Full text of DOI:10.1007/s004170100353

Graefe’s Arch Clin Exp Ophthalmol
2001) 239:876–881
(
S H O RT C O M M U N I C AT I O N
DOI 10.1007/s004170100353
Hiroko Terasaki
Tetsuro Nagasaka
Masashi Arai
Tomoko Harada
Yozo Miyake
Adenocarcinoma of the nonpigmented ciliary
epithelium: report of two cases
with immunohistochemical findings
Abstract Background: Acquired
neoplasms arising from the nonpig-
mented ciliary epithelium (NPCE)
are much less common than uveal
melanocytic proliferations. We re-
port two cases of acquired neo-
plasms arising from the NPCE with
immunohistochemical findings.
Methods: Case reports. Results and
conclusions: Patient 1 was a 39-
year-old man who presented with a
pigmented mass behind the iris and
secondary exudative retinal detach-
ment. The eye also developed neo-
vascular glaucoma. Patient 2 was a
44-year-old woman with a ciliary
body mass but without symptoms.
Both of these tumors were classified
histologically as low-grade adeno-
carcinomas of the NPCE from speci-
mens successfully removed by irido-
cyclectomy. Immunohistochemical
findings confirmed the origin of the
tumor cells; however, some changes
in the immunoreactivity to cytokera-
tin AE1 and epithelial membrane an-
tigen were found.
Received: 10 October 2000
Revised: 13 July 2001
Accepted: 13 July 2001
Published online: 25 October 2001
©
Springer-Verlag 2001
H. Terasaki ( ) · M. Arai · Y. Miyake
✉
Department of Ophthalmology,
Nagoya University School of Medicine,
6
5 Tsuruma-cho, Showa-ku,
Nagoya 466-8550, Japan
e-mail: terasaki@med.nagoya-u.ac.jp
Tel.: +81-52-7442277
Fax: +81-52-7442279
T. Nagasaka · T. Harada
Division of Pathology, Clinical Laboratory,
Nagoya University Hospital, Nagoya,
Japan
July 1994. There was no previous history of trauma or eye disease.
The best-corrected visual acuity in the left eye was 20/30, and the
intraocular pressure (IOP) was 18 mmHg OU. Slit-lamp examina-
Introduction
Acquired neoplasms arising from the nonpigmented cili- tion of the left eye revealed a trace of flare and cells. The iris was
ary epithelium (NPCE) are much less common than attached to the lens at the 6 o’clock position in the left eye. Dilat-
uveal melanocytic proliferations. It has been reported
that NPCE neoplasms have some characteristic clinical
features that differentiate them from melanomas, but in
ed examination revealed a pigmented mass behind the iris (Fig. 1).
The mass appeared to be indenting the lens, and thin focal opaci-
ties were seen in the adjacent lens. A shallow retinal detachment
was found with a yellow exudate extending from the mass to the
many cases a definitive diagnosis of tumors of the NPCE upper posterior pole of the fundus (Fig. 2). Scleral transillumina-
tion revealed neither a tumor margin nor a ciliary sulcus, possibly
has been made only after histopathological studies [3, 5,
because of the heavily pigmented Japanese eye. Fluorescein angi-
7
, 8, 10]. In this report, we present two eyes with a tu-
ography did not demonstrate a sentinel vessel. No metastases were
found.
mor of the ciliary body that were classified histologically
as low-grade adenocarcinomas of the NPCE. The results
of immunohistochemical studies are also presented.
A- and B-scan ultrasonography revealed a solid ciliary body
mass with moderate internal reflectivity. On magnetic resonance
imaging (MRI), the T1 sequence was hyperintense, and an en-
hancement was seen following the injection of gadolinium dieth-
ylenetriamine pentaacetic acid. The lesion was isointense to the
vitreous in T2-weighted images.
By September 1994, the IOP of the left eye had increased to
39 mmHg, and gonioscopic examination revealed neovasculariza-
tion of the peripheral iris and the trabecular meshwork. Although a
Case reports
Case 1
A 39-year-old man complained of a slight blurring of vision, and malignant melanoma was the most likely clinical diagnosis, a tu-
ophthalmoscopy revealed a ciliary body mass in his left eye in mor of the pigmented or the non-pigmented epithelium of the cili-

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Fig. 2 Fundus photographs showing a shallow retinal detachment
with massive yellow exudate extending from the mass to the upper
posterior pole of the fundus
na was reattached and the yellow exudate gradually faded away.
Secondary brachytherapy was not performed after surgery because
the histopathology of the tumor showed low-grade malignancy.
The patient had no signs of metastasis, and the visual acuity was
2
0/30 with a contact lens in the operated eye 5 years after surgery.
Case 2
A 44-year-old woman was found to have a ciliary body mass in
her left eye during a routine eye examination and was referred to
us in November 1995. Her best-corrected visual acuity was 20/16
in the left eye. Slit-lamp examination of the left eye revealed a
large brown mass occupying the posterior chamber in the 4 to 8
o’clock position with an indenting, thin, subcapsular cataract
(
Fig. 3). The retina appeared normal. No metastases were found.
Fig. 1A, B Clinical appearance of the ciliary body tumor in
case 1. A Slit-lamp photograph. The iris is adherent to the lens at
the 6 o’clock position. B In upward gaze, a pigmented hemispheri-
cal mass behind the iris can be seen
Preoperative A- and B-scan ultrasonography and MRI showed the
same findings as in case 1 except that the tumor was hypointense
to the vitreous in T2-weighted images.
The clinical differential diagnosis included tumor of the pig-
mented or nonpigmented epithelium of the ciliary body, or a malig-
nant melanoma. The pyramidal shape with an abrupt elevation led
us to suspect a tumor of the NPCE, even though MRI revealed a
pattern typical for melanoma. Primary brachytherapy was not per-
formed because the patient did not agree to this therapy until histo-
pathological diagnosis was made. It was decided after extensive
discussions with the patient to remove the tumor in the left eye. Iri-
docyclectomy under general anesthesia with limitation of the mean
blood pressure to 70 mmHg was performed in February 1996. Be-
cause of the wide-based pyramidal shape of the tumor, the corneo-
scleral window had to be large and a preserved scleral graft had to
be used for the reconstruction of the eye. Secondary brachytherapy
was not performed after surgery because the histopathology of the
tumor indicated low-grade malignancy, and the likelihood of me-
tastasis seemed very low. Three years after surgery, the patient had
no sign of metastasis with 20/200 visual acuity in the operated eye.
ary body was also suspected because of the clinical features, viz.,
chronic inflammation, atypical massive exudation, and atypical
MRI findings. Primary brachytherapy was not performed for these
reasons. It was decided after extensive discussions with the patient
to resect the tumor locally in the left eye, although the choices of
enucleation and radiation therapy were also presented.
Iridocyclectomy was successfully performed in November
1
994 under general anesthesia with limitation of the mean blood
pressure to 70 mmHg. The excision of the tumor with a safety
margin of 2 mm extended to the 4 o’clock position of the limbus
and beyond the ora serrata to the posterior retina. Cryopexy to seal
the border of the tumor was not performed before the operation
because the exudative retinal detachment seemed to prevent the at-
tachment of sensory retina and pigment epithelium. To be able to
reattach the site of the excised peripheral retina and to remove any
vitreous hemorrhage which might occur during surgery because
the expected area of excision would be extremely wide, lensecto- Histopathological findings
my, vitrectomy, drainage of subretinal fluid, and endophotocoagu-
lation were performed successively. After surgery, the neovascu- Gross examination of the specimens disclosed an 8×8×3 mm
larization of the iris and trabecular meshwork regressed. The reti- hemispherical brown mass of uveoscleral tissue in case 1 and an

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Immunohistochemical examination
Immunohistochemical study was performed using the streptavidin
method (Histofine SAB kit, Nichirei, Tokyo, Japan). Ethylcarb-
azol was used as the chromogen and the sections were counter-
stained with hematoxylin. The tumor cells in both cases showed
negative reactivity for melanoma-specific antigen HMB-45, neu-
ron-specific enolase (NSE 1:50, Dako, Kyoto, Japan) for detect-
ing neuronal differentiation, glial fibrillary acidic protein (GFAP,
1
:50, Dako) for detecting glial differentiation, alpha-smooth mus-
cle actin (1:50, Dako) for muscle differentiation. They were posi-
tive for S-100 protein (1:2000, Dako) and vimentin (1:50, Dako),
which provided support for their origin from the NPCE [1]. They
were also positive for cytokeratin KL-1(KL-1, 1:100, Immuno-
tech, Marseilles, France) and cytokeratin CAM 5.2, which are
monoclonal antibodies to a large spectrum of cytokeratins. The
cells did not stain with epithelial membrane antigen (EMA,
1
:200, Dako).
Anti-cytokeratins AE1 and AE3 recognize the keratin subfami-
ly. Anti-keratin AE1 recognizes keratins of the acidic subfamily,
and anti-keratin AE3 recognizes keratins of the basic subfamily.
The non-neoplastic ciliary epithelium did not stain with anti-cyto-
keratin AE1, but stained positively with anti-cytokeratin AE3 in
both cases. In case 1, positive immunoreactive stain to cytokeratin
AE1 was demonstrated in the tumor cells (Fig. 4C), showing a
clear contrast to the non-neoplastic cells. Both tumor cells and
non-neoplastic cells were stained positively for cytokeratin AE3
(
Fig. 4D). The tumor cells in case 2 showed the same pattern as
non-neoplastic cells, i.e., negativity to AE1 (Fig. 5C) and positiv-
ity to AE3 (Fig. 5D).
Discussion
Shields et al. reviewed 27 eyes with tumors of the non-
pigmented epithelium of the ciliary body and reported
that all eyes had signs of intraocular inflammation, but
neovascularization of the iris and trabecular meshwork
were not mentioned [8]. The findings in our case suggest
that iris neovascularization should be added to the list of
clinical signs associated with this type of tumor.
In another study, Shields et al. reported neovascular
glaucoma in one eye (1%) with a malignant melanoma
of the ciliary body in a study of 96 eyes of a total of
Fig. 3A, B Slit-lamp photograph of a large pyramidal mass be-
hind the iris in case 2
2
704 eyes with intraocular tumors [6]. They also report-
8
×8×5 mm brown mass of uveoscleral tissue in case 2. Microscop-
ically, the tumor cells were arranged in a nest-like pattern in case 1
Fig. 4A) and in a cord-like pattern in case 2 (Fig. 5A). Varying
amounts of extracellular eosinophilic material were observed, and
ed that of the 1913 eyes with choroidal melanomas, 18
eyes (0.9%) were found to have iris and angle neovascu-
larization, although the prevalence was relatively low
(
the cells had eosinophilic cytoplasm in both cases. The cells also compared to that of retinoblastoma, with an incidence of
showed moderate atypia and contained round or pleomorphic nu- 36/303 (11.9%). In this series four eyes with adenoma of
clei with prominent nucleoli at higher magnification (Fig. 4B in
the NPCE were reported, but a secondary glaucoma was
case 1 and Fig. 5B in case 2). Vascularization was not very promi-
not reported in any of the eyes. Adenocarcinoma was not
nent. Necrosis and mitotic figures were not present in both cases.
included in this series [6].
Pigment-containing macrophages and a small number of inflam-
matory cells were scattered in the tissue. There was no invasion
into the sclera and vascular tissue. Both tumors were located on
the inner surface of the ciliary body without stromal invasion. The
iris revealed many new vessels in case 1.
From the findings in our case 1, neovascular glauco-
ma may be another sign of an intraocular malignancy,
because malignant choroidal melanomas and retino-
blastomas have been found to have high levels of vascu-
The final diagnosis of the mass in both cases was a low-grade
adenocarcinoma of the non-pigmented epithelium of the ciliary lar endothelial growth factor (VEGF) and their receptors
body.
[
9]. Thus, malignant tumors could possibly release an-
giogenic factors which might induce new vessel forma-
tion in the trabecular meshwork.

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79
Fig. 4A–D Conventional histology and immunohistochemistry in velopment of neovascularization on the iris and angle.
case 1. A Photomicrograph of a low-power view of the tumor. The
arrow points to the border of the tumor cells and non-neoplastic
teraction among various factors in the development of
cells. Tumor cells show a nest-like arrangement. (Hematoxylin and
However, it has been reported that there is a complex in-
neovascularization [11].
eosin, original magnification ×40). B Photomicrograph of a high-
power view of the tumor showing moderate atypia. Tumor cells
have round or pleomorphic nuclei with prominent nucleoli. (Hema-
toxylin and eosin, original magnification ×200). D Neoplastic tis-
sue (lower right) showing positive immunohistochemical staining
for anti-cytokeratin AE1. Normal non-pigmented epithelium (up-
Patient 1 showed a secondary exudative retinal de-
tachment before surgery, which may suggest a malignan-
cy or intraocular inflammation with a pathogenesis simi-
lar to that of the neovascular glaucoma, because VEGF
per left) is not stained. (Original magnification ×40). D Immuno- is known to be a potent mediator of vascular permeabili-
histochemical staining for anti-cytokeratin AE3 of the neoplastic
ty in tissues including the retina [11, 12]. It is possible
that the local ischemic conditions induced by the retinal
detachment might increase angiogenic factors that con-
tissue. Staining for cytokeratin AE3 shows positivity in both neo-
plastic and non-neoplastic cells. (Original magnification ×100)
tributed further to the development of the neovascular-
ization [4].
It has also been reported that the common complica-
The retinal detachment was reattached during the op-
tions of ocular inflammation, such as glaucoma, keratic eration. The new vessels on the trabecular meshwork and
precipitates, macular edema, and neovascularization, yellow exudate were resolved after surgery, probably be-
may be mediated by cytokines [13]. Increased VEGF has cause the release of angiogenic factors or substances in-
been reported in eyes with ocular inflammatory disease ducing vascular permeability stopped after the removal
and in eyes with intraocular malignancy and ischemic re- of the tumor.
tinopathies [11]. In addition, it has been reported that
The tumor was the only finding in the second case. The
chronic uveitis from various causes is associated with in- pyramidal shape and indenting cataract suggests a slowly
traocular neovascularization [1]. Because of the charac- growing tumor such as adenoma or adenocarcinoma of the
teristic nature of tumors of the NPCE [8], long-standing NPCE; however, the MRI findings had the so-called char-
intraocular inflammation may have relevance to the de- acteristic appearance of a malignant melanoma.

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Fig. 5A–D Conventional histology and immunohistochemistry in ble for this MRI appearance. Because malignant melano-
case 2. A Photomicrograph of a low-power view of the tumor. The
mas sometimes do not have the characteristic appearance,
arrow shows the border between tumor cells and non-neoplastic
hyperintensity in T1-weighted images and hypointense in
cells. (Hematoxylin and eosin, original magnification ×40).
T2-weighted images in 50% of cases, MRI is usually not
B Photomicrograph of a high-power view of the tumor showing
moderate atypia. The tumor cells have eosinophilic cytoplasm and useful for the differentiation of these tumors [2, 8].
have proliferated into a cord-like arrangement. There is no mitosis
Other signs to differentiate the malignant melanoma
are the characteristic clinical features of this tumor [8].
Tumors of the NPCE are reported less likely to have sen-
and no necrosis. (Hematoxylin and eosin, original magnification
×
200). C Neoplastic tissue showing negative immunohistochemi-
cal staining for anti-cytokeratin AE1, as did the non-neoplastic tis-
sue. (Original magnification ×100). D Immunohistochemical tinel vessels, and, if present, they tend to be small and
staining for anti-cytokeratin AE3 of the neoplastic tissue. Staining
less prominent than in ciliary body melanomas. In our
two cases, sentinel vessels were not detected by fluores-
cein angiography. However, the presence of sentinel ves-
for cytokeratin AE3 shows positivity in both neoplastic and non-
neoplastic cells. (Original magnification ×100)
sels is not pathognomonic for melanomas.
The most important differential diagnosis in both cases
An additional characteristic feature of tumors of the
was malignant melanoma. On MRI, the T1 sequence was NPCE is the irregular surface with a shape of abrupt ele-
hyperintense and enhancement was seen following the in- vation, while the characteristic feature of melanomas is a
jection of gadolinium diethylenetriamine pentaacetic acid smooth surface with a mushroom shape. The pyramidal
in both cases. The lesion was isointense to the vitreous in shape of the tumor in case 2 suggested a tumor of the
T2-weighted images in case 1. In case 2 the lesion was hy- NPCE. The presence of longstanding inflammation in
pointense to the vitreous in T2-weighted images, which case 1, which included massive yellow lipid exudation,
has been reported to be the characteristic appearance of is highly atypical for melanomas. Thin cataract forma-
malignant melanomas [2]. This appearance has also been tion and indented formation of the lens in both cases are
observed with NPCE neoplasms [8], metastatic carcino- other signs of a slowly growing tumor of the NPCE.
mas, and various conditions [2] which suggested that only However, these signs are not conclusive for the differen-
the melanin pigment in malignant melanomas is responsi- tial diagnosis of a malignant melanoma.

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Iris neovascularization has been reported in one of 96 tivity to EMA may be related to the degree of differenti-
eyes (1%) with a malignant melanoma [6], while a tumor ation of the tumor.
of NPCE has never been reported to be accompanied by
Anti-cytokeratins AE1 and AE3 recognize the keratin
iris neovascularization except in our cases. The use of subfamily. The tumor cells in case 2 showed the same
iris neovascularization for the differential diagnosis has immunoreactive characteristics, namely, negative AE1
not been established, because tumors of the NPCE are and positive AE3, as does the non-neoplastic ciliary epi-
too rare to calculate an incidence rate. Iris neovascular- thelium. This would suggest that the origin of the tumor
ization with intraocular inflammation in the ciliary body was probably the NPCE. In case 1, positive immunoreac-
might suggest a tumor of the NPCE; however, further ac- tive stain to cytokeratin AE1 as well as AE3 was demon-
cumulation of patients will provide more information strated in the tumor cells. The reactivity may have
about the usefulness of iris neovascularization in the dif- changed during the de-differentiation of the tumor.
ferential diagnosis of the ciliary body tumors.
While it is difficult to differentiate between an adeno-
Immunohistochemical studies do not differentiate an ma and low-grade adenocarcinoma arising from the
adenoma from adenocarcinoma. However, they may help NPCE, we have diagnosed the two tumors as adenocarci-
elucidate the process of proliferation, dedifferentiation, nomas with low-grade malignancy based mainly on the
and the origin of tumor cells. Adenomas and adenocarci- pleomorphism and atypism of the tumor cells. Although
nomas of the iris and ciliary body have been reported to proliferation markers, which might help differentiate a
be positive for S-100 protein and for vimentin and nega- benign from a malignant tumor, were not used, the ab-
tive for HMB 45 [3, 8], as was found in our tumors. Be- sence of mitotic figures and necrotic areas support the
cause of the epithelial origin of these tumors, we hypoth- conclusion that these tumors were of low-grade malig-
esized that they would show immunoreactivity to cyto- nancy.
keratin even though different immunoreactivities to cyto-
Our results demonstrated that a reasonable course of
keratin have been reported [8]. In fact, the tumors in action when a tumor of the NPCE is suspected is local
both cases demonstrated positive immunoreactivity to a removal of the tumor, because acquired tumors of the
large spectrum of cytokeratin KL1 and CAM 5.2.
Conflicting results have been obtained for the immu-
NPCE are generally benign or of low-grade malignancy.
noreactivity to the epithelial membrane antigen, EMA. Acknowledgements We thank Professor Shigekuni Okisaka at
Anti-EMA staining was negative in our two specimens. the Department of Ophthalmology, National Defense Medical Col-
lege and Professor Takeo Minoda at the Department of Ophthal-
However, the tumor cells in case 2 were arranged in a
cord-like pattern, and the tumor cells in both cases were
mology, Teikyo University, Ichihara Hospital for assistance in
evaluating and treatment of our cases. This study was supported
not sufficiently highly differentiated to form gland-like by Grants-in-Aid11470363 and 12470361 from the Ministry of
or tubular structures. Thus, the absence of immunoreac- Education, Science, Sports and Culture, Japan.
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