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Mitochondria-Rich Epithelioid Leiomyoma of the Ciliary Body
Arch Ophthalmol. 2002;120:77-82.
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 x 8.2-mm tumor with low internal reflectivity. Results of
transillumination were inconclusive.
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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 x 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.
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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 x 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  -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 x 10.5-mm specimen showed a completely
resected, rounded, solid brownish tumor of the ciliary body measuring 9 x
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.
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Figure 2. A, Light microscopy shows a circumscribed
tumor occupying the ciliary body stroma and covered by the ciliary epithelium
(hematoxylin-eosin, original magnification x10). B, The densely packed
polygonal tumor cells show a strikingly granular eosinophilic cytoplasm (hematoxylin-eosin,
original magnification x375). C, The tumor cells are surrounded by prominent
basement membranes (periodic acid–Schiff, original magnification x250).
D, A capillary network but little extracellular matrix is present between
the tumor cells (Masson trichrome, original magnification x250).
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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 -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.
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Figure 3. Results of immunohistochemistry
show strong positive reactions for smooth muscle -actin (A), desmin
(B), and mitochondrial antigen (C) and a focally positive reaction for vimentin
(D) (original magnifications x250).
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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.
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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).
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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
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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.1-2,11-13
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.15-18
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.23-28
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
AUTHOR INFORMATION
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.
Ursula Schlötzer-Schrehardt, PhD;
Anselm Jünemann, MD;
Gottfried O. H. Naumann, MD
Erlangen, Germany
Corresponding author and reprints: Ursula Schlötzer-Schrehardt,
PhD, Department of Ophthalmology, University Erlangen-Nürnberg, Schwabachanlage
6, D-91054 Erlangen, Germany (e-mail: ursula.schloetzer{at}augen.imed.uni-erlangen.de).
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