Case 1
A 51-year-old woman presented with a 2-year history of numbness and left arm pain, with negative spine imaging and peripheral neuropathy workup. Due to new paresthesia of the left hip, MR imaging (MRI) of the brain was performed, which showed T2 hyperintensity in the right insula, associated with edema and mild contrast enhancement. Microscopic examination of the resected tumor showed hypercellular brain parenchyma infiltrated by small round monomorphic cells with perinuclear clearing resembling oligodendroglioma, microcalcifications and perivascular pseudorosettes. Mitotic activity was inconspicuous, and computer-assisted quantitation yielded a Ki67 proliferation index of 7.6% (Fig. 1). A diagnosis of oligodendroglioma, NOS, WHO grade II, was rendered following guidelines from the 2007 WHO classification system for tumors of the central nervous system (CNS), which was in force at the time of diagnosis. Fluorescence in situ hybridization (FISH) analysis for chromosomal arms 1p and 19q was negative for codeletion. The patient was treated with intensity-modulated radiation therapy (IMRT) to a total dose of 50.4Gy in 28 fractions, together with 12 cycles of temozolomide chemotherapy.
Imaging and histologic features of Patient #1. Preoperative MR imaging showing T2 FLAIR hyperintensity in the right temporal lobe (a) with minimal contrast enhancement in the T1 sequence with contrast (b). H&E-stained tumor tissue sections showing hypercellular brain parenchyma with microcalcifications. The brain parenchyma is infiltrated by monomorphic round glial cells with perinuclear clearing, resembling oligodendrocytes (c). Spindle cells in a perivascular distribution are noted (d). GFAP is positive in tumor cells (e), and Ki67 immunostaining shows a low proliferation index (f). Surveillance MR imaging showing T2 FLAIR hyperintensity around the surgical cavity (g) and new contrast enhancement along the resection cavity wall (h). H&E-stained tumor tissue sections show hypercellular brain parenchyma with oligo-like cells and perivascular pseudorosettes (i), and an endocrinoid (“chickenwire”) capillary network (j). The tumor cells are strongly positive for CD34 (k) and the Ki67 index is elevated (l) in comparison to the tumor resected in the first surgery (d)
The patient was placed on surveillance imaging every 3 months and was stable until ~ 3 years after presentation when a new area of contrast enhancement was identified adjacent to the resection cavity. Resection of the recurrent lesion was performed. Microscopic examination showed a compact, densely cellular glioma with morphologic features associated with the recently-described FGFR3-TACC3 fusion glioma [3, 6, 9]. The characteristic features evident in this case include a population of glioma cells with monomorphous ovoid nuclei, nuclear palisading and enfilading, thin parallel cytoplasmic processes, endocrinoid capillary network, microcalcifications and desmoplasia (Fig. 1) [1]. The tumor from the second resection showed foci of vascular proliferation, correlating with the presence of contrast enhancement on the preoperative MRI. In contrast to the low proliferation index of the initial tumor, the recurrent tumor showed a Ki67 index of 30.3%. GFAP was expressed in perivascular cell processes of the tumor cells, EMA was negative, and expression of the ATRX protein was retained.
Next generation sequencing analysis (NGS) for mutations (134 genes), copy number variations (47 genes), and fusions (51 genes), was performed on the recurrent tumor. The results showed FGFR3p.K650 T, NF1p.F443C and TERTc.-124C > T mutations, as well as the FGFR3-TACC3 (COSF1353) fusion. These findings prompted analysis of the initial tumor. NGS analysis revealed only the presence of FGFR3p.K650 T mutation; NF1 and TERT mutations were not identified in the tumor from the first surgery (Table 1). Conventional RT-PCR with FGFR3 and TACC3 specific primers (5′-AGGAGCTCTTCAAGCTGCTG-3′ and 5′-GGGGGTCGAACTTGAGGTAT-3′) generated a product of the expected size (225 bp) and confirmed the FGFR3-TACC3 fusion in the original tumor.