Medulloepithelioma is a rare intraocular tumor arising from the primitive medullary epithelium. This tumor usually originates from the nonpigmented ciliary epithelium, but may develop in the retina or optic nerve head.1–4 Ciliary body medulloepithelioma most commonly occurs in the first decade of life and is rare in adults.5–8 Patients with medulloepithelioma may present with reduced vision, anterior chamber or iris mass, uveitis, photophobia, pain, cataracts, glaucoma, enlarging globe, lens coloboma, and leukocoria.6,8,9
Intraocular medulloepithelioma is classified into teratoid type (presence of heteroplastic elements, particularly cartilage, skeletal muscle, and brain tissue) and nonteratoid type (pure proliferation of cells of the medullary epithelium).1,5 Both types of medulloepithelioma can be either benign or malignant1,5,10; criteria for malignancy include the presence of poorly differentiated areas resembling retinoblastoma, rhabdomyosarcomatous differentiation, high mitotic activity, uveal stromal invasion, scleral invasion, or extraocular tumor extension.2,8,10 Although metastasis is unusual, even local invasion can lead to death.5,8,11 Most cases of medulloepithelioma are managed with enucleation, but iridocyclectomy or plaque radiotherapy are options for less advanced cases.4,8,9
We report a rare, devastating case of clinically and histologically malignant medulloepithelioma with metastasis necessitating eyelid-sparing semi-exenteration of the orbit and subsequent external beam radiotherapy and chemotherapy.
This study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan (IRB104-8861B).
A 12-year-old girl without underlying systemic disease was referred to our institution for evaluation of uveitis in January 2014. Vision in her right eye had been poor since the age of 3 years and she was previously treated for amblyopia at a local clinic. Initial ocular examination revealed visual acuity of 6/100 in the right eye, exotropia, band keratopathy, anterior uveitis, iris neovascularization, secluded pupil, cataract, and elevated intraocular pressure (30 to 40 mm Hg). B-scan ultrasonography did not detect any specific anomaly. Topical timolol was given to lower the intraocular pressure.
The patient did not follow up for more than 1 year, during which time she received intravitreal injection of anti-vascular endothelial growth factor agent for iris neovascularization and progressive blurry vision in the right eye. She returned to our clinic because of persistent redness and proptosis of her right eye (Figure 1A). On examination, we found a reddish, irregular mass with prominent feeding vessels protruding from the upper nasal quadrant and displacing the globe inferolaterally. There was a perforated sclera with overlying intact conjunctiva located superiorly (Figure 1B). The anterior chamber was collapsed and filled with exudate and hyphema. The patient had no light perception in her right eye. Physical examination was otherwise negative except for a palpable, ill-defined mass in the right preauricular area.
Malignant ciliary body medulloepithelioma. (A) Right proptosis due to the intraocular mass with the globe displaced inferolaterally. (B) A congested, irregular mass with prominent feeding vessels protruding from the upper nasal quadrant of the right eye. A perforated sclera with visible dark uvea located superiorly; the overlying conjunctiva was intact (circle). (C) Orbital computed tomography showing a mass lesion with moderate enhancement in the ciliary body region (arrows). The tumor extended outside the globe nasally and into the vitreous (star). (D) Computed tomography scan revealing an enlarged lymph node at the right anterior parotid region (arrow).
Orbital computed tomography revealed a right intraocular mass in the medial canthus region with moderate enhancement and a smooth contour that pushed the right globe laterally (Figure 1C). A lymph node suspicious for metastasis at the right anterior parotid region was also found (Figure 1D). The patient underwent an incisional biopsy of the mass that suggested malignant medulloepithelioma. Considering the aggressiveness of the tumor and its possible life-threatening nature, we performed an eyelid-sparing semi-exenteration of the right orbit.
Histopathologic examination of the specimen demonstrated extension of the ciliary body tumor into the anterior and posterior chambers, with retinal, choroidal, and optic nerve invasion. The tumor was composed of primitive cells, atypical chondrocytes, atypical stromal cells, and dysplastic epithelial cells arranged in nest and trabecular patterns (Figure 2). The cells were strongly immunoreactive for vimentin, neuron-specific enolase, synaptophysin, and CD56, but negative for S-100, smooth-muscle actin, cytokeratin, chromogranin A, and desmin. These histopathologic features were compatible with malignant teratoid medulloepithelioma.
Histopathologic features of the medulloepithelioma. (A) Gross photograph showing grayish ciliary body tumor (arrow) extending into the anterior and posterior chambers. The tumor perforated through the anterior sclera (star) and extended into the orbit. Invasion of the optic nerve was found (circle). (B) Ciliary processes (arrows) surrounded by cords and sheets of hyperchromatic tumor cells. Inset shows formation of Flexner–Wintersteiner and Homer Wright rosettes (hematoxylin–eosin, original magnification ×100). (C) The retina and choroid filled with tumor cells (double-headed arrow). The tumor invaded through the sclera (arrow) and extended to the outside of the globe (star) (hematoxylin–eosin, original magnification ×40). (D) Section showing cartilaginous differentiation (hematoxylin–eosin, original magnification ×100) and inset demonstrating that the section is stained positively with alcian blue (hematoxylin–eosin, original magnification ×200).
After a comprehensive multidisciplinary discussion that included oncologists, pathologists, and radiation oncologists, the patient subsequently received external beam radiotherapy of 6,000 rad in 30 fractions to the tumor bed and right preauricular area. Seven months after the operation, she was found to have brain metastases on magnetic resonance imaging (Figures 3A–3C) after she complained of headaches, dizziness, and projectile vomiting. She received salvage chemotherapy with cisplatin (20 mg/m2) and etoposide (60 mg/m2). After six cycles of chemotherapy, the patient achieved complete remission, both clinically and radiologically (Figure 3D). The patient was disease free at 11 months of follow-up.
Magnetic resonance imaging of the brain metastases. (A) T1-weighted axial image revealing tumor masses (arrows) with hypointensity. (B) Contrast enhanced T1-weighted with fat-suppression axial image showing heterogenous enhanced lobulated masses in the right cavernous sinus and right medial temporal fossa (arrows). The tumor also extended into the Meckel's space (curved arrow). (C) Enhanced coronal T1-weighted image revealing perineural spread of tumor through foramen ovale (arrow) into masticator space (star). (D) Contrast enhanced T1-weighted with fat-suppression axial image after six cycles of salvage chemotherapy showing complete resolution of brain tumor.
Medulloepithelioma is a rare intraocular tumor most commonly found in young children. The tumor displays a variety of presentations, masquerading as unilateral uveitis, cataract, neovascular glaucoma, or a free-floating intraocular cyst. These features should prompt the clinician to investigate for this tumor as an underlying diagnosis.4,6,8,9,12 Misdiagnosis is not uncommon, with a rate of up to 88% reported in recent literature.8
In our case, the initial diagnosis of her right amblyopic eye was idiopathic uveitis and neovascular glaucoma and she was only given an anti-glaucoma agent. However, the long gap in follow-up prevented a more timely diagnosis because it delayed further investigations, such as ultrasound biomicroscopy, computed tomography, or magnetic resonance imaging.2 In cases with an idiopathic diagnosis, avoiding premature diagnostic closure and prompting a meticulous investigation are crucial to correctly identifying malignant ciliary medulloepithelioma.
Ciliary medulloepithelioma can often be managed with enucleation, iridocyclectomy, or plaque radiotherapy.4,8,9 However, delayed diagnosis results in poorer outcomes because metastasis can occur in cases with more advanced tumors and extrascleral extension.4,8
Exenteration can be performed for cases with extensive orbital involvement and it may be done in either total or subtotal fashion. The choice of exenteration should be individualized and take into account the location, size, and aggressiveness of the tumor, the reconstruction plan, and whether the primary goal of exenteration will be to achieve a surgical cure or local tumor control.13 In our case, considering the patient had parotid lymph node metastasis preoperatively, we performed eyelid-sparing exenteration to achieve local tumor control and prevent extensive hollowness of the orbit postoperatively. Compared with eyelid-sacrificing techniques, eyelid-sparing exenteration achieves more rapid healing with satisfactory cosmetic results and has few complications.14 Nonetheless, disfigurement after this procedure should be a routine part of the preoperative discussion with the patient.
Multidisciplinary care is essential for cases of metastasis because these patients may benefit from radiotherapy or chemotherapy. Different regimens of chemotherapy were used to treat metastatic ocular medulloepithelioma and the effectiveness varied among studies.6,8,11,15 In our case, the metastatic brain tumor responded remarkably with the combination chemotherapy of cisplatin and etoposide. Although the role of chemotherapy in intraocular medulloepithelioma is unclear, salvage chemotherapy could be a good treatment option for metastatic tumors in selected cases with advanced disease diagnoses.
Ciliary medulloepithelioma can be devastating and life-threatening. We share our experience in the management of a belatedly diagnosed and highly aggressive case. The importance of making an early diagnosis and avoiding misdiagnosis and mistreatment of this tumor cannot be overemphasized.
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