Intraocular medulloepithelioma is a congenital tumor of

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1 Intraocular Medulloepithelioma N Intraocular medulloepithelioma is a congenital tumor of the ciliary epithelium that typically presents during the first decade of life. The histologic diagnosis is based on characteristic ribbons of pseudostratified neuroepithelium admixed with loose mesenchymal tissue rich in hyaluronic acid, vaguely resembling developing retina and vitreous. More than a third of medulloepitheliomas contain heteroplastic tissue, which in some cases makes up most of the tumor. Malignant medulloepitheliomas consist of a proliferation of neuroblasts, which in areas can be indistinguishable from retinoblastoma. Unlike its highly malignant counterpart in the central nervous system, intraocular medulloepithelioma has a good prognosis as long as tumor has not spread beyond the eye. Definitive diagnosis and eyeconserving therapy is possible with fine-needle aspiration biopsy. The histologic differential diagnosis of medulloepithelioma is broad, ranging from retinoblastoma and sarcoma to ciliary epithelial adenoma and adenocarcinoma. (Arch Pathol Lab Med. 2012;136: ; doi: / arpa rs) Accepted for publication February 7, From the Departments of Ophthalmology (Drs Saunders and Margo) and Pathology (Dr Margo), University of South Florida, Tampa; and James A. Haley Veterans Hospital, Tampa, Florida (Dr Margo). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Curtis E. Margo, MD, MPH, Department of Pathology, University of South Florida, Bruce B. Downs Blvd, MCD Box 11, Tampa, FL ( cmargo@health.usf.edu). Timothy Saunders, MD; Curtis E. Margo, MD, MPH Intraocular medulloepithelioma is a congenital tumor of the nonpigmented ciliary epithelium, usually diagnosed in childhood. Rare in comparison to retinoblastoma, medulloepithelioma is still the second most common primary intraocular neoplasm during the first decade of life. Histologically, the tumor has a distinctive architecture characterized by a pseudostratified epithelium resembling the medullary epithelium of the embryonic neural tube or the developing neurosensory retina before the fourth month of gestation. It shares many histopathologic features with medulloepithelioma of the central nervous system, but its overall prognosis for life is considerably better. 1 Confusing names attached to intraocular medulloepithelioma in the past have hampered effective communication and probably delayed a logical system of classification for tumors of the ciliary epithelium. Frederick Verhoeff described medulloepithelioma in 1904, 2 naming it a terato-neuroma, presumably owing to heteroplastic tissue he observed within the tumor. Several years later, the Viennese ophthalmologist Ernst Fuchs introduced the term diktyoma (diktyon: Greek for net) because the microscopic appearance of interlacing bands of neuroepithelial cells were netlike. 3 Grinker, 4 in 1931, borrowed the term medulloepithelioma from the seminal work on the related brain tumor by Bailey and Cushing. In the 1970s, Lorenz Zimmerman 5,6 proposed a system for classifying primary tumors of the ciliary epithelium, as well as the conceptual framework for understanding the cellular polymorphism of medulloepithelioma. This nomenclature was adopted by the World Health Organization in 1980 and has been used since. 7 EPIDEMIOLOGY There is no population-based information on incidence or prevalence of medulloepithelioma. The literature consists largely of single case reports and small series The largest series was reported through the Armed Forces Institute of Pathology (AFIP) and involved 56 histologically confirmed cases from 56 patients, ranging in age at clinical presentation from 6 months to 41 years (mean, 3.8 years). 8 Shields et al 11 reported 10 patients with medulloepithelioma, 9 of whom ranged in age from 2 months to 10 years when referred for oncologic evaluation. One patient was 58 years old when diagnosed. Not uncommonly, medulloepitheliomas are managed inappropriately for months or years before the correct diagnosis is established. 8,11 At least 11 cases of medulloepithelioma have been reported in persons older than 20 years. 12 The oldest patient with a histologically documented tumor was 79 years. 13 Based on the series from the AFIP and previous literature reviews, there is no sex or racial predilection Tumors arise in the ciliary body, unilaterally. Exceptional cases have been reported in the optic nerve and retina. 8,10,14 Although most eyes are developmentally normal, as many as 20% show signs of persistent hyperplastic primary vitreous. 8 There are no known risk factors for intraocular medulloepithelioma. Other than pleuropulmonary blastoma family tumor and dysplasia syndrome, a rare syndrome related to germline mutation of DICER1 gene, most intraocular medulloepitheliomas occur sporadically and are not associated with congenital malformation or cytogenic abnormality. 15 CLASSIFICATION Medulloepitheliomas are considered congenital tumors of the nonpigmented ciliary epithelium. Those diagnosed later in life are thought to represent delayed manifestations of a preexistent retinal anlage. 8,16,17 The fact that most 212 Arch Pathol Lab Med Vol 136, February 2012 Medulloepithelioma Saunders & Margo

2 cases in adults are malignant suggests that clinical recognition may follow belated malignant transformation. 11,12,17 Benign tumors are presumably detected because decades of slow growth lead to eventual clinical detection. The terms acquired medulloepithelioma or adult medulloepithelioma are contradictions based on the current concept of tumor development. In a similar way, the term embryonal medulloepithelioma is redundant. 16 More than a third of medulloepitheliomas contain heteroplastic elements, usually hyaline cartilage, rhabdomyoblasts, or brainlike tissue Those with heteroplastic tissue are designated teratoid medulloepitheliomas. Nonteratoid and teratoid medulloepitheliomas are benign or malignant. The overall classification of epithelial tumors of the ciliary body is shown in the Table. CLINICAL FEATURES Small medulloepitheliomas of the ciliary body go undetected because they are hidden from view by the iris. Even after symptoms develop, clinical suspicion of tumor is often overlooked, as patients are treated for secondary complications of the tumor such as cataract or glaucoma before the underlying mass is discovered. 11 Medulloepitheliomas are slow-growing tumors that are not visible until they enlarge enough to protrude into the pupil, distort the iris, or invade adjacent tissues. Larger tumors degrade vision through a variety of mechanisms. 8,9,11 The most common causes of decreased vision are attributed to subluxation of the lens and cataract. 11 On slit lamp examination, medulloepitheliomas are irregularly shaped, with smooth surfaces and gray to fleshy pink color. Vessels are occasionally visible on or close to the surface. Approximately half of cases have cysts or tumor in the anterior chamber. 8,9,11 The differential diagnosis of an intraocular mass lesion is influenced by the age at presentation, since few tumors other than medulloepithelioma occur between 5 and 20 years of age. Most retinoblastomas (90%) are diagnosed by age Acquired neoplasms of the nonpigmented ciliary epithelium (also rare) develop during adult life. 19 A tumor mass associated with cyst, either tethered to the mass or free floating in the anterior or posterior chamber, or in the vitreous, is highly suggestive of medulloepithelioma (see Histopathology ). Metastatic carcinoma must always be considered in the differential diagnosis of a nonpigmented intraocular tumor and is usually a primary consideration in adults with medulloepithelioma along with amelanotic melanoma. Acquired tumors of the nonpigmented ciliary epithelium are classified as adenomatous hyperplasia (Fuchs adenoma), adenoma, and carcinoma. Their distinctions are based on traditional criteria of cellular pleomorphism, mitotic rate, and invasive growth. 5,19,20 The pigmented epithelium of the ciliary body can also give rise to adenoma and adenocarcinoma (Table). HISTOPATHOLOGY Intraocular medulloepitheliomas are characterized by cords of primitive neuroepithelial cells that resemble the embryonic retina or neural tube, surrounded by a loose mesenchymal tissue rich in hyaluronic acid (Figure 1). In many medulloepitheliomas the characteristic combination of primitive neuroepithelium and hypocellular stroma make up most of the tumor, but in some cases, especially Classification of Epithelial Tumors of the Ciliary Body a Congenital Glioneuroma Medulloepithelioma, nonteratoid Benign Malignant Medulloepithelioma, teratoid Benign Malignant Acquired Nonpigmented ciliary epithelium Hyperplasia (Fuchs adenoma) Solid Papillary Pleomorphic Glandular-papillary Pleomorphic Anaplastic Pigmented ciliary epithelium Mixed nonpigmented-pigmented epithelial tumor a Modified from Green 7 with permission from Elsevier. malignant medulloepitheliomas, these features can be inconspicuous. 21 Under high magnification, the cords of primitive neuroepithelium may display features of developing neurosensory retina. The neuroepithelial surface facing the hyaluronic acid rich stroma is lined by a thin basement membrane, corresponding to the internal limiting membrane of the neurosensory retina (Figure 2). The opposite surface is lined by a series of terminal bars, which corresponds to the external limiting membrane of the neurosensory retina. When the medullary epithelium folds so that the vitreous surface faces inwards, it creates cysts rich in hyaluronic acid. Such proliferating cysts can detach from the main tumor and appear as free-floating cysts in the anterior or posterior segment of the eye. The spaces between anastomosing cords of neuroepithelial cells may be filled in with sheets of undifferentiated neuroblasts, indistinguishable by light microscopy from cells seen in retinoblastoma. Both Homer Wright and Flexner-Wintersteiner rosettes can be observed among undifferentiated neuroblasts. Rosettes in medulloepithelioma, however, are often larger and more cellular than typical Flexner-Wintersteiner rosettes (Figure 3). Neuroepithelial tubules are also a feature of medulloepithelioma not found in retinoblastoma. While calcification is the hallmark of retinoblastoma, mineralization is uncommon in medulloepithelioma. Not uncommonly, patches of proliferating pigmented neuroepithelial cells are present. Highlighting the hyaluronic acid rich matrix of medulloepithelioma with Alcian blue stain may aid the diagnosis of medulloepithelioma, particularly in cases that are cellular or heavily pigmented (Figure 3, inset). The designation teratoid medulloepithelioma applies when heteroplastic tissue is present. Mature hyaline cartilage is the most common heteroplastic element, but neuroglial tissue resembling disorganized brain and rhabdomyoblasts are also described (Figure 4). On rare occasions, Arch Pathol Lab Med Vol 136, February 2012 Medulloepithelioma Saunders & Margo 213

3 Figure 1. Medulloepithelioma with cords and loops of medullary epithelium separated by pale vitreous-like stroma (hematoxylin-eosin, original magnification 325). Figure 2. Pseudostratified neuroepithelium of medulloepithelioma reflects retinal polarity. The inner smooth surface of tubules (arrows) corresponds to terminal bars of the external limiting membrane. The opposite surface is in contact with vitreous-like stroma (hematoxylineosin, original magnification 340). Figure 3. Rosettes in medulloepithelioma vary more in size and are more cellular than rosettes in retinoblastoma. Inset, Alcian blue staining in region consisting mostly of pigmented neuroepithelial cells (hematoxylin-eosin, original magnifications 325 and 340 [inset]). 214 Arch Pathol Lab Med Vol 136, February 2012 medulloepitheliomas consist almost entirely of heteroplastic tissue, in which case they can be mistaken for an intraocular choristoma, teratoma, or sarcoma.8,16,21 There are no universally agreed-upon histologic criteria for malignant medulloepithelioma. The 4 standards proposed by Zimmerman and Broughton are regarded as reasonable measures of biologic behavior.16 The first feature of malignancy is sheets of neuroblastic cells resembling those of retinoblastoma, with or without rosettes, admixed with medullary epithelium (Figure 5). There is no established minimum threshold of retinoblastoma-like tissue that is needed to diagnose malignancy. Invasion of ocular tissues (uveal tract, cornea, sclera, or optic nerve), or extraocular extension, is also indicative of malignant behavior. Sarcomatous change in heterologous tissue constitutes a third criterion for teratoid medulloepithelioma. Tumors arising in mesenchymal tissue are named according to their histogenesis (eg, rhabdomyosarcoma, embryonal sarcoma). The most subjective criterion concerns the degree of pleomorphism and/or mitotic activity within the cords and tubules of medullary epithelium (Figure 6). In this situation, the standard for benignancy is the expected appearance of developing neurosensory retina, a relatively obscure reference tissue. Gestational medullary epithelium has mitotic activity, but the range of normal proliferative activity has not been established. Metastatic small cell tumors in the pediatric age group, such as neuroblastoma, are in the differential diagnosis of medulloepithelioma. Retinoblastoma may be the most challenging diagnosis to exclude when typical medullary epithelium is sparse. Immunohistochemical markers have different patterns of reactivity depending on whether the tissue of interest is neuroepithelial or heteroplastic. The nonteratoid component is typically positive for vimentin and neuron-specific enolase Limited and conflicting results have been reported for chromogranin, synaptophysin, glial fibrillary acid protein, S100 protein, and HMB-45.12,22 30 Positive immunohistochemistry for pancytokeratins and cytokeratin (CK)18, with no reactivity for CK7, CK20, and epithelial membrane antigen, has been described and awaits confirmation.23 Fine-needle aspiration biopsy will probably have a greater role in diagnosing medulloepithelioma in the future.26,28 30 While cords of medullary epithelium may be diagnostic of medulloepithelioma, the absence of malignant neuroblasts, or cells with sarcomatous features, does not exclude the possibility of malignancy. The polymorphic nature of medulloepithelioma means that sample variation can affect the sensitivity of aspiration cytology. The risk of tumor seeding with fine-needle biopsy in medulloepithelioma is unknown, but until more information is available, it should default to the risk-equivalent of retinoblastoma. TREATMENT Surgical enucleation is standard therapy for intraocular medulloepithelioma once the diagnosis is established.8 11 With the goal of eye-sparing therapy increasing, clinicians have attempted surgical excision (eg, iridocyclectomy) with varying degrees of success.8,9,11 To date, reports of long-term survival after local resection are limited. Treatment of malignant medulloepithelioma with surgical excision and brachytherapy, or brachytherapy alone, has Medulloepithelioma Saunders & Margo

4 been explored.26,31 The effectiveness of radiation therapy and chemotherapy for high-risk tumors with spread beyond the eye is unknown. PROGNOSIS Given the rarity of medulloepithelioma, there is limited information on long-term survival. Follow-up on the 56 patients reported by Broughton and Zimmerman,8,16 though incomplete (23 patients lost to follow-up), revealed tumor-related deaths in 4 (12%). Of the original 56 tumors, 37 were judged histologically malignant and 10 had extraocular spread. All 4 tumor-related deaths occurred in patients with malignant tumors with extraocular extension detected on histopathologic examination. Deaths were preceded in 3 cases by orbital recurrence; 3 patients died with intracranial extension and the fourth with distant metastasis. Among the 56 tumors, teratoid elements were present in 4 benign medulloepitheliomas and in 17 malignant tumors. There were too few patients and limited follow-up in cases with teratoid medulloepithelioma (benign and malignant) to assess the effect of heteroplastic tissue on prognosis.8,16 The major predictor of death was extraocular extension for both nonteratoid and teratoid tumors. The value of radiation therapy and chemotherapy with extraocular spread was too limited to draw meaningful conclusions. SUMMARY Intraocular medulloepitheliomas are congenital tumors of the nonpigmented ciliary epithelium, typically diagnosed during the first decade of life. A small but not insignificant proportion is discovered in adults, presumably after decades of indolent growth or after delayed malignant transformation. The diagnosis of malignant medulloepithelioma is based on the presence of undifferentiated neuroblastic cells indistinguishable from those in retinoblastoma,high mitotic rate, and tissue invasion. Malignant mesenchymal tumors (eg, rhabdomyosarcoma, embryonal carcinoma) may also arise in teratoid medulloepithelioma. Tumor-related death is associated with spread outside the eye. Reza Setoodeh, MD, researched material on immunohistochemistry, cytology, and ultrastructure and critically reviewed the manuscript. Hans Grossniklaus, MD, provided the case with Alcian blue staining. References 1. Molloy PT, Yachnis AT, Rorke LB, et al. Central nervous system medulloepithelioma: a series of eight cases including two arising in the pons. J Neurosurg. 1996;84(3): Verhoeff FH. A rare tumor arising from the pars ciliaris retinae (teratoneuroma), of a nature hitherto unrecognized, and its relation to the so-called glioma retinae. Trans Am Ophthalmol Soc. 1904;10(pt 2): Fuchs E. Wucherungen und Geschwulste des Ziliarepithels. Graefe s Arch Ophthal. 1908; Grinker RR. Gliomas of the retina, including the results of studies with silver impregnation. Arch Ophthalmol. 1931;5(6): Zimmerman LE. The Norman McAlister Gregg Lecture: the remarkable polymorphism of tumours of the ciliary epithelium. Trans Aust Coll Ophthalmol. 1970;2(1) Figure 4. Malignant teratoid medulloepithelioma with large islands of hyaline cartilage (C) surrounded by undifferentiated neuroblastic cells. Inset, Higher magnification of hyaline cartilage adjacent to neuroblastic cells (hematoxylin-eosin, original magnifications 32 and 325 [inset]). Figure 5. Malignant medulloepithelioma with undifferentiated neuroblastic cells adjacent to neuroepithelial rosettes (hematoxylin-eosin, original magnification 340). Arch Pathol Lab Med Vol 136, February 2012 r Figure 6. Cells making up this ribbon of neuroepithelium show differing degrees of cellular pleomorphism (hematoxylin-eosin, original magnification 340). Medulloepithelioma Saunders & Margo 215

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