Diffuse gliomas with FGFR3‐TACC3 fusion have characteristic histopathological and molecular features

Abstract

Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n = 27 WHO grade IV and n = 3 WHO grade II) as well as their histological and molecular features. We observed recurrent morphological features (monomorphous ovoid nuclei, nuclear palisading and thin parallel cytoplasmic processes, endocrinoid network of thin capillaries) associated with frequent microcalcifications and desmoplasia. We report a constant immunoreactivity for FGFR3, which is a valuable method for screening for the FGFR3-TACC3 fusion with 100% sensitivity and 92% specificity. We confirmed the associated molecular features (typical genetic alterations of glioblastoma, except the absence of EGFR amplification, and an increased frequency of CDK4 and MDM2 amplifications). FGFR3 immunopositivity is a valuable tool to identify gliomas that are likely to harbor the FGFR3-TACC3 fusion for inclusion in targeted therapeutic trials.

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor

“…Notably, FGFR1 alterations are not commonly found in IDH-wildtype glioblastoma in adults, IDH-mutant astrocytoma, IDH-mutant and 1p/19q-codeleted oligodendroglioma, H3.3 G34-mutant diffuse hemispheric glioma, ganglioglioma, polymorphous low-grade neuroepithelial tumor of the young (PLNTY), papillary glioneuronal tumor, myxoid glioneuronal tumor, multinodular and vacuolating neuronal tumor, diffuse leptomeningeal glioneuronal tumor (DLGNT), central neurocytoma, and ependymomas of any location or subtype [ 5 , 6 , 8 , 9 , 16 , 17 , 23 , 24 , 26 , 28 , 29 ]. However, fusions involving other FGFR genes are recurrently found in PLNTY (mostly involving FGFR2 ) and IDH-wildtype glioblastoma in adults (mostly involving FGFR3 , typically with TACC3 as the fusion partner) [ 4 , 10 , 17 , 39 ]. Therefore, while the identification of an FGFR1 alteration in a CNS tumor of uncertain subtype may help to narrow the differential diagnosis and exclude certain tumor entities, this single genetic finding in and of itself does not enable precise classification.…”

FGFR- gene family alterations in low-grade neuroepithelial tumors

“…The reality is that the implications of FGFR3 fusion are clear: as previously stated, FGFR3 fusions, most commonly FGFR3-TACC3, are by and large a feature of IDH-wild type glioblastoma, WHO grade IV [18]. Although FGFR-fusion positive GBM constitutes a small subset of GBM as a whole (~3%), the sheer preponderance of GBM relative to other types of glioma renders this the most common scenario in which FGFR3 fusions will be encountered in most neuropathology practice settings [7,18,69].…”

“…FGFR3-TACC3 fusion gliomas, both low and high grade, exhibit characteristic histologic features, including monomorphous oligodendroglioma-like nuclei, "chicken-wire" capillary networks, and frequent microcalcifications [7]. While this may be reflective of the common end-result of FGFR fusions in all tumors (namely enhanced downstream signaling through MAP kinase pathway effectors), the histologic similarities suggest the possibility of FGFR3-fusion positive GBM arising from lower-grade precursor lesions.…”

Neuropathology in Pitié‐Salpêtrière hospital: Past, present and prospect

“…Substrate analysis of this enzyme opens up targeted therapeutic perspectives . Metabolic studies offer other perspectives: oxidative metabolism is increased in glioma cells with a FGFR3‐TACC3 fusion and treatments directed against oxidative stress like metformin can induce tumor cell death …”