Necrosis is a common feature of human cancer and is often related to a poor prognosis, especially in glioblastomas.1,2,3 Though the importance of necrosis in gliomas has already been addressed, necrosis was first incorporated into the determinant of the diagnosis for glioma grade in the fifth edition of the 2021 WHO classification of Tumors of the central nervous system (CNS), which highlighted and underlined the significant value of necrosis in the diagnosis and prognosis of adult diffuse gliomas.4 According to the latest classification, once histological necrosis is identified, a diagnosis of WHO grade 4 astrocytoma or glioblastoma is suggested. However, there is a diagnostic dilemma in grading gliomas by identifying necrosis.
Presently, necrosis is primarily determined by pathological examination, in which partial tumor specimens from specific sites of tumors obtained by surgery or biopsy at a single point in time are generally inspected.5 However, due to tumor heterogeneity and incompleteness of the pathological sample, some pathological necrosis is likely to be missed, which may result in an underestimation of tumor grades, especially when the molecular analysis is not available. As tumor grades influence therapeutic decisions and prognosis, it is imperative to make up for the problem of a missed diagnosis of necrosis on pathological evaluation.
Magnetic resonance imaging (MRI) is utilized for routine, noninvasive, preoperative examination in diagnosing gliomas. Pathological necrosis usually has corresponding imaging features.6,7 Imaging necrosis has been defined as a region within the tumor that does not enhance or shows markedly diminished enhancement, high signal intensity on T2WI, low signal intensity on T1WI, and an irregular border.6 Hence necrosis in gliomas, when substantially present, can be detected by conventional MRI and plays a vital role in diagnosing gliomas and predicting prognosis.6,8,9,10,11,12,13 Moreover, conventional and advanced MRI can acquire comprehensive morphological and pathophysiological images of entire tumors, which is impossible with pathological examinations.
Taking all of this into account, we speculated whether necrosis diagnosed by MRI (hereafter termed “imaging necrosis”, abbreviated as Imnecrosis) could be used as a correction or a supplement to necrosis diagnosed by pathological evaluation (hereafter termed “pathological necrosis”, abbreviated as Panecrosis), especially when there is no evidence of Panecrosis owing to limited sampling sites and sampling amounts. Consequently, herein, we retrospectively reviewed MRI findings of adult diffuse gliomas that were diagnosed based on the 2021 WHO CNS classification and assessed the role of Imnecrosis in grading, predicting the genotype and prognosis of gliomas. We also attempted to analyse tumor necrosis by dynamic contrastenhanced MR perfusion imaging (DCE-MRI) to validate quantitative imaging markers for probing tumor necrosis.
Patients with a primary diagnosis of glioma (June 2013–May 2021) were retrospectively included. Inclusion and exclusion criteria are presented in Supplementary Figure 1. Clinical information of patients was retrieved from the electronic medical records, and follow-up information was obtained through clinical interviews. Follow-up survival data were available until May 31, 2021. Overall survival (OS) was calculated from the initial surgery date to the date of death, or the date of the last follow-up visit if the patient was alive or lost to follow-up.
This retrospective analysis was in accordance with the ethical standards of the institutional and national research committee and was approved by the ethics committee of our institution ([2021]209). The requirement for written informed consent was waived due to the retrospective nature of this study.
Participants underwent conventional (T1/T2-weighted images [T1WI/T2WI], T2-weighted fluidattenuated inversion recovery [T2WI-FLAIR] and sagittal view of contrast-enhanced three-dimensional T1 MPRAGE images) and DCE-MRI imaging using a 3.0T MR system (Magnetom Verio, Siemens Medical Solutions, Erlangen, Germany) with a 64-channel head-neck coil. The parameter details of the conventional MRI and the DCE-MRI were elaborated in Supplementary Appendix 1.
All DCE-MRI data were transferred to the post-processing workstation (detailed in Supplementary Appendix 2). Pharmacokinetic parameters, including the transfer constant (
As mentioned in the introduction, examples of imaging necrosis, defined as a region within the tumor that does not enhance or shows markedly diminished enhancement, high signal intensity on T2WI, low signal intensity on T1WI, and an irregular border, are shown in Figure 2 and Supplementary Figure 2. Two experienced radiologists reviewed all conventional MRIs. Then they determined whether there was Imnecrosis by consensus. One of these two experienced radiologists and a third radiologist repeatedly assessed 68 cases after the initial assessment to assess the inter-observer agreement. The assessed images were randomized within each type of pathology, and the observers were blinded to the clinical and pathological information and thoroughly acquainted with the criteria.
Panecrosis was defined according to pathological reports provided by the Pathology department of our hospital, if available. The status of
Statistical Analysis Data were analyzed using IBM SPSS Statistics 26 software, the SPSSAU data scientific analysis platform (
We initially identified 150 eligible patients (median age = 46 years, range 21–79 years), and 104 (69.33%) were male (Table 1). All the diagnoses assigned to the patients according to the latest integrated histomolecular classification criterion were presented in Supplementary Figure 3 and Supplementary Table 1. Panecrosis was identified in 70/76 of highgrade gliomas (HGGs, CNS WHO grade 4) and 3/43 of low-grade gliomas (LGGs, CNS WHO grade 2 and 3) which were oligodendrogliomas, IDHmutant and 1p/19q-deleted, while Imnecrosis was identified in 70/76 of HGGs and 12/43 of LGGs.
Participant demographic findings
Age (n = 150) | - | 40.54±11.08 (n = 54) | 50.39±12.47 (n = 96) | - | −4.829& | p < 0.001 |
Sex (n = 150) | male | 36(66.67) | 68(70.83) | 104 | 0.282 | 0.595 |
female | 18(33.33) | 28(29.17) | 46 | |||
wildtype | 17(32.08) | 69(75.82) | 86 | 26.649 | p < 0.001 | |
mutant | 36(67.92) | 22(24.18) | 58 | |||
non-codeletion | 23(51.11) | 55(85.94) | 78 | 15.746 | p < 0.001 | |
codeletion | 22(48.89) | 9(14.06) | 31 | |||
non-deletion | 38(100.00) | 20(80.00) | 58 | 5.745b | 0.017* | |
deletion | 0(0.00) | 5(20.00) | 5 | |||
non-amplification | 8(66.67) | 45(65.22) | 53 | 0.054a | 0.817 | |
amplification | 4(33.33) | 24(34.78) | 28 | |||
chr7 gain/10 loss (n = 26) | negative | 10(83.33) | 13(92.86) | 23 | 0.552b | 0.457 |
positive | 2(16.67) | 1(7.14) | 3 | |||
Grade (n = 119) | high-grade | 6(16.22) | 70(85.37) | 76 | 52.828 | p < 0.001 |
low-grade | 31(83.78) | 12(14.63) | 43 | |||
WHO grade (n = 119) | WHO grade 2 | 26(70.27) | 4(4.88) | 30 | 62.664a | p < 0.001 |
WHO grade 3 | 5(13.51) | 8(9.76) | 13 | |||
WHO grade 4 | 6(16.22) | 70(85.37) | 76 | |||
Integrated histo-molecular diagnoses (n = 116) | Oligodendroglioma, IDH-mutant and 1p/19q-deleted | 17(45.95) | 7(8.86) | 24 | 41.238 | p < 0.001 |
Astrocytoma, IDH-mutant | 15(40.54) | 12(15.19) | 27 | |||
Glioblastoma, IDH-wildtype | 5(13.51) | 60(75.95) | 65 |
& = Student's t statistic in this cell, and other cells in the same column represent Chi-square values. a and b = chi-square tests with continuity correction and Fisher's exact tests, respectively;
= p < 0.05
There was 1/77 HGG without enhancement but with positive status of
In this study, the following four groups were determined: Im+Panecrosis group (representing patients with both Imnecrosis and Panecrosis, n = 74), nonecrosis group (representing patients without Imnecrosis nor Panecrosis, n = 28),
Detailed clinical, imaging and pathological information of Only Imnecrosis group and Only Panecrosis group
WHO CNS grade 4 | female | 63 | 2.5 | 1 | 0 | 0 | NA | NA | Astrocytoma, IDH-mutant | |
CNS WHO grade 4 | female | 55 | 20 | 0 | 0 | NA | 0 | NA | Glioblastoma, IDH-wildtype | |
CNS WHO grade 2 | female | 36 | NA | 1 | 1 | 0 | NA | NA | Oligodendroglioma, IDH-mutant and 1p/19q-deleted | |
NA | female | 34 | NA | 1 | NA | NA | NA | NA | IDH-mutation, NOS | |
CNS WHO grade 4 | male | 64 | 5 | 0 | 0 | NA | 1 | NA | Glioblastoma, IDH-wildtype | |
CNS WHO grade 2 | male | 40 | 25 | 1 | 0 | 0 | NA | NA | Astrocytoma, IDH-mutant | |
CNS WHO grade 3 | female | 55 | 60.06 | 1 | 1 | 0 | NA | NA | Oligodendroglioma, IDH-mutant and 1p/19q-deleted | |
CNS WHO grade 2 | male | 26 | 5.39 | 1 | 0 | 0 | 0 | 0 | Astrocytoma, IDH-mutant | |
NQ | male | 40 | 7.19 | 0 | 0 | NA | 0 | NA | IDH-wildtype, NOS | |
NA | male | 28 | 19.68 | 0 | 0 | NA | 0 | 0 | IDH-wildtype, NOS | |
CNS WHO grade 3 | male | 26 | 34.42 | 1 | 0 | 0 | NA | NA | Astrocytoma, IDH-mutant |
Besides, there was strong inter-observer agreement in identifying imaging necrosis (Kappa = 0.668, p < 0.001, 95%CI: 0.489–0.846). And the spotlike, dotted, long-strip, long tubular, and fissural enhancements (Figure 3) which were easily misdiagnosed as imaging necrosis should be avoided.
Most HGGs (85.37%) were found to have Imnecrosis, while most LGGs (83.78%) were without Imnecrosis. There were 4/30 WHO grade 2 patients with Imnecrosis. Of those, two were diagnosed as oligodendrogliomas, IDH-mutant and 1p/19q-deleted, and two as astrocytomas, IDH-mutant.
Significant differences in the presence of Imnecrosis with a large effect size were found between HGGs and LGGs and among different grades of gliomas (Table 1,
There were significant correlations between the expression of other molecular markers such as
One-hundred and thirty patients were included in the final survival analysis. Compared with gliomas with Imnecrosis, patients without Imnecrosis had a significantly longer survival time (
The differences among the OS of Im+Panecrosis, nonecrosis,
Further, when added significant variables such as age,
Since pathology is the golden standard for necrosis diagnosis, we analyzed the associations with Panecrosis and DCE-MRI metrics. Most DCE-MRI metrics demonstrated a significant difference in identifying gliomas with Panecrosis with a very large effect size (Table 3).
Representative results of non-parametric tests and ROC analyses between DCE-related data for gliomas with or without pathological necrosis/imaging necrosis
Panecrosis | |||||
Tumor- |
< 0.001 | 0.824 (0.711 ~0.936) | 0.94 | 0.625 | 0.07 |
Edema- |
0.031* | 0.655 (0.527 ~ 0.783) | 0.833 | 0.46 | 0.03 |
Tumor- |
< 0.001 | 0.891 (0.788 ~ 0.995) | 0.96 | 0.833 | 0.17 |
Edema- |
0.002** | 0.728 (0.613 ~ 0.842) | 0.34 | 1 | 0.16 |
Tumor- |
< 0.001 | 0.872 (0.761 ~ 0.983) | 0.833 | 0.86 | 2.48 |
Tumor- |
< 0.001 | 0.899 (0.803 ~ 0.996) | 1 | 0.75 | 0.07 |
Imnecrosis | |||||
Tumor- |
< 0.001 | 0.856 (0.772 ~ 0.939) | 0.877 | 0.757 | 0.08 |
Tumor- |
< 0.001 | 0.929 (0.872 ~ 0.986) | 0.892 | 0.919 | 0.17 |
Edema- |
0.005** | 0.667 (0.558 ~ 0.776) | 0.708 | 0.595 | 0.06 |
Tumor- |
< 0.001 | 0.914 (0.857 ~ 0.971) | 0.946 | 0.831 | 2.74 |
Tumor- |
< 0.001 | 0.909 (0.844 ~ 0.974) | 0.8 | 0.946 | 0.13 |
= p < 0.05;
= p < 0.01
Similarly, we performed the analysis regarding Imnecrosis (Table 3), and the Tumor-
In this study, we investigated the clinical implication of imaging necrosis in the preoperative evaluation of glioma. We found strong agreement between Imnecrosis and Panecrosis. Moreover, Imnecrosis was found to be significantly related to gliomarelated key gene mutations, such as
Our study indicated strong agreement between the inter-observer agreement of Imnecrosis and Panecrosis. And during the analysis, we found that the regions with an absence or marked decrease of enhancement inside the intensified areas were easily mistaken as Imnecrosis. While considering pathological samples were partial, imaging observation can capture full tumors. There was a pathologically proven astrocytoma, IDH-mutant, CNS WHO grade 2, with a very short OS (5 months). We reviewed the raw data and identified that this patient had a small extent of Imnecrosis, indicating high grade gliomas. The situation mentioned above can be avoided if a judgement of Imnecrosis is made, which is one unique advantage of radiographic examination. Besides, we identified seven patients with Imnecrosis who were diagnosed as oligodendrogliomas, IDH-mutant and 1p/19q-deleted, CNS WHO grade 2 or 3, indicating that necrosis plays a limited predictive value in oligodendrogliomas. Hence, if there is evidence of oligodendrogliomas, such as calcification and filiform or localized internal homogeneous enhancement, Imnecrosis does not indicate a high-grade tumor. Besides, Waqar
Previous studies have highlighted that Imnecrosis is an independent unfavorable prognosis factor. 5,6,10,18,19,20 Our results were in accordance with their findings. Besides, the latest WHO CNS classification emphasizes the role of molecular markers, such as
In this study, we also sought quantitative metrics for indicating tumor necrosis. Our results revealed that, compared with tumor without Imnecrosis/Panecrosis, DCE-derived metrics in tumor parenchyma, except
The current study has some limitations. First, since evidence of pathological necrosis was obtained from pathology reports of the same hospital, there may be an observation bias. However, this study, based on clinical real-world evidence, can exactly address the current clinical deficits. Second, this is a single-center study; subgroups analysis had a small sample, which might result in insufficient power to reach definite conclusions. Further multicenter studies with large sample sizes will help improve the efficacy of Imnecrosis in predicting the expression of molecular markers and prognosis.
Based on the latest WHO CNS guidelines, the present study depicted the importance of imaging necrosis in diagnosing gliomas. Detection of imaging necrosis in gliomas probably suggests an HGG unless there is imaging evidence for oligodendrogliomas, IDH-mutant and 1p/19q-deleted. Imaging necrosis was significantly associated with glioma-related key gene mutations, such as