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 Background
• Updated WHO in 2016
• Incorporates “Layered Diagnoses”
• Immunohistochemical markers
• Molecular
• WHO grade
• Re-classifies certain tumors and tumor groups Glial neoplasms: Infiltrating Gliomas – then (2007 WHO classification) • Astrocytic tumors • Oligoastrocytic tumors • Diffuse astrocytoma • Oligoastrocytoma • Anaplastic astrocytoma • Anaplastic oligoastrocytoma • Glioblastoma • Giant cell glioblastoma • Gliosarcoma
• Oligodendroglial tumors • Oligodendroglioma • Anaplastic oligodendroglioma Oligodendrogliomas
“Fried egg” appearance
Chicken wire capillaries
Micro-califications
Microcystic
Gemistocytic tumor cells
Photo courtesy of Dr. Edward B. Lee Astrocytomas
Hypercellularity
Nuclear atypia
+/- Mitotic activity
No necrosis
No microvascular proliferation
Photo courtesy of Aivi T. Nguyen Astrocytomas: Glioblastoma
Atypia
Necrosis
Pseuodpalisading
Geographic
Microvascular proliferation
Vessel thromboses
Photo courtesy of Aivi T. Nguyen Astrocytomas: Glioblastoma
Atypia
Necrosis
Pseuodpalisading
Geographic
Microvascular proliferation
Vessel thromboses
Photo courtesy of Aivi T. Nguyen Molecular Landscape of Gliomas Isocitrate dehydrogenase (IDH) mutations in gliomas
Yan et al., NEJM 2009 IDH: Isocitrate Dehydrogenase mutations in tumors
Presner et al., Nature Med, 2011 Prognostic impact of IDH mutation status
IDH1-mutation specific antibody
Hartmann et al., Acta Neuropathologica 2010 Concurent 1p and 19q chromosome loss in Oligodendrogliomas
lost
Whole-arm translocation Weller et al., Neuro-Oncology 2014
- Initially shown to be associated with better prognosis in diffuse gliomas
- Co-occurrence of 1p/19q deletion and IDH Griffin et al., Journal of Neuropathology and Experimental mutation defines Oligodendrogliomas Neurology 2006 Glial neoplasms: Infiltrating Gliomas – now (2016 WHO classification) • Astrocytic tumors • Oligoastrocytic tumors • Diffuse astrocytoma • Oligoastrocytoma • Anaplastic astrocytoma • Anaplastic oligoastrocytoma • Glioblastoma • Giant cell glioblastoma Integrated diagnosis incorporating • Gliosarcoma histology, immunohistochemistry and molecular findings to define tumor • Oligodendroglial tumors entities • Oligodendroglioma • Anaplastic oligodendroglioma Glial neoplasms: Infiltrating Gliomas – now (2016 WHO classification) • Astrocytic tumors • Diffuse astrocytoma • Anaplastic astrocytoma IDH wild type or IDH mutant • Glioblastoma 1p/19q non co-deleted • Giant cell glioblastoma • Gliosarcoma
• Oligodendroglial tumors • Oligodendroglioma IDH mutant and 1p/19q co-deleted (entity defining genetic alterations) • Anaplastic oligodendroglioma Louis et al., Acta Neuropathologica 2016 Mutations of Selected Genes in Glioma Subtypes
Glioblastoma
Astrocytoma
Oligodendroglioma
Oligoastrocytoma Killela et al., PNAS 2013 The New WHO Classification in Action 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 Workflow
Integrated Histology Molecular Diagnosis
H&E sections Molecular tests Molecular results ordered Tissue is processed Results returned ~2 (formalin fixation) and CPD, EGFRvIII, MGMT weeks put on slides promoter methylation Integrated diagnosis in Review slides and tests ordered after sign addendum (no longer immunostains, write out of case “pending”) pathology report Example: Histology
Photos courtesy of Dr. Edward B. Lee Example: Initial Diagnosis
Integrated diagnosis: Pending
Histologic diagnosis: Infiltrating high grade glioma
Histologic grade: At least WHO grade III
Molecular information: Pending Example: Final Diagnosis
Integrated diagnosis: Pending Integrated diagnosis: Glioblastoma, IDH-wildtype, WHO grade IV Histologic diagnosis: Infiltrating high grade glioma Histologic diagnosis: Glioblastoma
Histologic grade: At least WHO Histologic grade: WHO grade IV grade III Molecular information: IDH Molecular information: Pending negative, 1p/19q-intact Example: Final Diagnosis
Integrated diagnosis: Pending Integrated diagnosis: Glioblastoma, IDH-mutant, WHO grade IV Histologic diagnosis: Infiltrating high grade glioma Histologic diagnosis: Glioblastoma
Histologic grade: At least WHO Histologic grade: WHO grade IV grade III Molecular information: IDH Molecular information: Pending p.R132H positive, 1p/19q-intact Example: Final Diagnosis
Integrated diagnosis: Pending Integrated diagnosis: Anaplastic Oligodendroglioma, IDH-mutant, 1p/19q- Histologic diagnosis: Infiltrating codeleted, WHO grade III high grade glioma Histologic diagnosis: Oligodendroglioma Histologic grade: At least WHO grade III Histologic grade: WHO grade III
Molecular information: Pending Molecular information: IDH p.R132H, 1p/19q-codeleted Three different diagnoses
Glioblastoma - 1° Glioblastoma - 2 ° Anaplastic Oligo.
IDH-wildtype IDH-mutant IDH-mutant
IDH1 (R132H) negative IDH1 (R132H) positive IDH1 (R132H) positive
CPD negative IDH1 p.R132H IDH1 p.R132H
1p/19q-intact 1p/19q-intact 1p/19q-codeleted 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 Simplified algorithm for classification of diffuse gliomas based on histology and genetics
More genetic changes will be found.
Louis et al., Acta Neuropathologica 2016 27 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 Neuro-Oncology Molecular testing workflow Neuro-Oncology Molecular testing workflow Neuro-Oncology Molecular testing workflow Neuro-Oncology Molecular testing workflow Neuro-Oncology Molecular testing workflow Neuro-Oncology Molecular testing workflow Neuro-Oncology Molecular testing workflow