HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) CME Test (opens in a new window) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chung, E. M. Articles by Schroeder, J. W. Search for Related Content PubMed PubMed Citation Articles by Chung, E. M. Articles by Schroeder, J. W. Related Collections Head and Neck Neuroradiology Pediatric Radiology Oncologic Imaging

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.—