Biomarkers in Neuro-ophthalmic Tumors 12-28-2016 · 3/24/2017 2 Biomarkers in Neuro-Ophthalmic...
Transcript of Biomarkers in Neuro-ophthalmic Tumors 12-28-2016 · 3/24/2017 2 Biomarkers in Neuro-Ophthalmic...
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Biomarkers in Neuro-Ophthalmic TumorsFausto J. Rodríguez MDDepartment of PathologyJohns Hopkins University School of Medicine
Biomarkers in Neuro-Ophthalmic Tumors
Disclosure of Relevant Financial Relationships
USCAP requires that all planners (Education Committee) in a position to
influence or control the content of CME disclose any relevant financial
relationship WITH COMMERCIAL INTERESTS which they or their
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the content of this educational activity and creates a conflict of interest.
Biomarkers in Neuro-Ophthalmic Tumors
Disclosure of Relevant Financial Relationships
Dr. Fausto J. Rodriguez declares his affiliation with Johns Hopkins Pathology and may receive royalties from the Surgical Neuropathology App Illustrated in
Selected Slides
Biomarkers in Neuro-Ophthalmic Tumors
Biomarkers in Neuro-Ophthalmic TumorsOutline
• I-Optic Nerve Glioma• NF1• BRAF alterations• Diencephalic gliomas
• II-Orbital Meningioma• Anatomic and molecular subtypes
• III-Miscellaneous tumors
Biomarkers in Neuro-Ophthalmic Tumors
Optic Nerve Glioma
Variable clinical presentationVisual loss, proptosis, disc swellingFusiform expansionConfined by dural sheath
Predominantly pilocyticastrocytoma histologyObservation currently favored in many cases, particularly in NF1 settingMay stabilize or even regress
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Optic Nerve GliomaPilocytic Astrocytoma (PA) Histology
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Optic Nerve GliomaNeurofibromatosis 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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Neurofibromatosis type 1
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Pilocytic Astrocytoma WHO Grade I
“Piloid Area” Microcystic area
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Pilocytic AstrocytomaRosenthal Fibers EGBs
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Pilocytic AstrocytomaBRAF 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
Biomarkers in Neuro-Ophthalmic TumorsCopyright ©2008 American Association for Cancer Research
Jones, D. T.W. et al. Cancer Res 2008;68:8673-8677
Tandem duplication at 7q34 produces a fusion gene between KIAA1549 and BRAF
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Tandem duplication at 7q34 produces a fusion gene between KIAA1549 and BRAF
CAACT CA GCCTACA TC GGATGCCCA AC TT GA TTAGAGACCAA GG AT TT CGT GG
KIAA1549 (exon 14) BRAF (exon 9)
~2MB
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KIAA1549-BRAF fusions in paraffinFISH strategy
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BRAF duplication in paraffinFISH strategy
BRAF CEP7
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• BRAF duplication in 11 (of 15) patients
Non duplicated:• 1 GG• 3 NF1 patients
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BRAF point mutationsBRAFV600E
• 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 et al. 2011)
• 66% of pleomorphic xanthoastrocytomas• 18% of gangliogliomas• 9% of pilocytic astrocytomas
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BRAF point mutationBRAFV600E
Wild Type BRAFV600E
T A GCT ACA GT G AAA TC AGCTACAGAGAAATCTCG
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BRAF point mutationBRAF p.V600E Immunohistochemistry
Pleomorphic Xanthoastrocytoma
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BRAF point mutationBRAF p.V600E Immunohistochemistry
Ganglioglioma
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Diencephalic Glioma
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Diencephalic GliomaPilomyxoid 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 AstrocytomaChiasm/Hypothalamus
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Diencephalic GliomaPilomyxoid astrocytoma
GFAP
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Clinicopathologic Features of Diencephalic Pediatric Low-Grade Gliomas
Ho C. et al. Acta Neuropathol 2015
• 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
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Clinicopathologic Features of Diencephalic Pediatric Low-Grade Gliomas
Ho C. et al. Acta Neuropathol 2015
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Histologic Features of Diencephalic Pediatric Low-Grade Gliomas
No. of cases (%)BRAFV600-mutant LGG
19 casesBRAFV600-WT PA
21 casesBRAFV600-WT PMA
14 cases
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)
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)
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Clinicopathologic Features of Diencephalic Pediatric Low-Grade Gliomas
Ho C. et al. Acta Neuropathol 2015
a) All ages
b) Age 0-12
a) All ages
b) Age 0-12
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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 glioma proliferation.
Aparna Kaul et al. Neuro Oncol 2015;17:843-853
Sustained MEK inhibition decreases Nf1 mouse optic glioma volume and proliferation.
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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-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Orbital Meningioma
Biomarkers in Neuro-Ophthalmic Tumors
MeningiomasGeneral 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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MeningiomasGeneral 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 MeningiomaBackground
• 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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• 19 orbital meningioma
• WHO grade I (n=17) or grade II (n=2)
• NF2 associated (n=1)
• SNP array (Illumina 300K platform)
• Genomic alterations in 13/19 (68%)
2014
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Orbital Meningioma
Optic Nerve (n=5)
Ectopic Meningioma (n=4)
Sphenoid Wing Meningioma (n=10)
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Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis Defines Three Distinct Subtypes of Orbital Meningioma
Brain PathologyVolume 25, Issue 2, pages 193-201, 21 MAY 2014 DOI: 10.1111/bpa.12150http://onlinelibrary.wiley.com/doi/10.1111/bpa.12150/full#bpa12150-fig-0002
Biomarkers in Neuro-Ophthalmic Tumors
Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis Defines Three Distinct Subtypes of Orbital Meningioma
Brain PathologyVolume 25, Issue 2, pages 193-201, 21 MAY 2014 DOI: 10.1111/bpa.12150http://onlinelibrary.wiley.com/doi/10.1111/bpa.12150/full#bpa12150-fig-0003
Biomarkers in Neuro-Ophthalmic Tumors
Orbital Meningioma
• Sphenoid wing meningioma• Monosomy 22/22q loss in 7 (70%)• 1p, 6q, 19p loss in 5 (50%)• 1p and 6q most frequent in progressive tumors
• 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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Orbital Meningioma
• Non-chromosome 22 alterations• Sphenoid wing 3.2/case• Optic nerve 2.6/case• Ectopic 0.25/case
Biomarkers in Neuro-Ophthalmic Tumors
Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis Defines Three Distinct Subtypes of Orbital Meningioma
Brain PathologyVolume 25, Issue 2, pages 193-201, 21 MAY 2014 DOI: 10.1111/bpa.12150http://onlinelibrary.wiley.com/doi/10.1111/bpa.12150/full#bpa12150-fig-0004
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Genomic architecture of meningiomas
Victoria E. Clark et al. Science 2013;339:1077-1080
Published by AAAS
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MeningiomaRecurrent 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
Biomarkers in Neuro-Ophthalmic Tumors
MeningiomaRecurrent Somatic Mutations
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Case Presentations
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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
• Present with progressive optic disturbance
• Total resection usually not feasible
• Progression in ~ 1/3
• NF1-association or BRAF p.V600E frequent
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Case 2
• 29-year-old male
• Visual disturbances and hypopituitarism
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KIT OCT3/4
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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 CarcinomatosisFavor Gastrointestinal Tract Primary• Secondary optic nerve tumors more common than primary
tumors
• Spread from intraocular tumors (melanoma, retinoblastoma), hematolymphoid neoplasms, metastatic carcinoma
• Metastatic carcinoma may involve optic nerve proper or leptomeninges
• Common types include lung, breast and stomach
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Case 4
• 42-year-old woman with right visual loss
• Blurred vision in right eye for several days
• Visual acuity 20/25 OU, mild right dichromatopsia
• Modest hyperemic optic disc edema on the right with a flat, normal-appearing optic disc on the left
Biomarkers in Neuro-Ophthalmic Tumors
Case 4
• Extraocular motility and the remainder of her neurologic exam unremarkable
• A and B scan: dome-shaped lesion overlying the right optic disc
• Moderate to high internal reflectivity
• Maximal elevation ~3.1mm
• Right retrobulbar optic nerve enlarged posteriorly
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Case 4
• Worsening eye exam
• Vitreous opacity
• R vitrectomy
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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
Biomarkers in Neuro-Ophthalmic Tumors
IDH1 (R132H)
ATRX
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P53 ki67
Biomarkers in Neuro-Ophthalmic Tumors
Diagnosis:Involved by Glioblastoma, IDH1 mutant
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Vitreous involvement by tumor
• LBCL lymphoma• Vitreous floaters, visual loss• Elderly patients or younger immunosuppressed patients• Bilateral 60-90%• Manifestation of CNS lymphoma (eye involved before CNS is 50-80%)• Vitreous usually spared in secondary lymphoma
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Vitreous involvement by tumor
• Other tumors with vitreous involvement• Retinoblastoma• Metastatic melanoma
• DDx infectious process
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Intraocular Glial Lesions
• Astrocytomas• Syndrome associated (NF1, TSC) ~70%, sporadic ~30%
• Astrocytic Hamartoma (NF, TSC)
• Massive retinal gliosis (vasoproliferative tumors)
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Tuberous Sclerosis
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Glial HamartomaNF2
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IDH mutant gliomas
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IDH mutant Gliomas
• “Isocitrate dehydrogenase”(IDH)• IDH1: cytosolic form• IDH2: mitochondrial form
• Converts isocitrate to α-ketoglutarate
• Mutation impairs normal function• Gains ability to convert α-ketoglutarate to 2HG
• Mutations frequent in diffuse gliomas, rare in non-CNS tumors
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IDH mutant GliomasIDH1 Immunohistochemistry
-Recognizes most frequent mutation (R132H)-Works well in formalin fixed tissues-Useful diagnostically(gliosis vs. infiltrating glioma)-Useful prognostically(improved prognosis in positive high grade gliomas)
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The Cancer Genome Atlas Research Network. N EnglJ Med 2015;372:2481-2498.
Mutational Landscape of Somatic Alterations in Lower-Grade Glioma.
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Biomarkers in Neuro-Ophthalmic TumorsSummary• 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
Biomarkers in Neuro-Ophthalmic Tumors
Biomarkers in Neuro-Ophthalmic TumorsSummary• A variety of primary or secondary neoplasms may involve the
optic nerve and orbit
• Biomarker testing still guided by specific pathology
Acknowledgements•Charles Eberhart and Eric Raabe (JH)•Ming Lin and molecular Path Lab (JH)•Cheng‐Ying Ho (University of Maryland)•Adelita Vizcaino (Ophthalmic Path Fellow, JH)
Biomarkers in Neuro-Ophthalmic Tumors
Questions?