A diffuse glioma with oligodendroglial‐like cells and extensive calcifications

The tumor showed extensive microcalcifications and cells with oval, nuclei and a clear perinuclear halo (A), positive immunostaining for OLIG‐2 (B), GFAP (C), and CD34 (D), and intermingled Neu‐N‐positive neurons (E). FISH revealed multiple signals for the centromere of chromosome 7 (gains) (green probe) and the EGFR locus (red probe) (F, left), and a single signal for the centromere of chromosome 10 (loss) (F, right).


| CLINICAL HISTORY AND IMAGING
Following a generalized tonic-clonic seizure during sleep, a 53-year-old woman underwent a computerized tomographic scan that revealed a calcified lesion of 15 mm in the left parietal lobe.On magnetic resonance imaging, the lesion was hyperintense on FLAIR, heterogeneously hyperintense on T1 and T2-weighted images and showed focal nodular gadolinium contrast enhancement (Box 1, Figure 1).Treatment with antiepileptic drugs was initiated because of recurrent seizures.The lesion exhibited a modest increase in size over the following 10 months and was completely surgically removed 1 year after the initial radiological diagnosis.Three months after surgery, the patient was in good health with no radiological signs of recurrence, despite the lack of adjuvant treatment.

| FINDINGS
Histological examination revealed a tumor with extensive microcalcifications composed of neoplastic, oligodendroglial-like cells with oval, hyperchromatic, mild pleomorphic nuclei, and a clear perinuclear halo (Figure 2).Mitoses, necrosis, or microvascular proliferation were absent.
Fluorescent in situ hybridization revealed gains in chromosome 7 and loss in chromosome 10 (Figure 2) in the absence of EGFR amplification.

| DISCUSSION
Diffuse gliomas with FGFR3:TACC3 fusion display typical and recurrent morphological and immunohistochemical features, which consist of oligodendroglial-like cells with monomorphous ovoid nuclei, nuclear palisading, thin parallel cytoplasmic processes, an endocrinoid network of thin capillaries, frequent microcalcifications, and CD34 immunostaining.The presence of some of these findings in our case prompted us to investigate FGFR3::TACC3 fusion.
Diffuse gliomas with FGFR3:TACC3 fusion do not represent a distinct nosological entity in the 2021 WHO classification of CNS tumors.Most reported cases had a high-grade morphology, consisting of microvascular proliferation and necrosis [1,2] and were considered to represent a subgroup of IDH wild-type GBMs distinguished by prolonged overall survival.Within the minor proportion of diffuse gliomas with FGFR3::TACC3 fusion that lack histological signs of malignancy, some cases are also devoid of the molecular features of GBMs, whereas others have chromosomes 7 gain/10 loss and/or pTERT mutation [1,2], which supports a diagnosis of GBM, IDH-wildtype, according to the 2021 WHO CNS classification, as in the present case.It has been suggested that these tumors may represent precursors of GBM or undersampled GBMs.Two studies have shown that the majority exhibit a distinct DNA methylation profile [1,2].Indeed, of 27 histologically diffuse low-grade gliomas with FGFR3::TACC3 fusion and pTERT mutation and/or chromosomes 7 gain/10 loss, only five cases had a calibration score above 0.90 for the methylation class "GBM IDH-wildtype" using the 11b4 version of the Heidelberg classifier [1,2].Using the 12.5 version of the classifier, two tumors had calibration scores of 0.98 and 0.99 for the methylation class "ganglioglioma," and none of the remaining cases had a calibrated score above 0.90 for any methylation classes [1,2].Therefore, the precise classification and grading of diffuse gliomas with FGFR3:: TACC3 fusion appear controversial, and a diagnosis more descriptive than GBM IDH-wildtype may be adopted for these tumors.In the present case, the relatively indolent course over a 12-month interval, the lack of frank progression and the stability 3 months after surgery despite the lack of adjuvant treatment, so far suggest a clinical behavior more consistent with a low-grade diffuse glioma.Likewise, an overall survival exceeding 5 years has been reported in other patients with similar tumors.The morphological features observed in this case, along with the clinical history of seizures, might also suggest a diagnosis of polymorphous neuroepithelial tumor of the young (PLNTY), which is also characterized by oligodendroglioma-like components, few (if any) mitotic figures, conspicuous calcifications, regional CD34 immunostaining, IDH wild-type status, and fusions involving the FGFR3 gene [3].However, this CNS WHO grade 1 diffuse glioma generally occurs in children or young adults.In addition, all previously described cases with a diagnosis confirmed by DNA methylation profiling lacked the FGFR3::TACC3 fusion and pTERT mutation.

F
I G U R E 1 Magnetic resonance imaging showing hyperintensity on FLAIR (A) and heterogeneous hyperintensity on T1 (B) with focal nodular gadolinium contrast enhancement (inset).

F
I G U R E 2 The tumor showed extensive microcalcifications and cells with oval, nuclei and a clear perinuclear halo (A), positive immunostaining for OLIG-2 (B), GFAP (C), and CD34 (D), and intermingled Neu-N-positive neurons (E).FISH revealed multiple signals for the centromere of chromosome 7 (gains) (green probe) and the EGFR locus (red probe) (F, left), and a single signal for the centromere of chromosome 10 (loss) (F, right).