A, Bone marrow biopsy shows round tumor cells (hematoxylin-eosin, original magnification ×200). B, Desmin positivity (immunoperoxidase reaction, diaminobenzidine chromogen and hematoxylin counterstain, original magnification ×400). C, Top, positron emission tomographic scan with uptake (arrowhead) in left eye only. Bottom, magnetic resonance imaging demonstrates arclike mass posteriorly (arrowhead). D, White pupillary membrane. E, Solid tumor with multiple cysts (arrowheads). F, Freshly enucleated globe with hemorrhagic tumor, glaucoma valve (arrowhead), and inferior cavity of retracted vitreous. T indicates tumor; VR, vitreous retraction.
A, Partially hemorrhagic myxoid intravitreal tumor (T) with cysts (black arrowheads) and a fibrous plaque behind the iris (blue arrowhead) (hematoxylin-eosin, original magnification ×12.5). B, Vitreous tumor above invading optic nerve (arrowheads) (hematoxylin-eosin, original magnification ×25). C, Space where part of the valve was located with adjacent surgical wound. Fibrous metaplasia of the lens epithelium has caused a plaque (hematoxylin-eosin, original magnification ×25). The black arrowhead indicates neoplastic membrane; the blue arrowhead highlights distorted ciliary processes. D, Fibrous plaque delimited by lens capsule (black arrowheads) (periodic acid–Schiff, original magnification ×200). Inset: dystrophic calcification under lens capsule (arrowhead) (hematoxylin-eosin, original magnification ×200). E, Round rhabdomyoblasts in the vitreous (hematoxylin-eosin, original magnification ×100). F, Cytologic detail of rhabdomyoblasts (hematoxylin-eosin, original magnification ×200). C indicates cornea; FML, fibrous metaplasia of the lens epithelium; ON, optic nerve; V, valve; VR, vitreous retraction; W, wound.
A, Elongated and slender multipolar tumor cells (periodic acid–Schiff, original magnification ×200). B, Small units of primitive neuroepithelium near pars plana (top panel, hematoxylin-eosin, original magnification ×100; bottom panel, Masson trichrome, original magnification ×100). C, Neuroepithelium breaking up into solid units (arrowheads) and discohesive clusters (inset) with cysts seen above (hematoxylin-eosin, original magnification ×50; inset, hematoxylin-eosin, original magnification ×200). D, Desmin cytoplasmic positivity in round (left) and spindled (right) cells (immunoperoxidase reaction, diaminobenzidine chromogen and hematoxylin counterstain, original magnification ×200). E, Positive nuclear myogenin immunostaining (immunoperoxidase reaction, diaminobenzidine chromogen and hematoxylin counterstain, original magnification ×200). F, Top, pronounced Ki67 nuclear staining in neuroepithelial clusters (immunoperoxidase reaction, diaminobenzidine chromogen and hematoxylin counterstain, original magnification ×200). Bottom, lower proliferation index in mesencyhmal tumor (immunoperoxidase reaction, diaminobenzidine chromogen and hematoxylin counterstain, original magnification ×200). C indicates cysts.
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Jakobiec FA, Borkar DS, Stagner AM, Lee NG. Intraocular Teratoid Medulloepithelioma Presenting With a Completely Rhabdomyosarcomatous Distant Metastasis. JAMA Ophthalmol. 2016;134(8):919–923. doi:10.1001/jamaophthalmol.2016.1515
Medulloepithelioma is the second most common primary neuroepithelial tumor of the eye. The full range of its morphologic expressions and appearances in metastases have not been fully explored.
A patient in her 50s with glaucoma for decades had undergone multiple filtering surgical procedures, including the placement of a glaucoma drainage device. A paraspinal mass was discovered, and tumor and bone marrow biopsies disclosed rhabdomyosarcoma. This led to the discovery of a multicystic intraocular tumor. A metastatic rhabdomyosarcoma to the eye was considered unlikely because, to our knowledge, this event had never been reported. An enucleation was performed, and an intraocular tumor composed almost entirely of rhabdomyoblasts (desmin- and myogenin-positive) was discovered along with rare clusters of persistent neuroepithelial cells.
Conclusions and Relevance
To our knowledge, this is the first case of a medulloepithelioma in which teratoid rhabdomyoblasts effaced all but trace amounts of neuroepithelium and generated a distant metastasis entirely composed of rhabdomyoblasts. The prolonged history and filtering procedures probably led to these 2 phenomena.
Medulloepithelioma, a pediatric intraocular embryonic neoplasm usually arising from nonpigmented ciliary epithelium,1,2 rarely occurs in adults.3,4 Distant hematogenous metastases are rare and not described in detail, in contrast to the local, direct spread into the orbit or optic nerve.5,6 The former may be followed by regional lymphogenous metastases and the latter by intracranial dissemination through cerebral spinal fluid pathways. Medulloepitheliomas can exhibit heterologous (teratoid) differentiation, first reported in 1972 as rhabdomyoblastic7 and also noted to be cartilaginous.1 To our knowledge, this is the first report of a primary intraocular medulloepithelioma with predominant striated muscle differentiation presenting with distant hematogenous metastases diagnosed as rhabdomyosarcoma.
A woman in her 50s presented with lower back pain, bilateral lower extremity weakness, and urinary retention for several weeks. She had visual acuity of no light perception OS for at least 7 years secondary to end-stage glaucoma, which had been diagnosed decades earlier. She had undergone several intraocular surgical procedures, including implantation of a glaucoma drainage device, but had no recent ophthalmic follow-up. Magnetic resonance imaging of the thoracic and lumbar spine was obtained, demonstrating a compressive mass between thoracic nerves T4 and T5. Decompressive laminectomy with biopsy revealed a poorly differentiated alveolar rhabdomyosarcoma.
One month later, she was transferred to another hospital for further evaluation and management. Chemotherapy was introduced after a full metastatic workup, including bone marrow biopsy and positron emission tomographic and computed tomographic scans. The former revealed metastatic rhabdomyosarcoma (Figure 1A and B) and the latter disclosed diffuse enhancement and uptake of the left globe (Figure 1C, top panel). The patient noted no new visual symptoms or eye pain. On examination, her visual acuity was 20/40 OD and no light perception OS with a relative afferent pupillary defect and an intraocular pressure of 14 mm Hg OD and 85 mm Hg OS. No proptosis was noted on exophthalmometry.
Examination of the left eye was notable for dilated, tortuous episcleral vessels with mild conjunctival injection; a glaucoma drainage device eroded through the conjunctiva. A white mass was seen through the pupil (Figure 1D). B-scan ultrasonography demonstrated a nonmobile, mixed echogenic mass filling the vitreous cavity with multiple cystic areas near the pars plana (Figure 1E).
Based on the imaging studies, the possibility of a medulloepithelioma was entertained. Consideration was also given to an intraocular metastasis from the paraspinal rhabdomyosarcoma. The multiple previous filtering surgical procedures were also of concern as a source of a metastasis from the eye to the spinal area. Prior to enucleation, a magnetic resonance image of the orbits was obtained, revealing an enhancing left intraocular mass confined to the globe (Figure 1C, bottom panel).
Grossly, the globe measured 25 mm × 21 mm × 23 mm with a superior glaucoma valve. Microscopically, there was a myxoid tumor occupying part of the vitreous with small cysts (Figure 2A). The tumor extended into the optic nerve (Figure 2B) but did not reach its cut end. The anterior chamber was remarkable for obliteration by a retrocorneal fibrous membrane to which the iris was adherent (Figure 2C). There was a peripheral space anterior to the chamber angle that contained a portion of the drainage device but was devoid of tumor cells. There was no adjacent epibulbar tumor. The membrane behind the iris that was clinically apparent in the pupil was the result of fibrous metaplasia of the lens subcapsular epithelium (Figure 2D) with focal dystrophic calcification (Figure 2D, inset). The ciliary processes were preserved, but the retina had been destroyed without any uveal invasion. The tumor in the vitreous was composed of round rhabdomyoblastic cells (Figure 2E and F). A subpopulation of elongated spindle and multipolar cells was also observed (Figure 3A). There were extremely rare, small clusters of neuroepithelium in the periphery above the pars plana epithelium in the pupillo-optic sections and the calottes (Figure 3B). These units were seen to break up and merge imperceptibly into the myxoid tumor, which exhibited multiple cysts (Figure 3C). The round rhabdomyoblasts (Figure 3D, left panel) and elongated tumor cells (Figure 3D, right panel). were found to be desmin-positive after immunostaining . Myogenin (Figure3E) stained the nuclei of a majority of both types of cells. Ki67 positivity was higher in the scattered surviving neuroepithelial units than in the surrounding stromal tumor cells (Figure 3F).
The patient had a 3-decade history of glaucoma, requiring several surgical procedures that created openings in the ocular wall. An ultrasonographic evaluation disclosed an intraocular multicystic mass situated in the ciliary body region and vitreous, roughly contemporaneous with the discovery of a lumbosacral paraspinal mass. Given the echographic appearance, a medulloepithelioma was considered the most likely diagnosis before enucleation.
The combined histopathologic features of the present tumor were unique. The ciliary processes had been spared, and rare neuroepithelial units were limited to the pars plana region, which may have been the origin of the tumor, a finding noted in adult tumors.4 While rhabdomyoblastic differentiation (either benign or malignant) can be encountered as a focal component of an obviously neuroepithelial tumor,1,2 the longstanding growth of this patient’s tumor resulted in the effacement of all but a few traces of neuroepithelium. Spindled and round rhabdomyoblasts dominated 99% of the tumor and were shown to be desmin- and myogenin-positive. The rhabdomyoblasts constituted the entirety of the bone marrow biopsy and paraspinal metastasis to the exclusion of any neuroepithelial units.
A review of previous reports1,2 indicates that metastases from an intraocular medulloepithelioma occur only if there is extraocular spread. Intraparotid and regional lymph node metastases are then typically observed. To our knowledge, there has not been a case of an undetected ocular medulloepithelioma that presented with a distant metastasis in the absence of regional metastases, nor has a metastasis from a teratoid medulloepithelioma ever been described that was entirely composed of mesenchymal (rhabdomyoblastic) elements. Shunt devices used in this patient that breached the sclera probably served as conduits for tumor cell escape and ultimate metastasis, which has been described previously.8
There are 2 possible interpretations for the current paraspinal tumor. The first is that it was a primary tumor that metastasized to the eye. Primary paraspinal rhabdomyosarcomas are exceedingly rare. Furthermore, to our knowledge, a rhabdomyosarcoma of any nonocular site has never been reported to metastasize intraocularly; although periocular metastases are known to occur, particularly to the extraocular muscles, such tumors do not harbor fragments of neuroepithelium.9,10 The second and most defensible possibility is that the paraspinal rhabdomyosarcoma was derived from the intraocular teratoid medulloepithelioma, which came to dominate the histopathologic picture over time.
Both germline and sporadic somatic mutations of the DICER1 gene are now known to occur in intraocular medulloepitheliomas.11 This patient did not have a family history nor the stigmata of the DICER1 syndrome (eg, Sertoli-Leydig cell tumors, high-grade ovarian carcinoma, or thyroid goiter), which can appear sometime after a pleuropulmonary blastoma is diagnosed.12 A somatic DICER1 or KMT2D mutation (in a recent series,13 11 of 19 medulloepitheliomas had one or the other) seems a probable underlying trigger for this patient’s adult-onset neoplasm. It is conceivable that some previous reports of primary intraocular rhabdomyosarcoma14,15 may have been examples of medulloepitheliomas in which heterologous (teratoid) striated muscle component had destroyed all vestiges of the neuroepithelium.
Intraocular medulloepithelioma can metastasize through filtering wounds for glaucoma surgery. The metastases on rare occasions may be completely composed of a heterologous malignant mesenchymal (rhabdomyoblastic) component.
Corresponding Author: Frederick A. Jakobiec, MD, DSc, David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye and Ear Infirmary, 243 Charles St, Ste 328, Boston, MA 02114 (email@example.com).
Submitted for Publication: February 26, 2016; final revision received April 5, 2016; accepted April 10, 2016.
Published Online: June 2, 2016. doi:10.1001/jamaophthalmol.2016.1515.
Author Contributions: Dr Jakobiec had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Jakobiec, Stagner, Lee.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Jakobiec, Borkar, Lee.
Critical revision of the manuscript for important intellectual content: Jakobiec, Stagner, Lee.
Administrative, technical, or material support: Borkar, Stagner, Lee.
Study supervision: Lee.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Additional Contributions: We thank the patient for granting permission to publish this information.
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