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D R P R AV EEN K TR IPAT HI

Optic Pathway and Hypothalamic Glioma

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DEFINITION

The term ‘‘optic pathway glioma’’ is reserved for those tumors confined to the precortical visual pathway, sometimes with the involvement of the hypothalamus.

Their location makes them a surgical challenge. Controversy surrounds the optimal management.

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Epidemiology INCIDENCE1% of all intracranial tumours, 3–5% of paediatric brain tumours

and 6% of all orbital tumours. Gliomas account for two-thirds of all tumours in the optic nerve.About 25% of OPGs are in the optic nerve [Optic nerve glioma

(ONG)] and 60% involve the chiasm (Optic chiasm glioma). Nearly one-third of patients with OPG have neurofibromatosis-1

(NF-1). The mean age at diagnosis was 8.8 years. The male:female ratio is nearly equal but pure optic nerve

tumours are commoner in girls.

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OPTIC NERVE TUMORS

Optic nerve is actually a tract of central nervous system,so primary tumors of the optic nerve are more similar histopathologically to brain tumors than to peripheral nerve tumors.

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PATHOLOGYMacroscopic AppearanceONG can be purely intraorbital or purely intracranial.Often starts in one compartment and spreads to the other

through the optic foramen causing a dumb-bell pattern . The chiasmal variety may diffusely infiltrate the

hypothalamus and the floor of the third ventricle- dubbed as hypothalamic-chiasmatic glioma.

The non-NF-1 OPG in the chiasma may become a large mass and show areas of cystic change.

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Path images

Coronal brain slice through the hypothalamus.A large soft tissue

mass is shown expanding the hypothalamus.Histology exhibited juvenile pilocytic astrocytoma. (Images courtesy of Roy H. Rhodes, MD, PhD. Robert Wood Johnson University Hospital. Department of Pathology.)

Gross Pathology

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Histology: Low-grade Gliomas■Pilocytic astrocytomas

–WHO grade I circumscribed astrocytomas–Biphasic pattern

▪Rosenthal fibersand eosinophilic granular bodies are characteristic

▪Loose-textured astrocytes and microcysts▪Frequently not cystic in the optic pathway ▪The cells are positive for glial fibrillary acidic

protein. ▪A higher microvessel density (as assessed by

immunostaining for factor VIII) is thought to indicate progression

▪Adult patients may harbour anaplastic astrocytoma or glioblastoma multiforme rarely Ganglioglioma 23 May 2016

8 The tumour cells in optic nerve glioma have elongated or hair-like appearance (pilocystic).Hence the name pilocystic astrocytoma.

Rosenthal fibres in optic nerve glioma. These are degenerative  eosinophilic substances found within the cytoplasm of astrocytes. There are characteristic but not diagnostic of optic nerve glioma

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Symptoms at Presentation

Visual disturbances (85%) Headache (23%) Failure to thrive (20%)– Diencephalic syndrome

Nausea and vomiting (14%) Abnormal eye movement (14%) Symptoms of endocrine dysfunction (14%)

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Clinical Signs at Presentation

■ Decreased visual acuity (33%)- early■ Visual field deficit (33%)- bitemporal himeanopia – chiasmal

involvement.■ Optic atrophy (61%) ■ Proptosis

■ Painless axial proptosis is commoner in NF-1 patients with OPG, due to the frequent location of the tumour in the orbit.

■ Painful proptosis is seen only with large tumours and may be due to compression of branches of the ophthalmic div.

■ Abnormal extraocular muscle exam (21%)■ Signs of endocrine abnormalities (21%)■ Ataxia (12%)■ Papilledema (9%) 23 May 2016

Central scotomata altitudinal field defects and hemianopias have all been reported.

At ophthalmoscopy, the optic disk may be normal in appearance; alternatively, edema or atrophy of the optic disk may be present.

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Face photo of a 5-year-old girl who developed noticeable proptosis OD and found to harbor an optic nerve glioma.

(a) The right fundus of a 5-year-old girl with a right optic nerve glioma reveals an optic nerve with mild edema. Her visual acuity was moderately to severely reduced. (b) The left nerve was normal.

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In rare cases, the optic glioma can resolve spontaneously

Survival is typically reduced when hydrocephalus is present.

Foster Kennedy syndrome due to optic glioma presents with unilateral optic atrophy first followed by contralateral papilloedema but no anosmia

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Diencephalic Syndrome

The symptoms of hypothalamic dysfunction in OPG are commoner in non-NF-1 patients.

Emaciation despite normal caloric intake in an alert child is known as the “diencephalic syndrome of infancy”.

Attributed to the dysfunction of the leptin-ghrelin system.The somatic growth rate is normal in spite of the emaciation Normal pituitary hormonal function.Overactivity and pleasantnessEscalating to euphoria & Initial growth accelerationAutonomic disturbance Skin pallor, erratic temperature control, diaphoresis, heat intoleranceSpasmus nutans consists of disconjugate nystagmus, torticollis and

titubation. 23 May 2016

16MALIGNANT GLIOMA OF ADULTHOOD

Since the advent of CT and MRI, the exceedingly rare malignant gliomas of the optic nerve and chiasm are more frequently being diagnosed before death.

Almost invariably, patients present with rapidly progressive unilateral or bilateral visual loss.

Eye pain or headache may accompany the visual loss and blindness occurs within weeks of onset.

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OCHGs and Neurofibromatosis type 1■ Associated with

neurofibromatosis type 1 (NF-1)– 14-40% of NF-1 patients

will develop OCHGs

■ Vast majority of tumors arise prior to six years of age

■ Traditionally– Tumors associated with NF-1

are considered to behave less aggressively

– Higher incidence of spontaneous regression

■ NF-1 not

necessarily protective

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Imaging Characteristics

■General characteristics– Solid, cystic, or combination– Classically described as globular/ exophytic

suprasellar mass■CT– Low-density to isodense– Intense enhancement with contrast■MRI– T1: Low-intensity with marked gadolinium

enhancement- tubular or fusiform nerve in axial– T2: Hyperintense mass■Found to grow postero-superiorly with invagination

of the third ventricle■With lateral progression, may involve the Circle of

Willis

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•-(A and B)(CECT) of a 4-year-old boy without neurofibromatosis-1

•Note the non-uniform enhancement in the suprasellar mass, which fills the thirdventricle.

•The boy underwent right pterional craniotomy and partial excision of chiasmal pilocytic astrocytoma followed bybilateral shunt placement. (C and D) The CECT scans after surgery—note the residual tumour. He was given chemotherapy initially. Radiation was given after he completed 7 years of age.

•(E and F) The CECT scans obtained 5 years after initialpresentation—note the tumour shrinkage. The vision remains stable in the left eye and the growth is near normal

A BC

D E

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MRI(A) Non-contrast coronal magnetic resonance (MR). (B) Contrast sagittal MR of a 20-year-old female with nonneurofibromatosis-1 hypothalamic-chiasmal glioma.

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Fat-suppressed T1 axial MRI, without (A) and with (B) gadolinium showing bulbous enlargement of the right optic nerve (arrow), consistent with an optic nerve glioma.

The right eye is proptotic. Enhancement extended into the optic canal (not shown), but there was no enhancement or enlargement of the chiasm.

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Differenial diagnosis

Pituitary adenomaCraniopharyngiomaGerm cell tumourHypothalamic hamartoma

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Natural History■Natural history of OCHGs is erratic and highly variable

■Debate in the literature▪Congenital, non-neoplastic, self-limiting,

hamartomatous lesions▪Progressive, prone to recurrence, associated with significant

morbidity and mortality

■Ambiguity and inconsistency in the literature– Failure to classify tumors with a consistent/ reproducible

system

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Problems in the Literature: Sources

■The existing literature is derived from a wide range of sources– NF-1 clinics predominately see indolent tumors– Neuro-oncologists and radiation oncologists see mostly

those children with progressive disease– Neuro-ophthalmologists primarily see intra-orbital optic nerve

tumors– Neurosurgeons

▪Typically, patients present to neurosurgical service following the first diagnostic CT or MRI

▪Broad spectrum of disease prior to the evolution of the natural course

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Problems in the Literature: The Importance of Anatomic Location

■Tumors grouped together regardless of anatomic location– Tumors of the optic apparatus– Optic pathway gliomas

■Survival in relation to involvement of the chiasm– Gliomas confined to the optic nerve are amenable to

complete resection with limited morbidity and mortality– Low-grade gliomas confined to the optic nerve

▪85% long-term survival– Low-grade gliomas involving the optic chiasm

▪44% long-term survivalRush et al23 May 2016

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Problems in the Literature: The Importance of Anatomic Location

Survival

Tumor Location 5 years 10 yearsType I (Retrobulbar-prechiasmatic lesions)

100% 88.8%

Type II (Optic tract lesions) 75% 41.6%Type IIIa (Chiasmatic lesions) 87.5% 54.1%Type IIIb (Chiasmatic-hypothalamic lesions)

22.2% 0%

Survival at 5 and 10 Years in Patients with Low-Grade Optic Pathway Gliomas Initially Treated With Radical Resection

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The Dodge Classification Systems for Optic Pathway Gliomas

The Dodge Classification System (DC), 1958

The Modified Dodge Classification (MDC) System, 2008■ The DC breaks down tumors into pre-chiasmatic,

chiasmatic, and post-chiasmatic

■ The MDC provides a more detailed anatomical description based on the images obtained by modern-day MRI.– Not currently in widespread usage

Taylor T, et al.,British Journal of Radiology (2008) 81, 761-766.

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MANAGEMENT

The variables affecting management of OPG age Presence or absence of NF-1, Location in optic pathway, size and symptoms (visual acuity, proptosis, raised pressure).

The available methods of management are observation, surgery, chemotherapy and radiotherapy.

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Observation

Since the growth rate of most OPGs is low, mere watchful expectancy is an acceptable choice of initial management. The wait-and-watch approach applies to Incidentally detected asymptomatic tumours, Small tumours, Patients who have well-preserved vision with little proptosis and Those with NF-1.

The surgeon has to instruct the family about the signs of progression and maintain a meticulous clinical, neuroophthalmic and imaging follow-up.

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Spontaneous Regression

Piccirilli et al., Childs Nerv Syst 2006;22:1332. Parrazzini et al., Am J Neurorad 1995;16:711

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Surgery

In contrast to the cerebellar juvenile pilocytic astrocytoma, surgery plays only a limited role in OPG

Radical surgery has not been proved to increase the length or quality of survival.

Indications for surgery in optic pathway glioma Biopsy for tumours with atypical imaging findings Mass reduction by cyst drainage and tumour decompression for relieving

raised pressure symptoms or neighbourhood compression syndromes Disfiguring or painful proptosis Total excision for orbital optic nerve tumours with total visual loss, so as to

prevent intracranial extension and to provide cure without adjuvant therapies Excision of exophytic masses (mainly chiasmal) Ventricular shunt placement for hydrocephalus

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intraorbital tumours

Biopsy of intraorbital tumours can be performed by Lateral orbitotomy or by fine needle aspiration.

Resection of ONG requires transcranial superior orbitotomy . Transcranial orbitotomy can be done through an eyebrow incision but the

traditional method is to raise a flap from behind the hairline. Removing the superior orbital rim allows a lower trajectory and reduces frontal lobe retraction. The orbital rim may be taken with the frontal bone flap or as a separate

osteotomy piece. Extradural approach is reserved for lesions that do not

extend to the optic canal. Intradural approach is done for gliomas that reach into the

canalicular or the intracranial portions of the optic nerve.23 May 2016

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Approaches for chiasmal hypothalamic glioma

• Subfrontal– Lateral (pterional)– Anterior• Transventricular– Interhemispheric transcallosal– Anterior interhemispheric, trans-lamina terminalis– Endoscopic transventricular

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Enucleation specimen with optic nerve glioma from a patient with NF1.

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Chemotherapy

■Attempt to delay or eliminate need for radiation

■Trial results difficult to compare due to variability in:– Indication to begin treatment– Classification of response to treatment– Evaluation of time to response

■Multiple small studies of single agents in recurrent OCHGs– Show limited rates of tumor regression– Higher rates of disease stabilization– Etoposide (VP16) as example–27% regression rate

–54% disease stabilization23 May 2016

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Chemotherapy

The risks of irradiating young children have caused a swing towards the “chemotherapy-first” approach.

Carboplatin based regimes are the most studied. Packer regimen

Concurrent carboplatin and vincristine in a 10-week induction phase, followed by 48 weeks of maintenance carboplatin/vincristine

Resulted in progression- free survival of 75% at 2 years and 50% at 5 years.

Imaging evidence of tumour shrinkage was seen in 63% of patients . Children 5 years of age or younger had a more favourable rate of

response.Recently, single agent temozolomide therapy has also been

found to be successful. 23 May 2016

40■Front-Line: Vincristine and Carboplatin

– Highest progression free survival– Well-tolerated

■Problems with chemotherapeutic regimens– Carboplatin allergy– Concerns for leukemia with multiple agents

▪Lomustine (CCNU), Procarbazine, Cyclophosphamide, or Etoposide

– High frequency hearing loss with CPPDLafay-Cousin et al., Cancer 2008;112:892

Chemotherapy

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Recent Chemotherapeutic Protocols

■ Temozolomide (Temodar)– Gururangan ’07: N=30, 54% disease

stabilization, 5yr PFS = 30%– Nicholson ’07: N=21, 57% disease

stabilization

■ Vinblastine: N=51, 24% partial response or complete remission, 74% disease stabilization (34/46)– Some with initial minor progression, then responseGururangan et al., Neuro-Oncol

22000077;;99::116611.. Nicholson et al., Cancer 2007;110:1542.Lafay-Cousin et al., Cancer 2005;103:2636 23 May 2016

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Future Potential Regimens■ Target angiogenesis

■ Vascular prolif in PA, increased VEGF■ Avastin/CPT11

■Adult Phase II in Recurrent HGG: 63% resp rate

■Open trial for HGG in PBTC■Packer et al.: 10 Recurrent LGG. 1CR, 5 PR■Thalidomide, Celebrex, Fenofibrate, Oral VP16

■ Target molecular abnormalities■ Activity in H-ras mutants not K-ras defective

pathways (more common in NF1)■ mTOR inhibitor - RAD001■ Multi-institutional trial for Rec-LGG in non-NF1

pts■ NF consortium considering for Rec-OPG

■ CXCR4 G-protein coupled receptor pathway inhibitors – AMD3100, Rolipram (increases cAMP)

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Radiotherapy■ Significant toxicity

– Vision worse in 7-14%– Endocrine dysfunction: Panhypopituitarism, GH deficiency– Cerebrovascular Disease

▪ Moya Moya in 3/5 (60%) NF+, 2/23 (9%) NF- (Kestle ’93 )▪Vascular disease in 11/37 (30%) NF+, 2/32 (6%) NF- (Grill

’99 )■ Secondary tumors■ Neurocognitive Deficits

▪Cappelli ’98: 18/51 (35%), 12 with mental retardation, all had received radiation

▪Lacaze ’03: Mean IQ 19 points lower in the patients receiving radiation

▪Sutton ’95: N=33– 43% in special education (all received RT, mean age 5.7

yrs, only 3 > 6yo)– 57% in regular school (4 no RT) (12 RT, mean age 11yrs, 4

were 5-8yo) 23 May 2016

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Radiotherapy

The recognition of endocrine and cognitive side effects of radiotherapy in young children has made chemotherapy the choice in this age.

69% children below 10 years developed hypothalamic- pituitary endocrine deficiency after radiation

Initial modality in older children >10 year and adults. The standard prescription is 45–50 Gy in 2 Gy daily fractions to the

tumour and the surrounding 0.5–1 cm margin. Progression-free survival probabilities after radiotherapy were 82% at 5 years and

77% at 10 years after radiotherapy for OPG The visual acuity improved in 36%, remained stable in 52% and deteriorated in

12% after radiotherapy in a German series of 25 patients. The risk of developing a second (usually malignant and lethal) tumour after

radiotherapy is real and is more so for NF-1 patients.23 May 2016

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Radiotherapy

Fractionated stereotactic radiotherapy has been recently reported to provide 90% survival at 5 years while reducing the endocrine side effects and the possibility of a second tumour.

There are case reports of gamma knife radiosurgery for OPG.

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Classification of Optic Glioma by Factors Influencing Prognosis

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CONCLUSION

Optic pathway gliomas are slow growing tumours but may behave erratically.

The treatment recommendation is to observe the course and intervene only when one is forced to.

Chemotherapy for younger children and radiotherapy for older patients is effective in achieving long-term tumour control.

Surgery does little to alterthe natural course of the tumour.

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