The New WHO Classification and the Role of Integrated Molecular Profiling in the Diagnosis of Malignant Gliomas
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1 The New WHO Classification and the Role of Integrated Molecular Profiling in the Diagnosis of Malignant Gliomas Stefan Prokop, MD Neuropathology Fellow Hospital of the University of Pennsylvania
2 Background Updated WHO in 2016 Incorporates Layered Diagnoses Histology Immunohistochemical markers Molecular WHO grade Re-classifies certain tumors and tumor groups
3 Glial neoplasms: Infiltrating Gliomas then (2007 WHO classification) Astrocytic tumors Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma Giant cell glioblastoma Gliosarcoma Oligoastrocytic tumors Oligoastrocytoma Anaplastic oligoastrocytoma Oligodendroglial tumors Oligodendroglioma Anaplastic oligodendroglioma
4 Photo courtesy of Dr. Edward B. Lee Oligodendrogliomas Fried egg appearance Chicken wire capillaries Micro-califications Microcystic Gemistocytic tumor cells
5 Photo courtesy of Aivi T. Nguyen Astrocytomas Hypercellularity Nuclear atypia +/- Mitotic activity No necrosis No microvascular proliferation
6 Photo courtesy of Aivi T. Nguyen Astrocytomas: Glioblastoma Atypia Necrosis Pseuodpalisading Geographic Microvascular proliferation Vessel thromboses
7 Photo courtesy of Aivi T. Nguyen Astrocytomas: Glioblastoma Atypia Necrosis Pseuodpalisading Geographic Microvascular proliferation Vessel thromboses
8 Molecular Landscape of Gliomas
9 Isocitrate dehydrogenase (IDH) mutations in gliomas Yan et al., NEJM 2009
10 IDH: Isocitrate Dehydrogenase mutations in tumors Presner et al., Nature Med, 2011
11 Prognostic impact of IDH mutation status IDH1-mutation specific antibody Hartmann et al., Acta Neuropathologica 2010
12 Concurent 1p and 19q chromosome loss in Oligodendrogliomas lost Whole-arm translocation Weller et al., Neuro-Oncology Initially shown to be associated with better prognosis in diffuse gliomas Griffin et al., Journal of Neuropathology and Experimental Neurology Co-occurrence of 1p/19q deletion and IDH mutation defines Oligodendrogliomas
13 Glial neoplasms: Infiltrating Gliomas now (2016 WHO classification) Astrocytic tumors Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma Giant cell glioblastoma Gliosarcoma Oligodendroglial tumors Oligodendroglioma Anaplastic oligodendroglioma Oligoastrocytic tumors Oligoastrocytoma Anaplastic oligoastrocytoma Integrated diagnosis incorporating histology, immunohistochemistry and molecular findings to define tumor entities
14 Glial neoplasms: Infiltrating Gliomas now (2016 WHO classification) Astrocytic tumors Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma Giant cell glioblastoma Gliosarcoma IDH wild type or IDH mutant 1p/19q non co-deleted Oligodendroglial tumors Oligodendroglioma Anaplastic oligodendroglioma IDH mutant and 1p/19q co-deleted (entity defining genetic alterations)
15 Louis et al., Acta Neuropathologica 2016
16 Mutations of Selected Genes in Glioma Subtypes Glioblastoma Astrocytoma Oligodendroglioma Oligoastrocytoma Killela et al., PNAS 2013
17 The New WHO Classification in Action
18 WHO 2016: Layered Diagnosis Integrated Diagnosis Incorporating all aspects of tissue diagnosis Histological Classification WHO Grade reflects natural history, based on histology Molecular information Louis et al., Brain Pathology 2014
19 Workflow Histology H&E sections Tissue is processed (formalin fixation) and put on slides Review slides and immunostains, write pathology report Molecular Molecular tests ordered CPD, EGFRvIII, MGMT promoter methylation tests ordered after sign out of case Integrated Diagnosis Molecular results Results returned ~2 weeks Integrated diagnosis in addendum (no longer pending )
20 Example: Histology Photos courtesy of Dr. Edward B. Lee
21 Example: Initial Diagnosis Integrated diagnosis: Pending Histologic diagnosis: Infiltrating high grade glioma Histologic grade: At least WHO grade III Molecular information: Pending
22 Example: Final Diagnosis Integrated diagnosis: Pending Histologic diagnosis: Infiltrating high grade glioma Histologic grade: At least WHO grade III Molecular information: Pending Integrated diagnosis: Glioblastoma, IDH-wildtype, WHO grade IV Histologic diagnosis: Glioblastoma Histologic grade: WHO grade IV Molecular information: IDH negative, 1p/19q-intact
23 Example: Final Diagnosis Integrated diagnosis: Pending Histologic diagnosis: Infiltrating high grade glioma Histologic grade: At least WHO grade III Molecular information: Pending Integrated diagnosis: Glioblastoma, IDH-mutant, WHO grade IV Histologic diagnosis: Glioblastoma Histologic grade: WHO grade IV Molecular information: IDH p.r132h positive, 1p/19q-intact
24 Example: Final Diagnosis Integrated diagnosis: Pending Histologic diagnosis: Infiltrating high grade glioma Histologic grade: At least WHO grade III Molecular information: Pending Integrated diagnosis: Anaplastic Oligodendroglioma, IDH-mutant, 1p/19qcodeleted, WHO grade III Histologic diagnosis: Oligodendroglioma Histologic grade: WHO grade III Molecular information: IDH p.r132h, 1p/19q-codeleted
25 Three different diagnoses Glioblastoma - 1 IDH-wildtype IDH1 (R132H) negative CPD negative 1p/19q-intact Glioblastoma - 2 IDH-mutant IDH1 (R132H) positive IDH1 p.r132h 1p/19q-intact Anaplastic Oligo. IDH-mutant IDH1 (R132H) positive IDH1 p.r132h 1p/19q-codeleted
26 Do we need a microscope? Yes! Must make histological diagnosis of glioma first WHO grade is based mainly on histology Some gliomas do not have these diagnostic genetic changes
27 Simplified algorithm for classification of diffuse gliomas based on histology and genetics More genetic changes will be found. Louis et al., Acta Neuropathologica
28 Summary Integration of molecular and histologic findings improves the definition of tumor entities Molecular profiling of gliomas and glioma subtypes will guide targeted and personalized therapeutic approaches
29 Neuro-Oncology Molecular testing workflow
30 Neuro-Oncology Molecular testing workflow
31 Neuro-Oncology Molecular testing workflow
32 Neuro-Oncology Molecular testing workflow
33 Neuro-Oncology Molecular testing workflow
34 Neuro-Oncology Molecular testing workflow
35 Neuro-Oncology Molecular testing workflow
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