Malignant transformation of a polymorphous low grade neuroepithelial tumor of the young (PLNTY)

PLNTY comprise an indolent group of tumors in children and young adults harboring MAPK pathway alterations [2, 5, 6] including FGFR3-TACC3 fusions, which also characterize a subset of glioblastomas [1]. To date, there have been no reports of aggressive behavior and malignant transformation in tumors meeting diagnostic criteria for PLNTY. Here, we present a pediatric patient diagnosed with PLNTY with FGFR3-TACC3 fusion, who experienced recurrent glioblastoma-like disease within <18 months.

A 15-year old female with unremarkable prior medical history presented with a seizure; MRI demonstrated a 1.2 cm heterogeneously T1 and T2 hyperintense, contrast-enhancing and mineralized left medial temporal lesion with trace edema (Fig 1.a). Gross total resection was performed. Histopathology demonstrated a moderately cellular glial proliferation with bland oligodendroglioma-like cytology, perivascular pseudo-rosetting, microcalcifications, and patchy CD34 expression (Fig.1c–f), consistent with PLNTY. Ki-67 proliferation index was low (<2%, focally up to 4.2%, Fig.1d); a single mitotic figure was identified. Two small foci of hyalinizing-type necrosis were identified (Fig.1e). An in-frame fusion involving FGFR3 (Exon 18) and TACC3 (Exon 11) was detected using MSK-Solid Fusion Assay [10] (Supplemental Fig.1, online resource). No adjuvant therapy was recommended.

Figure 1:

a. Diagnostic T1-weighted post-contrast MRI b. T2 post-contrast MRI at recurrence. c-f. PLNTY features in the primary tumor. Recurrent tumor shows abundant mitoses (g), microvascular proliferation (h), markedly elevated proliferative index (Ki-67, i), and pseudopalisading necrosis (k), without CD34 expression (i). Scale bar= 100 μm (c, g); 200 μm (d-f, h, i, k, l). j. Sequencing results m. DNA methylation-based classification results. T-SNE dimensionality reduction was performed on the primary (▼) and recurrent (▲) tumors and a subset of CNS tumors from the DKFZ reference set (color coded according to methylation cluster assignation) with the Rtsne package version 0.15. Analyses were performed using the mnp.v11b6 package in R version 3.6.1; as described by Capper et al.[3]

17 months post resection, surveillance MRI demonstrated a 4.1 cm partially solid and cystic lesion within the left temporal lobe with extensive edema, consistent with local recurrence (Fig. 1b). Upon near-total resection, the recurrent tumor was entirely devoid of CD34 expression and demonstrated high-grade foci, at the level of glioblastoma, WHO Grade IV (Fig.1g–I,k,l). The patient was treated with focal proton radiotherapy with concurrent temozolomide, followed by maintenance temozolomide without definitive disease recurrence at last follow up (~34 months).

Molecular characterization by a 468-gene tumor sequencing assay (MSK-IMPACT™) [4] re-demonstrated the FGFR3-TACC3 fusion, plus additional somatic alterations in TP53, ATRX, PTEN, TEK and RB1 typically seen in high-grade glioma. Excepting the RB1 variant, all alterations were also present at initial diagnosis. (Fig.1K, Supplemental Table 1, online resource). Both tumors displayed gains of chromosome 7 and 20, with widespread loss of heterozygosity (Supplemental Fig.1, online resource).[8]

No high-confidence matches to established methylation classes were obtained using the Infinium methylationEPIC/850k platform and DKFZ CNS tumor classifier [3]. As in previous reports of PLNTY, the original tumor matched closest to “methylation class low grade glioma, ganglioglioma” (calibration score 0.63, Fig.1m) [6].

PLNTY display a distinguishing DNA methylation signature, (to be included in forthcoming versions of the brain tumor classifier [M. Sill, personal communication]) with recurrent MAP kinase pathway activating alterations [2, 5–7, 9]. Notably, the sole FGFR3-TACC3 fusion positive patient among the original description of PLNTY was negative for disease after 89 months follow up [6]. While initial histologic features and DNA methylation data in our patient supported a diagnosis of PLNTY, the presence of additional genomic alterations portended more aggressive behavior.

FGFR3-TACC3 fusion gliomas exhibit shared histologic features [1, 2], but malignant progression of an initially low-grade tumor has not been previously reported. This report highlights the importance of comprehensive genomic analysis to aid in prognostication, particularly among PLNTY.