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Biomarkers in Neuro-Ophthalmic Tumors
Fausto J. Rodríguez MD Department of Pathology Johns Hopkins University School of Medicine
Biomarkers in Neuro-Ophthalmic Tumors
Disclosure of Relevant Disclosure of Relevant Financial Relationships Financial Relationships
USCAP requires that all planners (Education Committee) in a position to Dr. Fausto J. Rodriguez declares his affiliation with Johns Hopkins Pathology influence or control the content of CME disclose any relevant financial and may receive royalties from the Surgical Neuropathology App Illustrated in Selected Slides relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest.
Biomarkers in Neuro-Ophthalmic Tumors
Biomarkers in Neuro-Ophthalmic Tumors Optic Nerve Glioma Outline .Variable clinical presentation • I-Optic Nerve Glioma .Visual loss, proptosis, disc •NF1 swelling • BRAF alterations .Fusiform expansion • Diencephalic gliomas .Confined by dural sheath • II-Orbital Meningioma .Predominantly pilocytic • Anatomic and molecular subtypes astrocytoma histology .Observation currently favored • III-Miscellaneous tumors in many cases, particularly in NF1 setting .May stabilize or even regress
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Optic Nerve Glioma Pilocytic Astrocytoma (PA) Histology
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Optic Nerve Glioma Neurofibromatosis type 1 Neurofibromatosis type 1 • Genetic tumor- predisposing syndrome
• ~1/3000
• Caused by germline mutations in the NF1 gene located at 17q11.2
• Predisposed to peripheral and CNS tumors
• Distinctive predilection to involve the optic nerve, chiasm, and hypothalamus.
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Pilocytic Astrocytoma Pilocytic Astrocytoma WHO Grade I Rosenthal Fibers EGBs “Piloid Area” Microcystic area
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Pilocytic Astrocytoma BRAF duplication • Tandem duplication of the BRAF kinase domain resulting in KIAA1549:BRAF fusion • Multiple independent publications in 2008: • Bar, E.E., et al., JNEN 2008 • Jones, D.T., et al., Cancer Res, 2008 • Pfister, S., et al., J Clin Invest, 2008 • Sievert, A.J., et al., Brain Pathol, 2008
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Tandem duplication at 7q34 produces a fusion Tandem duplication at 7q34 produces a fusion gene between KIAA1549 and BRAF gene between KIAA1549 and BRAF
KIAA1549 (exon 14) BRAF (exon 9)
CAACT CA GCCTACA TC GGATGCCCA AC TT GA TTAGAGACCAA GG AT TT CGT GG
~2MB
Jones, D. T.W. et al. Cancer Res 2008;68:8673-8677
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Copyright ©2008 American Association for Cancer Research
KIAA1549-BRAF fusions in paraffin FISH strategy BRAF duplication in paraffin FISH strategy
BRAF CEP7
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BRAF point mutations BRAFV600E • Frequent in papillary thyroid carcinoma and melanoma • Absent to extremely rare in GBM, oligodendroglial tumors, ependymomas • Present in a subset of low grade/pediatric gliomas (Schindler G • BRAF duplication in et al. 2011) 11 (of 15) patients • 66% of pleomorphic xanthoastrocytomas Non duplicated: • 18% of gangliogliomas • 1 GG • 9% of pilocytic astrocytomas • 3 NF1 patients
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BRAF point mutation BRAF point mutation BRAFV600E BRAF p.V600E Immunohistochemistry Pleomorphic V600E Wild Type BRAF Xanthoastrocytoma
T A GCT ACA GT G AAA TC AGCTACAGAGAAATCTCG
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BRAF point mutation BRAF p.V600E Immunohistochemistry
Ganglioglioma
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Diencephalic Glioma Diencephalic Glioma Pilomyxoid Astrocytoma
• Pilocytic Variant • Infants, hypothalamic region • Higher propensity for aggressive behavior, CSF dissemination • Grade II on past WHO (2007) • WHO update: no grade • No Rosenthal fibers, EGBs rare to absent
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Pilomyxoid Astrocytoma Diencephalic Glioma
Chiasm/Hypothalamus Pilomyxoid astrocytoma
GFAP
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Clinicopathologic Features of Diencephalic Clinicopathologic Features of Diencephalic Pediatric Low-Grade Gliomas Pediatric Low-Grade Gliomas
• 56 Diencephalic pediatric low grade gliomas • BRAF p.V600E mutation in 36% • Predilection for infants and young children • Nodular, yet infiltrative in neuroimaging • Monophasic, compact, partially infiltrative • 75% not classifiable upon initial review • 5-year PFS lower than BRAF p.V600E wild type PA Ho C. et al. Acta Neuropathol 2015 Ho C. et al. Acta Neuropathol 2015
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Histologic Features of Diencephalic Pediatric Clinicopathologic Features of Diencephalic Low-Grade Gliomas Pediatric Low-Grade Gliomas BRAFV600-mutant LGG BRAFV600-WT PA BRAFV600-WT PMA No. of cases (%) 19 cases 21 cases 14 cases a) All ages a) All ages
Monophasic pattern 17 (89.5) 2 (9.5) 8 (57.1) Biphasic pattern 2 (10.5) 19 (90.5) 6 (42.9) Pilomyxoid features* 0 (0) 0 (0) 14 (100) Microcysts 1 (5.3)# 16 (76.2) 5 (35.7)
Oligo-like cells 0 (0) 3 (14.3) 1 (7.1) b) Age 0-12 b) Age 0-12 Rosenthal fibers 3 (15.8) 18 (85.7) 2 (14.3) EGBs 5 (26.3) 7 (33.3) 0 (0) Microcalcifications 5 (26.3) 3 (14.3) 0 (0) Mitotic activity 0 - 2/10 hpf 0 - 1/10 hpf 0 – 3/10 hpf
Ki67 (median) 3% (15 cases) < 1% (19 cases) 5% (11 cases) Ho C. et al. Acta Neuropathol 2015
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• MEK and Akt pathways activated in Nf1 deficient astrocytes and murine optic gliomas • PI3K/AKT and MEK inhibitors • Decreased tumor volume and proliferation • Decreased optic glioma–associated retinal ganglion cell loss and nerve fiber layer thinning • May become feasible therapies for optic nerve glioma
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PI3K inhibition decreases optic nerve volume and Sustained MEK inhibition decreases Nf1 mouse glioma proliferation. optic glioma volume and proliferation. PI3K and MEK inhibition attenuates retinal dysfunction in FMC mice in vivo.
Aparna Kaul et al. Neuro Oncol 2015;17:843-853
© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro- Aparna Kaul et al. Neuro Oncol 2015;17:843-853 Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Meningiomas Orbital Meningioma General Molecular Pathology
• Cytogenetic abnormalities • Chr 22 loss (most common) • Also 1p, Chr 6, 10, 14, 18 and 19 loses • Additional alterations in atypical and anaplastic subsets • Molecular genetic abnormalities • NF2 mutations frequent
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Meningiomas General Molecular Pathology • Syndrome associations • Meningiomas, commonly multiple, occur in majority of NF2 patients • Germline SMARCB1/INI1 mutations present in 30% of patients with familial schwannomatosis • Germline SMARCB1/INI1 mutation, and somatic NF2 mutations, in one family with multiple meningiomas •SMARCB1/INI1 mutations very rare in familial multiple meningiomas
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Orbital Meningioma Background
• Meningiomas account for ~4% of intraorbital tumors • May be subclassified anatomically as optic nerve sheath, primary intraorbital (“ectopic”), or secondary (i.e. extensions of an intracranial/sphenoid wing primary) • Most common tumors of the optic nerve sheath • Most commonly identified in middle age women • Painless progressive visual loss (optic nerve sheath) or proptosis (intracranial with secondary extension)
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2014 Orbital Meningioma
Optic Nerve (n=5)
• 19 orbital meningioma Ectopic Meningioma • WHO grade I (n=17) or grade II (n=2) (n=4) • NF2 associated (n=1) Sphenoid Wing • SNP array (Illumina 300K platform) Meningioma • Genomic alterations in 13/19 (68%) (n=10)
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Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis Analysis Defines Three Distinct Subtypes of Orbital Meningioma Defines Three Distinct Subtypes of Orbital Meningioma
Brain Pathology Brain Pathology Volume 25, Issue 2, pages 193-201, 21 MAY 2014 Volume 25, Issue 2, pages 193-201, 21 MAY 2014 DOI: 10.1111/bpa.12150 DOI: 10.1111/bpa.12150 http://onlinelibrary.wiley.com/doi/10.1111/bpa.12150/full#bpa12150-fig-0002 http://onlinelibrary.wiley.com/doi/10.1111/bpa.121 50/full#bpa12150-fig-0003
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Orbital Meningioma Orbital Meningioma
• Sphenoid wing meningioma • Non-chromosome 22 alterations • Monosomy 22/22q loss in 7 (70%) • Sphenoid wing 3.2/case • 1p, 6q, 19p loss in 5 (50%) • Optic nerve 2.6/case • 1p and 6q most frequent in progressive tumors • Ectopic 0.25/case • Optic nerve sheath meningioma • Monosomy 22/22q loss infrequent, only 1 (20%) • Ectopic meningioma • Monosomy 22/22q loss in 3 (75%)
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Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis Genomic architecture of meningiomas Defines Three Distinct Subtypes of Orbital Meningioma
Brain Pathology Volume 25, Issue 2, pages 193-201, 21 MAY 2014 DOI: 10.1111/bpa.12150 http://onlinelibrary.wiley.com/doi/10.1111/bpa.12150/full#bpa12150-fig- 0004 Victoria E. Clark et al. Science 2013;339:1077-1080
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Meningioma Recurrent Somatic Mutations • Recurrent mutations in POLR2A in meningioma (6% of benign cases) • Encodes catalytic subunit of RNA polymerase II • Meningothelial histology, genomic stability • Favor the tuberculum sellae region
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Meningioma Case Presentations Recurrent Somatic Mutations
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Case 1
• 23-year-old woman • Followed for 4 years for presumptive optic glioma • Recent decline in visual field exam and changing MRI • Decreased vision on the right eye • Incongrous left homonymous hemianopsia
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SYNAPTOPHYSIN CHROMOGRANIN
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Gangliogliomas of the Optic Pathways Case 2
• Present with progressive optic disturbance • 29-year-old male • Total resection usually not feasible • Visual disturbances and hypopituitarism • Progression in ~ 1/3 • NF1-association or BRAF p.V600E frequent
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KIT OCT3/4 Germinoma
• Relatively common in suprasellar region • Associated with excellent prognosis in pure form • Immunohistochemistry: OCT3/4 +, SALL4+, KIT+, PLAP+ • Frequent KIT and RAS mutations (~60%) • Rare as intrinsic optic nerve/chiasmatic tumors • Young men, non-exophytic tumors
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Case 3
• 48-year-old woman presented for a routine hysterectomy for adenomyosis • Large pelvic masses identified intraoperatively • Intractable headaches and nausea • Atypical cells in CSF suggestive of metastatic carcinoma • Progressive decline with alterated mental status, hypotension and seizures • Respiratory failure, died 1 month after presentation
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CAM5.2 CK20
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Leptomeningeal Carcinomatosis Case 4 Favor Gastrointestinal Tract Primary • Secondary optic nerve tumors more common than primary • 42-year-old woman with right visual loss tumors • Blurred vision in right eye for several days • Spread from intraocular tumors (melanoma, retinoblastoma), • Visual acuity 20/25 OU, mild right dichromatopsia hematolymphoid neoplasms, metastatic carcinoma • Modest hyperemic optic disc edema on the right with a flat, • Metastatic carcinoma may involve optic nerve proper or normal-appearing optic disc on the left leptomeninges • Common types include lung, breast and stomach
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Case 4 Case 4
• Extraocular motility and the remainder of her neurologic exam • Worsening eye exam unremarkable • Vitreous opacity • A and B scan: dome-shaped lesion overlying the right optic disc • R vitrectomy • Moderate to high internal reflectivity • Maximal elevation ~3.1mm • Right retrobulbar optic nerve enlarged posteriorly
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Clinical History
• History of anaplastic astrocytoma diagnosed 5 years prior • Treated with surgery and chemotherapy • Progression to glioblastoma, IDH1 mutant/ATRX lost, 1 year prior • Treated with Avastin and PD1 inhibitor
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Vitrectomy Specimen
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GFAP OLIG2 IDH1 ATRX (R132H)
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P53 ki67
Diagnosis: Involved by Glioblastoma, IDH1 mutant
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Vitreous involvement by tumor Vitreous involvement by tumor
• LBCL lymphoma • Other tumors with vitreous involvement • Vitreous floaters, visual loss • Retinoblastoma • Elderly patients or younger immunosuppressed patients • Metastatic melanoma • Bilateral 60-90% • DDx infectious process • Manifestation of CNS lymphoma (eye involved before CNS is 50-80%) • Vitreous usually spared in secondary lymphoma
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Tuberous Sclerosis Intraocular Glial Lesions
• Astrocytomas • Syndrome associated (NF1, TSC) ~70%, sporadic ~30% • Astrocytic Hamartoma (NF, TSC) • Massive retinal gliosis (vasoproliferative tumors)
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Glial Hamartoma NF2
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IDH mutant gliomas
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IDH mutant Gliomas IDH mutant Gliomas IDH1 Immunohistochemistry -Recognizes most • “Isocitrate dehydrogenase”(IDH) frequent mutation (R132H) • IDH1: cytosolic form -Works well in formalin • IDH2: mitochondrial form fixed tissues • Converts isocitrate to α-ketoglutarate -Useful diagnostically • Mutation impairs normal function (gliosis vs. infiltrating glioma) • Gains ability to convert α-ketoglutarate to 2HG -Useful prognostically • Mutations frequent in diffuse gliomas, rare in non-CNS tumors (improved prognosis in positive high grade gliomas)
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Mutational Landscape of Somatic Alterations in Lower-Grade Glioma.
The Cancer Genome Atlas Research Network. N Engl J Med 2015;372:2481-2498.
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Biomarkers in Neuro-Ophthalmic Tumors Summary • Testing for BRAF alterations is evolving as an important biomarker for optic pathway gliomas • BRAF duplication/fusion in gliomas of the optic nerve proper • BRAF duplication/fusion or p.V600E in diencephalic tumors • Testing for relevant alterations in meningioma is currently feasible through a variety of next generation sequencing gene panels • Some of these alterations are targetable and being tested in clinical trials
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Biomarkers in Neuro-Ophthalmic Tumors Acknowledgements Summary •Charles Eberhart and Eric Raabe (JH) • A variety of primary or secondary neoplasms may involve the •Ming Lin and molecular Path Lab (JH) • optic nerve and orbit Cheng‐Ying Ho (University of Maryland) • Biomarker testing still guided by specific pathology •Adelita Vizcaino (Ophthalmic Path Fellow, JH)
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Questions?
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