Is primary optic nerve sheath schwannoma a misnomer? Report of two cases and literature review.

Aims: To report clinicopathological characteristics of two patients with optic nerve sheath schwannoma (ONSS) and review the literature. Method: The first patient (22-year-old man) presented with left eye proptosis and decreased vision in 2012 whose orbital imaging showed a large cystic lesion around the optic nerve. The second patient (52-year-old man) presented with decreased vision in the left eye (without proptosis) in the 2006. His imaging showed a small orbital apex lesion between the medial rectus and optic nerve. Both lesions were histopathologically consistent with ONSS. ONSS has previously been reported in 12 patients. Results: Orbital biopsy and subsequently external beam radiotherapy were performed for the first patient who showed a temporary improvement of vision. However, his proptosis progressed and vision decreased to light perception (LP) a few months after radiotherapy when the lesion was resected in April 2013. Second patient declined any procedure until his vision gradually decreased to LP in October 2007. It was then removed through a combined medial and lateral orbitotomy procedure. Both patients ended up with visual acuity of no LP and no recurrence in their last follow up visits in April 2018. No histopathological evidence was found to show that optic nerve sheath could be the origin for presenting and previously reported cases in the literature. Conclusion: Presenting cases and literature review imply that ONSS is a misnomer and all the lesions are different types of orbital schwannomas with optic nerve sheath attachment.

Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights.

Children with neurofibromatosis type 1 (NF1) are predisposed to develop central nervous system neoplasms, the most common of which are low-grade gliomas (LGGs). The absence of human NF1 associated LGG-derived cell lines, coupled with an inability to generate patient-derived xenograft models, represents barriers to profile molecularly targeted therapies for these tumors. Thus, genetically engineered mouse models have been identified to evaluate the interplay between Nf1-deficient tumor cells and nonneoplastic stromal cells to evaluate potential therapies for these neoplasms. Future treatments might also consider targeting the nonneoplastic cells in NF1-LGGs to reduce tumor growth and neurologic morbidity in affected children.

Optic nerve glioma: case series with review of clinical, radiologic, molecular, and histopathologic characteristics.

PURPOSE: This study was designed to better understand the biologic nature of optic nerve gliomas (ONGs) and to investigate staining techniques that might improve the pathologic interpretation of surgical margins. METHODS: In this retrospective case series, clinical data on patient presentation, MRI, surgical visualization, and initial pathologic interpretation were gathered. Specimens were then reexamined using analysis of p53, isocitrate dehydrogenase 1 (IDH1), MIB-1, and B-rapidly accelerated fibrosarcoma (BRAF) duplication. RESULTS: Six patients were studied. All were diagnosed with World Health Organization grade 1 ONGs on original pathology. On reexamination, BRAF tandem duplication was found in 2 patients with neurofibromatosis Type 1 association. P53 immunoreactivity was noted in a third case. No cases had IDH1 immunoreactivity. Focal elevations of MIB-1 up to 7.5% were noted in 2 cases. CONCLUSIONS: ONGs are neoplasms with variable degrees of aggressiveness. As more is understood regarding their varied genetic underpinnings, improved pathologic classification and individualized treatment regimens may be achieved. The authors hope that this study helps guide the oculoplastic community toward a multi-institutional, prospective study of ONG genomic sequencing.

Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system.

Pilocytic astrocytoma is a low-grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is occasionally associated with neurofibromatosis type 1. In earlier studies, this subtype was considered within the larger category of 'optic pathway glioma,' which included infiltrating astrocytomas and other hypothalamic tumors. However, there have been suggestions that gliomas in the optic nerve, and especially pilocytic astrocytoma of the optic nerve, are biologically different from tumors within the hypothalamus and other parts of the optic tract. Furthermore, the recent discovery of BRAF duplication and fusion with the KIAA1549 gene is reported to be more typical for posterior fossa tumors, and the rate of this aberration is not well known in pilocytic astrocytoma of the optic nerve. To determine the distinction of pilocytic astrocytoma of the optic nerve from pilocytic astrocytoma of the posterior fossa and to investigate the prevalence of BRAF aberrations, we reviewed the clinicopathological and molecular features of all such patients in our institution. Our study demonstrates that BRAF duplication is more frequent in posterior fossa tumors compared with pilocytic astrocytoma of the optic nerve (P=0.011). However, the rates of phospho-MAPK1 and CDKN2A expression were high in both pilocytic astrocytoma of the optic nerve and posterior fossa pilocytic astrocytoma, suggesting that the MAPK pathway is active in these tumors. Our study supports the notion that BRAF duplication is more typical of posterior fossa pilocytic astrocytoma and that molecular alterations other than KIAA1549 fusion may underlie MAPK pathway activation in pilocytic astrocytoma of the optic nerve.

Platinum compounds and sodium metabolism in children with diencephalic glioma.

In this brief report we have described eight children affected by optic pathway/hypothalamus gliomas and treated with carboplatin and/or cisplatin, which developed a derangement of sodium and water metabolism, due to diabetes insipidus (DI) or to syndrome of inappropriate antidiuretic hormone secretion (SIADH) after surgical resection. In four out of these eight patients the treatment with platinum compounds produced prolonged haematological toxicity and in five out of them it caused neurosensorial bilateral hypoacusia. In addition cisplatin worsened electrolytes disturbances. Hence children with DI or SIADH should be carefully monitored before, during and after the treatment with platinum compounds.

Growth hormone excess in children with neurofibromatosis type 1-associated and sporadic optic pathway tumors.

OBJECTIVE: To describe the clinical manifestations of growth hormone (GH) excess in children with optic pathway tumors (OPT). STUDY DESIGN: Descriptive case series of 5 children with OPT, 3 with associated neurofibromatosis type 1, referred for evaluation of accelerated linear growth. GH excess was evaluated by oral glucose tolerance tests with frequent sampling of GH levels. Precocious puberty was evaluated by basal luteinizing hormone and sex steroid hormone levels. Stimulation testing with leuprolide acetate (20 µg/kg subcutaneously) was conducted in patients with normal baseline testing. RESULTS: All patients had OPT involving both the hypothalamus and optic chiasm. All patients had elevated levels of the growth factor insulin-like growth factor 1 and on stimulation testing demonstrated an inability to suppress GH levels to < 1.0 ng/mL, indicating the presence of unregulated GH secretion. Additionally, all patients displayed biochemical evidence of precocious puberty. CONCLUSIONS: GH excess may be an under-recognized occurrence in the setting of neurofibromatosis type 1 and OPT. GH excess in such patients may contribute to continued brain tumor growth. Given the potential adverse consequences of unrestrained GH excess, all children with chiasmal or hypothalamic tumors who have rapid growth should be evaluated for both precocious puberty and GH excess.

Somatostatin receptor scintigraphy for optic nerve sheath meningiomas.

OBJECTIVE: To investigate the value of somatostatin receptor scintigraphy (SSRS) in the diagnosis of optic nerve sheath meningiomas (ONSMs). DESIGN: Prospective, comparative case series. PARTICIPANTS: SSRS was used to investigate 68 orbits in 61 patients diagnosed with an orbital tumor. METHODS: Patients were injected intravenously with 200 MBq of indium-111 ((111)In)-octreotide. SSRS with single photon emission computed tomography (SPECT) was performed 24 hours after injection. MAIN OUTCOME MEASURES: The (111)In-octreotide uptake in orbital lesions was determined by semiquantitative uptake-ratio analysis (lesion/brain) on attenuation-corrected transverse SPECT slices. RESULTS: All orbital meningiomas, including 14 ONSMs and 12 spheno-orbital meningiomas, showed high median (111)In-octreotide uptake ratios of 7.2 (range, 4.6-15.4) and 16.3 (range, 4.6-15.4), respectively. In 7 patients with a diagnosis of ONSM, the SSRS uptake ratio was significantly decreased 2.7 (1-6.8) after treatment with 54 Gy of radiotherapy. Median uptake ratios of other tumors were vascular anomalies/vascular tumors, 1.2 (range, 0.5-3.3); non-Hodgkin lymphomas, 2.9 (range, 0.9-4.2); optic nerve gliomas, 1.5 (range, 0.2-3.3); and idiopathic orbital inflammation, 1.6 (range, 1.4-1.9). By using a threshold uptake ratio of 5.9, the sensitivity of SSRS with (111)In-octreotide for ONSM was 100%, with a specificity of 97.2%. CONCLUSIONS: SSRS is a useful additional tool in diagnosing ONSM and has 100% sensitivity and 97% specificity at a threshold uptake ratio of 5.9.

Ocular clusterin expression in von Hippel-Lindau disease.

PURPOSE: Clusterin is a multifunctional glycoprotein. Its mRNA is ubiquitously expressed, with high levels in von Hippel-Lindau (VHL) target organs such as the brain, liver, kidney, and adrenal medulla. Decreased clusterin secretion has been reported in renal cell carcinoma associated with VHL disease. The purpose of this study was to investigate ocular clusterin expression in VHL disease. METHODS: This retrospective case series included nine eyes with retinal hemangioblastoma/hemangioma associated with VHL disease, one eye from a patient with a history of VHL disease and central nervous system hemangioblastomas but without ocular lesions, one surgically-excised optic nerve with optic nerve hemangioblastoma/hemangioma, and three normal control eyes. Ocular specimens were evaluated by routine histology, immunohistochemistry for clusterin expression, and molecular detection of clusterin transcripts within ocular VHL hemangioblastomas compared with normal tissue from the same eye using microdissection and quantitative real-time PCR. RESULTS: All retinal hemangioblastoma were composed of typical VHL tumor cells admixed with small vascular channels as well as glial cells. Marked decrease of clusterin immunoreactivity was detected in all retinal hemangioblastoma and the optic nerve hemangioblastoma, whereas positive clusterin reactivity of the vascular and glial components was similar to that of normal retina. Quantitative real-time PCR analysis confirmed the decrease of clusterin mRNA in the VHL associated retinal hemangioblastoma and optic nerve hemangioblastoma in five cases. CONCLUSIONS: Clusterin shows possible important functions in tumor suppression by the VHL gene product (pVHL) and the potential to be a novel biomarker in retinal hemangioblastoma associated VHL disease. Further investigation of clusterin may provide better understanding of retinal hemangioblastoma associated with VHL disease.

[Diagnosis of pigment-free optic tract tumors: clinical and morphoimmunohistochemical aspects].

The authors present the results of comparison of clinical, instrumental and histological, immunohistochemical and electron microscopic data on two pigment-free ciliochoroidal tumors. Differential diagnosis was made at each of the above stages of diagnosis. There is evidence that despite the similarity of the clinical syndrome, the spindle-cell type of the histological structure of both tumors, the latter were of various histogenesis. This was confirmed by the results of immunohistochemical and electron microscopic studies. Retrospective analysis of the data of immunohistochemical and echographic studies revealed the distinctive signs that could differentiate these two types of tumors at the stage of clinical and instrumental diagnosis.

Orbital granular cell tumours: clinical and pathologic characteristics of six cases and literature review.

OBJECTIVE: To retrospectively assess the clinicopathological characteristics of orbital granular cell tumours (GCTs). METHODS: A non-comparative review of the clinical characteristics, imaging, histopathological features, management, and prognosis of five cases of benign GCT and one case of malignant GCT (MGCT) was conducted, along with a review of the English language literature. RESULTS: Among the six cases, four tumours were adherent to the extraocular muscle (EOM), and three tumours to the optic nerve (ON). Morphologic examinations revealed polygonal cells containing periodic-acid-Schiff-positive eosinophilic granules. All tumours (100%) were positive for VIM and NSE, five (83.3%) tumours were positive for S-100, and three (50%) tumours were positive for CD68. The follow-up examination of the MGCT witnessed recurrence and brain metastasis despite several thorough resections, but the patient remained alive; the follow-up examination of the four benign GCTs that had received incomplete excision revealed recurrence in one patient and dramatic shrinkage of the residual tumour in another; there was no recurrence in the other two patients. CONCLUSIONS: GCT should be considered in the differential diagnosis of orbital tumours, which may affect EOMs and ON. The natural course of GCT can include tumour progression, stability, or spontaneous regression. To avoid recurrence, complete resection is recommended for orbital GCT. To the best of our knowledge, primary orbital MGCT is reported for the first time.

Optic nerve sheath meningioma detected by single- photon emission computed tomography/computed tomography somatostatin receptor scintigraphy: a case report.

BACKGROUND: Optic nerve sheath meningiomas account for only 2% of orbital lesions and 42% of optic nerve tumors. Diagnosis remains difficult because histologic confirmation carries a high risk of visual loss. Therefore, a less invasive and specific diagnostic method for differentiating optic nerve sheath meningiomas from other optic nerve lesions is needed to overcome the limitations of computed tomography and magnetic resonance imaging, and make the best individualized treatment decision. This case is a good illustration of the clinical and imaging difficulties inherent in this rare tumor, which may be hard to differentiate from other causes. CASE PRESENTATION: A 51-year-old Caucasian woman developed a central scotoma, visual loss, and abnormal visual evoked potentials. The first magnetic resonance imaging scan classified the optic nerve damage as retrobulbar optic neuritis. After magnetic resonance imaging follow-up at 3 months, a negative lumbar puncture and biological workup, and clinical worsening, an optic nerve sheath meningioma was suspected. We confirmed this diagnosis with 111In-pentetreotide single-photon emission computed tomography, which is able to bind with very high affinity to somatostatin receptor subtype 2 expressed on meningiomas. CONCLUSIONS: In the diagnosis of optic nerve sheath meningiomas, [111In]-pentetreotide single-photon emission computed tomography-fused magnetic resonance imaging is a valuable additional tool, optimizing the diagnosis and obviating the need for a more invasive procedure.

3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma.

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions. BIOLOGICAL SIGNIFICANCE: The current work addresses a number of challenges in 3-D MALDI IMS, driven by the small size of the mouse optic nerve and the need to maintain consistency across multiple 2-D IMS experiments. The 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions, which could then be targeted for identification and related back to the biology observed in gliomas of the optic nerve.

Expression of stem cells markers in ocular hemangioblastoma associated with von Hippel-Lindau (VHL) disease.

PURPOSE: To better understand the histogenesis of ocular hemangioblastomas associated with von Hippel-Lindau (VHL) disease. METHODS: We found that co-expression of Epo and EpoR may mediate developmental stagnation and induce proliferation of hemangioblastoma. All lesions were frozen and/or fixed in formalin and embedded in paraffin. The specimens were sectioned and subjected to routine histology, immunohistochemistry and molecular analyses. Avidin-biotin-complex immunoperoxidase was used to evaluate the expression of erythropoietin (Epo), Epo receptor (EpoR), CD31, CD34, CD117, and CD133. Ocular hemangioblastoma cells were microdissected in order to determine expression of Epo and EpoR transcripts using reverse transcription-polymerase chain reaction. RESULTS: Tumorlet-like cells were identified in retinal and optic nerve hemangioblastomas. Co-expression of Epo and EpoR at both protein and messenger levels was detected in many hemangioblastoma cells. In addition, ocular VHL lesions expressed several stem cell markers including CD133 to various degrees. CONCLUSIONS: The data suggest that VHL disease-associated ocular hemangioblastomas are comprised of developmentally arrested stem cells including hemangioblasts, endothelial, and neuronal progenitor cells. We found that co-expression of Epo and EpoR may not only mediate developmental stagnation, but may also induce proliferation. Suppression of the growth of AC133/CD133 positive stem cells might be considered as one of the therapeutic targets for VHL-associated hemangioblastoma.

Isolated optic nerve lymphoma diagnosed by optic nerve biopsy.

PURPOSE: To report a case of isolated optic nerve lymphoma diagnosed by optic nerve biopsy. DESIGN: Case report. METHODS: A 66-year-old woman was referred to the Neuro-Ophthalmology Service because of a decrease in visual acuity and right optic disk edema. RESULTS: A magnetic resonance image of the brain showed only enhancement of the optic nerve. An examination that included ANA, c-ANCA, p-ANCA, Lyme titers, FTA-ABS, ACE level, chest x-ray, and lumbar puncture was negative. Because of rapid progression on clinical examination and serial imaging, an optic nerve biopsy was performed, which showed B-cell lymphoma. CONCLUSION: Optic nerve lymphoma can be confused with a variety of inflammatory and neoplastic infiltrations of the optic nerve on clinical and radiographic examinations. Optic nerve biopsy can be valuable in diagnosing isolated optic nerve lymphoma if other diagnostic tests are unrevealing, but the procedure carries considerable risk of loss of visual acuity and should be recommended judiciously.

The impact of coexisting genetic mutations on murine optic glioma biology.

BACKGROUND: Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology. METHODS: Nf1+/- mice were intercrossed with Nf1(flox/flox) mice, which were then crossed with Nf1(flox/flox); GFAP-Cre mice, to generate Nf1(flox/mut); GFAP-Cre (FMC) mice. These mice were additionally mated with conditional KIAA1549:BRAF knock-in or Pten(flox/wt) mice to generate Nf1(flox/mut); f-BRAF; GFAP-Cre (FMBC) mice or Nf1(flox/mut); Pten(flox/wt); GFAP-Cre (FMPC) mice, respectively. The resulting optic gliomas were analyzed for changes in tumor volume, proliferation, and retinal ganglion cell loss. RESULTS: While KIAA1549:BRAF conferred no additional biological properties on Nf1 optic glioma, FMPC mice had larger optic gliomas with greater proliferative indices and microglial infiltration. In addition, all 3 Nf1 murine optic glioma strains exhibited reduced retinal ganglion cell survival and numbers; however, FMPC mice had greater retinal nerve fiber layer thinning near the optic head relative to FMC and FMBC mice. CONCLUSIONS: Collectively, these experiments demonstrate genetic cooperativity between Nf1 loss and Pten heterozygosity relevant to optic glioma biology and further underscore the value of employing genetically engineered mouse strains to define the contribution of discovered molecular alterations to brain tumor pathogenesis.

Second chances.

An 81-year-old woman presented with light perception vision in her left eye and had pallid swelling of the left optic disk. Temporal artery biopsy was normal. Magnetic resonance imaging revealed enlargement and enhancement of the left orbital optic nerve. There were vitreous cells, but a vitrectomy specimen showed only a benign lymphocytic population. Her vision deteriorated to no light perception in the left eye, and an optic nerve biopsy revealed a diffuse astrocytoma of World Health Organization grade II.

Progesterone receptors are expressed with higher frequency by optic nerve sheath meningiomas.

Optic nerve sheath meningiomas are infrequent neuropathological specimens as conservative management of these benign tumors is often adopted. It is established that progesterone receptor expression in meningiomas may be of functional significance in the growth of these neoplasms and is related to the tumor grade and likelihood of recurrence. In addition, progesterone receptor expression can be indicative of a potential response of surgically less accessible meningiomas to hormonal treatments. We analyzed 30 surgically resected optic nerve sheath meningiomas and showed high levels of progesterone receptor expression compared to benign meningiomas from other intracranial sites suggesting these tumors may be amenable to hormonal therapy.

Von Hippel-Lindau gene deletion and expression of hypoxia-inducible factor and ubiquitin in optic nerve hemangioma.

PURPOSE: Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome expressed in multiple organs caused by germline alterations of the VHL gene. We have shown VHL deletion in the "stromal" cells of retinal angiomas. The VHL protein-associated complex is a primary ubiquitin ligase for the ubiquitination of hypoxia-inducible factor (HIF). This study examines VHL and ubiquitin expression in optic nerve hemangiomas and juxtapapillary angiomas. METHODS: Using microdissection and polymerase chain reaction, four optic nerve hemangiomas (one also had juxtapapillary angioma) associated with VHL disease were analyzed for loss of heterozygosity in the VHL gene. In addition, expression of HIF and ubiquitin was evaluated in these tumors by immunohistochemistry. RESULTS: All informative optic nerve and juxtapapillary lesions showed loss of heterozygosity in the VHL gene detected in vacuolated "stromal" cells. Both HIF and ubiquitin were highly expressed in the hemangiomas of all four VHL cases. CONCLUSIONS: Like retinal angiomas and other VHL tumor lesions, VHL gene deletion is found in optic nerve hemangiomas and juxtapapillary angiomas. These tumor cells also express HIF and ubiquitin, the protein responsible for the negative regulation of HIF that results in the hypervascularization characteristic of VHL disease.

Clinical protocols for ³¹P MRS of the brain and their use in evaluating optic pathway gliomas in children.

INTRODUCTION: In vivo (31)P Magnetic Resonance Spectroscopy (MRS) measures phosphorus-containing metabolites that play an essential role in many disease processes. An advantage over (1)H MRS is that total choline can be separated into phosphocholine and glycerophosphocholine which have opposite associations with tumour grade. We demonstrate (31)P MRS can provide robust metabolic information on an acceptable timescale to yield information of clinical importance. METHODS: All MRI examinations were carried out on a 3T whole body scanner with all (31)P MRS scans conducted using a dual-tuned (1)H/(31)P head coil. Once optimised on phantoms, the protocol was tested in six healthy volunteers (four male and two female, mean age: 25±2.7). (31)P MRS was then implemented on three children with optic pathway gliomas. RESULTS: (31)P MRS on volunteers showed that a number of metabolite ratios varied significantly (p<0.05 ANOVA) across different structures of the brain, whereas PC/GPC did not. Standard imaging showed the optic pathway gliomas were enhancing on T1-weighted imaging after contrast injection and have high tCho on (1)H MRS, both of which are associated with high grade lesions. (31)P MRS showed the phosphocholine/glycerophosphocholine ratio to be low (<0.6) which suggests low grade tumours in keeping with their clinical behaviour and the histology of most biopsied optic pathway gliomas. CONCLUSION: (31)P MRS can be implemented in the brain as part of a clinical protocol to provide robust measurement of important metabolites, in particular providing a greater understanding of cases where tCho is raised on (1)H MRS.

Intraocular astrocytoma and its differential diagnosis.

Astrocytomas arising within the eye display 2 distinct histologies: one comprises interlacing bundles of spindle-shaped cells mixed with a minority of polygonal cells, and the other consists of large cells with abundant glassy cytoplasm (gemistocytic astrocytes) indistinguishable from cells found in subependymal giant cell astrocytoma. Both histologic patterns express glial fibrillary acid protein diffusely, are biologically benign, and are frequently associated with dysgenic syndromes, particularly tuberous sclerosis complex. Tumors with gemistocytes, however, demonstrate a greater propensity for invasive growth. The clinical history may provide information to guide the pathologist in distinguishing intraocular astrocytoma from reactive astrocytosis, conditions that are histologically similar. It remains to be determined if other types of primary intraocular glioma exist or whether some degree of ependymal or oligodendroglial differentiation can accompany reactive astrocytosis.