Case Presentation: USCAP Jason T. Huse, MD, PhD Assistant Member Department of Pathology Memorial Sloan Kettering Cancer Center

Transcription

1 Case Presentation: USCAP 2016 Jason T. Huse, MD, PhD Assistant Member Department of Pathology Memorial Sloan Kettering Cancer Center

2 Case History 53 year old female with a long standing history of migraines with visual aura. MRI in 2009 revealed a non enhancing abnormality in the right frontal lobe. The patient was apparently told at the time that no treatment was necessary. In 2014, developed vertigo and a second MRI revealed growth of the mass with new punctate regions of contrast enhancement. Received subtotal resection

3 Representative Imagining FLAIR T1 post contrast

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10 IDH1 R132H

11 IDH1 R132H

12 p53

13 p53

14 ATRX

15 ATRX

16 1p FISH Oligodendroglial Astrocytic Oncoscan MIP

17 p53

18 ATRX

19 MIB 1

20 Diagnosis Composite oligodendroglioma and astrocytoma, with malignant transformation in astrocytic component

21 Case Discussion Gliomas have historically been classified based on morphological criteria into astrocytic, oligodendroglial, and mixed lineages Recent molecular profiling studies have called this scheme into question, particularly with regard to mixed lineage tumors (oligoastrocytomas)

22 Defined biomarker sets designate glioma subclasses that transcend histopathology IDH wt tumors tend to behave like primary GBM, regardless of histopathology IDH mutant tumors consist of those with 1p/19q codeletion and TERT mutation, and those with ATRX mutation and TP53 mutation While oligodendroglial and astrocytic features are enriched in these subclasses, respectively, there is significant morphological heterogeneity Oligoastrocytomas have no defining molecular features and tend to fall into either one of the IDH mutant subclasses

23 Molecular subclasses outperform histopathological designations prognostically Histopathology Wiestler, B. et. al., Acta Neuropath, 2013 Molecular Classification

24 Glioma subclasses are easily designated in the clinical environment Acta Neuropath, 2015 IDH1 R132H ATRX 1p FISH

25 Profiling reveals true oligoastrocytomas with molecularly and histopathologically distinct components Acta Neuropath, case (shown today) Acta Neuropath, cases

26 Pathogenesis of composite gliomas IDH1/2 mutation 1p/19q loss Neuroepithelial precursor ATRX/TP53 loss WHO II/III Astro Oligodendroglial and astrocytic components arise sequentially from the same foundational IDH mutant clone Staged evolutionary process permitted by the indolence of the neoplasm(s) WHO II/III Oligo WHO II/III Mixed Glioma

27 Additional questions Incidence? Likely more common than is currently appreciated. Larger resections and more detailed profiling may reveal higher rates moving forward. Behavior? The astrocytic portion will likely behave more aggressively in most cases. Treatment?

28 References 1. Brat, D.J. et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower Grade Gliomas. N Engl J Med 372, (2015). 2. Eckel Passow, J.E. et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med 372, (2015). 3. Killela, P.J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self renewal. Proc Natl Acad Sci U S A 110, (2013). 4. Jiao, Y. et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3, (2012). 5. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 360, (2009). 6. Kannan, K. et al. Whole exome sequencing identified ATRX mutation as a key molecular determinant in lower grade glioma. Oncotarget 3, (2012). 7. Reuss, D.E. et al. ATRX and IDH1 R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol 129, (2015). 8. Huse, J.T., Diamond, E.L., Wang, L. & Rosenblum, M.K. Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true "oligoastrocytoma"? Acta Neuropathol 129, (2015). 9. Wilcox, P. et al. Oligoastrocytomas: throwing the baby out with the bathwater? Acta Neuropathol 129, (2015).