Malignant Teratoid Medulloepithelioma with Rhabdomyosarcomatous Differentiation

Abstract

Introduction

The objective of this study was to identify and report the clinicopathologic features of two cases of intraocular malignant teratoid medulloepitheliomas with rhabdomyosarcomatous differentiation.

Case Presentations

The clinical and pathologic findings in 2 patients who underwent enucleation for intraocular tumors were reviewed. The eyes were sectioned routinely, and immunohistochemical stains were performed to evaluate the intraocular tumors. The left eyes that were enucleated from 3- to 14-year-old females contained intraocular tumors that filled the posterior compartments. The tumors contained both neuroepithelial and mesenchymal components. Immunohistochemical stains were positive for neuron-specific enolase and S-100 in the neuroepithelial components. The mesenchymal components contained rhabdoid cells, which stained for desmin and myogenin. Mutational analysis revealed DICER1 mutations in both tumors. Both tumors were classified as malignant teratoid medulloepithelioma with rhabdomyosarcomatous differentiation.

Conclusions

Intraocular medulloepithelioma may contain areas with rhabdomyosarcomatous differentiation and have DICER1 mutations.

Introduction

Medulloepithelioma is a rare intraocular tumor that occurs primarily in children in the first decade of life. It is derived from neuroepithelial cells lining the cavity of the primitive neural tube and optic vesicle [1]. While medulloepithelioma most often arises from non-pigmented ciliary epithelium, it can rarely arise from the iris, retina, or optic nerve [1]. The two subgroups of medulloepithelioma are non-teratoid and teratoid. Non-teratoid medulloepithelioma is composed of a proliferation of embryonic neural tube epithelium, with cells resembling ciliary epithelium. In contrast, teratoid medulloepithelioma also contains cells with mesenchymal differentiation, including cartilage, neural tissue, and skeletal muscle. Although most medulloepitheliomas are benign, they may become malignant or have malignant potential. Initial presenting symptoms may include blurred vision, painful red eye, leukocoria, and strabismus [2]. Due to the slow-growing nature of these tumors and because they occur in children who may not report symptoms in a timely fashion, the tumors may not be detected until they are large. At this time, there may be some difficulty in the pathologic diagnosis, as the mesenchymal component may predominate in the tumor.

Rhabdomyosarcomatous differentiation as the mesenchymal component of a malignant medulloepithelioma is rare and may result in confusion in the histologic diagnosis. Herein, we describe two cases of malignant teratoid medulloepithelioma with rhabdomyosarcomatous differentiation.

Case Presentation

Case 1

A three-year-old female presented with a 3-week history of left eye redness and pain. She had previously been prescribed polymyxin/trimethoprim eye drops, with no improvement in her symptoms. Notable family history included thyroid and breast cancer in her maternal grandmother, as well as breast cancer, ovarian cancer, and possible thyroid growths in her maternal aunt.

The patient’s visual acuity was fix and follow in the right eye, no fix or follow in the left eye. Slit lamp examination was notable for 2+ conjunctival injection, neovascularization of the iris, and a yellow-white pupillary reflex. Dilated fundus examination was attempted, but no view was obtained in the left eye secondary to vitreous opacity. A B-scan of the left eye showed a large hyperechoic opacity involving most of the vitreous cavity, as well as an area of possible calcification abutting the optic nerve. MRI of the brain and orbits with and without contrast revealed a large left intraocular tumor with predominantly exophytic growth, subretinal fluid, and possible choroidal invasion. No optic nerve invasion or metastases were noted. MRI of the right orbit and brain were normal.

Upon further questioning, it was discovered that she had been evaluated at the age of two at an outside hospital for intermittent exotropia in the left eye. She was initially thought to have retinoblastoma but was later diagnosed with presumed combined hamartoma of the retina and optic nerve. Fundus photographs and a fluorescein angiogram were obtained at that time (Fig. 1).

Fig. 1.

Case 1. Initial clinical appearance of the patient at age 2 years showing small nodular mass overlying the optic nerve (left) that exhibited angiographic hyperfluorescence.

After extensive discussion with the family regarding the very low likelihood of any visual recovery, as well as the potential for progression and metastasis, the eye was enucleated. The enucleation specimens showed a fleshy mass occupying most of the posterior compartment (Fig. 2). Microscopic examination showed that the mass had two components, an epithelial component (Fig. 3) and a mesenchymal component (Fig. 4). Some of these cells contained PAS-positive intracytoplasmic hyaline like droplets. The epithelial component contained pigmented and non-pigmented epithelium that formed tubuloacinar configurations, and in areas was associated with alcian-blue positive vitreous like material. Immunohistochemical stains of this component were positive for neuron-specific enolase and S-100. Cells in the mesenchymal component of the tumor exhibited nuclear pleomorphism, mitotic activity, and was classified as having a sarcomatous appearance. Scattered cells in this component of the lesion had a rhabdoid appearance with distended, eosinophilic, globular cytoplasm. Immunohistochemical stains were positive for desmin, myogenin; intact for INI-1, particularly in the rhabdoid cells, intact for RB1, and positive Ki67 in 60% of tumor cells, and negative for PAX8, HMB45, melan A, and pan cytokeratin.

Fig. 2.

Case 1. The enucleated eye of the patient at age 3 years shows that the mass (*) now fills most of the posterior compartment of the eye.

Fig. 3.

Case 1. a The tumor is composed of mesenchymal and epithelial elements. Occasional pigmented epithelial cells are adjacent to heterologous cartilage (*). b The epithelial component of the tumor exhibits tubuloacinar, gland-like configurations. Immunohistochemical stains are positive for neuron-specific enolase (c) and S-100 (d) in the epithelial component. H&E, ×25 (a), ×100 (b); peroxidase anti-peroxidase, ×100 (c, d).

Fig. 4.

Case 1. a The mesenchymal component of the tumor contains rhabdoid appearing cells. b There are numerous mitotic figures (circles) in the mesenchymal component of the tumor, as well as rhabdoid cells (arrow). Immunohistochemical stains are positive for desmin (c) and myogenin (d), especially in the rhabdoid cells. H&E, ×100 (a, b); peroxidase anti-peroxidase (c, d).

Cerebrospinal fluid and bone marrow analyses were negative for malignant cells. Key tumor markers, including AFP and Beta HCG, were negative, and germline testing for retinoblastoma (RB1) showed no pathogenic variants. Solid tumor assessment revealed multiple pathogenic variants, including DICER1 mutations (p.D1709E and p.Y1701*) and a SUFU frameshift mutation (p.E283fs). Amplifications of the MDM2, PTPRB, and FRS2 genes were identified as likely pathogenic. Microsatellite instability was low, with only 1.19% (1 of 84) instability detected, and the tumor mutation burden was moderate, at 7.6 mutations/Mb.

Given the DICER1 mutation, a screening chest X-ray was obtained and showed no abnormalities. A CT scan of the chest without contrast performed 5 months post-surgery was also normal. Follow-up imaging, including an MRI of the brain and orbits, at 3.5 months post-surgery demonstrated no evidence of recurrence or intracranial metastasis. The patient was tested for a somatic DICER1 mutation which was negative. She and her family are following with a genetics counselor.

Case 2

A 14-year-old female with a history of bilateral granulomatous panuveitis (HLA-DR4 positive) presented to the emergency department in Jordan with eye pain and a 2-week history of left eye swelling. Other ophthalmic history included cataract extraction with intraocular lens placement of the left eye 3 years prior and retinal detachment of the left eye status post repair 2 years prior with NLP vision since. Initial clinical impression was panophthalmitis with orbital cellulitis. Two weeks later, she underwent enucleation of the left eye.

Pathologic analysis revealed that the eye was nearly completely filled with malignant neoplasm (Fig. 5). The tumor was composed mainly of mesenchymal cells with a sarcomatous appearance (Fig. 6), including rhabdoid cells, and rare collections of pigmented and non-pigmented epithelial cells that formed tubuloacinar configurations. Immunohistochemial stains in the epithelial component of the tumor were positive for S-100 and in the mesenchymal component of the tumor for vimentin and myogenin/desmin especially in the rhabdoid cells. Immunohistochemical stains were negative for AE1,3, synaptophysin, chromogranin and intact for INI-1. There was no extraocular extension of the tumor. Genetic testing revealed mutations in DICER1 and TP53 in the tumor.

Fig. 5.

Case 2. The enucleated eye is enlarged and shows a tan mass that fills most of the posterior compartment with an area of yellow-white necrosis anteriorly.

Fig. 6.

Case 2. a The epithelial component of the tumor contains epithelial cells forming tubuloacinar, gland-like, configurations. b The mesenchymal component of the tumor contains poorly differentiated, sarcomatous like cells. Immunohistochemical stains are positive for S-100 (c) in the epithelial component of the tumor and desmin (d), especially in rhabdoid cells in the tumor. H&E, ×150 (a, b); peroxidase anti-peroxidase, ×100 (c, d).

Discussion

Rhabdomyosarcomatous differentiation in malignant teratoid medulloepithelioma has been rarely reported. One case was described in 2003, in which a 5-year-old boy presented with pain, redness, and protrusion of his right eye, which was ultimately enucleated [3]. In another case described in 2013, a 1-month-old girl born at 31 weeks gestation was found to have a stalk extending from the posterior pole to the lens during retinopathy of prematurity screening, clinically consistent with persistent hyperplastic primary vitreous [4]. Further testing, including an ultrasound, revealed a large intraocular mass without calcification. Enucleation was performed at 3 months of age due to concern for retinoblastoma. Instead, pathology revealed a malignant teratoid medulloepithelioma with retinoblastic and rhabdomyoblastic differentiation. Finally, several other cases were noted in a 2013 review of 41 medulloepithelioma cases from 1970 to 2012 at Wills Eye Institute and Prasad Eye Institute [5]. Of the 30 cases with histology, thirteen were malignant teratoid medulloepithelioma, and only 3 of the 13 had rhabdomyosarcomatous differentiation.

Of particular interest was that a DICER1 mutation was detected in both of our patients. DICER1 syndrome is an autosomal dominant cancer predisposition syndrome caused by germline variants that disrupt the function of the DICER1 gene. This gene encodes an RNA endonuclease (Dicer), which modulates microRNAs and, therefore, affects gene expression at the post-transcriptional level [6]. Individuals with DICER1 syndrome have increased risks for a variety of cancerous and benign tumors. The risk of neoplasm before the age of 10 is 5.3% and 31.5% before the age of 60 [6]. Tumors reported in DICER1 syndrome include pleuropulmonary blastoma (PPB), ovarian sex-cord stromal tumors, cystic nephroma, lung cysts, renal sarcoma, Wilms Tumor, thyroid nodules, thyroid cancer, ciliary body medulloepithelioma, pineoblastoma/pituitary blastoma, and genitourinary embryonal rhabdomyosarcoma. The most common life-threatening manifestation of DICER1 syndrome is PPB, making it crucial to perform a screening chest X-ray in any patient with suspected DICER1 mutation [6]. In these patients, systemic correlation with PPB has been documented in 5% of cases [7]. Prior cases of DICER1 associated medulloepithelioma have arisen in the ciliary body; our cases appear to have arisen in the optic nerve area. Interestingly, some of the cells in tumor in Case 1 contained intracytoplasmic PAS-positive hyalin-like droplets, similar to what has been reported in DICER1 associated central nervous system sarcoma [8].

Our first case was initially clinically diagnosed as retinoblastoma, and medulloepithelioma remains in the differential diagnosis of retinoblastoma. As medulloepithelioma enlarges, the mesenchymal component may overgrow the epithelial component, thus adding difficulty to the pathologic diagnosis. Our two cases illustrate that the mesenchymal component may contain areas reminiscent of rhabdomyosarcoma, and the pathologist should be diligent in searching for an epithelial component in the tumor as well as heterologous elements to secure the correct diagnosis.

Statement of Ethics

This study was exempt from IRB approval (Emory University). Written and informed consent for publication of the information in the manuscript was obtained by the parent/legal guardian of the patients for publication of the details of their medical case and any accompanying images. The authors completed the CARE checklist for this case report, which is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545825).

Conflict of Interest Statement

Hans E. Grossniklaus was a member of the Journal’s Editorial Board at the time of submission.

Funding Sources

The study was funded in part from a Departmental Core Grant (P30-EY06360) and an unrestricted departmental grant from Research to Prevent Blindness (HEG).

Author Contributions

Conception or design of the work: A.A.M. and H.E.G. Acquisition, analysis, or interpretation of data for the work; drafting the work or reviewing it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: A.A.M., G.B.H., M.A., A.L., H.E.G.

Funding Statement

The study was funded in part from a Departmental Core Grant (P30-EY06360) and an unrestricted departmental grant from Research to Prevent Blindness (HEG).

Data Availability Statement

Data on these cases are not publicly available due to patient privacy. Further inquiries can be made to the corresponding author.