Early-Stage Glioblastomas: MR Imaging–Based Classification and Imaging Evidence of Progressive Growth

Discussion

In this study, we propose an MR imaging–based classification for early-stage GBs. Lesions were classified into 3 types on the basis of the involvement of GM and/or WM and their patterns of contrast enhancement. The 3 types of MR imaging lesions may represent sequential stages of human GB growth. To the best of our knowledge, an MR imaging–based classification for early-stage GBs does not exist.

Among the 3 types of lesions, type I was the earliest, followed by type II, and then type III, according to the morphologic changes observed on follow-up MR imaging studies. The order of appearance suggests that some GBs start as T2-weighted or FLAIR hyperintense lesions in the GM (ie, cerebral cortex [type I]). Then, both the cortex and subcortical WM become involved (type II). Later, focal contrast enhancement develops at the GM-WM junction, within the area of T2-weighted or FLAIR hyperintensity (type III). Enlargement of the contrast-enhancing focus then evolves into the classic appearance of GB.

Our review of the literature shows that there were 19 cases of early-stage GBs with MR imaging studies included when they were published.^{1⇓⇓⇓⇓⇓⇓⇓⇓⇓–11} With our proposed classification, 2 of 19 lesions may be classified as type I^2,8; 12, as type II^{1⇓–3,8⇓⇓–11}; and 5, as type III.^4,6⇓–8 Oyama et al⁸ emphasized the role of DWI in early tumor detection when they reported a GB that first appeared as a type I lesion, then transformed to a type II lesion, and finally transformed to a classic GB before the operation. A type I lesion reported by Thaler et al² was described as a “right medial frontal nondiagnostic T2-weighted hyperintensity.”

It is difficult to study the cell of origin and growth of human GB because the tumors are typically large and in their late stage when diagnosed. Therefore, genetically engineered mouse models in which gliomas are induced by manipulation of the mouse genome at the molecular level are important tools for studying gliomagenesis.^13,14 Using mosaic analysis with a double marker genetic mouse model, Liu et al¹⁵ discovered that an oligodendrocyte precursor cell was the cell of origin of malignant gliomas and that the earliest neoplastic lesions were found in the GM. Furthermore, they observed tumor extension in subcortical regions along WM tracts.¹⁵ Another study also found that a glioblastoma could originate from cortical neurons.¹⁶ However, there is always concern about whether results from animal studies can be transferred to humans. It is not known whether gliomas growing in mice with genetic alterations and different microenvironments resemble spontaneous human GBs.

In our present study, we found that GM lesions were the earliest MR imaging–detectable abnormalities during human GB growth. We believe this finding may serve as indirect evidence, along with that found in the mouse glioma models,^15,16 to suggest that some GBs may originate from GM. Moreover, the WM FLAIR/T2-weighted hyperintensity of type II lesions may correspond to GB infiltration rather than just edema. GBs have also been reported to originate and recur in the subventricular zone, and it is possible that tumors arising in the cortex are due to secondary outward migration of abnormal brain tumor cells.^17,18 These issues are beyond the scope of this article, and we wish to only describe and emphasize a subset of GBs that originate in the cortex and are probably from a different cell origin than periventricular or deep WM GBs.

In the present study, the diagnosis of GB in 16 patients was confirmed after their MR imaging lesions progressed to classic ones. Thus, it is possible that those 16 patients initially had low-grade gliomas, which later transformed to secondary GBs. IDH1 mutation status has recently been considered a molecular marker of secondary GBs. The reported IDH1 mutation rates for clinically diagnosed primary and secondary GBs are about 4%–7% and 73%–88%, respectively.¹⁹ Among those 16 patients, IDH1 mutation status was available in 11 with 2 being positive. The mutation rate of our patients is lower than expected for secondary GBs. As reported in previous studies, the median intervals for low-grade gliomas to transform to GBs ranged from 2.1 to 10.1 years.²⁰ The MR imaging lesions of those 16 patients progressed to the classic appearance of GBs in <14 months. Among these, the 2 lesions with IDH1 mutations progressed to classic GB in 7 and 10 months, respectively. In light of rapid progression to GBs and the low incidence of IDH1 mutation, we believe the MR imaging lesions of those 16 patients were not low-grade gliomas but high-grade from their origin.

The differential diagnosis for type I lesions should include postictal change because focal seizures were the clinical presentation for 3 patients with type I lesions. However, in previous reports, most seizure-induced MR imaging abnormalities were transient and reversible.²¹ Permanent structural abnormalities such as gliosis and focal atrophy are more likely to occur in status epilepticus.²¹ In this study, no patients with type I lesions had status epilepticus, and their abnormalities in the cerebral cortex persisted even when these lesions transformed to type II or classic GBs. Moreover, seizure-induced abnormalities tend to involve both the cortex and subcortical WM and are seldom limited to GM only.²¹ Therefore, our type I lesions likely reflect tumor in GM.

According to the histologic classification of the World Health Organization, the presence of microvascular proliferation or pseudopalisading necrosis differentiates GBs from lower-grade gliomas. These 2 histologic hallmarks are typically present in the contrast-enhancing component of GB.^22,23 Microvascular proliferation is known to result in neovascularity with a disrupted blood-brain barrier and increased permeability to gadolinium-based contrast agents and thus contrast enhancement in GB. Barajas et al²² reported that tissue samples obtained from nonenhancing tumor components of GBs demonstrated less microvascular proliferation than those from contrast-enhancing components. GBs without contrast enhancement, though relatively rare, have been reported.^23⇓–25 In the study of Utsuki et al,²³ purely non-contrast-enhancing glioblastomas demonstrated only pseudopalisading necrosis and no neovascularity. Although histopathologic diagnosis was only available in 2 type II lesions, we believe that the other 10 type II lesions were also GBs without contrast enhancement. The implication of these observations may be that advanced imaging techniques such as perfusion and permeability may not reflect the true nature of these small GBs as they do in larger, classic ones.

The present study helps radiologists be familiar with imaging findings of early-stage GBs. For a type I or II lesion, early-stage GB should be included in the differential diagnosis in addition to a self-limited non-neoplastic lesion. It is challenging to prospectively diagnose early-stage GBs; therefore, aggressive surgical resection of these lesions is unlikely. Biopsy may be an alternative other than short-interval imaging follow-up. Advanced MR imaging such as diffusion, perfusion, and MR spectroscopy may have a role, but further studies are needed.

There are some limitations to our study. First, the diagnosis of GB was confirmed in only 10 patients who underwent an early operation. Thus, for the other 16 patients, we can only assume that their MR imaging lesions were early-stage GBs because they all eventually developed the typical MR imaging appearance and histopathology of GBs. Second, because our routine MR imaging protocol did not include advanced MR imaging techniques such as diffusion, perfusion, and spectroscopy, we could not assess their roles in early-stage GBs. Third, the MR imaging findings describe only macroscopic growth of GBs and not their microscopic changes. Although GBs may arise from GM, their cell of origin remains unknown. Fourth, tumors included in this study probably represent only a subset of GBs. GBs arising from the hippocampus and subventricular zone may have different growth patterns on MR imaging. Finally, due to a limited number of patients and the retrospective nature of our study, we were unable to determine whether our MR imaging–based classification correlates with outcomes.