Medulloepithelioma is recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature:
C69.40 - Malignant neoplasm of unspecified ciliary body
C69.41 - Malignant neoplasm of right ciliary body
C69.42 - Malignant neoplasm of left ciliary body
D31.40 - Benign neoplasm of unspecified ciliary body
D31.41 - Benign neoplasm of right ciliary body
D31.42 - Benign neoplasm of left ciliary body
Medulloepithelioma is an embryonal neuroectodermally derived tumor with an intraocular predilection for the non-pigmented ciliary epithelium (NPCE). Besides the ciliary epithelium, medulloepithelioma has been noted in the CNS and even orbit. Ciliary body medulloepithelioma is the most common tumor arising from the non-pigmented ciliary epithelium and second most common pediatric intra-ocular tumor behind retinoblastoma.
Most intraocular medulloepitheliomas occur sporadically and are not associated with congenital malformations or cytogenetic abnormalities. However, an association exists between medulloepithelioma and Pleuropulmonary Blastoma Family Tumor and Dysplasia Syndrome (PPB-FTDS) in about 5% of cases. This syndrome is associated with the DICER-1 gene, which is a member of the ribonuclease III family and is inherited in an autosomal dominant fashion. About 3% of DICER-1 positive patients will manifest a ciliary body medulloepithelioma. Tumors associated with this mutation include cystic nephromas, pleuropulmonary blastoma, ovarian tumors and thyroid hyperplasia. DICER-1 mutations have been associated with a higher rate of retinal abnormalities. KMT2D may represent another somatic mutation mutually exclusive to DICER-1 implicated in ciliary body medulloepithelioma pathogenesis. Rare occurrences of medulloepithelioma in patients with retinoblastoma have also been reported, although the exact mechanism of the association remains to be elucidated.
There are no large population-based studies on the incidence or prevalence of medulloepitheliomas. The literature largely consists of isolated case reports and case series. The Armed Forces Institute of Pathology (AFIP) reported the largest case series consisting of 56 histologically proven cases of medulloepitheliomas . They reported a range of age of presentation from 6 months to 41 years, with a mean age of 3.8 years. The typical reported age of presentation was between 2 to 10 years, with most cases manifesting within the first decade. However, there have been reports of isolated cases documented in adulthood. Based on the reports from AFIP and other case-series, there is no predilection towards any specific race or either gender. Zimmerman et al. reported comorbid persistent hyperplastic primary vitreous in up to 20% of cases.
General Pathology and Pathophysiology
Medulloepitheliomas are thought to arise from neuroepithelial cells. In the eye, they commonly arise from within the non-pigmented ciliary epithelium. They may also be found intracranially in periventricular areas. Its unique microstructural appearance arises from pseudostratified primitive neuroepithelial cells forming neural tube-like structures with distinct internal and external limiting membranes visualized with periodic acid-Schiff (PAS) staining. Previously classified as primitive neuroectodermal tumors (PNET), the current WHO classification system for CNS embryonal tumors designates the category encompassing medulloepithelioma as “embryonal tumor with multilayered rosettes (ETMR)” and further designates genetic markers for amplification of the C19MC region of chromosome 19 or DICER-1 mutations. In the absence of C19MC, tumors may be designated as medulloepithelioma provided they meet histological requirements. Although histopathologically similar, intra-ocular medulloepithelioma does not express C19MC amplification suggesting a different origin from CNS medulloepithelioma and different behavior pattern portending better prognosis.
According to the Zimmerman classification, medulloepitheliomas can be histopathologically classified into teratoid and non-teratoid types, and each of these can be further sub-classified into benign or malignant types (Figure 1).The non-teratoid type consists of cells that resemble the ciliary epithelium. The teratoid type may demonstrate cells of diverse origins, including cartilage, rhabdomyoblasts and brain. Both teratoid and non-teratoid types may contain cysts that contain a hyaluronidase-sensitive mucopolysaccharide that is secreted by tumor cells. Large case series have reported that 50-63% of tumors were nonteratoid and 38-50% were teratoid. Flexner-Wintersteiner and Homer Wright rosettes may also be visualized.
Benign or malignant classification depends upon factors that conventionally signify malignant potential:
· Retinoblastoma-like elements
· Sarcoma-like elements
· Poor cellular differentiation and cellular pleomorphism
· Abnormal mitotic activity
· Extension into surrounding ocular structures (optic nerve, sclera, uvea, cornea)
Most medulloepitheliomas tend towards malignancy. Although metastasis is rare, mortality is often associated with intracranial extension. Benign and malignant lesions have been further sub-classified by the Zimmerman classification into solid, papillary and pleomorphic types. Unfortunately, histological classification of ciliary body medulloepithelioma does not consistently correlate with clinical behavior.
There are currently no preventative measures for Medulloepithelioma.
Diagnosis of Medulloepithelioma is based on ocular exam findings and ancillary testing. Definitive diagnosis is made by histopathological analysis of tissue sample.
Medulloepithelioma can affect individuals of all races and genders. Most cases are reported within the first decade. Patients usually present with secondary complaints such as visual loss or pain in either eye. A careful family history is also helpful given the known association of medulloepithelioma with the familial cancer syndrome PPB-FTDS.
Due to the slow-growing nature of medulloepithelioma, patients frequently do not experience symptoms until tumor size is clinically observable or large enough to induce secondary symptoms. Initial clinical findings may include decreased vision, elevated intraocular pressure (IOP), angle closure, leukocoria, and eye redness. Causes of visual loss include cataracts, lens subluxation, lens coloboma, retrolental membranes, or neovascular glaucoma.
The tumor can typically be found in the ciliary body on slit lamp exam or gonioscopy and appears whitish-pink with chalky calcified opacities (Figure 3) . However, cases of these tumor arising from the optic nerve have been described(Figure 3). Multiple grayish-white areas of cartilage or cysts may be seen within the tumor (Figure 4). These cysts may dislodge and be observed floating in the anterior chamber or vitreous in up to 50% of patients. One characteristic early feature, a congenital lens notch, results from the absence of zonules adjacent to the tumor.
Other anterior segment findings include ectropion uveae, corectopia or iris neovascularization (Figure 5a). Neoplastic tissue growing over the anterior hyaloid and the posterior lens capsule may form a vascular retrolental membrane present in up to 60% of patients. The body of the mass may also extend into the vitreous (Figure 6).
Medulloepithelioma may produce secondary effects such as unilateral cataracts and neovascular glaucoma, both of which may be seen in up to 50% of cases. Secondary glaucoma is almost always due to iris neovascularization and subsequent angle closure, but direct tumor invasion into the angle may serve as another mechanism. Medical treatment of secondary glaucoma should be prioritized over surgical until regression of the primary tumor is achieved.
Other less frequent masquerading manifestations include uveitis, hyphema, vitreous hemorrhage, retinal detachment, and extraocular extension of the tumor. The presence of these features can often delay diagnosis of the tumor. Such delay may portend poor prognosis including orbital invasion, distant metastases and even death.
Presenting phenotype may differ between congenital and childhood presentations of ciliary body medulloepithelioma. Neonatal medulloepithelioma may present in more advanced stages with leukocoria, buphthalmos, larger posterior chamber mass, and elevated IOP. Childhood medulloepithelioma may demonstrate more neovascular features, secondary glaucoma, and lens subluxation with a ciliary body mass.
Patients with medulloepithelioma present with the following symptoms (Table):
The diagnosis of medulloepithelioma may be suspected using a combination of patient's history, clinical exam findings, and with the help of various imaging modalities. Definitive diagnosis is made using histopathological analysis of tissue sample.
Ultrasound B-Scan shows a pattern of heterogenous areas of high internal reflectivity (Figure 7). Clear cysts may also be visualized within the mass (Figure 8b). Areas of cartilage within the tumor can produce dense echoes that may mimic the echoes produced by calcifications in retinoblastoma lesions. For smaller tumors ultrasound biomicroscopy is also an effective way to determine the location and size of the tumor (Figure 8b).
Fluorescein angiography demonstrates vessels arising within the tumor peripherally. These lesions demonstrate early hyperfluorescence and gradual late staining of the mass. (Figure 5 c-d and Figure 8)
Magnetic Resonance Imaging (MRI)
MRI is useful as a preoperative investigative modality. The tumor typically appears as a retrolental mass that is either isointense or hyperintense to the vitreous and enhances with gadolinium contrast (Figure 9). Contrast enhancement usually appears homogeneous, but may appear heterogeneous due to cysts. On T1 weighted imaging, the masses appear hypointense and on T2 weighted imaging they appear hyperintense. Lens notching or subluxation is highly suggestive of medulloepithelioma. Extra scleral, or extraocular invasion of the tumor may also be identified on this imaging modality.
Differentiating medulloepithelioma from other intraocular tumors, particularly retinoblastoma can prove to be quite difficult on clinical assessment and imaging alone. Needle biopsy can make a definitive diagnosis. The histopathology of medulloepithelioma is distinctive as described above.
Laboratory testing is not routinely used for diagnosis or management.
The differential diagnosis of medulloepithelioma is similar to that of leukocoria on presentation. Most notably it includes retinoblastoma, Coats disease, persistent hyperplastic primary vitreous and uveal melanoma. Additionally, differential diagnosis may vary based on demographics when considering ciliary body masses not causing leukocoria.
1. Retinoblastoma: Medulloepithelioma can be frequently misdiagnosed as retinoblastoma. Retinoblastoma is characterized by the presence of calcification, which may be confused with the presence of intratumoral cartilage in medulloepithelioma. Medulloepitheliomas can be differentiated based on their location in the ciliary body. The presence of a retrolental cyclitic membrane in medulloepithelioma serves as an important differentiating feature. Fluorescein angiography in medulloepitheliomas will demonstrate haphazard filling of vessels across the hyaloid face, whereas in retinoblastoma the vessels appear to be regular and organized. In addition, classic retinoblastoma lacks intratumoral cysts, which are a hallmark of medulloepithelioma.
2. Coats Disease: Coats Disease is characterized by the presence of lipoproteinaceous exudates in the subretinal space differentiating it from medulloepithelioma.In addition, no calcifications are visualized in Coats Disease on imaging.
3. Juvenile Xanthogranuloma (JXG): Juvenile Xanthogranuloma is characterized by a fleshy tumor restricted to the iris (unlike medulloepithelioma) associated with spontaneous hyphema.
4. Persistent Hyperplastic Primary Vitreous (PHPV): The retrolental cyclitic membrane in medulloepithelioma may be confused with PHPV. The cyclitic membrane represents proliferation of a neoplastic tissue from the main tumor across the anterior vitreous face. Unlike PHPV this is not associated with a stalk extending to the optic disc.
1. Anterior Retinoblastoma
2. Ciliary Body Cyst
4. Juvenile Xanthogranuloma
Adult Ciliary Body Mass Differential:
1. Ciliary Epithelial (Pigmented or Nondpigmented) Adenoma/Adenocarcinoma
2. Mesoectodermal Leiomyoma
6. Granuloma (including intraocular toxocariasis)
Enucleation is the standard therapy for advanced ciliary body medulloepithelioma. In cases with orbital involvement an extended enucleation or exenteration may be required. Local resection may be attempted for smaller tumors occupying less than 3-4 clock hours, but high rates of recurrence resulting in secondary enucleation have been previously reported. Other options for smaller tumors include cryotherapy or radiotherapy. Plaque brachytherapy has been used in small to medium sized tumors with some success. The process is shorter, and produces better outcomes than local resection. Standard external beam radiotherapy is less effective and has been used primarily as adjuvant therapy. Intracameral and intravitreal chemotherapy were shown to achieve tumor regression in one case report. In a case of orbital medulloepithelioma, an intraconal tumor was first treated with chemoradiation prior to resection, which avoided enucleation. The role of systemic chemotherapy remains to be fully explored in patients with medulloepithelioma, but a combination of vincristine, etoposide, and carboplatin has been reported in one case series to prevent recurrence and metastasis for advanced medulloepithelioma patients.
Patients with DICER-1 mutations may require routine chest x-ray screening, CT, and ultrasonographic screening (thyroid, abdominal, and pelvic) for extra-ocular manifestations of PPB-FTDS. DICER-1 positive patients without ocular involvement should receive annual ophthalmic examination yearly from age 3 to at least age 10 . Genetic testing should be offered to "at-risk" family members.
Given the rarity of the disease, there have been few studies on the long-term prognosis in these patients. Tumors that remain confined to the globe have excellent prognosis, with a 5-year survival rate of 90-95% after enucleation. Broughton and Zimmerman et al. reported tumor-related deaths in 4 of 33 patients (12%), all these deaths occurred in patients with malignant tumors demonstrating extraocular extension. Thus extraocular spread proves to be a major predictor of mortality in these patients. However, cases have been reported of successful management of patients with orbital extension and metastatic disease with adjuvant chemotherapy, radiotherapy and surgery.
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