis and reported less than 3% discrepancy between FS diagnoses and final histopathology.[
Discrepancies between FS and FFPE diagnoses seldom have direct consequences for the treatment of the patient. However, there can be exceptions. Surgical strategies, that is, aggressiveness can be different depending on the type of lesion. For example, in meningiomas, aggressive removal of underlying bone and associated dura may perhaps be less important benign lesions,[
As seen, the positive predictive value of FS is high in high-grade gliomas (91.6%). FS is not optimal when there is much edema because of freezing artefacts. As a consequence of artefacts, FS do not always show the histological characteristic needed to sub-classify high-grade gliomas. It may, for example, be particularly difficult to distinguish between oligodendroglioma and astrocytoma from FS.[
FS is good for distinguishing meningioma from other entities. If we also consider the fact that meningiomas often are diagnosed with quite good trustworthiness from neuroimaging,[
In metastases the positive predictive value of FS is high and neurosurgeons can be quite sure that the final diagnosis will agree with the intraoperative diagnosis. In later confirmed metastases that were not diagnosed with FS, about 80% was classified as “unspecified malignant tumor” on FS. In many cases, a primary tumor outside the CNS is known and neuroimaging characteristics can also indicate metastases. Thus, “unspecific malignant tumor” as the FS diagnosis presumably seldom causes much confusion.
For CNS lymphomas, fast diagnostics is important as early chemotherapy is warranted and surgical resection will likely increase morbidity.[
We found lower diagnostic accuracy of FS if patients had undergone previous brain surgery. There are more diagnostic pitfalls for both radiologists and neuropathologists (pseudoprogression, radiation gliosis/necrosis, enhancement due to small peritumoral infarctions following first surgery or radiation, etc.) in reoperations. Also, re-do operations are common in cases with suspected malignant transformation. Such lesions may be particularly associated with sampling error as they contain both low- and high-grade tissue. Even if FS diagnoses may be less accurate in re-do operations, these patients already have a diagnosis from their last operation and a wrong FS diagnosis will perhaps usually not have clinical consequences for the treatment given. Still, for both patients and clinicians, it can be important to know if the new lesion is just radiation gliosis or pseudo-progression, and not a tumor relapse.
In general, intraoperative FS diagnoses demonstrate high diagnostic accuracy. However, the agreement varies among histopathological entities and is lower in WHO low-grade tumors than in high-grade tumors. Sensitivity for diagnosing CNS lymphomas is low. A variable degree of reservation is always necessary when interpreting and communicating FS diagnoses.
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