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Biomarkers in Neuro-Ophthalmic Tumors

Fausto J. Rodríguez MD Johns Hopkins University Biomarkers in Neuro-Ophthalmic Tumors Outline • I-Optic Nerve – NF1 – BRAF alterations – Diencephalic • II-Orbital – Anatomic and molecular subtypes • III-Miscellaneous tumors I-

.Variable clinical presentation .Visual loss, proptosis, disc swelling .Fusiform expansion .Confined by dural sheath .Predominantly pilocytic histology .Observation currently favored in many cases, particularly in NF1 setting .May stabilize or even regress Optic Nerve Glioma (PA) Histology

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. type 1 Pilocytic Astrocytoma WHO Grade I “Piloid Area” Microcystic area Pilocytic Astrocytoma

Rosenthal Fibers EGBs

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., Res, 2008 – Pfister, S., et al., J Clin Invest, 2008 – Sievert, A.J., et al., Brain Pathol, 2008 Tandem duplication at 7q34 produces a fusion gene between KIAA1549 and BRAF

Jones, D. T.W. et al. Cancer Res 2008;68:8673-8677

Jones et al. 2008 Copyright ©2008 American Association for Cancer Research Tandem duplication at 7q34 produces a fusion gene between KIAA1549 and BRAF

~2MB

KIAA1549 (exon 14) BRAF (exon 9)

CAACT CA GCCTACA TC GGATGCCCA AC TT GA TTAGAGACCAA GG AT TT CGT GG KIAA1549-BRAF fusions in paraffin FISH strategy BRAF duplication in paraffin FISH strategy

BRAF CEP7 BRAF duplication/fusion in PA

Rodriguez FJ, Lim KS, Bowers D, Eberhart CG. Ann Rev Pathol 2013 • BRAF duplication in 11 (of 15) patients Non duplicated: • 1 GG • 3 NF1 patients BRAF point mutations BRAFV600E • Frequent in papillary thyroid carcinoma and • Absent to extremely rare in GBM, oligodendroglial tumors, • Present in a subset of low grade/pediatric gliomas (Schindler G et al. 2011) – 66% of pleomorphic xanthoastrocytomas – 18% of – 9% of pilocytic BRAF point mutation V600E Wild Type BRAF BRAFV600E

T A GCT ACA GT G AAA TC AGCTACAGAGAAATCTCG BRAF point mutation BRAF p.V600E Immunohistochemistry

Pleomorphic PXA Xanthoastrocytoma BRAF point mutation BRAF p.V600E Immunohistochemistry

Ganglioglioma

Diencephalic Glioma Gliomas 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 Pilomyxoid Astrocytoma

Chiasm/Hypothalamus Gliomas Pilomyxoid astrocytoma

GFAP Clinicopathologic Features of Diencephalic 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 Clinicopathologic Features of Diencephalic Pediatric Low-Grade Gliomas

Ho C. et al. Acta Neuropathol 2015 Histologic Features of Diencephalic Pediatric Low-Grade Gliomas

BRAFV600-mutant LGG BRAFV600-WT PA BRAFV600-WT PMA No. of cases (%) 19 cases 21 cases 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) Clinicopathologic Features of Diencephalic Pediatric Low-Grade Gliomas

Ho C. et al. Acta Neuropathol 2015

• MEK and Akt pathways activated in Nf1 deficient 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 PI3K inhibition decreases optic nerve volume and Sustained MEK inhibition decreases Nf1 mouse glioma proliferation. optic glioma volume and proliferation.

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]. 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]. II-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 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

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)

Arch Pathol Lab Med 2010 • n=51 intraorbital meningiomas • Mean age 45 years, 5 arose in children • NF2 in two patients • Most commonly meningothelial or transitional • Majority WHO grade I (92%), 4 tumors WHO grade II (8%) 2014

• 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%) Orbital Meningioma

Optic Nerve (n=5)

Ectopic Meningioma (n=4)

Sphenoid Wing Meningioma (n=10) Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis 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-0002 Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis 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-0003 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%) Orbital Meningioma

• Non-chromosome 22 alterations – Sphenoid wing 3.2/case – Optic nerve 2.6/case – Ectopic 0.25/case Genetic Profiling by Single‐Nucleotide Polymorphism‐Based Array Analysis 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 Genomic architecture of meningiomas

Victoria E. Clark et al. Science 2013;339:1077-1080

Published by AAAS

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 Meningioma Recurrent Somatic Mutations III-Miscellaneous Tumors Tuberous Sclerosis Giant Cell Astrocytoma Tuberous Sclerosis Giant Cell Astrocytoma Tuberous Sclerosis Giant Cell Astrocytoma • Inherited tumor predisposition syndrome resulting from mutations in TSC1 or TSC2 genes leading to mTOR pathway activation • Small lesions involving nerve fiber layer of in ~ 50% of TSC patients • Larger lesions may grow and cause • Histologically similar to SEGA Von Hippel Lindau Von Hippel Lindau Hemangioblastoma Von Hippel Lindau Hemangioblastoma • VHL gene encodes VHL protein – E3 ubiquitin ligase – Major regulator of hypoxic response by targeting hypoxia inducible factor (HIF) for degradation • Most common lesion associated with VHL • Clinicopathologic features similar in sporadic and VHL- associated tumors • Cerebellum, spinal cord tumors major CNS manifestations – 60-84% of patients Von Hippel Lindau Retinal Hemangioblastoma • Retinal are typical ocular lesions of VHL disease • Previously referred to as hemangiomas, but histologically identical to CNS counterparts • Multifocal and bilateral • Painless loss of visual acuity or visual field • Hemorrhage, leading to secondary and loss of vision dramatic presentation in some cases Case Presentations 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

SYNAPTOPHYSIN CHROMOGRANIN 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 Case 2

• 29-year-old male • Visual disturbances and hypopituitarism

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 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

CAM5.2 CK20 Leptomeningeal Carcinomatosis Favor 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 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 Biomarkers in Neuro-Ophthalmic Tumors Summary • A variety of primary or secondary neoplasms may involve the optic nerve and orbit • Biomarker testing still guided by specific pathology Questions? Bibliography 1: Ho CY, Mobley BC, Gordish-Dressman H, VandenBussche CJ, Mason GE, Bornhorst M, Esbenshade AJ, Tehrani M, Orr BA, LaFrance DR, Devaney JM, Meltzer BW, Hofherr SE, Burger PC, Packer RJ, Rodriguez FJ. A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation. Acta Neuropathol. 2015 Oct;130(4):575-85.

2: Ho CY, Mosier S, Safneck J, Salomao DR, Miller NR, Eberhart CG, Gocke CD, Batista DA, Rodriguez FJ. Genetic profiling by single-nucleotide polymorphism-based array analysis defines three distinct subtypes of orbital meningioma. Brain Pathol. 2015 Mar;25(2):193-201.

3: Rodriguez FJ, Raabe EH. mTOR: a new therapeutic target for pediatric low-grade glioma? CNS Oncol. 2014 Mar;3(2):89-91.

4: Hütt-Cabezas M, Karajannis MA, Zagzag D, Shah S, Horkayne-Szakaly I, Rushing EJ, Cameron JD, Jain D, Eberhart CG, Raabe EH, Rodriguez FJ. Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target. Neuro Oncol. 2013 Dec;15(12):1604-14.

5: Rodriguez FJ, Lim KS, Bowers D, Eberhart CG. Pathological and molecular advances in pediatric low-grade astrocytoma. Annu Rev Pathol. 2013 Jan 24;8:361-79.

6: Rodriguez FJ, Ligon AH, Horkayne-Szakaly I, Rushing EJ, Ligon KL, Vena N, Garcia DI, Cameron JD, Eberhart CG. BRAF duplications and MAPK pathway activation are frequent in gliomas of the optic nerve proper. J Neuropathol Exp Neurol. 2012 Sep;71(9):789-94.

7: Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. 2008 Sep;67(9):878-87.

8: Jones DT, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz HJ, et al. International Cancer Genome Consortium PedBrain Tumor Project.. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013 Aug;45(8):927-32.

9: Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7.

10: Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008 May;118(5):1739-49.

11: Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, Schmieder K, Wesseling P, Mawrin C, Hasselblatt M, Louis DN, Korshunov A, Pfister S, Hartmann C, Paulus W, Reifenberger G, von Deimling A. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011 Mar;121(3):397-405.

12: Koelsche C, Wöhrer A, Jeibmann A, Schittenhelm J, Schindler G, Preusser M, Lasitschka F, von Deimling A, Capper D. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol. 2013 Jun;125(6):891-900.

13: Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, Resnick AC, Sutton LN, Storm PB, Shaikh TH, Biegel JA. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 2009 Jul;19(3):449-58.

14: Sievert AJ, Lang SS, Boucher KL, Madsen PJ, Slaunwhite E, Choudhari N, Kellet M, Storm PB, Resnick AC. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):5957-62. doi: 10.1073/pnas.1219232110. Erratum in: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8750.

15: Ida CM, Vrana JA, Rodriguez FJ, Jentoft ME, Caron AA, Jenkins SM, Giannini C. Immunohistochemistry is highly sensitive and specific for detection of BRAF V600E mutation in pleomorphic xanthoastrocytoma. Acta Neuropathol Commun. 2013 May 30;1:20.

16: Kaul A, Toonen JA, Cimino PJ, Gianino SM, Gutmann DH. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol. 2015 Jun;17(6):843-53.

17: Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH. Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev. 2012 Dec 1;26(23):2561-6.

18: Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 2005 Apr 1;65(7):2755-60. 19: Clark VE, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013 Mar 1;339(6123):1077-80.

20: www.expertpath.com (Familial Cancer Syndromes)

21: Rolston JD, Han SJ, Cotter JA, El-Sayed IH, Aghi MK. Gangliogliomas of the optic pathway. J Clin Neurosci. 2014 Dec;21(12):2244-9.

22: Fukushima S, Otsuka A, Suzuki T, Yanagisawa T, Mishima K, Mukasa A, Saito N, Kumabe T, Kanamori M, Tominaga T, Narita Y, Shibui S, Kato M, Shibata T, Matsutani M, Nishikawa R, Ichimura K; Intracranial Germ Cell Tumor Genome Analysis Consortium (iGCT Consortium). Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas. Acta Neuropathol. 2014;127(6):911-25

23: Font RL, Croxatto JO, Rao NA. Tumors of the Eye and Ocular Adnexa. AFIP Atlas of Tumor Pathology, Series 4. ARP press. 2006.