Medulloepithelioma

Medulloepithelioma (diktyoma, teratoneuroma) is a congenital tumor that is generally believed to arise from the epithelium of the medullary tube. This tumor usually arises from the ciliary body epithelium, but medulloepitheliomas of the retina and the optic nerve also occur. The first detailed histologic description of the tumor was by Verhoeff,¹ who called it a teratoneuroma, despite the absence of teratomatous features. Fuchs² reported his observations of a medulloepithelioma and coined the term diktyoma because of the netlike appearance of cells composing the tumor. Grinker³ was the first to use the term “medulloepithelioma,” which has become the preferred name because it refers to the correct cell of origin.

Three large series of medulloepitheliomas have been reported^4–6 and provide the bulk of our knowledge of the clinical features of this tumor. In Broughton and Zimmerman’s series,⁵ the median age at occurrence of initial symptoms was 3.8 years, with a range of 6 months to 41 years. Andersen⁴ reported that the average age at the time of enucleation was 4.5 years for benign medulloepitheliomas and 7 years for malignant tumors. In the series of Canning et al.⁶ the median age at diagnosis was 3 years. In all three series, all tumors were unilateral and single, and there was no racial or hereditary predisposition.

The signs and symptoms of the 56 patients reported on by Broughton and Zimmerman⁵ are summarized in Tables 154.1 and 154.2.

Table 154.1 Medulloepithelioma – symptoms and signs

(Reproduced with permission from Broughton WL, Zimmerman LE. A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. Am J Ophthalmol 1978;85:407–18.)

Table 154.2 Medulloepithelioma – clinical findings on initial examination

(Reproduced with permission from Broughton WL, Zimmerman LE. A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. Am J Ophthalmol 1978;85:407–18.)

One remarkable feature of medulloepitheliomas is the frequent presence of cysts, which are formed by the production of mucopolysaccharide by the epithelial cells. These cysts can be present within the body of the tumor but also may be free-floating in the anterior or posterior chamber and vitreous (Figs 154.1–154.4). The presence of vitreous or anterior chamber cysts should alert the clinician to consider the possibility of a diagnosis of medulloepithelioma, although vitreous cysts have also been described with malignant melanoma.⁷

Fig. 154.1 External photograph showing ciliary body mass.

(Case presented by Milton Boniuk, Verhoeff Society, 1997.)

Fig. 154.2 Gross appearance of medulloepithelioma demonstrating ciliary body mass and cysts in the posterior chamber.

(Case presented by Milton Boniuk, Verhoeff Society, 1997.)

Fig. 154.3 Histopathology showing epithelial nature of the tumor with cysts formed by epithelium surrounding mucopolysaccharide-filled spaces. (H&E; ×100.)

Fig. 154.4 Histopathology demonstrating cystic spaces overlying ciliary body epithelium. (H&E; ×400.)

Another noteworthy feature of medulloepithelioma is that the intraocular pressure is frequently elevated at the time of diagnosis (see Table 154.2). This may result from secondary angle closure by the ciliary body mass, iris neovascularization, or growth of tumor cells across the trabecular meshwork.

Medulloepitheliomas usually contain, as their most significant component, sheets and cords of poorly differentiated neuroepithelial tissue. The cellular cords may line cystic spaces filled with acid mucopolysaccharide. Homer Wright and Flexner–Wintersteiner rosettes may be present, but more commonly the rosettes in medulloepithelioma are larger than those seen in retinoblastoma. Typically, the lumina of the rosettes are surrounded by multiple cell layers, which resemble primitive ciliary epithelium, rather than photoreceptors.

In addition to the neuroepithelial tissue, medulloepitheliomas may contain heteroplastic tissues, in which case they are called teratoid medulloepitheliomas. Hyaline cartilage, striated muscle, undifferentiated mesenchymal cells, and neurologic tissue resembling the brain have all been described in teratoid medulloepitheliomas.

Medulloepitheliomas may be benign or malignant. Broughton and Zimmerman⁵ considered 66% of the tumors in their series to be malignant. Andersen,⁴ using more stringent criteria, classified 26% of the tumors in his series as malignant. From a practical point of view, even cytologically benign medulloepitheliomas can be locally invasive, extending into the iris, cornea, sclera, or orbit. For that reason all medulloepitheliomas should be considered as potentially malignant tumors, as recommended by Andersen.⁴

The initial treatment in all reported cases has been surgical – iridectomy, iridocyclectomy, or enucleation – and with total excision, the prognosis is excellent. Canning et al.⁶ have stressed the importance of attempting local resection (i.e., iridocyclectomy) only in patients with very small tumors. Of the four patients in their series who were treated by iridocyclectomy, all subsequently required enucleation. A total of 45 (80%) of the patients in Broughton and Zimmerman’s series⁵ treated by iridocyclectomy subsequently required enucleation.

In both Broughton and Zimmerman’s⁵ and Anderson’s⁴ series of patients, the most important prognostic factor appeared to be extension of tumor into the orbit. In Broughton and Zimmerman’s series,⁵ 11 patients had extraocular extension; of this group, four died of tumor-related causes. Intracranial spread of tumor was the usual cause of death, although one patient died of lymphatic spread to the mediastinum. The effectiveness of exenteration, radiation therapy, or chemotherapy – used individually or in combination – in managing extraocular extension is not established at this time. Such methods should be considered in cases with extrascleral extension because of the high tumor-related morbidity and mortality in this group of patients.

Glioneuroma

Glioneuromas are choristomatous malformations that arise from the medullary epithelium of the anterior portion of the optic cup. They are extremely rare, and only a few cases have been reported.^8–12

Glioneuromas usually appear as a mass involving the peripheral iris and ciliary body and are usually evident within the first 6 months of life. The tumor may involve the choroid and the retina, and extraocular extension has been described. Associated ocular abnormalities are frequently present and have included persistent hyperplastic primary vitreous in the same or contralateral eye and coloboma of the iris and ciliary body. Progressive enlargement of the tumor may lead to corneal opacification, cataract, or glaucoma.

These tumors are composed of well-differentiated neural tissue, including neurons and astrocytes. All the reported cases^8–12 have eventually required enucleation because of complications of the enlarging tumor or suspected malignancy. Because this is a benign tumor, it could conceivably be managed by local resection.

Astrocytoma

Only two cases of astrocytoma of the ciliary body have been reported.^13,14 One patient was 24 years old, and the other was 52 years old. At presentation, both had solid tumors of the ciliary body, and in one patient the astrocytoma was associated with neovascular glaucoma. Growth of the tumor was not documented in either case. These tumors were probably choristomas of the anterior portion of the optic cup. Both lesions consisted of pilocytic astrocytes. Both tumors were treated by iridocyclectomy. Interestingly, in the patient with neovascular glaucoma, the rubeosis was observed to diminish after removal of the tumor.

Pseudoadenomatous hyperplasia: reactive

Hyperplasia of the ciliary epithelium may occur as a nonspecific response to trauma or inflammation. The hyperplastic tissue is primarily composed of nonpigmented ciliary body epithelium but may contain pigmented ciliary epithelium and blood vessels. Rarely, reactive hyperplasia may result in a mass that could be confused with a ciliary body neoplasm. More commonly, the hyperplastic tissue forms in sheets or as a cyclitic membrane.

Senile hyperplasia

Senile hyperplasia (Fuchs adenoma) is a benign tumor. The frequency with which it is seen increases with age; this tumor may be observed in approximately 20% of postmortem eyes. Because these tumors are almost always <2 mm in size, they are usually of no clinical significance. However, they may cause a sectorial cataract¹⁵ and have been removed because of clinical suspicion of malignancy.^15,16

Fuchs adenomas are white lesions located in the pars plicata. They consist of sheets and tubules of hyperplastic nonpigmented ciliary body epithelium, with alternating areas of material that is like basement membrane. These lesions are significant because, when noted through gonioscopy, cycloscopy, or ultrasonography, they may be confused with malignant lesions. Fuchs adenomas require no treatment.

Adenomas and adenocarcinomas

Adenomas and adenocarcinomas have been described by various names, including benign and malignant epitheliomas and adult medulloepitheliomas. Adenomas and adenocarcinomas of the ciliary epithelium appear as solid tumors of the ciliary body. In Andersen’s review of 30 of these cases, the presenting symptom was an observed mass in nine cases and decreased visual acuity in eight cases.⁴ Other manifestations included glaucoma, cataract, pain, and proptosis. The average age of the patients with adenomas at the time of enucleation was 43 years. For the patients with adenocarcinomas, the average age at the time of enucleation was 55 years. It is noteworthy that several of the reported adenocarcinomas were present in blind eyes involving a previous history of trauma, suggesting that the adenocarcinomas may have represented malignant transformation of reactive hyperplasia of the ciliary epithelium.

The pathologic basis of these tumors has been more thoroughly described elsewhere.⁷ Briefly, the adenomas consist of cuboidal or columnar cells resembling the nonpigmented or pigmented ciliary epithelium. These cells may have a tubular or papillary arrangement and may be closely packed or enmeshed in a mucoid material.

The malignant lesions may be well differentiated, in which case they resemble the adenomas but have more cytologic features of malignancy. The poorly differentiated lesions are more pleomorphic and may resemble a metastatic adenocarcinoma or even a sarcoma.

Because these lesions cannot be reliably differentiated from melanomas, they are usually treated by enucleation or brachytherapy. It is evident that extraocular extension is an important factor in prognosis. Andersen reported two cases of adenocarcinoma that had extended outside the globe at the time of enucleation.⁴ Both of the patients developed intracranial extension of the tumor. In another series of 21 cases of adenocarcinoma of the ciliary epithelium, follow-up information was available for 16 patients.¹⁷ Of those 16 patients, five died of tumor extension into the central nervous system or of widespread metastatic disease; four of the five patients had extraocular extension at the time of initial surgery. The role of exenteration, radiation therapy, or chemotherapy in extraocular extension has not been defined.

Melanocytoma

The term melanocytoma was first used by Zimmerman and Garron¹⁸ to describe a benign pigmented tumor of the optic nerve. Other names that have been used to designate this same lesion include magnocellular nevus and benign melanoma. Melanocytomas of the optic nerve and peripapillary choroid are described in Chapter 136 (Congenital hypertrophy of the retinal pigment epithelium). Therefore only melanocytomas limited to the uvea are discussed here.

Uveal melanocytomas appear as very darkly pigmented tumors of the choroid, ciliary body, or iris (Fig. 154.5). Although they are probably congenital lesions, the age range at the time of presentation is not sufficiently different from that of malignant melanomas to be useful in differential diagnosis. In a review of ciliary body melanocytomas, Frangieh et al.¹⁹ found that most of the reported cases have been in whites. Therefore, unlike optic nerve melanocytomas, uveal melanocytomas do not occur predominantly in blacks. Distinguishing this benign tumor from malignant melanoma is further complicated by the ability of melanocytomas to undergo slow growth. Such slow growth may result in extension of the tumor through the sclera to the episclera. Also, melanocytomas may undergo necrosis, resulting in pigment dispersion, uveitis, and melanomalytic glaucoma. Kathil et al. have described the clinical features of anterior uveal melanocytomas that may be useful in distinguishing melanocytomas in the anterior segment from melanoma.²⁰

Fig. 154.5 Fundus photograph showing a choroidal melanocytoma.

Melanocytomas are composed of plump, polyhedral, densely pigmented cells, with small eccentrically placed nuclei that lack prominent nucleoli (Figs 154.6, 154.7). These cells are indistinguishable from the plump, polyhedral cells described by Naumann et al.²¹ as the exclusive component in approximately 10% of choroidal nevi. Evidence that malignant melanomas may develop from uveal melanocytomas has been provided by cases in which melanomas were present and adjacent to lesions that were indistinguishable from melanocytomas.^22–24

Fig. 154.6 Melanocytoma: the cells are characteristically darkly pigmented. (H&E; ×400.)

Fig. 154.7 Bleached sections demonstrate the bland peripherally located nucleus typical of melanocytoma. (Bleached sections; ×400.)

Melanocytomas require no treatment, except for secondary complications. Because these tumors may have the potential for malignant transformation, they should be followed to document changes suggestive of malignancy. However, it may be impossible, on the basis of noninvasive studies, to differentiate melanomas from enlarging melanocytomas, so some melanocytomas inevitably will be treated surgically.

Bilateral diffuse uveal melanocytic proliferation associated with systemic malignant neoplasms

In 1982 Barr et al.²⁵ described a syndrome characterized by bilateral diffuse melanocytic tumors of the uvea in patients with nonocular malignancy. This condition was originally reported by Machemer²⁶ and has been recently reviewed by Satio et al.²⁷ Gass et al.²⁸ summarized the clinical features of this syndrome, which are: (1) multiple, round or oval, red-to-brown patches at the level of the retinal pigment epithelium in the posterior fundus; (2) a striking fluorescein angiographic pattern of early hyperfluorescence corresponding with these patches; (3) development of multiple, elevated, variably pigmented uveal melanocytic tumors and diffuse thickening of the uveal tract; (4) exudative retinal detachment; and (5) rapid progression of cataract.

Patients with this syndrome have had various nonocular malignancies, including adenocarcinomas of the gallbladder, ovary, colon, or pancreas and squamous cell carcinoma of the lung and cervix. Most patients with this syndrome have died within 12–24 months after diagnosis, but long-term survival, although rare, has been reported.

Histopathologic study of the uvea in patients with this syndrome has disclosed uveal melanocytic tumors. The cytologic features of the tumors are variable, with most of the cells having benign cytologic features. However, cytologic features of malignancy have been present in several cases,^25,29 although no metastatic disease has been documented.

Neurilemmoma (schwannomas)

Shields et al.³⁰ have reviewed the reported cases of choroidal and ciliary body neurilemmomas. The mean age at the time of diagnosis in the reported cases was 38 years, with a range from 4 to 68 years. Unlike neurofibromas, uveal neurilemmomas are not usually associated with neurofibromatosis. The clinical presentation of these tumors is that of a solid ciliary body or choroidal tumor. Although cytologically benign, they may progressively enlarge at a rate similar to, or greater than, that of choroidal melanomas. In the case studied by Shields et al.³⁰ preoperative ultrasound demonstrated acoustic hollowness, choroidal excavation, and low internal reflectivity. These findings are identical to those of choroidal melanoma. In two subsequently reported cases of anterior uveal neurilemmomas, the tumors were noted to transilluminate brightly.^31,32 This may be a helpful clinical finding because it is unusual for anterior uveal melanomas to transilluminate in this way. With increased suspicion, fine needle biopsy and local resection may be considered.

Neurilemmomas are encapsulated tumors consisting of a pure proliferation of Schwann cells. The cells in these tumors are characteristically arranged as either solid sheets of cells (Antoni A pattern) or stellate-to-ovoid cells in a mucinous background (Antoni B pattern).

Because these tumors are cytologically benign, they require treatment only to prevent visual loss resulting from their progressive enlargement. Unfortunately, as with many primary uveal tumors, it is difficult to distinguish neurilemmomas from amelanotic malignant melanomas.

In the case studied by Shields et al.³⁰ there was no clinical or histologic evidence that the tumor was responsive to radiation therapy.

Neurofibroma

Unlike neurilemmomas, uveal neurofibromas are associated with neurofibromatosis. Choroidal neurofibromas are diffuse lesions and appear as diffuse thickening of the choroid, sometimes with an overlying sensory retinal detachment.³³

Neurofibromas are nonencapsulated lesions composed of Schwann cells, axons, and fibroblasts. An increase in the number of dendritic uveal melanocytes may be present, simulating congenital melanosis oculi. No treatment is required except to manage vision-threatening complications. (Additional material on neurofibromas may be found in Chapter 134, Remote effects of cancer of the retina.)

Granular cell tumor

The cell type from which granular cell tumors originate is not definitely known; these tumors have features suggestive of a myogenic or neuroectodermal origin. A single case of granular cell tumor, involving the iris and ciliary body of a 24-year-old woman, has been reported.³⁴ The tumor was partially excised, but 1 year after treatment no enlargement of the remaining tumor was reported. Other cases of intraocular granular cell tumor have not been reported.

Leiomyoma

Leiomyomas are rare intraocular tumors that appear as a solid mass of the ciliary body or choroid (Fig. 154.8). As with other solid tumors in these locations, they may cause secondary cataract, glaucoma, and retinal detachment. Leiomyomas arise from the smooth muscle of the ciliary body. In the choroid they probably arise from the smooth muscle or pericytes of the choroidal vessels. They are composed of densely packed, nonpigmented, spindle-shaped cells with oval nuclei (Fig. 154.9). This histologic feature correlates with the very low internal reflectivity seen on A-scan echography of these lesions (Fig. 154.10). It is difficult to differentiate these tumors from amelanotic spindle melanomas solely on the basis of light microscopic features. Immunohistochemical stains and ultrastructural evaluation (Fig. 154.10) are essential in making this distinction.

Fig. 154.8 Clinical photograph of ciliary body leiomyoma.

Fig. 154.9 Leiomyoma: the tumor is composed of typical smooth muscle cells with indistinct cell borders and spindle-shaped nuclei. (H&E; ×400.)

Fig. 154.10 A-scan echography reveals very low reflectivity of the tumor.

Clinically, it is very difficult to differentiate leiomyomas from malignant melanomas. As a result, leiomyomas are usually clinically diagnosed and treated as malignant melanomas. A recent report by Shields et al.³⁵ emphasized that leiomyomas of the ciliary body demonstrate increased transillumination. This feature may allow clinical distinction of this tumor from ciliary body melanomas, which generally do not transilluminate in this way. If the diagnosis is established clinically (e.g., by fine-needle biopsy), treatment should consist of managing the secondary complications of this benign tumor.

Mesectodermal leiomyoma

Mesectodermal leiomyoma has been used to describe a benign tumor of the ciliary body that has histologic and ultrastructural features of both smooth muscle and neural tissue (Fig. 154.11).^35–37 The peculiar combination of features in this tumor may be explained by the embryologic origin of the ciliary body smooth muscle from the neural crest. The designation mesectodermal leiomyoma should be reserved for tumors that have light or electron microscopic evidence of neurogenic tumors.

Fig. 154.11 Transmission electron microscopy reveals the Z bands typical of smooth muscle.

Reactive lymphoid hyperplasia and lymphoma

Lymphocytic tumors may involve the eye in a myriad of ways. Reactive lymphoid hyperplasia and lymphoma may both present as choroidal tumors (Figs 154.12, 154.13). Choroidal tumors due to lymphocytic infiltration tend to have a more irregular contour to the base of the tumor, and often extend in a more circumferential fashion than is typical of melanocytic or neurogenic tumors of the choroid. In some cases, there will be simultaneous involvement of the orbit or ocular adnexa. Lymphocytic tumors presenting in this fashion can represent isolated extranodal lymphoma (primary uveal lymphoma) or may be present in association with lymphoma at other sites (secondary lymphoma). The diagnosis can be made by incisional biopsy (Fig. 154.14). Patients with lymphoma should undergo staging and treatment appropriate to the type and extent of lymphoma.

Fig. 154.12 Uveal lymphoma: peripheral choroidal mass with the clinical appearance of choroidal detachment.

Fig. 154.13 B-scan echography reveals the solid nature of the tumor.

Fig. 154.14 Ciliary body biopsy reveals a diffuse infiltrate of mature-appearing small lymphocytes. (H&E; ×200.)

Juvenile xanthogranuloma

The iris and ciliary body are usually the sites of intraocular involvement with juvenile xanthogranuloma. However, prominent involvement of the peripapillary choroid, retina, and optic nerve led to enucleation in one case because of the clinical suspicion of a malignant lesion.³⁸

Hemangiopericytoma

Uveal hemangiopericytoma is an extremely rare neoplasm^41–43 The clinical features of these tumors are similar to those of uveal melanomas, including the frequent presence of a sentinel vessel in cases of ciliary body hemangiopericytomas. In one of the reported cases of hemangiopericytoma the magnetic resonance (MR) signal characteristics of the tumor were different from those of choroidal melanomas.¹⁵ The authors suggested that MR imaging may provide a mechanism for distinction of this rare tumor from uveal melanoma.

Hemangiopericytomas may be benign or malignant. Complete surgical resection is the treatment of choice in either case.

Rhabdomyosarcoma

A remarkable case of rhabdomyosarcoma of the ciliary body in a 12-year-old boy has been reported.⁴⁴ It is possible that this case represents the one-sided or complete differentiation of a teratoid medulloepithelioma along the line of a rhabdomyosarcoma. At the last reported follow-up examination (2 years after enucleation), the child was alive without evidence of metastasis or local recurrence. Three additional cases of primary rhabdomyosarcoma of the iris have been reported.^44–47