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Clinicopathologic Reports, Case Reports, and Small Case Series
January 2002

Mitochondria-Rich Epithelioid Leiomyoma of the Ciliary Body

Author Affiliations
 

W. RICHARDGREENMD

Arch Ophthalmol. 2002;120(1):77-82. doi:

Leiomyoma is a rare benign, smooth muscle–derived tumor that can arise from all parts of the uveal tract.1,2 This tumor can cause diagnostic difficulties, because it may appear clinically as an amelanotic melanoma. Fewer than 30 leiomyomas of the ciliary body have been reported, but often these have not been well documented by immunohistochemical and/or electron microscopic studies.

Herein we report an unusual variant of a ciliary body leiomyoma, which to our knowledge has not been documented in the literature. This tumor was clinically suspected of being a malignant melanoma, with histopathologic resemblence to a granular cell tumor. Results of more detailed immunohistochemical and electron microscopic studies showed smooth muscle differentiation and marked mitochondrial abundance of the tumor, which was finally classified as an epithelioid leiomyoma particularly rich in mitochondria.

Report of a Case

A 30-year-old Greek patient was referred to our hospital because of a tumor of the ciliary body in his right eye that had been detected on results of routine ophthalmologic examination. No visual disturbances were found. The patient was otherwise healthy, with no family history of any ocular or systemic disease.

Results of the clinical examination showed a solid brownish tumor of the ciliary body between the 7- and 9-o'clock positions (Figure 1A-B). The tumor mass invaded the anterior chamber through the iris root. The lens was indented and disclosed an associated posterior subcapsular cataract. There was no collateral detachment of the retina, and the posterior fundus and the optic discs were normal in both eyes. Best-corrected visual acuity was 20/20 OU, and intraocular pressure was 16 mm Hg in both eyes. The flare values of aqueous humor measured using a laser flare-cell meter (FC-1000; Kowa, Tokyo, Japan) were increased in the right eye (19.8 counts per 0.5 seconds; reference, <8 counts per 0.5 seconds), indicating a compromised blood-aqueous barrier,3 but no other ocular abnormalities were seen. Results of ultrasonography disclosed a solid 9.8 × 8.2-mm tumor with low internal reflectivity. Results of transillumination were inconclusive.

Figure 1.
A, Preoperative findings show
a ciliary body tumor protruding through the iris root into the anterior chamber
in a 30-year-old man. B, Gonioscopy of the tumor. C, Postoperative appearance
after a 11.0 × 11.3-mm en bloc excision and tectonic corneoscleral graft.
D, Macroscopic appearance of the excised tissue with the rounded solid tumor.
Dilated vessels are visible within the tumor mass along the cut surface.

A, Preoperative findings show a ciliary body tumor protruding through the iris root into the anterior chamber in a 30-year-old man. B, Gonioscopy of the tumor. C, Postoperative appearance after a 11.0 × 11.3-mm en bloc excision and tectonic corneoscleral graft. D, Macroscopic appearance of the excised tissue with the rounded solid tumor. Dilated vessels are visible within the tumor mass along the cut surface.

The clinical differential diagnoses included malignant melanoma of the ciliary body with infiltration of iris and anterior chamber angle and adenoma of the nonpigmented ciliary epithelium, although myogenic, neurogenic, and vascular neoplasms were also considered. Because evidence of tumor progression by means of history and tumor size was found, we decided to perform an en bloc excision of the tumor.

After cryocoagulation of the adjacent retina, the tumor and the overlying sclera in full thickness were excised en bloc.4 A tectonic penetrating sclerokeratoplasty (11.0 × 11.3 mm) was performed (Figure 1C) with an extracapsular cataract extraction and posterior chamber lens implantation. Postoperatively, a vitreous hemorrhage occurred, and the patient had a best visual acuity of 20/400 eight months after surgery. Otherwise, the follow-up was uneventful.

The excised tissue block was fixed in buffered 4% paraformaldehyde and 1% glutaraldehyde and processed for light microscopy and transmission electron microscopy. Paraffin-embedded sections were stained with hematoxylin-eosin, periodic acid–Schiff (PAS), Masson trichrome, and Fontana-Masson. Immunohistochemistry was performed using the streptavidin-biotin method with antibodies against S-100 protein, desmin, smooth muscle α-actin, muscle-specific actin, vimentin, neuron-specific enolase, cytokeratin, glial fibrillary acid protein, HMB-45, and CD68, with appropriate negative controls. Ultrathin sections were stained with uranyl acetate and lead citrate.

Macroscopically, the excised 9.0 × 10.5-mm specimen showed a completely resected, rounded, solid brownish tumor of the ciliary body measuring 9 × 8 mm in diameter and 5 mm in prominence, and resting on a normal sclera. Several dilated vessels were visible within the pale yellow tumor mass along the cut surface (Figure 1D).

By light microscopy, the well-circumscribed, highly vascularized tumor occupied the stroma of the ciliary body and was covered by the intact, double-layered ciliary epithelium. There was no invasion of the sclera (Figure 2A). The tumor was well demarcated against the compressed ciliary muscle, but continuity between the tumor and the most anterior portion of the ciliary muscle was evident in some sections.

Figure 2.
A, Light microscopy shows a circumscribed
tumor occupying the ciliary body stroma and covered by the ciliary epithelium
(hematoxylin-eosin, original magnification ×10). B, The densely packed
polygonal tumor cells show a strikingly granular eosinophilic cytoplasm (hematoxylin-eosin,
original magnification ×375). C, The tumor cells are surrounded by prominent
basement membranes (periodic acid–Schiff, original magnification ×250).
D, A capillary network but little extracellular matrix is present between
the tumor cells (Masson trichrome, original magnification ×250).

A, Light microscopy shows a circumscribed tumor occupying the ciliary body stroma and covered by the ciliary epithelium (hematoxylin-eosin, original magnification ×10). B, The densely packed polygonal tumor cells show a strikingly granular eosinophilic cytoplasm (hematoxylin-eosin, original magnification ×375). C, The tumor cells are surrounded by prominent basement membranes (periodic acid–Schiff, original magnification ×250). D, A capillary network but little extracellular matrix is present between the tumor cells (Masson trichrome, original magnification ×250).

The tumor mass consisted of large, densely packed polygonal cells with abundant cytoplasm and round-to-oval uniform nuclei with moderately prominent nucleoli. Mitotic figures and necrotic or degenerative changes were not observed. In sections stained with hematoxylin-eosin, the eosinophilic cytoplasm of the tumor cells had a striking granular appearance (Figure 2B). Results of PAS staining showed prominent basement membranes surrounding individual tumor cells but a PAS-negative cytoplasm (Figure 2C). The cytoplasm appeared red on results of the Masson trichrome staining (Figure 2D). Fontana-Masson staining for melanin was negative. Little extracellular matrix and a moderately developed capillary network were present between the densely packed tumor cells. On the basis of light microscopic criteria, the tumor was preliminarily classified as a granular cell tumor.

Immunohistochemistry showed the tumor cells to be strongly positive for smooth muscle α-actin (Figure 3A), muscle-specific actin, desmin (Figure 3B), and mitochondrial antigen (Figure 3C); weakly positive for vimentin (Figure 3D), neuron-specific enolase, and cytokeratin; and negative for melanoma-specific antigen (HMB-45), macrophage marker CD68, glial fibrillary acidic protein, and S-100 protein. The pattern of immunoreactivity was consistent with that of a tumor of smooth muscle origin, with the ciliary muscle and blood vessels serving as internal positive controls.

Figure 3.
Results of immunohistochemistry
show strong positive reactions for smooth muscle α-actin (A), desmin
(B), and mitochondrial antigen (C) and a focally positive reaction for vimentin
(D) (original magnifications ×250).

Results of immunohistochemistry show strong positive reactions for smooth muscle α-actin (A), desmin (B), and mitochondrial antigen (C) and a focally positive reaction for vimentin (D) (original magnifications ×250).

Electron microscopy showed that the cytoplasm of the distended tumor cells was densely packed with mitochondria (Figure 4A), which were enlarged and showed a number of structural anomalies, eg, abnormal and centrally stacked cristae and granular and lamellar inclusion bodies (Figure 4B). In addition to mitochondria, glycogen particles (Figure 4B) and bundles of 9-nm myofilaments with characteristic fusiform densities (anchoring plaques) were present in the peripheral cytoplasm in some of the tumor cells (Figure 4C-D). Occasionally, lipid droplets and granules with particulate contents, presumably glycogenosomes, could be found among the mitochondria (Figure 4D). Lysosomal inclusions were only seldom seen. Single smaller cells with prominent Golgi complexes, cisterns of rough endoplasmic reticulum, and clusters of cytoplasmic granules resembling neurosecretory granules were scattered between the mitochondria-laden cells. The tumor cells were surrounded by continuous basement membranes (Figure 4B-C). Specific intercellular junctions could not be observed. Few collagen fibers could be demonstrated in the sparse extracellular space.

Figure 4.
Results of transmission electron
microscopy of the tumor cells. A, The cytoplasm of the distended tumor cells
is packed with swollen mitochondria. B, Detail of tumor cells shows structural
anomalies of mitochondria and glycogen granules (arrows). Arrowheads indicate
the basement membrane. C, Myofilament bundles (MF) are present in the periphery
of tumor cells, which are surrounded by a prominent basement membrane (arrowheads).
D, Detail of tumor cells showing a prominent myofilament bundle (MF) with
fusiform densities and a glycogenosome (arrow).

Results of transmission electron microscopy of the tumor cells. A, The cytoplasm of the distended tumor cells is packed with swollen mitochondria. B, Detail of tumor cells shows structural anomalies of mitochondria and glycogen granules (arrows). Arrowheads indicate the basement membrane. C, Myofilament bundles (MF) are present in the periphery of tumor cells, which are surrounded by a prominent basement membrane (arrowheads). D, Detail of tumor cells showing a prominent myofilament bundle (MF) with fusiform densities and a glycogenosome (arrow).

The final diagnosis, based on electron microscopy and immunohistochemistry, was a particularly mitochondria-rich epithelioid leiomyoma of the ciliary body with iris and anterior chamber invasion.

Comment

The clinically suspected diagnosis of a malignant melanoma or an epithelial tumor of the ciliary body could not be confirmed on histopathologic and immunohistochemical examination using melanoma-specific and epithelial markers. Instead, the light microscopic pattern of the tumor cells strikingly resembled that of a granular cell–type tumor.

Large eosinophilic granular cells occurring in normal and neoplastic tissues have long been the subject of speculation and controversy. Cytoplasmic granularity in tumor cells may be caused by an ultrastructural abundance of lysosomes (granular cell tumors and granular cell myoblastomas), mitochondria (oncocytomas), or other organelles, eg, microcrystals (alveolar soft part sarcomas), smooth endoplasmic reticulum (hepatocellular neoplasms), and secretory granules (apudomas and paragangliomas).5 Typical granular cell tumors are characterized by a PAS-positive cytoplasm, positive immunoreactions for S-100 protein and neuron specific enolase, and increased amounts of lysosomal inclusions (autophagosomes, myelin figures, and angulate bodies) by electron microscopy, indicating a neurogenic origin, most probably derived from Schwann cells.6 These tumors are known as rare tumors of the orbit and ocular adnexa,7 but intraocular occurrence appears to be limited to a single report, based on light microscopic findings, of a granular cell myoblastoma of the iris and ciliary body.8

Although the granular cells in our case were histologically indistinguishable from those in typical granular cell tumors, PAS-negative staining characteristics, immunonegativity of the cytoplasm for S-100 protein, and lack of lysosomal structures distinguished the present case from a classic granular cell tumor. The comparison with the granular cell myoblastoma originally described by Abrikossoff9 remains superficial owing to a lack of immunohistochemical and ultrastructural examinations. However, electron microscopy has shown that the apparent granularity and eosinophilia of the tumor cells in the present case, detected using light microscopy, were due to an augmentation of mitochondria. The abundance of mitochondria raised the possibility of an oncocytoma,10 but this was not considered to be substantiated by the location of the tumor below the ciliary epithelium or by the lack of epithelial features such as desmosomes on electron microscopy.

Instead, the marked expression of the myogenic markers desmin, smooth muscle actin, and muscle-specific actin, the tumor location, and the electron microscopic demonstration of myofilaments, subplasmalemmal fusiform densities, glycogen particles, and continuous basement membranes clearly proved a myogenic origin with smooth muscle differentiation of the tumor cells. Therefore, findings suggested a leiomyoma.1,2,1113 The weak staining for cytokeratin is difficult to interpret, but cytokeratin immunoreactivity has been reported in smooth muscle and smooth muscle tumors.14

Leiomyomas exhibiting marked granular changes (granular cell leiomyoma) have been rarely described at various extraocular locations, eg, the breast or the urogenital tract.1518 These tumors showed polygonal or epithelioid rather than spindle-shaped cells with granular eosinophilic cytoplasm and smooth muscle differentiation. The granular cytoplasmic changes were generally related to an increase in lysosomal elements within the neoplastic cells, thus resembling classic granular cell schwannomas. However, some cases of leiomyoma, leiomyoblastoma, and leiomyosarcoma have also been reported to disclose numerous mitochondria filling the cytoplasm of the tumor cells and giving a granular appearance by light microscopy.19,20 A large series of 70 smooth muscle neoplasms from various body sites has shown that abundant mitochondria associated with a paucity of myofilaments represented a particular feature of epithelioid smooth muscle tumors, eg, epithelioid leiomyomas, leiomyoblastomas, or epithelioid components of leiomyosarcomas.21 For instance, in 14 of 15 leiomyoblastomas, the numerous mitochondria were the most striking feature, virtually filling the cytoplasm to the exclusion of other organelles. Tumor cells packed with mitochondria contained fewer myofilaments and were often round to polygonal in shape. By contrast, spindle cells contained sparse mitochondria but numerous myofilaments.

Leiomyomas of the ciliary body have been generally classified into mesodermal tumors originating from vascular smooth muscle and mesectodermal tumors arising from the ciliary muscle, which is a neural crest derivative.2,22 Among the few cases of mesectodermal leiomyomas of the ciliary body reported, various amounts of mitochondria, from sparse to abundant, have been described in the tumor cells.2328

In concordance with these observations and on the basis of our light microscopic, immunohistochemical, and ultrastructural findings, we diagnosed the tumor histopathologically as an unusual granular cell variant of a leiomyoma of the ciliary body. Positive desmin staining and focal continuities between the tumor and the circular portion of the ciliary muscle suggest its origin from the ciliary muscle. The present case differs from those of previous reports on mesectodermal leiomyomas by the marked abundance of abnormal mitochondria as its most prominent feature. Thus, we believe that the term mitochondria-rich epithelioid leiomyoma is the most accurate description of the tumor presented.

Interestingly, the cells of the circular and inner reticular portions of the ciliary muscle of cynomolgus monkeys showed more mitochondria and fewer myofibrils than cells of the longitudinal portion.29 Although not so pronounced, an increased number of mitochondria could also be demonstrated in the circular part of the ciliary muscle in the present case and in normal human donor eyes, substantiating the supposed origin of the tumor.

Although extremely rare, this case highlights the clinical and histopathologic difficulties in diagnosing ocular smooth muscle tumors and the definite need for electron microscopy and immunohistochemistry to establish a correct diagnosis. Local resection by means of en bloc excision has been proven to be beneficial in the management of these tumors.4

This study was presented in part at the Annual Meeting of German-speaking Ophthalmo-Pathologists, Berlin, Germany, September 19, 2000.

We thank Carmen Rummelt for excellent technical assistance and Heinrich Witschel, MD, for helpful discussions at the Annual Meeting of German-speaking Ophthalmo-Pathologists.

Corresponding author and reprints: Ursula Schlötzer-Schrehardt, PhD, Department of Ophthalmology, University Erlangen-Nürnberg, Schwabachanlage 6, D-91054 Erlangen, Germany (e-mail: ursula.schloetzer@augen.imed.uni-erlangen.de).

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