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From the Archives of the AFIP

Pediatric Orbit Tumors and Tumorlike Lesions: Neuroepithelial Lesions of the Ocular Globe and Optic Nerve¹

¹ From the Department of Radiologic Pathology (E.M.C.) and Ophthalmic Pathology Section, Department of Neuropathology (C.S.S.), Armed Forces Institute of Pathology, Alaska and Fern streets NW, Washington, DC 20306-6000; and the National Capitol Radiology Consortium, National Naval Medical Center, Bethesda, Md, and Walter Reed Army Medical Center, Washington, DC (J.W.S.). Received January 31, 2007; revision requested April 3 and received May 4; accepted May 4. All authors have no financial relationships to disclose. Address correspondence to E.M.C. (e-mail: chunge{at}afip.osd.mil ).

	Abstract

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
Tumors and tumorlike lesions of the globe and optic nerve in children represent a different histologic spectrum than in adults; the imaging appearances of these lesions reflect their pathologic features. Retinoblastoma is a tumor of infancy and the most common intraocular tumor in children. There are heritable and nonheritable forms. The most common clinical finding is leukocoria. The differential diagnoses of this sign include several nonneoplastic lesions: Persistent hyperplastic primary vitreous is a congenital persistence of an embryonic structure causing a retrolental mass. The primitive vasculature may produce a septum in the posterior chamber. Coats disease is a vascular malformation of the retina that produces a lipoproteinaceous subretinal exudate. The vascular malformation enhances with intravenous contrast material, and the fat-containing subretinal exudate does not. Larval endophthalmitis is a granulomatous reaction to the dead or dying larvae of Toxocara canis or T cati. The most important feature that allows differentiation of retinoblastoma from these so-called pseudoretinoblastomas is the presence of calcification in the former. Medulloepithelioma has two histologic forms; the teratoid type may contain calcifications, but it usually arises anteriorly from the ciliary body rather than posteriorly from the retina. Optic nerve glioma is the most common tumor of the optic nerve in children and is frequently associated with neurofibromatosis type 1. These gliomas are usually pilocytic astrocytomas and cause fusiform enlargement of the nerve.

	LEARNING OBJECTIVES FOR TEST 6

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
After reading this article and taking the test, the reader will be able to:

• Describe the imaging features and pathologic bases of ocular and optic nerve neuroepithelial neoplasms in children.
  
• Identify the features of each of these neoplasms that may allow differentiation from other ocular or optic nerve masses in children.
  
• Discuss the differential diagnosis and management of ocular masses in pediatric patients.
  

	Introduction

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
Intraocular and optic nerve tumors and tumorlike lesions are rare in the pediatric population and comprise a different spectrum of clinical and histologic features than in adults. Most neoplasms of the ocular globe and optic nerve are of neuroepithelial origin. Retinoblastoma is an embryonal tumor arising from the retina in infants. Children with retinoblastoma most commonly present with the clinical sign of white pupillary reflex, or leukocoria, so the differential diagnosis for retinoblastoma includes nonneoplastic causes of leukocoria, including persistent hyperplastic primary vitreous (PHPV), Coats disease, and larval endophthalmitis. The most important feature that allows differentiation of retinoblastoma from these other causes of leukocoria is the presence of calcification.

Medulloepithelioma is a very rare embryonal tumor arising from the medullary epithelium of the ciliary body, which, like retinoblastoma, arises from and is composed of primitive neuroepithelial tumor cells and may also contain calcification. In such cases, radiologic differentiation between these two entities may be quite difficult. When either of these neoplasms is considered, recognition of extraocular extension with imaging studies is of prognostic importance and represents important information for consideration of surgical and adjuvant treatment protocols.

Optic nerve gliomas are the most common neoplasm of the optic nerve in children, usually manifesting in the first decade of life. Almost all are histologically World Health Organization (WHO) grade I pilocytic astrocytomas. These may affect the intraorbital, intracanalicular, or retrocanalicular optic nerve, as well as the optic chiasm. Determination of the extent of this generally well-circumscribed lesion with imaging studies is required for optimal surgical therapy.

Predisposing genetic abnormalities may have important implications for imaging, follow-up, and treatment. Genetic mutations may be associated with both retinoblastoma and optic nerve glioma. In both cases, the children are more likely to have bilateral tumors and are at risk of developing nonocular tumors, especially if the eye tumor is treated with radiation therapy.

In this article, the clinical, pathologic, and imaging features as well as the differential diagnosis and prognosis of these tumors and tumorlike lesions are reviewed, illustrated, and correlated.

	Retinoblastoma

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
Retinoblastoma, though rare, is the most common intraocular tumor of childhood. This aggressive malignant tumor arises from the immature retina and manifests before the age of 5 years. Retinoblastoma accounts for 11% of all cancers in the first year of life (1).

The first description of the tumor now known as retinoblastoma has long been credited to James Waldorp in 1809 (2,3), but the case reported in 1597 by Pieter Pauw of a 3-year-old boy with a fungating eye tumor is likely the first described case of retinoblastoma (2,4). Waldorp was the first to postulate its retinal origin. Virchow considered the tumor to be a glioma of the retina. Flexner in 1881 and Wintersteiner in 1897 both described the characteristic histologic rosettes that bear their names and proposed the designation neuroepithelioma of the retina. The term retinoblastoma was suggested by Verhoeff in the 1920s and adopted by the American Ophthalmological Society (3).

In 1969, Ts’o et al (5) described benign cells within retinoblastomas with a greater degree of histologic differentiation than the Flexner-Wintersteiner rosettes. These cells were organized into configurations similar to small floral bouquets called fleurettes and exhibited features of photoreceptor differentiation. In 1983, Margo et al (6) described completely benign-appearing tumors composed of numerous fleurettes and called these retinocytomas.

Epidemiologic Features
The incidence of retinoblastoma varies little worldwide, ranging from 1:17,000 to 1:24,000 live births (3,7–9). The incidence of retinoblastoma has not changed since 1945 (7). There is no gender or race predilection (1,7,10,11).

There are both heritable and nonheritable forms of retinoblastoma. Bilateral or multifocal tumors occur in patients with heritable retinoblastoma as a manifestation of a germline mutation in the RB gene (3,12). Bilateral tumors account for 20%–34% of cases of retinoblastoma (8,11,13, 14), although the proportion of bilateral tumors in patients younger than age 1 year is higher (1).

In 90%–95% of patients with retinoblastoma, the tumor is diagnosed before the age of 5 years, and the neoplasm rarely occurs in utero (1,11, 15,16). The immature retina is still developing in these young patients. The tumor has very rarely been reported in older children or young adults (1,3,10,17). The age at diagnosis is younger for patients with hereditary retinoblastoma. The mean age at presentation for bilateral tumors is 7–16 months, while that for unilateral tumors is 24–29 months (9,13,18).

Genetics and Pathogenesis
Heritable retinoblastoma accounts for 30%–60% of cases. Ten percent to 30% of these are familial, and the remainder are caused by sporadic (new) germline mutations (3,7–9). Both forms are transmitted to offspring in an autosomal dominant fashion with 90%–95% penetrance (3,19,20).

The cause of all hereditary retinoblastoma is deletion or loss of function of the tumor suppressor gene RB1 on the long arm of chromosome 13 (13q14). RB1 codes for the RB protein (p107), which normally functions to control cell proliferation. The absence of this control permits the development of neoplasia. RB1 was the first tumor suppressor gene ever cloned (21). Although the disease is inherited in an autosomal dominant fashion, the gene mutation itself is recessive, so that loss of function of both alleles is necessary for malignant transformation. According to the "two hit" theory of Knudson (12), the first allelic abnormality, or "hit," is inherited, and the second "hit" is a sporadic somatic mutation.

The "two hit" theory explains the differences between heritable and nonheritable retinoblastoma. Bilateral or multifocal tumors are always associated with heritable disease, and 60%–75% of patients with heritable disease have multiple tumors (3,12). Furthermore, patients with inherited retinoblastoma present earlier than those with nonheritable tumors. Since the first hit in the heritable form is a germ cell mutation, every cell in the body already has the first hit. The second hit occurs in the somatic cell. Although the background mutation rate is low, there are millions of cells in the developing retina. When only one more hit is required to cause neoplastic transformation, it is likely that more than one cell in the retina will become capable of neoplastic growth, hence the propensity for multiple tumors. Moreover, cells in other tissues may also develop the second hit and thus form a second primary tumor. On the other hand, with nonheritable retinoblastoma, there is no germline mutation, and two independent mutations or hits must occur in the same somatic cell. This is unlikely to occur in more than one cell and will take longer to occur, explaining the solitary tumors and older age at presentation in patients with nonheritable disease (3,8).

Patients with RB1 germline mutations are predisposed to the development of additional tumors elsewhere in the body (3,22). The second mutation needed for development of these neoplasms is influenced by environmental factors, including exposure to therapeutic ionizing radiation. Consequently, patients with heritable retinoblastoma are at high risk of developing additional malignancies within the field of external-beam radiation used to treat their bilateral ocular tumors.

The incidence of second malignancy is 30% within the radiation field and 8% outside the field and in untreated patients (8,23). The most common second primary is osteosarcoma, both within and distant from the radiation field, followed in order of decreasing frequency by other sarcomas, melanoma, and carcinomas (23,24). The most common sites of second tumors are the soft tissues of the head, skin, bones, and brain (23,25).

Children with inherited retinoblastoma have an increased risk of primary intracranial neuroblastic tumors that are histologically identical to the retinal tumors. These neoplasms are usually located in the pineal or parasellar regions. In a patient with a history of bilateral retinoblastoma, this syndrome may be called trilateral retinoblastoma, a term coined by Bader et al (26) in 1980, based on the observation that pinealocytes share features with photoreceptor cells. The intracranial tumor is usually diagnosed about 2 years after the ocular tumors (27).

Clinical Features
Leukocoria, in which the normal red reflex of the retina is replaced by a yellowish or grayish white color, occurs in 56%–72% of patients with retinoblastoma and is the most common presenting sign (Fig 1). Retinoblastoma is the most common cause of leukocoria (28,29). Leukocoria may be observed by the child’s family in low light when the pupil reflexively dilates (19,28,30).

View larger version (81K): [in this window] [in a new window] [Download PPT slide]   Figure 1.  Leukocoria in a 2-year-old boy with right retinoblastoma. In the right eye, the normal red pupillary reflex has been replaced by a grayish white reflex. The left eye shows the normal red reflex.

Strabismus (lack of binocular vision) is the second most common presenting sign, occurring in 22%–24% of cases. This symptom occurs in patients with macular lesions and may be noted by family members (9,19,28). Less commonly, children with retinoblastoma may present with visual disturbance, heterochromia iridis, glaucoma, pain, spontaneous hyphema, anisocoria, and periocular inflammation. This periocular inflammation may simulate orbital cellulitis, a common condition affecting the same age group, causing delay in diagnosis.

Funduscopic and Gross Pathologic Findings
Five different patterns of retinoblastoma are recognizable with gross examination. Endophytic tumors grow from the inner, sensory retina toward the vitreous (Figs 2a, 3a). These tumors are well visualized with a funduscope, appearing translucent if small or white if large. Dilated, tortuous vessels typically extend into the tumor. Large tumors may shed cells into the vitreous, and these can proliferate to form small (1–2 cm), cottonlike tumor nodules. If these then seed the retina, they can suggest a true multicentric tumor with the attendant genetic implications (3,9).

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 2a.  Endophytic retinoblastoma in a 2-year-old boy with left leukocoria who had impaired vision in the left eye at ophthalmologic examination. (a) Photograph of the sectioned gross specimen shows a pinkish white mass in the posterior globe that abuts the retina (arrowhead) and has a nodular cut surface. * = lens. (b) Axial unenhanced computed tomographic (CT) image shows the nodular hyperattenuating mass (arrow), which occupies the posterior left globe and contains foci of calcification. (c) Axial T2-weighted magnetic resonance (MR) image shows that the tumor is fairly homogeneous and hypointense relative to the vitreous. (d, e) MR images (d obtained at a higher level than e) acquired with intravenous contrast material but without fat saturation show that the mass is hyperintense relative to the adjacent vitreous.

View larger version (87K): [in this window] [in a new window] [Download PPT slide]   Figure 2b.  Endophytic retinoblastoma in a 2-year-old boy with left leukocoria who had impaired vision in the left eye at ophthalmologic examination. (a) Photograph of the sectioned gross specimen shows a pinkish white mass in the posterior globe that abuts the retina (arrowhead) and has a nodular cut surface. * = lens. (b) Axial unenhanced computed tomographic (CT) image shows the nodular hyperattenuating mass (arrow), which occupies the posterior left globe and contains foci of calcification. (c) Axial T2-weighted magnetic resonance (MR) image shows that the tumor is fairly homogeneous and hypointense relative to the vitreous. (d, e) MR images (d obtained at a higher level than e) acquired with intravenous contrast material but without fat saturation show that the mass is hyperintense relative to the adjacent vitreous.

View larger version (100K): [in this window] [in a new window] [Download PPT slide]   Figure 2c.  Endophytic retinoblastoma in a 2-year-old boy with left leukocoria who had impaired vision in the left eye at ophthalmologic examination. (a) Photograph of the sectioned gross specimen shows a pinkish white mass in the posterior globe that abuts the retina (arrowhead) and has a nodular cut surface. * = lens. (b) Axial unenhanced computed tomographic (CT) image shows the nodular hyperattenuating mass (arrow), which occupies the posterior left globe and contains foci of calcification. (c) Axial T2-weighted magnetic resonance (MR) image shows that the tumor is fairly homogeneous and hypointense relative to the vitreous. (d, e) MR images (d obtained at a higher level than e) acquired with intravenous contrast material but without fat saturation show that the mass is hyperintense relative to the adjacent vitreous.

View larger version (112K): [in this window] [in a new window] [Download PPT slide]   Figure 2d.  Endophytic retinoblastoma in a 2-year-old boy with left leukocoria who had impaired vision in the left eye at ophthalmologic examination. (a) Photograph of the sectioned gross specimen shows a pinkish white mass in the posterior globe that abuts the retina (arrowhead) and has a nodular cut surface. * = lens. (b) Axial unenhanced computed tomographic (CT) image shows the nodular hyperattenuating mass (arrow), which occupies the posterior left globe and contains foci of calcification. (c) Axial T2-weighted magnetic resonance (MR) image shows that the tumor is fairly homogeneous and hypointense relative to the vitreous. (d, e) MR images (d obtained at a higher level than e) acquired with intravenous contrast material but without fat saturation show that the mass is hyperintense relative to the adjacent vitreous.

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Figure 2e.  Endophytic retinoblastoma in a 2-year-old boy with left leukocoria who had impaired vision in the left eye at ophthalmologic examination. (a) Photograph of the sectioned gross specimen shows a pinkish white mass in the posterior globe that abuts the retina (arrowhead) and has a nodular cut surface. * = lens. (b) Axial unenhanced computed tomographic (CT) image shows the nodular hyperattenuating mass (arrow), which occupies the posterior left globe and contains foci of calcification. (c) Axial T2-weighted magnetic resonance (MR) image shows that the tumor is fairly homogeneous and hypointense relative to the vitreous. (d, e) MR images (d obtained at a higher level than e) acquired with intravenous contrast material but without fat saturation show that the mass is hyperintense relative to the adjacent vitreous.

View larger version (106K): [in this window] [in a new window] [Download PPT slide]   Figure 3a.  Endophytic retinoblastoma in a 2-year-old girl with a white pupillary reflex in the right eye. (a) Photograph (hematoxylin-eosin [H-E] stain) of the whole-mount specimen shows a mass growing from the medial retina (arrowhead) toward the vitreous posterior to the lens (curved arrow). Calcifications are seen in the tumor (straight arrow). The tumor does not involve the optic nerve (*). (b) Unenhanced CT image shows the densely calcified mass abutting the retina in the medial right globe.

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 3b.  Endophytic retinoblastoma in a 2-year-old girl with a white pupillary reflex in the right eye. (a) Photograph (hematoxylin-eosin [H-E] stain) of the whole-mount specimen shows a mass growing from the medial retina (arrowhead) toward the vitreous posterior to the lens (curved arrow). Calcifications are seen in the tumor (straight arrow). The tumor does not involve the optic nerve (*). (b) Unenhanced CT image shows the densely calcified mass abutting the retina in the medial right globe.

The fourth pattern is diffuse, infiltrating growth with plaquelike thickening of the retina and is seen in only 1%–2% of retinoblastomas (Fig 4a) (3). The absence of a discrete mass makes diagnosis difficult. Unlike the other types, infiltrating tumors usually lack calcium deposits. Cells may be discharged into the vitreous and seed the anterior chamber, mimicking an inflammatory process (pseudohypopyon) (9).

View larger version (112K): [in this window] [in a new window] [Download PPT slide]   Figure 4a.  Retinoblastoma with an infiltrative growth pattern and optic nerve invasion in a 2-year-old adopted Chinese girl whose parents noted squinting of the right eye. Leukocoria was noted by the referring physician. (a) Photograph (H-E stain) of the whole-mount specimen shows diffuse thickening and nodularity of the detached retina (arrowheads) with extension of the tumor into the optic nerve (arrow). (b) Axial thin-section T2-weighted MR image obtained with fat saturation shows the diffusely nodular detached retina, which is hypointense relative to the vitreous. (c) Axial fat-saturated T1-weighted MR image, obtained by using a surface coil after intravenous administration of gadolinium contrast material, shows that the thickened detached retina is hyperintense relative to the vitreous. Invasion of the optic nerve is also evident (arrowhead).

View larger version (105K): [in this window] [in a new window] [Download PPT slide]   Figure 4b.  Retinoblastoma with an infiltrative growth pattern and optic nerve invasion in a 2-year-old adopted Chinese girl whose parents noted squinting of the right eye. Leukocoria was noted by the referring physician. (a) Photograph (H-E stain) of the whole-mount specimen shows diffuse thickening and nodularity of the detached retina (arrowheads) with extension of the tumor into the optic nerve (arrow). (b) Axial thin-section T2-weighted MR image obtained with fat saturation shows the diffusely nodular detached retina, which is hypointense relative to the vitreous. (c) Axial fat-saturated T1-weighted MR image, obtained by using a surface coil after intravenous administration of gadolinium contrast material, shows that the thickened detached retina is hyperintense relative to the vitreous. Invasion of the optic nerve is also evident (arrowhead).

View larger version (101K): [in this window] [in a new window] [Download PPT slide]   Figure 4c.  Retinoblastoma with an infiltrative growth pattern and optic nerve invasion in a 2-year-old adopted Chinese girl whose parents noted squinting of the right eye. Leukocoria was noted by the referring physician. (a) Photograph (H-E stain) of the whole-mount specimen shows diffuse thickening and nodularity of the detached retina (arrowheads) with extension of the tumor into the optic nerve (arrow). (b) Axial thin-section T2-weighted MR image obtained with fat saturation shows the diffusely nodular detached retina, which is hypointense relative to the vitreous. (c) Axial fat-saturated T1-weighted MR image, obtained by using a surface coil after intravenous administration of gadolinium contrast material, shows that the thickened detached retina is hyperintense relative to the vitreous. Invasion of the optic nerve is also evident (arrowhead).

Retinocytoma, the differentiated, benign form of the tumor, is well circumscribed and has a smooth surface (Fig 5a).

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Figure 5a.  Retinocytoma in a 3-year-old boy with left strabismus and leukocoria. (a) Photograph of the sectioned gross specimen shows a homogeneous white, smooth, biconvex mass (arrowhead) in the posterior pole that abuts the retina. (b) Axial unenhanced CT image shows the smooth, hyperattenuating focal thickening of the posterior retina of the left eye (arrowhead).

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 5b.  Retinocytoma in a 3-year-old boy with left strabismus and leukocoria. (a) Photograph of the sectioned gross specimen shows a homogeneous white, smooth, biconvex mass (arrowhead) in the posterior pole that abuts the retina. (b) Axial unenhanced CT image shows the smooth, hyperattenuating focal thickening of the posterior retina of the left eye (arrowhead).

View larger version (163K): [in this window] [in a new window] [Download PPT slide]   Figure 6.  Retinoblastoma in an 11-month-old boy who was noted by a pediatrician to have leukocoria. Photomicrograph (original magnification, x200; H-E stain) shows sheets of discohesive basophilic cells with scant cytoplasm (*) and foci of calcification in areas of necrosis (arrowheads).

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 7a.  Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye. (a) Photomicrograph (original magnification, x400; H-E stain) shows Flexner-Wintersteiner rosettes with central lumina (straight arrows). Numerous mitotic figures are noted (arrowheads) as well as areas of necrosis (*). Also note the central focus of proliferative vessels with plump endothelial cells (curved arrow). (b) Photomicrograph (original magnification, x20; H-E stain) shows a homogeneous mass of tumor cells in the posterior globe (*) that invade the optic nerve (arrows). (c) Photomicrograph (original magnification, x100; H-E stain) shows basophilic neoplastic cells in the optic disc (*) crossing the lamina cribrosa (arrows) into the optic nerve (arrowheads). (d) Photograph of the sectioned gross specimen shows an irregular whitish mass (*) arising from the thickened retina (arrowhead). (e) Ultrasonographic (US) image obtained with a high-frequency linear transducer shows the heterogeneous, nodular mass (arrow) in the globe apposed to the retina and posterior to the lens (arrowhead). (f) US image shows posterior acoustic shadowing (arrow).

View larger version (166K): [in this window] [in a new window] [Download PPT slide]   Figure 7b.  Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye. (a) Photomicrograph (original magnification, x400; H-E stain) shows Flexner-Wintersteiner rosettes with central lumina (straight arrows). Numerous mitotic figures are noted (arrowheads) as well as areas of necrosis (*). Also note the central focus of proliferative vessels with plump endothelial cells (curved arrow). (b) Photomicrograph (original magnification, x20; H-E stain) shows a homogeneous mass of tumor cells in the posterior globe (*) that invade the optic nerve (arrows). (c) Photomicrograph (original magnification, x100; H-E stain) shows basophilic neoplastic cells in the optic disc (*) crossing the lamina cribrosa (arrows) into the optic nerve (arrowheads). (d) Photograph of the sectioned gross specimen shows an irregular whitish mass (*) arising from the thickened retina (arrowhead). (e) Ultrasonographic (US) image obtained with a high-frequency linear transducer shows the heterogeneous, nodular mass (arrow) in the globe apposed to the retina and posterior to the lens (arrowhead). (f) US image shows posterior acoustic shadowing (arrow).

View larger version (179K): [in this window] [in a new window] [Download PPT slide]   Figure 7c.  Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye. (a) Photomicrograph (original magnification, x400; H-E stain) shows Flexner-Wintersteiner rosettes with central lumina (straight arrows). Numerous mitotic figures are noted (arrowheads) as well as areas of necrosis (*). Also note the central focus of proliferative vessels with plump endothelial cells (curved arrow). (b) Photomicrograph (original magnification, x20; H-E stain) shows a homogeneous mass of tumor cells in the posterior globe (*) that invade the optic nerve (arrows). (c) Photomicrograph (original magnification, x100; H-E stain) shows basophilic neoplastic cells in the optic disc (*) crossing the lamina cribrosa (arrows) into the optic nerve (arrowheads). (d) Photograph of the sectioned gross specimen shows an irregular whitish mass (*) arising from the thickened retina (arrowhead). (e) Ultrasonographic (US) image obtained with a high-frequency linear transducer shows the heterogeneous, nodular mass (arrow) in the globe apposed to the retina and posterior to the lens (arrowhead). (f) US image shows posterior acoustic shadowing (arrow).

View larger version (102K): [in this window] [in a new window] [Download PPT slide]   Figure 7d.  Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye. (a) Photomicrograph (original magnification, x400; H-E stain) shows Flexner-Wintersteiner rosettes with central lumina (straight arrows). Numerous mitotic figures are noted (arrowheads) as well as areas of necrosis (*). Also note the central focus of proliferative vessels with plump endothelial cells (curved arrow). (b) Photomicrograph (original magnification, x20; H-E stain) shows a homogeneous mass of tumor cells in the posterior globe (*) that invade the optic nerve (arrows). (c) Photomicrograph (original magnification, x100; H-E stain) shows basophilic neoplastic cells in the optic disc (*) crossing the lamina cribrosa (arrows) into the optic nerve (arrowheads). (d) Photograph of the sectioned gross specimen shows an irregular whitish mass (*) arising from the thickened retina (arrowhead). (e) Ultrasonographic (US) image obtained with a high-frequency linear transducer shows the heterogeneous, nodular mass (arrow) in the globe apposed to the retina and posterior to the lens (arrowhead). (f) US image shows posterior acoustic shadowing (arrow).

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   Figure 7e.  Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye. (a) Photomicrograph (original magnification, x400; H-E stain) shows Flexner-Wintersteiner rosettes with central lumina (straight arrows). Numerous mitotic figures are noted (arrowheads) as well as areas of necrosis (*). Also note the central focus of proliferative vessels with plump endothelial cells (curved arrow). (b) Photomicrograph (original magnification, x20; H-E stain) shows a homogeneous mass of tumor cells in the posterior globe (*) that invade the optic nerve (arrows). (c) Photomicrograph (original magnification, x100; H-E stain) shows basophilic neoplastic cells in the optic disc (*) crossing the lamina cribrosa (arrows) into the optic nerve (arrowheads). (d) Photograph of the sectioned gross specimen shows an irregular whitish mass (*) arising from the thickened retina (arrowhead). (e) Ultrasonographic (US) image obtained with a high-frequency linear transducer shows the heterogeneous, nodular mass (arrow) in the globe apposed to the retina and posterior to the lens (arrowhead). (f) US image shows posterior acoustic shadowing (arrow).

View larger version (103K): [in this window] [in a new window] [Download PPT slide]   Figure 7f.  Retinoblastoma in a 7-year-old girl who complained of blurry vision in her right eye. (a) Photomicrograph (original magnification, x400; H-E stain) shows Flexner-Wintersteiner rosettes with central lumina (straight arrows). Numerous mitotic figures are noted (arrowheads) as well as areas of necrosis (*). Also note the central focus of proliferative vessels with plump endothelial cells (curved arrow). (b) Photomicrograph (original magnification, x20; H-E stain) shows a homogeneous mass of tumor cells in the posterior globe (*) that invade the optic nerve (arrows). (c) Photomicrograph (original magnification, x100; H-E stain) shows basophilic neoplastic cells in the optic disc (*) crossing the lamina cribrosa (arrows) into the optic nerve (arrowheads). (d) Photograph of the sectioned gross specimen shows an irregular whitish mass (*) arising from the thickened retina (arrowhead). (e) Ultrasonographic (US) image obtained with a high-frequency linear transducer shows the heterogeneous, nodular mass (arrow) in the globe apposed to the retina and posterior to the lens (arrowhead). (f) US image shows posterior acoustic shadowing (arrow).

Some tumors contain regions of cells that are quite differentiated. These cluster to form photoreceptor elements organized into fleurettes. Mitotic figures are few, and necrosis is absent. Tumors composed entirely of such elements are designated retinocytomas. These are the most differentiated neoplasms in the spectrum of retinoblastoma (32,33).

Extraocular Extension and Metastatic Disease
Retinoblastoma, like other embryonal tumors of childhood, behaves aggressively, employing several modes of dissemination. The neoplastic cells are poorly cohesive with a natural tendency to spread. Invasion through the optic disc into the optic nerve is common (Fig 7b). From there, neoplastic cells may then spread into the intracranial optic pathways or breach the pia to reach the subarachnoid space. Invasion of the choroid and sclera may occur with subsequent extension into the orbit, conjunctiva, or eyelid. The risk of distant metastasis increases markedly with extraocular extension. The tumor in the orbit may extend into the cranium through paranasal sinuses or neural foramina. Tumor in the orbit, conjunctiva, or eyelid may gain access to blood and lymphatic vessels. Hematogenous metastases go to the lungs, bones, brain, and other viscera, while lymphatic metastases may be found in regional lymph nodes (3).

In patients with heritable retinoblastoma, tumors histologically very similar to retinoblastoma may occur in the pineal and parasellar region (Fig 8). These represent additional primary tumors of the so-called trilateral retinoblastoma syndrome and should not be confused with metastases. Unlike most metastases, these are solitary lesions and are frequently very well differentiated, with rosettes and fleurettes (34).

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 8a.  Trilateral retinoblastoma in a child of unknown age. (a) Axial CT image enhanced with intravenous contrast material shows bilateral hyperattenuating nodular masses containing dense foci of calcification (arrowheads). (b) Axial CT image enhanced with intravenous contrast material shows a large, round, intensely enhancing mass in the pineal region, which causes hydrocephalus.

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   Figure 8b.  Trilateral retinoblastoma in a child of unknown age. (a) Axial CT image enhanced with intravenous contrast material shows bilateral hyperattenuating nodular masses containing dense foci of calcification (arrowheads). (b) Axial CT image enhanced with intravenous contrast material shows a large, round, intensely enhancing mass in the pineal region, which causes hydrocephalus.

Orbital US has no known risk of adverse biologic effect and is reportedly well tolerated in young children without sedation (35). US is sensitive to calcification, the most important distinguishing feature of retinoblastoma. This modality can show tumor extension through the choroid and optic nerve but is much less sensitive in evaluation for extraocular spread than CT and MR imaging. Evaluation of posterior invasion can be improved through the additional use of a lower-frequency transducer (35). Three-dimensional US techniques may increase the sensitivity and specificity of tumor evaluation with US (36).

Sonographically, most retinoblastomas appear as irregular, solid masses of heterogeneous echogenicity (Fig 7). Seventy-five percent have calcifications detectable at sonography with posterior acoustic shadowing (35). Calcifications are usually focal and may be quite fine. Retinal detachment is readily diagnosed with US and is a common though nonspecific finding in retinoblastoma. Cystic areas may be seen, likely corresponding to necrosis (35). Echogenic foci seen in the vitreous may represent tumor seedlings or particles of hemorrhage (37).

CT has the disadvantage of ionizing radiation and its attendant risk of inducing cataract formation but is the most sensitive imaging examination for calcification. Consequently, CT is the primary modality for evaluation of children with leukocoria. CT also shows choroidal and optic nerve invasion well (38,39) but is less sensitive than MR imaging for intracranial extension.

The findings of retinoblastoma at CT consist of a hyperattenuating mass in the posterior globe (Figs 2, 3). Calcifications are apparent at CT in 95% of cases (38–40). The margin may be smooth or irregular (29). The mass may extend into the vitreous or the subretinal space, causing retinal detachment. Contrast enhancement is seen in 27.5% of cases (38). The size of the globe is normal and symmetric to the contralateral eye.

MR imaging has the advantage of lack of ionizing radiation, but in this age group, the need for sedation is practically universal. MR is less sensitive than CT for calcification, the most specific diagnostic imaging feature of retinoblastoma (39,41,42). MR imaging is more sensitive for extension into the optic pathways and subarachnoid spaces than CT and more sensitive for posterior than anterior tumor extension, particularly vitreous seeding (Fig 4) (43,44). Consequently, MR imaging is the modality of choice for patients with clinical symptoms suggesting intracranial spread and for bilateral eye findings. Furthermore, MR imaging is the modality of choice for follow-up evaluations.

MR examinations should include dedicated orbit imaging and imaging of the entire brain. If there is evidence of subarachnoid spread, then imaging of the spinal canal is also indicated. Dedicated orbit sequences should include gadolinium-enhanced imaging with fat suppression to increase the conspicuity of enhancing tumor within the orbital fat. The use of high-field-strength magnets and surface coils may improve detection of tumor spread (Fig 4).

In general, retinoblastoma follows the signal intensity of gray matter (39). At T1-weighted imaging, the tumor is slightly hyperintense to the ipsilateral vitreous. At T2-weighted imaging, the tumor is most commonly dark compared to the vitreous (Fig 2c) (39,41–43,45). Calcification within the tumor may make the tumor appear heterogeneous. The tumor enhances with intravenous gadolinium contrast material (Fig 2d) (43). Optic pathway invasion is indicated by enhancement and enlargement of the nerve, although reactive gliosis has been reported to cause a similar imaging appearance (Fig 4) (46). Vitreous seedlings, which rarely exceed 1–2 mm in size, are very difficult to diagnose (43,45,46).

Currently, there is no clinical role for positron emission tomography (PET) in evaluation or follow-up of retinoblastoma, but a preliminary study by Moll and colleagues (47) showed that PET allows detection of new retinoblastomas and it is feasible to use PET to evaluate for recurrence in treated patients.

Diffuse, Infiltrative Form
The small percentage of retinoblastomas with the infiltrative growth pattern poses a diagnostic challenge at imaging due to their unusual pathologic appearance (Fig 4). These lack calcification and appear as diffuse retinal thickening without a discrete mass. The retina may be detached. Enhancement with intravenous contrast material is typically uniform. Tiny micronodules may be visualized at US or MR imaging. These plaquelike tumors rarely extend through the choroid or into the optic nerve (39,48).

Differential Diagnosis
Bilateral lesions should be considered retinoblastoma until proved otherwise. The differential diagnosis for unilateral involvement includes other lesions that cause leukocoria in young children. PHPV is a congenital lesion that is due to persistence of fetal vasculature. PHPV may be distinguished from retinoblastoma by the absence of calcification and the presence of microphthalmia. In some cases, the diagnostic finding of a vertical septum between the optic disc and posterior lens allows a confident diagnosis.

Coats disease is a unilateral retinal telangiectasia that produces a lipoproteinaceous exudate in the subretinal space. This condition affects a slightly older age group than does retinoblastoma. In contrast to retinoblastoma, imaging studies reveal no calcifications and no enhancement of the subretinal space in Coats disease.

Toxocara (larval) endophthalmitis is a chronic granulomatous inflammatory response due to Toxocara larvae, which radiologically is nearly identical to Coats disease. Patients are generally over the age of 5 years, and a history of contact with dogs may be elicited. Serologic studies may indicate the proper diagnosis.

Retinopathy of prematurity, or retrolental fibroplasia, was related to excessive oxygen therapy previously used to treat hyaline membrane disease, but is now uncommon due to advances in respiratory therapy and the advent of exogenous surfactant therapy. Although the condition is bilateral, it is asymmetric and rarely calcifies. Affected eyes are small, and there is an associated history of low birth weight. In addition, associated findings of periventricular leukomalacia may be seen in the brain and suggest the appropriate diagnosis (3,29,39,49).

Finally, retinal astrocytic hamartomas of the elevated, nodular type may be calcified. These are called giant drusens and are challenging to differentiate from retinoblastoma; however, these well-circumscribed lesions are confined to the sensory retina or optic disc, generally lack hemorrhage or necrosis, and may be associated with findings of associated tuberous sclerosis or neurofibromatosis type 1 in the brain (29,39).

Treatment and Prognosis
Over the past century, the treatment and prognosis of retinoblastoma in developed countries have changed dramatically. Enucleation had long been the mainstay of therapy, except in cases of bilateral tumors. Previously, patients presented with advanced disease and survival was virtually nil, but more recently patients have been diagnosed much earlier, and 90%–95% of patients survive their retinoblastoma (1,7,9,10,50). In the past two decades, the focus of therapy has shifted from preservation of life to preservation of sight through the development of focal therapies.

Early detection and treatment are imperative to survival with this rapidly growing, aggressive neoplasm. Decreased survival may be associated with the clinical presentation with periocular inflammation (3), which suggests the diagnosis of the much more common orbital cellulitis, leading to delay in tumor diagnosis. Once metastatic disease has developed, the prognosis becomes much worse. Extraocular extension, through the optic nerve or sclera, is the most important risk factor for the development of metastatic disease (14,51–53). The risk from optic nerve involvement increases with the length of penetration. There is no risk of metastases if there is no penetration beyond the lamina cribrosa (9,50,52). Another risk factor is delay of therapy by more than 120 days (8,53).

Patients with heritable disease have lower long-term survival rates due to the increased risk of additional primary cancers associated with germline RB1 mutations. This is especially true for children with bilateral retinoblastoma treated with external-beam radiation. Second primaries in patients with the RB1 mutation have a greater negative impact on survival than does retinoblastoma itself (9). Moll et al (24), in a large registry-based follow-up study, found that the cumulative incidence of second primary tumor in these patients was 3.7% at age 10 years and 17.7% at age 35 years. Radiation greatly increases the risk, especially if administered before 1 year of age (54,55). Eng and coworkers (25) found that 35% of patients treated with external-beam radiation died within 40 years from a second neoplasm compared to only 6% of patients who did not receive radiation. This discovery has led to a drastic reduction in the use of external-beam radiation, which had previously been commonly used to treat bilateral retinoblastoma.

Treatment is best selected on an individual basis by a multidisciplinary team at a center with substantial experience treating this tumor. Selection of treatment is based on the size, location, and extent of the neoplasm. Small tumors, depending on their location relative to the optic disc and macula, are treated with a variety of focal therapies including cryoablation, laser photocoagulation, chemothermotherapy, and brachytherapy or plaque radiation therapy. Larger tumors are treated with chemoreduction followed by local surgical therapy. Tumors larger than half the volume of the globe are still treated with enucleation. Chemotherapy is used in some cases of advanced local disease and in metastatic disease. Use of external-beam radiation is now limited to select advanced cases (8,9).

	Pseudoretinoblastoma

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
The differential diagnosis of retinoblastoma includes several nonneoplastic lesions that also cause leukocoria, the so-called pseudoretinoblastomas. After retinoblastoma, which accounts for 47%–58% of cases of leukocoria, other causes in decreasing order of frequency include PHPV, Coats disease, larval granulomatosis, retinopathy of prematurity, and retinal astrocytic hamartoma (56,57). Before the advent of advanced imaging techniques to differentiate retinoblastoma from pseudoretinoblastoma, a significant number of globes enucleated for suspicion of retinoblastoma were instead affected by pseudoretinoblastoma (3). Now this number is much smaller, but there are still occasional cases with overlapping findings. The infiltrative form of retinoblastoma has no calcification or focal mass, while advanced pseudoretinoblastoma can appear very masslike and can rarely contain calcification.

The main purpose of imaging is to distinguish nonneoplastic causes of leukocoria from retinoblastoma, but imaging is also useful in diagnosing nonneoplastic conditions when ophthalmologic evaluation is limited by opacity in the refractive ocular media, as may occur in any of these conditions.

Persistent Hyperplastic Primary Vitreous
PHPV is caused by persistence and hyperplasia of fibrovascular tissue derived from the embryonic primary vitreous and its hyaloid arterial supply. This condition is the second most common cause of leukocoria, accounting for 19%–28% of cases (56,58).

Epidemiologic and Clinical Findings.— PHPV is congenital and usually noted at birth or within a few weeks of life in healthy term infants, although rare cases manifesting in adults have been reported, and a small minority of patients have associated neurologic or systemic anomalies (59,60). The condition is not hereditary. A predilection for whites is suggested (59,61).

PHPV is unilateral in 90%–98% of cases (59,61,62). Rare bilateral cases of similar findings have been reported in association with Norrie disease, Warburg syndrome, and other neurologic and systemic anomalies (59). The two most common presenting signs are leukocoria and microphthalmia. Less common findings include cataract, strabismus, painful glaucoma, hyphema, and uveitis (59). Microphthalmia is seen in 61%–92% and is marked in bilateral cases (59,61,62). On the other hand, 13% of patients have been reported to have normal-sized globes, and up to 26% may be buphthalmic (59). All bilateral and one-third of unilateral cases have other associated ocular anomalies that may negatively affect their visual prognosis. These eyes are more likely to be more severely microphthalmic (59).

Pathogenesis and Pathologic Findings.— During embryonic life, the primary vitreous extends from the posterior lens to the retina and is gradually replaced by the secondary vitreous, which develops into the definitive vitreous body. The primary vitreous regresses until it occupies only the small, central, S-shaped Cloquet canal between the middle of the posterior lens and the optic disc. When this primitive mesenchymal tissue persists and continues to proliferate, a retrolental mass is formed (Fig 9). The fibrovascular tissue behind the lens varies in extent and thickness. It is densest in the center and may be focal or cover the entire posterior lens. The thickness varies from that of a thin membrane to greater than the thickness of the lens. A constant feature is elongation of the ciliary processes, which may be drawn into the periphery of the mass (59,62, 63). A persistent hyaloid artery may be seen within the Cloquet canal, extending from the optic disc to the center of the posterior lens, in more than one-half of cases (59).

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 9a.  PHPV in a 3-month-old healthy term infant whose mother noted an abnormal left pupil. (a) Photograph (H-E stain) of the whole-mount specimen shows chronic total retinal detachment with leaves of the retina coapted (straight arrow). The subretinal space is filled with eosinophilic serous fluid (curved arrows). The peripheral thickened retina (arrowheads) is adherent to the posterior aspect of the cataractous lens (*). (b) Photomicrograph (original magnification, x20; H-E stain) obtained at a higher magnification shows the dysplastic retina (arrowheads) adherent to a condensation of primary vitreal mesenchymal tissue (*) apposed to the posterior surface of the cataractous lens (arrow). (c) Sagittal T1-weighted MR image of the left eye shows a triangular mass (arrow) abutting the posterior lens and abnormal low signal intensity in the lens. Note also the abnormal increased signal intensity in the subretinal fluid, an appearance possibly due to protein content. (d) Sagittal T1-weighted MR image of the normal right eye shows normal configuration and high signal intensity of the lens (arrow) relative to the vitreous.

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Figure 9b.  PHPV in a 3-month-old healthy term infant whose mother noted an abnormal left pupil. (a) Photograph (H-E stain) of the whole-mount specimen shows chronic total retinal detachment with leaves of the retina coapted (straight arrow). The subretinal space is filled with eosinophilic serous fluid (curved arrows). The peripheral thickened retina (arrowheads) is adherent to the posterior aspect of the cataractous lens (*). (b) Photomicrograph (original magnification, x20; H-E stain) obtained at a higher magnification shows the dysplastic retina (arrowheads) adherent to a condensation of primary vitreal mesenchymal tissue (*) apposed to the posterior surface of the cataractous lens (arrow). (c) Sagittal T1-weighted MR image of the left eye shows a triangular mass (arrow) abutting the posterior lens and abnormal low signal intensity in the lens. Note also the abnormal increased signal intensity in the subretinal fluid, an appearance possibly due to protein content. (d) Sagittal T1-weighted MR image of the normal right eye shows normal configuration and high signal intensity of the lens (arrow) relative to the vitreous.

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   Figure 9c.  PHPV in a 3-month-old healthy term infant whose mother noted an abnormal left pupil. (a) Photograph (H-E stain) of the whole-mount specimen shows chronic total retinal detachment with leaves of the retina coapted (straight arrow). The subretinal space is filled with eosinophilic serous fluid (curved arrows). The peripheral thickened retina (arrowheads) is adherent to the posterior aspect of the cataractous lens (*). (b) Photomicrograph (original magnification, x20; H-E stain) obtained at a higher magnification shows the dysplastic retina (arrowheads) adherent to a condensation of primary vitreal mesenchymal tissue (*) apposed to the posterior surface of the cataractous lens (arrow). (c) Sagittal T1-weighted MR image of the left eye shows a triangular mass (arrow) abutting the posterior lens and abnormal low signal intensity in the lens. Note also the abnormal increased signal intensity in the subretinal fluid, an appearance possibly due to protein content. (d) Sagittal T1-weighted MR image of the normal right eye shows normal configuration and high signal intensity of the lens (arrow) relative to the vitreous.

View larger version (116K): [in this window] [in a new window] [Download PPT slide]   Figure 9d.  PHPV in a 3-month-old healthy term infant whose mother noted an abnormal left pupil. (a) Photograph (H-E stain) of the whole-mount specimen shows chronic total retinal detachment with leaves of the retina coapted (straight arrow). The subretinal space is filled with eosinophilic serous fluid (curved arrows). The peripheral thickened retina (arrowheads) is adherent to the posterior aspect of the cataractous lens (*). (b) Photomicrograph (original magnification, x20; H-E stain) obtained at a higher magnification shows the dysplastic retina (arrowheads) adherent to a condensation of primary vitreal mesenchymal tissue (*) apposed to the posterior surface of the cataractous lens (arrow). (c) Sagittal T1-weighted MR image of the left eye shows a triangular mass (arrow) abutting the posterior lens and abnormal low signal intensity in the lens. Note also the abnormal increased signal intensity in the subretinal fluid, an appearance possibly due to protein content. (d) Sagittal T1-weighted MR image of the normal right eye shows normal configuration and high signal intensity of the lens (arrow) relative to the vitreous.

Imaging Findings.— Imaging findings depend on the size, thickness, and degree of vascularity of the fibrovascular mass and on the presence and extent of secondary findings. US in PHPV demonstrates an echogenic mass of variable size posterior to the lens with a hyperechoic band extending from the posterior pole of the globe to the posterior surface of the retrolental mass, corresponding to the Cloquet canal. The hyaloid artery may be seen in this canal with Doppler imaging. Associated retinal detachment may be seen as an echogenic curvilinear structure within the anechoic vitreous. Occasionally, heterogeneous increased echogenicity is noted in the vitreous, representing hemorrhage (35,65).

CT almost always demonstrates microphthalmos. Usually, a variably sized, cone-shaped retrolental focus of increased attenuation representing the primary vitreous is seen. At the apex, a linear band or septum extending to the posterior pole may be noted, a finding that allows confident diagnosis of PHPV (Fig 10). Occasionally, increased attenuation of the entire vitreous body is seen, likely corresponding to the fibrovascular tissue and blood products related to recurrent hemorrhage. Layered attenuating hemorrhage may be seen in the globe. The layering of the blood products localizes them to the subhyaloid or subretinal space, as blood does not layer in the extremely viscous vitreous humor. The lens may appear abnormally small, lucent, or rounded due to absorption or swelling. Calcification is absent. Administration of intravenous contrast material generally reveals enhancement of the vascular retrolental mass (39,40,49,59,62,63).

View larger version (157K): [in this window] [in a new window] [Download PPT slide]   Figure 10.  PHPV in a 2-year-old boy with an abnormal left eye at examination by a pediatrician. Axial CT image obtained after administration of intravenous contrast material shows a vertical septum posterior to the left lens with anterior tenting of the posterior retina (arrowhead).

Treatment and Prognosis.— Clinically, there are two forms of the condition, depending on which portion of the primary vitreous persists and becomes hyperplastic. The anterior form is supplied by the ciliary artery system and does not have associated posterior ocular abnormalities. This form has a better visual prognosis. In contrast, the posterior form is supplied by the hyaloid artery system and may be associated with a posterior retinal fold or tractional detachment and other abnormalities of the optic disc and macula, leading to a poor visual outcome (59,61). Factors predictive of a better prognosis are lesser extent of the fibrovascular tissue and early age of diagnosis and intervention (60,62).

Untreated PHPV frequently progresses to phthisis bulbi or enucleation due to recurrent intraocular hemorrhage and secondary glaucoma. Surgical efforts to preserve vision are usually unrewarding, except in patients with the anterior form of the disease. In the remainder, the goal of therapy should be to preserve the globe, treat amblyopia, and attain a black pupil for cosmetic reasons (62).

Coats Disease
Coats disease is a congenital, nonhereditary, unilateral vascular malformation of the retina with telangiectasis and aneurysm formation (57).

Pathogenesis.— The underlying abnormality is a breakdown in the blood-retina barrier at the level of the endothelial cell, allowing leakage of blood products into the retina and subretinal space. This fluid contains cholesterol crystals and lipid-laden macrophages. Over time, the accumulation of this lipoproteinaceous fluid thickens the retina and causes massive, exudative retinal detachment (63,66).

Epidemiologic and Clinical Findings.— The peak prevalence of this condition is in children 6–8 years of age (63,67), but the range of age at presentation is quite wide (5 months to 71 years) (67). There is a male predominance of 69%–85%, and the disease is unilateral in 83%–95% of patients. If bilateral, one eye is usually minimally affected (63,67–69). By far the most common presenting sign is leukocoria, but patients may also present with strabismus, painful glaucoma, or loss of vision (63).

Gross Pathologic and Funduscopic Findings.— Early Coats disease manifests as focal areas of retinal telangiectasia, with tortuosity and dilatation of retinal vessels. Peripheral and temporal portions of the retina are affected early (63,69). As the disease progresses, increasing amounts of yellowish fluid are secreted into the retina and subretinal space, causing thickening and massive bullous detachment of the retina, progressively obliterating the vitreous space (Fig 11a). Hemorrhage from the abnormal vessels occasionally occurs (63,68).

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 11a.  Coats disease in an 18-month-old boy with right leukocoria. (a) Photograph of the sectioned gross specimen shows massive retinal detachment with the leaves of the retina apposed (arrow). The vitreous body is obliterated between the leaves of the retina, and the subretinal space (*) is filled with material containing brightly reflecting cholesterol crystals. (b) Photomicrograph (original magnification, x40; H-E stain) shows telangiectatic vessels (arrowheads) in the thickened retina with eosinophilic subretinal serous fluid containing cholesterol clefts (straight arrows), which are elongated spaces left behind by cholesterol crystals dissolved in the fixation process. Curved arrow = lens. (c) Photomicrograph (original magnification, x200; H-E stain) obtained at a higher magnification shows dilated, thin-walled vessels (arrows) in the gliotic retina. Note the intraretinal lipoproteinaceous exudates (*) and the lipid-laden macrophages (arrowheads) in the subretinal serous fluid. (d) Axial unenhanced CT image shows diffuse increased attenuation without calcifications in the vitreous body of the right eye relative to that in the left eye. (e) Axial fat-saturated T1-weighted MR image, obtained after intravenous administration of gadolinium contrast material, shows the V configuration of severely detached leaves of the retina (arrows) with no enhancement of the subretinal space.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   Figure 11b.  Coats disease in an 18-month-old boy with right leukocoria. (a) Photograph of the sectioned gross specimen shows massive retinal detachment with the leaves of the retina apposed (arrow). The vitreous body is obliterated between the leaves of the retina, and the subretinal space (*) is filled with material containing brightly reflecting cholesterol crystals. (b) Photomicrograph (original magnification, x40; H-E stain) shows telangiectatic vessels (arrowheads) in the thickened retina with eosinophilic subretinal serous fluid containing cholesterol clefts (straight arrows), which are elongated spaces left behind by cholesterol crystals dissolved in the fixation process. Curved arrow = lens. (c) Photomicrograph (original magnification, x200; H-E stain) obtained at a higher magnification shows dilated, thin-walled vessels (arrows) in the gliotic retina. Note the intraretinal lipoproteinaceous exudates (*) and the lipid-laden macrophages (arrowheads) in the subretinal serous fluid. (d) Axial unenhanced CT image shows diffuse increased attenuation without calcifications in the vitreous body of the right eye relative to that in the left eye. (e) Axial fat-saturated T1-weighted MR image, obtained after intravenous administration of gadolinium contrast material, shows the V configuration of severely detached leaves of the retina (arrows) with no enhancement of the subretinal space.

View larger version (134K): [in this window] [in a new window] [Download PPT slide]   Figure 11c.  Coats disease in an 18-month-old boy with right leukocoria. (a) Photograph of the sectioned gross specimen shows massive retinal detachment with the leaves of the retina apposed (arrow). The vitreous body is obliterated between the leaves of the retina, and the subretinal space (*) is filled with material containing brightly reflecting cholesterol crystals. (b) Photomicrograph (original magnification, x40; H-E stain) shows telangiectatic vessels (arrowheads) in the thickened retina with eosinophilic subretinal serous fluid containing cholesterol clefts (straight arrows), which are elongated spaces left behind by cholesterol crystals dissolved in the fixation process. Curved arrow = lens. (c) Photomicrograph (original magnification, x200; H-E stain) obtained at a higher magnification shows dilated, thin-walled vessels (arrows) in the gliotic retina. Note the intraretinal lipoproteinaceous exudates (*) and the lipid-laden macrophages (arrowheads) in the subretinal serous fluid. (d) Axial unenhanced CT image shows diffuse increased attenuation without calcifications in the vitreous body of the right eye relative to that in the left eye. (e) Axial fat-saturated T1-weighted MR image, obtained after intravenous administration of gadolinium contrast material, shows the V configuration of severely detached leaves of the retina (arrows) with no enhancement of the subretinal space.

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 11d.  Coats disease in an 18-month-old boy with right leukocoria. (a) Photograph of the sectioned gross specimen shows massive retinal detachment with the leaves of the retina apposed (arrow). The vitreous body is obliterated between the leaves of the retina, and the subretinal space (*) is filled with material containing brightly reflecting cholesterol crystals. (b) Photomicrograph (original magnification, x40; H-E stain) shows telangiectatic vessels (arrowheads) in the thickened retina with eosinophilic subretinal serous fluid containing cholesterol clefts (straight arrows), which are elongated spaces left behind by cholesterol crystals dissolved in the fixation process. Curved arrow = lens. (c) Photomicrograph (original magnification, x200; H-E stain) obtained at a higher magnification shows dilated, thin-walled vessels (arrows) in the gliotic retina. Note the intraretinal lipoproteinaceous exudates (*) and the lipid-laden macrophages (arrowheads) in the subretinal serous fluid. (d) Axial unenhanced CT image shows diffuse increased attenuation without calcifications in the vitreous body of the right eye relative to that in the left eye. (e) Axial fat-saturated T1-weighted MR image, obtained after intravenous administration of gadolinium contrast material, shows the V configuration of severely detached leaves of the retina (arrows) with no enhancement of the subretinal space.

View larger version (146K): [in this window] [in a new window] [Download PPT slide]   Figure 11e.  Coats disease in an 18-month-old boy with right leukocoria. (a) Photograph of the sectioned gross specimen shows massive retinal detachment with the leaves of the retina apposed (arrow). The vitreous body is obliterated between the leaves of the retina, and the subretinal space (*) is filled with material containing brightly reflecting cholesterol crystals. (b) Photomicrograph (original magnification, x40; H-E stain) shows telangiectatic vessels (arrowheads) in the thickened retina with eosinophilic subretinal serous fluid containing cholesterol clefts (straight arrows), which are elongated spaces left behind by cholesterol crystals dissolved in the fixation process. Curved arrow = lens. (c) Photomicrograph (original magnification, x200; H-E stain) obtained at a higher magnification shows dilated, thin-walled vessels (arrows) in the gliotic retina. Note the intraretinal lipoproteinaceous exudates (*) and the lipid-laden macrophages (arrowheads) in the subretinal serous fluid. (d) Axial unenhanced CT image shows diffuse increased attenuation without calcifications in the vitreous body of the right eye relative to that in the left eye. (e) Axial fat-saturated T1-weighted MR image, obtained after intravenous administration of gadolinium contrast material, shows the V configuration of severely detached leaves of the retina (arrows) with no enhancement of the subretinal space.

Imaging Findings.— At US, Coats disease appears as a hyperechoic mass in the posterior vitreous without posterior acoustic shadowing. Vitreous and subretinal hemorrhage are frequently seen (35,65).

CT demonstrates increased attenuation in the globe compared to normal vitreous, due to the proteinaceous subretinal exudate (Fig 11d). The exudate may occupy almost the entire globe and obliterate the vitreous space in advanced cases. There is no calcification. The globe appears normal in size, but volumetric measurements reveal the involved globe to be smaller than the fellow globe in most cases (72). After administration of intravenous contrast material, linear enhancement of the anterior margin of the subretinal exudate is seen, corresponding to the thickened retina with telangiectatic and aneurysmal vessels at pathologic examination. Because the retina is fixed posteriorly at the optic disc, this linear enhancement has a V-shaped configuration. There is no enhancement of the subretinal space (Fig 11) (63).

MR imaging in Coats disease generally reveals the subretinal exudate to be of uniform high signal intensity on both T1- and T2-weighted images due to its high fat content. The presence of hemorrhage or fibrosis may confer a heterogeneous appearance, especially on T2-weighted images. The subretinal space does not enhance after intravenous administration of gadolinium contrast material. There is mild to moderate linear enhancement at the border between the exudate and the remaining vitreous (Fig 11). Proton MR spectroscopy of the lipoproteinaceous exudate demonstrates a large peak at 1–1.6 ppm (73).

Treatment and Prognosis.— Although spontaneous regression has rarely been reported, the typical natural history of Coats disease is progression to visual loss over a variable time course. In early disease, prior to retinal detachment, conservative therapies including photocoagulation, cryoablation, or laser ablation of the abnormal vessels will stabilize the disease and may preserve some useful vision. After retinal detachment, surgical procedures are much less useful. Most patients eventually develop massive retinal detachment and secondary changes, including cataract, painful neovascular glaucoma, and phthisis bulbi, often necessitating enucleation (63,71).

Toxocara Endophthalmitis
Toxocara endophthalmitis, also called ocular larva migrans, is a granulomatous reaction in the vitreous or uvea in response to infestation by the larval form of the nematode T canis or T cati. The definitive host is the domestic dog or cat. The human becomes an aberrant host through ingestion of eggs in fecally contaminated soil or sandboxes. The eggs hatch and the larvae gain entry into the bloodstream through the intestinal wall. These may reach any organ but most commonly infest the liver, lungs, brain, and eye. Ocular involvement tends to occur in the absence of systemic infestation (74).

Epidemiologic Features.— T canis and T cati are distributed worldwide. Children at risk are those who play in parks or sandboxes frequented by domestic animals, especially children with the behavioral derangement of pica. A litter of puppies or kittens at home is another risk factor, as they may acquire the infection transplacentally. Ocular disease usually occurs in children 5–10 years of age (74).

Clinical Features.— Signs and symptoms are caused by hypersensitivity and granulomatous inflammatory reaction to the dead or dying larvae. The most common presenting symptom is unilateral visual impairment. Less frequently, patients present with strabismus, pain, and redness. The infestation can cause diffuse endophthalmitis. Contraction of the reactive mass can cause secondary retinal detachment. Invasion of the retina with granuloma formation distorts the retina and macula. The condition often progresses to blindness. Immunologic studies used to diagnose the systemic form of the disease are less reliable in ocular disease (29,74).

Pathologic Findings.— Although Toxocara infection is in the clinical differential diagnosis of leukocoria, it is pathologically quite distinct from other causes of this sign. The Toxocara larvae may cause a posterior pole granuloma, a peripheral choroidal sclerosing inflammation with distortion of the retina extending into the optic disc, or diffuse endophthalmitis with tractional retinal detachment. Secondary subretinal exudate may also form and detach the retina. Inflammatory change involves the adjacent choroid often with prominence of eosinophils. The larvae themselves are quite small and difficult to detect within the inflammatory reaction (3,75).

Imaging Findings.— Imaging findings in nematode endophthalmitis are nonspecific. The most important finding is the absence of calcification, which allows this condition to be distinguished from retinoblastoma. The size of the globe is normal. At US, an echogenic mass is seen within the vitreous. Retinal detachment or debris within the vitreous may also be apparent (29,65). Often, the CT appearance is identical to that of Coats disease. CT may demonstrate high attenuation with or without a discrete mass (Fig 12). There is no calcification. Secondary retinal detachment is frequently visualized (49,65,75). A report of a case in a 6 year old showed no enhancement of the mass with intravenous injection of contrast material (75).

View larger version (77K): [in this window] [in a new window] [Download PPT slide]   Figure 12.  Toxocara endophthalmitis in a 1-year-old girl. Axial unenhanced CT image shows a nonspecific mass of increased attenuation without calcification in the posterior left globe (arrowhead). (Case courtesy of Charles M. Glasier, MD, Arkansas Children’s Hospital, Little Rock.)

Treatment and Prognosis.— The natural history of untreated ocular larva migrans frequently leads to blindness. The treatment of choice is the antihelminthic albendazole with vitrectomy, as necessary (74).

	Medulloepithelioma

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
Medulloepithelioma (diktyoma or teratoneuroma) is a rare embryonal intraocular neoplasm of young children, arising from primitive medullary epithelium in the ciliary body. As such, it represents a form of primitive neuroepithelial neoplasm. These tumors are classified into nonteratoid and teratoid types, on the basis of an additional component of heteroplastic tissue in the latter. Either type may be benign or malignant based on histologic criteria.

Epidemiologic and Clinical Features
The mean age at diagnosis is 5 years (3,76). Rare cases have been reported manifesting in adulthood (76–78). There is no known gender or racial predilection. The most common presenting symptoms are poor vision and pain. Poor vision is often related to secondary lens subluxation, glaucoma, or cataract formation. The most common signs are leukocoria and a mass of the iris or ciliary body (3,76). Other clinical findings and complaints include lens notching, cataract, exophthalmos, buphthalmos, strabismus, and ptosis. Frequently, there is a significant delay in diagnosis in many of the patients lasting for months or years (3,76,78–80).

Funduscopic and Gross Pathologic Findings
Almost all intraocular medulloepitheliomas are unilateral and arise in the ciliary body. Rarely, they can originate from the optic nerve head or retina (76). The tumor is white, gray, or yellow. The surface is typically irregular, often studded with small visible cysts. Some tumors may have a smooth surface and small internal cysts on the cut section. Sometimes these cysts break off the surface and float freely in aqueous or vitreous humor, a finding seen in up to 60% of cases (77,78). Occasionally, chalky grayish white particles are seen within the fleshy tumor. At histologic examination, these correspond to foci of cartilage. Retinal detachment is seen in many cases (76,78).

In a significant number of patients, a semi-translucent membrane covers the lens. The ciliary processes may be elongated and incorporated into the periphery of the membrane, creating an appearance reminiscent of PHPV. Microscopic evaluation reveals that this membrane is composed of spreading neoplastic cells (78,80). The tumor frequently extends locally to involve the iris or the adjacent anterior retina. Growth within the vitreous is frequently seen in cases of extensive intraocular involvement. The tumor can also invade through the cornea or sclera. In advanced cases, a fungating mass can even fill the entire globe in a manner similar to retinoblastoma.

Histologic Findings
Medulloepithelioma arises from primitive medullary epithelium and exhibits components resembling the embryonic sensory retina or nonpigmented ciliary epithelium. Early in the development of the retina, the medullary epithelial cells acquire polarity. On one side, a basement membrane is formed that becomes the internal limiting membrane of the retina, which is intimately associated with the vitreous. On the opposite side, terminal bars form the outer limiting membrane. Similarly, the proliferating primitive epithelium of medulloepithelioma has the same polarity, and it is arranged in cords and sheets that fold back on themselves. Depending on the direction of the folding, some folds surround fluid collections predominantly composed of hyaluronic acid like vitreous humor, and some folds have no fluid between them (76). This pattern of folded cords and sheets has been thought to resemble a fisherman’s net, the so-called diktyomatous pattern (Fig 13a). The fluid-filled spaces constitute the clinically visible cysts.

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 13a.  Malignant teratoid medulloepithelioma of the optic disc and retina in a 13-month-old girl with right exotropia and intermittent periocular redness. (a) Photomicrograph (original magnification, x400; H-E stain) shows irregular skeins of neoplastic cells arranged in the netlike or diktyomatous pattern (arrow) surrounded by basophilic fluid (*). Residual gliotic retina (R) is noted adjacent to the neoplasm. (b) Axial unenhanced CT image of the right globe shows a posterior hyperattenuating mass without calcification (arrowhead). At pathologic examination, the tumor arose from the posterior retina and optic disc.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   Figure 13b.  Malignant teratoid medulloepithelioma of the optic disc and retina in a 13-month-old girl with right exotropia and intermittent periocular redness. (a) Photomicrograph (original magnification, x400; H-E stain) shows irregular skeins of neoplastic cells arranged in the netlike or diktyomatous pattern (arrow) surrounded by basophilic fluid (*). Residual gliotic retina (R) is noted adjacent to the neoplasm. (b) Axial unenhanced CT image of the right globe shows a posterior hyperattenuating mass without calcification (arrowhead). At pathologic examination, the tumor arose from the posterior retina and optic disc.

Determination of malignancy is made on histopathologic grounds. As described by Broughton and Zimmerman (76), the tumor is classified as malignant if there are areas composed of poorly differentiated neuroblasts, findings of nuclear pleomorphism or markedly abnormal mitotic activity, sarcomatous components, or portions invading the uvea, cornea, or sclera without extraocular extension. Malignant heteroplastic elements may resemble rhabdomyosarcoma, spindle cell sarcoma, or even chondrosarcoma. The majority of tumors are classified as malignant (76,78).

Imaging Findings
US well demonstrates the cystic collections of vitreouslike fluid generally found in medulloepitheliomas and may show calcifications in the teratoid type. Typically, these tumors appear as echogenic, irregularly shaped to ovoid masses (79,80).

At CT, medulloepitheliomas typically appear as dense irregular masses in the region of the ciliary body, although they can arise in the retina (Fig 13). CT is quite sensitive for detecting the dystrophic calcifications that may develop in the hyaline cartilage component found in 30% of teratoid medulloepitheliomas (78,80). Intravenous contrast material administration causes moderate to marked enhancement (81).

MR imaging is sensitive for detection of tumors as small as 2 mm (82). The mass is slightly to moderately hyperintense to vitreous on T1-weighted images and hypointense on T2-weighted images. After intravenous contrast material administration, marked homogeneous enhancement is generally seen, although prominent cystic components can impart a heterogeneous appearance (80).

Differential Diagnosis
Localization of the tumor to the ciliary body suggests the diagnosis of medulloepithelioma, but if the tumor spreads to or arises in the retina and contains dystrophic calcifications, differentiation from retinoblastoma is impossible without histologic examination.

Prognosis
Although most medulloepitheliomas are histologically classified as malignant, and local recurrence leading to eventual enucleation is common, distant metastatic disease and mortality are relatively uncommon. Mortality is rare and occurs in patients with extraocular extension due to intracranial spread rather than systemic metastases (76,78,80).

	Optic Nerve Glioma

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
Most so-called optic nerve gliomas are histologically juvenile pilocytic astrocytomas, WHO grade I (83,84). As these may involve any portion of the optic pathways as well as the hypothalamus, the designation optic pathway/hypothalamic glioma is preferred. These represent 4% of orbital tumors in the AFIP Registry of Ophthalmic Pathology (83). They usually manifest in the first decade of life and represent the most common intraconal tumor of childhood (85). More than half of patients have neurofibromatosis type 1 (NF1), and optic pathway glioma is the most common central nervous system (CNS) neoplasm in NF1.

Epidemiologic Features
The vast majority of patients present in the first two decades of life (83,86). The mean age at diagnosis is 4–5 years (87–91). The mean age at diagnosis of symptomatic patients is slightly younger compared to that of patients found with screening neuroimaging (86,87,91–94). There is a slight female predominance of 60% in the subgroup of optic glioma patients with NF1 (87,93). The racial distribution for optic pathway glioma patients with NF1 is the same as for the general NF1 population, showing a predilection for whites (95).

The relationship between optic pathway tumors and NF1 is well established. The frequency of neurofibromatosis in the population of patients with optic pathway gliomas is 30%–58% (86,88, 90,96–98), while the prevalence of optic pathway gliomas in the NF1 population is between 1.5% and 19%. The lower figures in this range are gleaned from unselected population-based studies and reflect symptomatic cases only (88,90,91, 95,99–101), while the higher estimates are generated from referral center populations and include asymptomatic patients (87,89,95,102,103).

Clinical Features
Optic pathway gliomas are generally slow growing, so that symptoms develop insidiously and may go unrecognized for long periods, especially in very young children. Unsuspected optic pathway tumors may be found in children diagnosed with NF1 at imaging examinations performed for screening or nonophthalmologic CNS symptoms. Listernick et al (89) found that only 20% of patients diagnosed with optic pathway tumor from an unselected NF1 population imaged for nonophthalmologic indications had definitive ophthalmologic abnormalities. Decreased visual acuity is the most common finding at presentation, as the tumor arises within the nerve itself, but young children often do not complain of visual loss despite even marked decreased acuity at ophthalmologic examination (90,91,93,96,103–105). Loss of visual acuity is more common in the sporadic cases than in those associated with NF1 (87,90, 91,93).

An abnormality of the fundus, including optic disc edema, pallor, or atrophy, is the next most common sign (91,93,103). Abnormal pupillary light reflex is also a common finding (93,103). Proptosis is a less common sign in slow-growing tumors like optic glioma (105). Children without NF1 are more likely to present with symptoms of increased intracranial pressure, nystagmus, and strabismus (93,98,103). Astrocytomas of the chiasm and hypothalamus cause endocrinopathies, particularly accelerated linear growth and precocious puberty in NF1 patients (103–105).

Gross Pathologic Findings
Pilocytic astrocytomas can involve any portion of the optic pathway. About half are limited to the intraorbital optic nerve, and most of these occur in children with NF1 (83,86,93,94,98,103). Unilateral tumors are most common, but multifocal or bilateral tumors may occur in association with NF1 and are rare in the absence of NF1 (91,94, 103). Chiasmal involvement is also common in both groups but is more common in the sporadic cases, especially isolated chiasmal involvement (91,93,94,103).

At macroscopic examination, two different architectural forms can be discerned. In the more common form, the tumor diffusely involves the optic nerve, producing fusiform enlargement with minimal infiltration of the leptomeninges (Fig 14a). The boundary between tumor and nerve is often indistinguishable at gross examination. The overlying dura mater is stretched thin but intact. In the second form, the tumor is still contained by dura but infiltrates through the pia mater to predominantly involve the subarachnoid space surrounding the relatively spared nerve (Fig 15a). This pattern should not be interpreted as a sign of malignancy (83,84,86,105).

View larger version (93K): [in this window] [in a new window] [Download PPT slide]   Figure 14a.  Pilocytic astrocytoma of the optic nerve in a 16-year-old girl who complained of progressive loss of vision in the right eye. (a) Photograph of the resected specimen shows fusiform enlargement of the optic nerve. (b) Contrast-enhanced fat-saturated T1-weighted MR image shows the fusiform enhancing mass (arrow) in the right orbital apex. (c) T1-weighted MR image shows enlargement of the isointense right optic nerve (arrow) relative to the normal left optic nerve.

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 14b.  Pilocytic astrocytoma of the optic nerve in a 16-year-old girl who complained of progressive loss of vision in the right eye. (a) Photograph of the resected specimen shows fusiform enlargement of the optic nerve. (b) Contrast-enhanced fat-saturated T1-weighted MR image shows the fusiform enhancing mass (arrow) in the right orbital apex. (c) T1-weighted MR image shows enlargement of the isointense right optic nerve (arrow) relative to the normal left optic nerve.

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 14c.  Pilocytic astrocytoma of the optic nerve in a 16-year-old girl who complained of progressive loss of vision in the right eye. (a) Photograph of the resected specimen shows fusiform enlargement of the optic nerve. (b) Contrast-enhanced fat-saturated T1-weighted MR image shows the fusiform enhancing mass (arrow) in the right orbital apex. (c) T1-weighted MR image shows enlargement of the isointense right optic nerve (arrow) relative to the normal left optic nerve.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 15a.  Pilocytic astrocytoma of the optic pathway in a 5-year-old girl with right proptosis and headaches who was otherwise healthy. (a) Photomicrograph (original magnification, x20; H-E stain) shows a thick layer of neoplastic cells mingled with reactive leptomeningeal tissue (*) between the optic nerve (arrows) and the dura (arrowhead). (b) Photomicrograph (original magnification, x400; H-E stain) of an area of transition between compactly and loosely distributed neoplastic astrocytes shows piloid neoplastic cells with ellipsoid nuclei and long eosinophilic cytoplasmic processes (arrowheads). Note also the eosinophilic piloid Rosenthal fiber (arrow). (c) Photomicrograph (original magnification, x400; H-E stain) shows a curvilinear area of proliferative vessels (arrowheads) surrounding a cystic space (C) adjacent to an area of loosely arranged neoplastic astrocytes (*). (d) Axial T2-weighted MR image shows an intraconal hyperintense oblong mass (*) that causes proptosis on the right. (e) Sagittal T1-weighted MR image shows the bilobed mass of intermediate signal intensity (*) in the intraorbital, intracanalicular, and retrocanalicular portions of the optic nerve. (f) Sagittal fat-suppressed T1-weighted MR image, obtained in the same plane after intravenous administration of gadolinium contrast material, shows marked peripheral enhancement of the mass. The unenhancing central portion corresponded to cystic spaces seen at pathologic examination.

View larger version (141K): [in this window] [in a new window] [Download PPT slide]   Figure 15b.  Pilocytic astrocytoma of the optic pathway in a 5-year-old girl with right proptosis and headaches who was otherwise healthy. (a) Photomicrograph (original magnification, x20; H-E stain) shows a thick layer of neoplastic cells mingled with reactive leptomeningeal tissue (*) between the optic nerve (arrows) and the dura (arrowhead). (b) Photomicrograph (original magnification, x400; H-E stain) of an area of transition between compactly and loosely distributed neoplastic astrocytes shows piloid neoplastic cells with ellipsoid nuclei and long eosinophilic cytoplasmic processes (arrowheads). Note also the eosinophilic piloid Rosenthal fiber (arrow). (c) Photomicrograph (original magnification, x400; H-E stain) shows a curvilinear area of proliferative vessels (arrowheads) surrounding a cystic space (C) adjacent to an area of loosely arranged neoplastic astrocytes (*). (d) Axial T2-weighted MR image shows an intraconal hyperintense oblong mass (*) that causes proptosis on the right. (e) Sagittal T1-weighted MR image shows the bilobed mass of intermediate signal intensity (*) in the intraorbital, intracanalicular, and retrocanalicular portions of the optic nerve. (f) Sagittal fat-suppressed T1-weighted MR image, obtained in the same plane after intravenous administration of gadolinium contrast material, shows marked peripheral enhancement of the mass. The unenhancing central portion corresponded to cystic spaces seen at pathologic examination.

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 15c.  Pilocytic astrocytoma of the optic pathway in a 5-year-old girl with right proptosis and headaches who was otherwise healthy. (a) Photomicrograph (original magnification, x20; H-E stain) shows a thick layer of neoplastic cells mingled with reactive leptomeningeal tissue (*) between the optic nerve (arrows) and the dura (arrowhead). (b) Photomicrograph (original magnification, x400; H-E stain) of an area of transition between compactly and loosely distributed neoplastic astrocytes shows piloid neoplastic cells with ellipsoid nuclei and long eosinophilic cytoplasmic processes (arrowheads). Note also the eosinophilic piloid Rosenthal fiber (arrow). (c) Photomicrograph (original magnification, x400; H-E stain) shows a curvilinear area of proliferative vessels (arrowheads) surrounding a cystic space (C) adjacent to an area of loosely arranged neoplastic astrocytes (*). (d) Axial T2-weighted MR image shows an intraconal hyperintense oblong mass (*) that causes proptosis on the right. (e) Sagittal T1-weighted MR image shows the bilobed mass of intermediate signal intensity (*) in the intraorbital, intracanalicular, and retrocanalicular portions of the optic nerve. (f) Sagittal fat-suppressed T1-weighted MR image, obtained in the same plane after intravenous administration of gadolinium contrast material, shows marked peripheral enhancement of the mass. The unenhancing central portion corresponded to cystic spaces seen at pathologic examination.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 15d.  Pilocytic astrocytoma of the optic pathway in a 5-year-old girl with right proptosis and headaches who was otherwise healthy. (a) Photomicrograph (original magnification, x20; H-E stain) shows a thick layer of neoplastic cells mingled with reactive leptomeningeal tissue (*) between the optic nerve (arrows) and the dura (arrowhead). (b) Photomicrograph (original magnification, x400; H-E stain) of an area of transition between compactly and loosely distributed neoplastic astrocytes shows piloid neoplastic cells with ellipsoid nuclei and long eosinophilic cytoplasmic processes (arrowheads). Note also the eosinophilic piloid Rosenthal fiber (arrow). (c) Photomicrograph (original magnification, x400; H-E stain) shows a curvilinear area of proliferative vessels (arrowheads) surrounding a cystic space (C) adjacent to an area of loosely arranged neoplastic astrocytes (*). (d) Axial T2-weighted MR image shows an intraconal hyperintense oblong mass (*) that causes proptosis on the right. (e) Sagittal T1-weighted MR image shows the bilobed mass of intermediate signal intensity (*) in the intraorbital, intracanalicular, and retrocanalicular portions of the optic nerve. (f) Sagittal fat-suppressed T1-weighted MR image, obtained in the same plane after intravenous administration of gadolinium contrast material, shows marked peripheral enhancement of the mass. The unenhancing central portion corresponded to cystic spaces seen at pathologic examination.

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   Figure 15e.  Pilocytic astrocytoma of the optic pathway in a 5-year-old girl with right proptosis and headaches who was otherwise healthy. (a) Photomicrograph (original magnification, x20; H-E stain) shows a thick layer of neoplastic cells mingled with reactive leptomeningeal tissue (*) between the optic nerve (arrows) and the dura (arrowhead). (b) Photomicrograph (original magnification, x400; H-E stain) of an area of transition between compactly and loosely distributed neoplastic astrocytes shows piloid neoplastic cells with ellipsoid nuclei and long eosinophilic cytoplasmic processes (arrowheads). Note also the eosinophilic piloid Rosenthal fiber (arrow). (c) Photomicrograph (original magnification, x400; H-E stain) shows a curvilinear area of proliferative vessels (arrowheads) surrounding a cystic space (C) adjacent to an area of loosely arranged neoplastic astrocytes (*). (d) Axial T2-weighted MR image shows an intraconal hyperintense oblong mass (*) that causes proptosis on the right. (e) Sagittal T1-weighted MR image shows the bilobed mass of intermediate signal intensity (*) in the intraorbital, intracanalicular, and retrocanalicular portions of the optic nerve. (f) Sagittal fat-suppressed T1-weighted MR image, obtained in the same plane after intravenous administration of gadolinium contrast material, shows marked peripheral enhancement of the mass. The unenhancing central portion corresponded to cystic spaces seen at pathologic examination.

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   Figure 15f.  Pilocytic astrocytoma of the optic pathway in a 5-year-old girl with right proptosis and headaches who was otherwise healthy. (a) Photomicrograph (original magnification, x20; H-E stain) shows a thick layer of neoplastic cells mingled with reactive leptomeningeal tissue (*) between the optic nerve (arrows) and the dura (arrowhead). (b) Photomicrograph (original magnification, x400; H-E stain) of an area of transition between compactly and loosely distributed neoplastic astrocytes shows piloid neoplastic cells with ellipsoid nuclei and long eosinophilic cytoplasmic processes (arrowheads). Note also the eosinophilic piloid Rosenthal fiber (arrow). (c) Photomicrograph (original magnification, x400; H-E stain) shows a curvilinear area of proliferative vessels (arrowheads) surrounding a cystic space (C) adjacent to an area of loosely arranged neoplastic astrocytes (*). (d) Axial T2-weighted MR image shows an intraconal hyperintense oblong mass (*) that causes proptosis on the right. (e) Sagittal T1-weighted MR image shows the bilobed mass of intermediate signal intensity (*) in the intraorbital, intracanalicular, and retrocanalicular portions of the optic nerve. (f) Sagittal fat-suppressed T1-weighted MR image, obtained in the same plane after intravenous administration of gadolinium contrast material, shows marked peripheral enhancement of the mass. The unenhancing central portion corresponded to cystic spaces seen at pathologic examination.

Histologic Findings
Almost all optic pathway gliomas are histologically pilocytic astrocytomas, WHO grade I, and are identical to pilocytic astrocytomas found elsewhere in the CNS (Fig 15). Histologically, these relatively circumscribed tumors are biphasic and consist of varying proportions of compacted bipolar cells and looser multipolar cells. The compact portions are composed of bipolar, spindle-shaped cells with hairlike (pilocytic) processes (Fig 15b). The nuclei are typically uniform and elongated or ovoid. These cells are fibril rich and immunoreactive for glial fibrillary acidic protein. The cells are relatively cohesive and form intersecting bundles that distend the pial septa of the optic nerve.

The cells that form the loose component are multipolar with many short cytoplasmic processes. These have round to oval nuclei and are fibril poor. This pattern is associated with eosinophilic granular bodies as well as microcystic spaces that frequently contain extracellular acid mucopolysaccharides. In cases where these spaces predominate, the tumor is described as myxomatous.

Rosenthal fibers, which are degenerative structures derived from astrocytes, are commonly seen in association with the compact component of the tumor (Fig 15b). These appear as markedly eosinophilic, spherical, cylindrical, or helical swellings containing aggregates of degenerated glial filaments. They are not specific for pilocytic astrocytoma or even for neoplasia, as they may be encountered in reactive gliosis (84,86).

Cystic components are common features. The cyst fluid contains vasculogenic factors, so neovascularity often lines the walls of the cysts (Fig 15c). External to this lining, compacted tissue with Rosenthal fibers is commonly seen. Necrosis is occasionally seen and has no prognostic significance.

Imaging Findings
The appearance at imaging depends on the macroscopic growth pattern of the tumor and the proportion of mucoid or cystic components. The classic appearance at CT or MR imaging is specific and is considered diagnostic of optic pathway glioma. Bilateral tumors are virtually pathognomonic for NF1 (93,102,103,105).

There is little literature regarding the imaging features of optic pathway glioma at US because the tumor is largely inaccessible to that modality. Berrocal et al (35) report that optic nerve glioma appears as a well-defined, homogeneous enlarged optic nerve.

CT allows good evaluation of the optic nerve due to the intrinsic contrast between the nerve and the conal fat, but is less sensitive than MR imaging for intracranial extension. In general, the tumor manifests as iso- to slightly hypoattenuating fusiform enlargement of the optic nerve, sometimes with kinking or tortuosity of its course. Less commonly, the enlargement may be eccentric or a discrete mass may be seen arising from the nerve. High attenuation and calcification are rare (104). Enlargement of the optic canal may be seen with bone windows. Enhancement with intravenous contrast material is variable but may be intense, although less so than generally seen with meningioma (Fig 16). Cystic tumors typically show enhancement of the wall of the cyst, reflecting the mural neovascularity seen at histologic examination (Fig 15) (39,84,85,89).

View larger version (188K): [in this window] [in a new window] [Download PPT slide]   Figure 16.  Optic pathway glioma in a 5-month-old girl with proptosis and afferent pupillary defect in the right eye. Axial CT image obtained after intravenous administration of contrast material shows an enhancing intraconal mass (arrowhead) that causes right proptosis; the mass extends along the optic nerve to involve the chiasm and right optic tract and radiations (arrow). Enhancing tumor surrounds the optic chiasm.

The tumor most commonly causes fusiform, or less commonly eccentric globoid, enlargement of the optic pathway (Figs 14, 15). The size and course of the optic nerve are best evaluated on T1-weighted images without fat saturation. The normal maximum diameter is 5 mm or less in children (39,106). In general, the tumor appears iso- to hypointense to the optic pathway on T1-weighted images and slightly hyperintense on T2-weighted images (107,108). Areas of hemorrhage or calcification are rare (108).

Enhancement with intravenous gadolinium is quite variable and is seen in slightly more than half of cases (104). MR images obtained with intravenous contrast material allow differentiation of the two architectural forms of optic pathway tumors. In the diffuse type, which grows predominantly within the optic nerve parenchyma, the nerve is enlarged and the surrounding subarachnoid space is effaced; in the other form, enhancing tumor in the subarachnoid space surrounds the normal-sized, minimally enhancing optic nerve. Dural ectasia, commonly seen in NF1, should not be confused with involvement of the subarachnoid space by tumor. In dural ectasia, the enlarged subarachnoid space is filled with fluid that follows the signal intensity of cerebrospinal fluid and does not enhance (39). Posterior extension of the tumor may be visible only at postcontrast imaging (Fig 16) (85,108). Involvement of the intracanalicular and retrocanalicular portions of the optic nerve has important implications regarding treatment (Fig 15). Extension posterior to the lateral geniculate bodies into the optic radiations is rare (85).

Some imaging findings of optic pathway tumors differ between children with and without associated neurofibromatosis. Bilateral optic nerve tumors are pathognomonic for NF1 (Fig 17). Isolated optic nerve involvement is much more common in patients with NF1, while chiasmal involvement and extension beyond the optic pathways are more common in children without NF1 (94). The tumor causes thickening or enlargement of the optic pathway without altering its configuration in over 90% of patients with neurofibromatosis (Fig 17) but in only a small minority of patients without NF1 (94). The presence of cystic components is significantly more common in children without neurofibromatosis, and these components may predominate (Fig 15). Cystic components are seen at imaging in less than 10% of patients with NF1 (94,104). The diameter and volume of the tumor are greater in non-NF1 cases (94), and the additional finding of hydrocephalus is almost exclusive to patients without NF1 (94,103).

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 17a.  Bilateral optic pathway gliomas in a 2-year-old boy with NF1. (a) Axial T2-weighted MR image shows diffuse enlargement and tortuosity of both optic nerves (arrows). Also note the ill-defined foci of T2 prolongation in the pons (arrowhead), which are consistent with neurofibromatosis spots. (b) Coronal T2-weighted MR image shows T2 prolongation within the enlarged optic nerves (arrows).

View larger version (127K): [in this window] [in a new window] [Download PPT slide]   Figure 17b.  Bilateral optic pathway gliomas in a 2-year-old boy with NF1. (a) Axial T2-weighted MR image shows diffuse enlargement and tortuosity of both optic nerves (arrows). Also note the ill-defined foci of T2 prolongation in the pons (arrowhead), which are consistent with neurofibromatosis spots. (b) Coronal T2-weighted MR image shows T2 prolongation within the enlarged optic nerves (arrows).

Differential Diagnosis
Because the imaging appearance of optic pathway glioma involving the optic nerves is so specific, the differential diagnosis is quite limited. Optic nerve sheath meningiomas are generally found in patients of middle age but occasionally occur in childhood. These are different from gliomas at CT because they are typically hyperattenuating, whereas gliomas are iso- or hypoattenuating. They also may have plaquelike calcifications, which are absent in gliomas. At MR imaging, meningiomas may appear dark on T2-weighted images while gliomas are slightly hyperintense. Also, their origin from the meninges rather than the nerve is usually apparent with the superior tissue resolution of MR imaging. In addition, meningiomas generally enhance intensely after administration of intravenous contrast material, while gliomas enhance less, if at all.

Treatment and Prognosis
The natural history of optic pathway gliomas is quite variable, and there are no pathologic or radiologic criteria that can be used to predict the biologic behavior of a given tumor; however, optic pathway tumors are more likely to remain stable or grow slowly in patients with NF1 than in patients without NF1. Some tumors behave aggressively and may even cause mortality due to complications of local growth, especially those involving the chiasm in non-NF1 patients (96, 102,104,109,110). Conversely, several reports exist of spontaneous regression (104,109,111). Nevertheless, most optic pathway gliomas grow slowly or remain stable for long periods. Many studies comparing clinical and radiologic progression of optic pathway glioma in patients with and without NF1 have shown a more indolent course in NF1 patients (87,93,94,96,98,103,112). On the other hand, series with large numbers of neurofibromatosis patients and long follow-up intervals have shown that up to half of patients eventually show progression and require therapy (91, 98). Overall 5-year survival is about 87%–97% for all patients (96,102,104,110).

Patients with NF1 and optic pathway glioma are at baseline increased risk of developing a second CNS neoplasm (113) and at greater risk if treated with radiation (90). Sharif et al (114) reported that the relative risk of developing a second CNS neoplasm after radiation therapy for optic pathway tumor was 5.53 for NF1 patients under the age of 15 years compared to NF1 patients not treated with radiation. The median time between diagnosis of the optic pathway tumor and the development of the second tumor was 12 years. Secondary intracranial tumors in irradiated patients are frequently high grade (114). There have also been reports of development of malignant peripheral nerve sheath tumors after radiation (84,90,103,104,114).

Recommendation for screening neuroimaging in children diagnosed with neurofibromatosis without ophthalmologic symptoms is quite controversial. The most recent National Institutes of Health consensus report on neurofibromatosis and report of the optic pathway glioma task force do not promote screening neuroimaging but rather regular ophthalmologic examinations. The rationale for this recommendation is that optic pathway gliomas are not treated until clinical signs and symptoms develop, so earlier diagnosis does not alter patient management (105,113). On the other hand, some authors advocate screening neuroimaging in selected patient populations, for example, very young children, who rarely complain about visual deficits and who are difficult to examine clinically.

Because of their tendency to follow an indolent course, optic pathway gliomas in NF1 are generally managed conservatively. Patients are closely followed up with ophthalmologic examination and neuroimaging, and treatment is withheld until clinical or radiologic progression is noted. Up to half of cases will progress and require therapy to preserve visual function (91). Patients without neurofibromatosis are almost always symptomatic, and, given the likelihood of progression, they are usually treated at the time of diagnosis.

The most appropriate mode of therapy depends on the location of the tumor, the age of the patient, and the presence or absence of NF1. Surgical resection is generally reserved for patients with unilateral anterior pathway tumors with severe visual loss and proptosis. Otherwise, patients are treated with either chemotherapy or radiation therapy. Radiation therapy is highly effective but is reserved for patients over 5 years of age due to increased risk of endocrinopathies and cognitive deficits in this age group. Radiation therapy is now used only very selectively in patients with NF1 because the risk of tumor progression does not outweigh the risks of secondary tumor induction and cerebral vasculopathies in these patients (92,104,114). Chemotherapy is effective in young children in delaying the need for radiation therapy until they are out of the age range at greatest risk, although 60% experience relapse (96).

	Conclusions

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Retinoblastoma Pseudoretinoblastoma Medulloepithelioma Optic Nerve Glioma Conclusions References

 
The imaging features of the tumors and tumorlike lesions of the globe and optic nerve in children reflect their pathologic features. Retinoblastoma, the most common intraocular tumor of childhood, is distinguished from nonneoplastic lesions by the finding of dystrophic calcification of the necrotic areas between viable cells surrounding vessels. Patients with the heritable forms of the disease are more likely to have multifocal or bilateral lesions.

PHPV is classically seen as a retrolental mass representing the persistent primary vitreous with a linear projection between the mass and the optic disc, which represents the Cloquet canal containing the primitive hyaloid artery. There is no calcification and the globe is small. Coats disease produces an enhancing vascular malformation of the retina, which is detached by unenhancing lipid-containing subretinal exudate. In Toxocara endophthalmitis, the granulomatous reaction is seen as a central vitreous mass without calcification. Dense fibrosis may cause T2 shortening.

Medulloepithelioma is very rare and generally arises anteriorly from the ciliary body. Small cysts on the surface of or within the tumor may be seen at imaging. The teratoid type may contain calcifications at imaging, representing dystrophic calcification of heteroplastic hyaline cartilage seen histologically. If the tumor involves the retina and contains calcifications, differentiation from retinoblastoma is impossible without histologic examination.

Optic nerve glioma is a typically slow-growing tumor that diffusely involves the optic pathways, causing fusiform enlargement at imaging. Bilateral lesions are virtually pathognomonic for NF1.

	Acknowledgments

 
The authors wish to acknowledge Regino Cube for his assistance in preparation of the manuscript and figures.

	Footnotes

 

Abbreviations: CNS = central nervous system, H-E = hematoxylin-eosin, NF1 = neurofibromatosis type 1, PHPV = persistent hyperplastic primary vitreous, WHO = World Health Organization

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official nor as representing the views of the Departments of the Army, Navy, or Defense.

See Chung et al in the November 2007 issue for Part 2 of this two-part series of articles.

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