Frequent Diagnostic Under-Grading in Isocitrate Dehydrogenase Wild-Type Gliomas due to Small Pathological Tissue Samples

Abstract

BACKGROUND In contrast to isocitrate dehydrogenase (IDH) mutation analysis, which is homogenous within a given tumor, diagnostic errors in histological analysis following the 2016 World Health Organization (WHO) classification could be due to small samples because of histological heterogeneity. OBJECTIVE To assess whether the sample size sent to histopathology influences the tumor grading in IDH wild-type gliomas. METHODS Histologically diagnosed WHO grade, sample volume, and preoperative tumor volume data of 111 patients aged who received resection of IDHwt gliomas between January 2007 and December 2015 at our hospital were evaluated. The differences between absolute and relative pathological sample sizes stratified by WHO grade were conducted using One-Way-Permutation-Test. RESULTS With a mean sample size of 10.9 cc, 83.8% of patients were histologically diagnosed as WHO grade IV, while 16.2% of patients with a mean sample size of 2.62 cc were diagnosed as WHO grade II/III. One-Way-Permutation-Test showed a significant difference between absolute tissue samples stratified by WHO grade (P = .0374). The distribution of preoperative tumor volumes with WHO grade IV vs WHO grade II/III showed no significant difference (P = .8587). Of all tumors with a sample size >10 cc 100% were pathologically diagnosed as WHO grade IV and those with sample size >5 cc 93.5% were diagnosed as WHO grade IV. CONCLUSION Small sample sizes are associated with a higher risk of under-estimating malignancy in histological grading in IDHwt gliomas. This study suggests a standard minimum sample size (>5cc) in every resection. Modalities of adjuvant treatment for IDHwt, WHO grade II/III gliomas need to reflect a prognosis that is only marginally better than of a glioblastoma.

The histological representativeness of glioblastoma tissue samples

“…Previous studies have demonstrated the risk of histological undergrading of GBMs on small tissue samples [ 4 , 8 , 11 , 12 , 16 , 19 , 25 , 26 , 29 , 36 , 45 ]. In contrast to our study, these studies were focused on grading, whereas our study assessed the representativeness of individual histological features.…”

“…In contrast to our study, these studies were focused on grading, whereas our study assessed the representativeness of individual histological features. These previous studies also only focused on biopsied cases [ 4 , 8 , 11 , 16 , 25 , 26 , 29 , 36 , 45 ] or on the volume of the pathological specimen sent for analysis [ 12 , 19 ]. Hence, the role of sampling errors in resected tumors is less studied.…”

“…Sections from previously frozen FFPE tissue generally had quite small areas of viable tumor that contributed to a minor degree to the total amount. We also estimated the tissue volume (cm 3 ) in each case from the diameter of the tissue samples sent for neuropathology, using the formula of an ellipsoid volume described by Gutt-Will et al [ 12 ].

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“…Previous studies have found a correlation between a smaller volume of the pathological specimens and a lower rate of GBM diagnosis [ 12 , 19 ]. However, to our knowledge, no previous studies have investigated relationships between the amount of viable tissue on hematoxylin-eosin (HE) slides and the presence of individual histological features in GBMs.…”

Perfusion MR prior to radiotherapy is a strong predictor of survival in high-grade gliomas after proton and carbon ion radiotherapy

“…Numerous demographic and tumor-related factors, particularly molecular characteristics including IDH gene, MGMT and TERT promoter status ( 1 , 6 ), have been identified as strong survival predictors in HGG. However, the nature of high heterogeneity within glioma tissue can induce significant sampling error of accurate pathologic and molecular assessment for the whole tumor area ( 7 ). Besides, intra-tumor cell populations with distinct molecular markers can react diverse treatment response ( 8 , 9 ).…”