2017 Diagnostic Slide Session Case 3
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1 2017 Diagnostic Slide Session Case 3 Andrew Gao, MD Lili-Naz Hazrati, MD, PhD Cynthia Hawkins, MD, PhD Hospital for Sick Children and University of Toronto, Toronto, Canada
2 Disclosures: none
3 Clinical History 9-year-old girl from El Salvador with longstanding history of partial seizures and occasional headaches
4 Complex solid-cystic cortical/subcortical mass within the left superior temporal and parietooccipital lobes 7.1 x 4.2 x 3.6 cm T2 FLAIR Biopsy (El Salvador): Slide #1 T1+C
5 Biopsy (El Salvador): Slide #1
6 Biopsy (El Salvador): Slide #1 GFAP Olig2 MIB1
7 Biopsy (El Salvador) Slide #1: Oligodendroglioma Resection, 6 months later (Sick Kids): Slide #2
8 Resection (Sick Kids): Slide #2
9 Resection (Sick Kids): Another block
10 Resection (Sick Kids): Another block
11 Differential diagnosis? Additional stains/studies?
12 GFAP Olig2 CD34 MIB1
13 GFAP Olig2 CD34 MIB1
14 Additional stains and molecular pathology Reticulin EMA Synaptophysin Chromogranin NeuN negative negative negative negative negative 1p/19q-codeletion KIAA1549-BRAF fusion negative negative IDH1 R132H ATRX BRAF V600E negative retained negative
15 Low-grade neuroepithelial tumours Adult type Pediatric type Diffuse astrocytoma Oligodendroglioma IDH1/2 ATRX TP53 IDH1/2 1p/19q-codeletion Pilocytic astrocytoma Diffuse astrocytoma Angiocentric glioma KIAA1549-BRAF fusion BRAF V600E NF1 MYB/MYBL1 amplification, rearrangement BRAF V600E, fusion FGFR1/3 ITD, fusion MYB-QKI fusion Ganglioglioma BRAF V600E PXA BRAF V600E DLGNT diffuse leptomeningeal glioneuronal tumour DNET dysembryoplastic neuroepithelial tumour PXA pleomorphic xanthoastrocytoma ITD internal tandem duplication SNV single nucleotide variant Adapted from: Chiang and Ellison. J Pathol 2016;241: Oligodendroglioma DNET DLGNT FGFR1 SNV, ITD, fusion FGFR1 SNV, ITD KIAA1549-BRAF fusion and 1p deletion
16 SNP array Chromosome kb deletion with no coding gene 3.3Mb deletion
17 24kb deletion 3.3Mb deletion FGFR2 <- NM_ Breakpoint: Intron 16/16 = between exons 16 and 17 KIAA1598 (SHTN1) <- NM_ Breakpoint: Intron 6/16 = between exons 6 and 7 Breakpoint: Intron 2/16 = between exons 2 and 3
18 Sanger sequencing FGFR2 Exon17 KIAA1598 (STHN1) Exon7 RT-PCR Our case Normal brain1 Normal brain2 Neural stem cell Negative control 200bp FGFR2(ex17)-KIAA1598(ex7) fusion 100bp
19 Huse JT, Snuderl M, Jones DT, Brathwaite CD, Altman N, Lavi E, et al. Acta Neuropathologica 2017;133: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway GFAP Olig2 BRAF V600E CD34
20 Huse JT, Snuderl M, Jones DT, Brathwaite CD, Altman N, Lavi E, et al. Acta Neuropathologica 2017;133: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway
21 Coiled coil domain in KIAA1598 Constitutive dimerization Autophosphorylation Activation Blumke et al. Nature Reviews Neurology 2016;12:
22 Sick Kids archive FGFR2(ex17)-INA(ex2) FGFR2(ex17)-CTNNA3(ex14) FGFR2(ex18)-ERC1(ex2) 17M (5) 8F (6) 16M (4)
23 FGFR2-INA ganglioglioma FGFR2-CTNNA3 oligoastrocytoma FGFR2-ERC1 oligodendroglioma FGFR2-KIAA1598 (current case)
24 Outcome Sick Kids cases: 1 9 F Seizures long L parietal GTR 1 Plan for radiation Neg FGFR2-KIAA M Seizures 12 y L frontal GTR 1? Neg FGFR2-INA 3 8 F Seizures 2 y L parietal GTR 24 NED Neg FGFR2-CTNNA M Seizures 12 y L occipital GTR 24 NED Neg FGFR2-ERC1
25 Summary: PLNTY Epilepsy-associated tumour of the young Polymorphous with oligodendroglial-like component, CD34+ fibrillary, spindled, pleomorphic astrocytic perivascular pseudorosettes ganglioglioma Our case: high-grade histology prognosis? MAPK pathway (BRAF V600E, FGFR2/3)
26 References Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Huse JT, Snuderl M, Jones DT, Brathwaite CD, Altman N, Lavi E, et al. Acta Neuropathol 2017;133: Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD, et al. Acta Neuropathol 2016;131: Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B et al. Nat Gen 2013;45: An integrative molecular and genomic analysis of pediatric hemispheric low-grade gliomas: an update. Lassaletta A, Zapotocky M, Bouffet E, Hawkins C, Tabori U. Childs Nerv Syst 2016;32:
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