Medulloepithelioma

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Disease Entity

Medulloepithelioma is recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature:

ICD-10

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

Disease

Medulloepithelioma is a non-hereditary tumor of the non-pigmented ciliary epithelium (NPCE). It is the most common tumor arising from the non-pigmented ciliary epithelium.

Etiology

Most intraocular medulloepitheliomas occur sporadically and are not associated with congenital malformations or cytogenetic abnormalities. However, medulloepitheliomas do have a known association with the 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. Tumors associated with this mutation include cystic nephromas, pleuropulmonary blastoma, ovarian tumors and thyroid hyperplasia[1][2][3]. Rare occurrences of medulloepithelioma in patients with retinoblastoma have also been reported, although the exact mechanism of the association remains to be elucidated[4].

Risk Factors

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[5] . They reported a range of age 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[6]. 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[7][8][9]. Zimmerman et al. have reported a coexistence of persistent hyperplastic primary vitreous in up to 20% of cases.

Figure 1 – A simplified classification of Medulloepithelioma *According to Zimmerman each tumor can be further classified as solid, papillary, and pleomorphic

General Pathology and Pathophysiology

Medulloepitheliomas are thought to arise from neuroepithelial cells. They commonly arise from within the non-pigmented ciliary epithelium. A distinct microstructural appearance comprising of pseudostratified primitive neuroepithelial cells surrounded by a hyaluronic acid rich stroma is seen[10]. 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[11]. Flexner-Wintersteiner and Homer Wright rosettes may also be visualized.[6]

Figure 2 – Histopathological examination post-enucleation of an eye with a ciliary body tumor shows a: (A) Large mass arising from the ciliary body (arrow) (B). The ciliary body mass shows basophilic cells forming ribbons and tubes with interspersed largely dilated vessels and cysts (C). Tumor cells appear to invade the choroid, with adjacent exudative retinal detachment (D). The tumor cells are round, small and deeply basophilic with some retinoblastoma differentiation. Multiple mitotic figures are present diagnostic of a malignant non-teratoid medulloepithelioma. 



The benign or malignant classification is dependent upon four factors that tend to promote a malignant diagnosis:

  • 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).

It appears that most of these tumors are malignant. Benign and malignant lesions have been further sub-classified by the Zimmerman classification into solid, papillary and pleomorphic types[6][12][13].

Primary prevention

There are currently no preventative measures for Medulloepithelioma.

Diagnosis

Diagnosis of Medulloepithelioma is based on ocular exam findings and ancillary testing. Definitive diagnosis is made by histopathological analysis of tissue sample.

History

Medulloepithelioma can affect individuals of all races and either gender. 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.

Figure 3 - A fleshy vascularised mass is visualized in the right eye (arrow), confirmed on fine needle aspiration biopsy to have ciliary body medulloepithelioma with angle involvement. – (Adapted with permission from Honavar et al. 2019 Indian Journal of Ophthalmology)

Clinical Findings

Medulloepitheliomas are slow-growing tumors, therefore patients are usually asymptomatic until the tumor is either large enough to be seen clinically, or after it causes secondary symptoms. Initial clinical findings may include decreased vision, raised intraocular pressure (IOP), angle closure, leukocoria, and eye redness. Causes of visual loss include cataracts, lens subluxation, lens coloboma, a retrolental membrane or neovascular glaucoma[9][13]. On exam, the tumor is in the region of the ciliary body and appears whitish-pink in color (Figure 3).

On exam, the tumor is in the region of the ciliary body usually, but cases of these tumor arising from the optic nerve have been described[14][15][16] and appears whitish-pink in color (Figure 3). Multiple grayish-white areas of cartilage or cysts may also be seen within the tumor[12] (Figure 4). These cysts which can break away and float in the anterior chamber or vitreous have been reported to be present in up to 50% of patients[6]. A characteristic early feature includes a congenital lens notch, which is caused by the absence of a zonule in the area of the tumor. Calcifications are characteristic of medulloepithelioma and are usually seen as chalky opacities in the ciliary body[13].

Figure 4 – Translucent iris cysts (arrows) and areas of neovascularization are visualized in an eye with a ciliary body medulloepithelioma (Picture courtesy of Dr. Manpreet Singh).
Figure 5 - A 5-year-old girl with (a) leukocoria was noted to have iris neovascularization and retrolental neoplastic cyclitic membrane with vessels (arrow) arising from the ciliary body. (b) Ultrasound biomicroscopy depicted the ciliary body mass with intratumoral cysts, lens subluxation and neoplastic cyclitic membrane (arrow). Fluorescein angiography in the (c) early and (d) late frames highlight the vessels in the retrolental membrane. Following enucleation, the (e) gross specimen reveals an amelanotic ciliary body tumor (arrow) with pigmented areas and with neoplastic cyclitic membrane (arrowhead). Histopathology (f) shows tubules and nests of basophilic neoplastic cells (black arrow) surrounded by loose mucopolysaccharide rich matrix. (Hematoxyline eosin stain; 2.5x magnification) – (Adapted with permission from Honavar et al. 2019 Indian Journal of Ophthalmology)

Other features that may be seen include ectropion uveae, corectopia or iris neovascularization (Figure 5a). The neoplastic tissue may grow over the anterior hyaloid and the posterior lens capsule forming a vascular retrolental membrane. This may be seen in up to 60% of patients[5][6][12]. A mass may also be visualized in the vitreous (Figure 6).

Secondary effects produced by the tumor include unilateral cataracts and neovascular glaucoma, both of which may be seen in up to 50% of cases[5][6][11]. Secondary glaucoma is almost always due to iris neovascularization and subsequent angle closure, but can also be secondary to direct tumor invasion into the angle.[17]

Other less frequent manifestations include uveitis, hyphema, vitreous hemorrhage, retinal detachment and extraocular extension of the tumor. The presence of these secondary features can often lead to a delay in the diagnosis of the tumor. Such delays may result in orbital invasion, distant metastases and even death[18][19].

Figure 6 – The left eye of a patient with medulloepithelioma showing a vascularized yellow mass filling the vitreous cavity with echoes in the vitreous likely representing vitreous hemorrhage.

Symptoms

Patients with medulloepithelioma present with the following symptoms (Table)[9]:

Medulloepithelioma - Table.jpg

Clinical diagnosis

The diagnosis of medulloepithelioma is made 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.

Diagnostic procedures

Ultrasound B-scan

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[20]. For smaller tumors ultrasound bio microscopy is also an effective way to determine the location and size of the tumor (Figure 8b).
Figure 7 - Ultrasound shows a large mass arising from the ciliary body region that covers almost the entire vitreous cavity.

Fluorescein Angiography

Fluorescein angiography will demonstrate vessels arising within the tumor peripherally. These lesions demonstrate early hyperfluorescence and gradual late staining of the mass[21]. (Figure 5 c-d and Figure 8)

Figure 8: Iris Fluorescein Angiography: A) – A normal iris angiogram of the right eye; B) – Iris angiogram of the left eye shows neovascularization of the iris and a vascularized retrolental mass

Magnetic Resonance Imaging (MRI)

MRI is used as a preoperative investigative modality. The tumor appears as retrolental mass that is either isointense or hyperintense to the vitreous, that enhances with contrast (Figure 9). These masses enhance with contrast, which usually appear 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.[13][22] Extra scleral, or extraocular invasion of the tumor may also be identified on this imaging modality.

Figure 9 -T2 MRI Images of a patient with A) Axial, B) Coronal and C) Sagittal sections showing an irregular soft tissue lesion within the left globe occupying nearly half of the vitreous region. The lesion is of mixed signal intensity. No obvious macroscopic retrobulbar extension is visualized.

Differentiating medulloepithelioma from other intraocular tumors, particularly retinoblastoma can prove to be quite difficult on clinical assessment and imaging alone.[23] Needle biopsy can make a definitive diagnosis. Diagnostic needle biopsy may be utilized to make a definitive diagnosis[24]. The histopathology of medulloepithelioma is distinctive as described above.

Laboratory testing

Laboratory testing is not routinely used for diagnosis or management.

Differential diagnosis

The differential diagnosis of medulloepithelioma is similar to that of leukocoria. Most notably it includes retinoblastoma, coats disease, persistent hyperplastic primary vitreous and uveal melanoma.

  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. [25]In addition, no calcifications are visualized in coats disease on imaging.
  3. Juvenile Xanthogranuloma: this is characterized by a fleshy tumor with diffuse involvement of the iris that is associated with spontaneous hyphema. This process is mostly restricted to the iris.
  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.

Management

Enucleation is the standard therapy for advanced ciliary body medulloepithelioma[12]. 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.[5][6][12].Other options for smaller tumors include cryotherapy or radiotherapy. Plaque brachytherapy has been used in small to medium sized tumors with some success[26][27][28]. 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 was shown to achieve tumor regression in one case report[29]. In a case of orbital medulloepithelioma, an intraconal tumor was first treated with chemoradiation prior to resection, which avoided enucleation.[30] The role of systemic chemotherapy remains to be fully explored in patients with medulloepithelioma.

Prognosis

Given the rarity of the disease, there have been limited 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[6][27]. Broughton and Zimmerman et al. reported tumor-related deaths in 4 of 33 patients (12%), all these deaths occurred in patients with malignant tumors with extraocular extension. The major predictor of death in these patients was the presence of extraocular spread. However, cases have been reported with successful management of patients with orbital extension and metastatic disease with adjuvant chemotherapy, radiotherapy and surgery[31].

References

  1. Cai S, Zhao W, Nie X, et al. Multimorbidity and Genetic Characteristics of DICER1 Syndrome Based on Systematic Review. Journal of pediatric hematology/oncology. 2017;39(5):355-361.
  2. Ramasubramanian A, Correa ZM, Augsburger JJ, Sisk RA, Plager DA. Medulloepithelioma in DICER1 syndrome treated with resection. Eye (London, England). 2013;27(7):896-897.
  3. Durieux E, Descotes F, Nguyen AM, Grange JD, Devouassoux-Shisheboran M. Somatic DICER1 gene mutation in sporadic intraocular medulloepithelioma without pleuropulmonary blastoma syndrome. Human pathology. 2015;46(5):783-787.
  4. Minoda K, Hirose Y, Sugano I, Nagao K, Kitahara K. Occurrence of sequential intraocular tumors: malignant medulloepithelioma subsequent to retinoblastoma. Japanese journal of ophthalmology. 1993;37(3):293-300.
  5. 5.0 5.1 5.2 5.3 Broughton WL, Zimmerman LE. A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. American journal of ophthalmology. 1978;85(3):407-418.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Kaliki S, Shields CL, Eagle RC, Jr., et al. Ciliary body medulloepithelioma: analysis of 41 cases. Ophthalmology. 2013;120(12):2552-2559.
  7. Sansgiri RK, Wilson M, McCarville MB, Helton KJ. Imaging features of medulloepithelioma: report of four cases and review of the literature. Pediatric radiology. 2013;43(10):1344-1356.
  8. Shields JA, Eagle RC, Jr., Ferguson K, Shields CL. TUMORS OF THE NONPIGMENTED EPITHELIUM OF THE CILIARY BODY: The Lorenz E. Zimmerman Tribute Lecture. Retina (Philadelphia, Pa). 2015;35(5):957-965.
  9. 9.0 9.1 9.2 Tadepalli SH, Shields CL, Shields JA, Honavar SG. Intraocular medulloepithelioma - A review of clinical features, DICER 1 mutation, and management. Indian journal of ophthalmology. 2019;67(6):755-762.
  10. Saunders T, Margo CE. Intraocular medulloepithelioma. Archives of pathology & laboratory medicine. 2012;136(2):212-216.
  11. 11.0 11.1 Saunders T, Margo CE. Intraocular medulloepithelioma. Archives of pathology & laboratory medicine. 2012;136(2):212-216.
  12. 12.0 12.1 12.2 12.3 12.4 Shields JA, Eagle RC, Jr., Shields CL, Potter PD. Congenital neoplasms of the nonpigmented ciliary epithelium (medulloepithelioma). Ophthalmology. 1996;103(12):1998-2006.
  13. 13.0 13.1 13.2 13.3 Vajaranant TS, Mafee MF, Kapur R, Rapoport M, Edward DP. Medulloepithelioma of the Ciliary Body and Optic Nerve: Clinicopathologic, CT, and MR Imaging Features. Neuroimaging Clinics of North America. 2005;15(1):69-83.
  14. Corrêa ZM, Augsburger JJ, Spaulding AG. Medulloepithelioma of the optic disc. Hum Path. 2011;42(12):2047-51.
  15. Bakhshi S, Bhat GM, Sen S, Sharma S, Sharma DN. Malignant medulloepithelioma of optic nerve head. J Pediatr Hematol Oncol. 2008;30(6):478-80.
  16. Chidambaram B, Santosh V, Balasubramaniam V. Medulloepithelioma of the optic nerve with intradural extension--report of two cases and a review of the literature. Childs Nerv Syst. 2000;16(6):329-33.
  17. Camp DA, Yadav P, Dalvin LA, Shields CL. Glaucoma secondary to intraocular tumors: mechanisms and management. Glaucoma. 2019;30(2):71-81.
  18. Zhou L, Meng Y, Yang H, et al. [A teratoid malignant medulloepithelioma of the optic nerve]. Yanke xue bao = Eye science. 2008;24(1):68-70.
  19. Sosinska-Mielcarek K, Senkus-Konefka E, Jaskiewicz K, Kordek R, Jassem J. Intraocular malignant teratoid medulloepithelioma in an adult: clinicopathological case report and review of the literature. Acta ophthalmologica Scandinavica. 2006;84(2):259-262.
  20. Hennis HL, Saunders RA, Shields JA. Malignant teratoid medulloepithelioma of the ciliary body. Journal of clinical neuro-ophthalmology. 1990;10(4):291-292.
  21. Sharma P, Shields CL, Turaka K, Eagle RC, Jr., Shields JA. Ciliary body medulloepithelioma with neoplastic cyclitic membrane imaging with fluorescein angiography and ultrasound biomicroscopy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2011;249(8):1259-1261.
  22. Galluzzi P, Casseri T, Cerase A, Guglielmucci D, Toti P, Hadjistilianou T. Conventional, diffusion, and permeability findings in ocular medulloepithelioma. Neuroradiology. 2018;60:1213-1222.
  23. Lee J, Choung HK, Kim YA, Kim N, Khwarg SI. Intraocular medulloepithelioma in children: clinicopathlologic features itself hardly differentiate it from retinoblastoma. Int J Ophthalmol. 2019;12(7):1227-1230.
  24. Potter PD, Shields CL, Shields JA, Flanders AE. The role of magnetic resonance imaging in children with intraocular tumors and simulating lesions. Ophthalmology. 1996;103(11):1774-1783.
  25. Viswanathan S, Mukul D, Qureshi S, Ramadwar M, Arora B, Kane SV. Orbital medulloepitheliomas -- with extensive local invasion and metastasis: a series of three cases with review of literature. International journal of pediatric otorhinolaryngology. 2008;72(7):971-975.
  26. Davidorf FH, Craig E, Birnbaum L, Wakely P, Jr. Management of medulloepithelioma of the ciliary body with brachytherapy. American journal of ophthalmology. 2002;133(6):841-843.
  27. 27.0 27.1 Ang SM, Dalvin LA, Emrich J, Komarnicky L, Shields JA, Shields CL. Plaque Radiotherapy for Medulloepithelioma in 6 Cases From a Single Center. Asia-Pacific journal of ophthalmology (Philadelphia, Pa). 2019;8(1):30-35.
  28. Attiku Y, Rishi P, Biswas J, Krishnakumar S. Plaque radiation for ciliary body medulloepithelioma presenting with neovascular glaucoma and vitreous hemorrhage in 13-year-old Asian girl. American Journal of Ophthalmology Case Reports. 2020;18:100719.
  29. Stathopoulos C, Gaillard MC, Schneider J, Munier FL. Successful treatment of ciliary body medulloepithelioma with intraocular melphalan chemotherapy: a case report. BMC Ophthalmology. 2020;20(239).
  30. Gallo RA, Shoag J, Johnson TE, Solomon DA, Perry A, Podda A, Lee JY, Rong AJ. Eye-sparing treatment of localized orbital medulloepithelioma with neoadjuvant chemoradiation. Ophthalmic Plastic Reconstructive Surgery. 2020;epub ahead of print.
  31. Viswanathan S, Mukul D, Qureshi S, Ramadwar M, Arora B, Kane SV. Orbital medulloepitheliomas -- with extensive local invasion and metastasis: a series of three cases with review of literature. International journal of pediatric otorhinolaryngology. 2008;72(7):971-975.