SURVEY OF OPHTHALMOLOGY VOLUME 57
NUMBER 4
JULY–AUGUST 2012

CLINICAL PATHOLOGIC REVIEWS

STEFAN SEREGARD AND MILTON BONIUK, EDITORS

An Improved Approach to Diagnosing and Treating

Conjunctival Mucoepidermoid Carcinoma
Jessica K. Rankin, MD,1,2 Frederick A. Jakobiec, MD, DSc,1,2 Fouad R. Zakka, MD,1,2
and C. Stephen Foster, MD1,3

1
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts,
USA; 2Cogan Eye Pathology Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA; and
3
Massachusetts Eye Research and Surgery Institution, Cambridge, Massachusetts, USA

Abstract. The current case of conjunctival mucoepidermoid carcinoma offers features that expand the
biologic spectrum afforded by this tumor. More focused strategies should be developed for its earlier
histopathologic diagnosis and improved management (historical recurrence rate of 85%). A 63-year-old
woman with a history of rheumatoid arthritis and idiopathic sclerosing cholangitis developed scleral
thinning, anterior chamber cells and flare, and uveal prolapse. Biopsies of the epibulbar lesion were
initially misinterpreted as a squamous cell carcinoma but on review harbored CK7-positive cells and
contained rare goblet cells brought out with Alcian blue and mucicarmine staining. Intraocular
extension exhibited micro-and macrocysts with minimal goblet cells. Focal CK7 immunopositivity in any
epibulbar squamous dysplasia or in invasive carcinoma should lead to suspicion of a mucoepidermoid
carcinoma. Behaviorally aggressive or rapidly recurrent epithelial squamous tumors with ‘‘inflamma-
tory’’ features or unusual clinical characteristics should be initially stained at multiple levels for the
detection of parsimonious mucus secretion. Surgical options include wide excision and partial
sclerectomy with cryotherapy for superficial invasion and/or interferon therapy. Results with
radiotherapy and cryotherapy for deep scleral invasion have been unpredictable or unacceptable
compared with surgery. (Surv Ophthalmol 57:337--346, 2012. Ó 2012 Elsevier Inc. All rights reserved.)

Key words. mucoepidermoid carcinoma
squamous cell carcinoma
conjunctiva
salivary

glands
intraocular invasion
goblet cells
mucus
Alcian blue
mucicarmine

immunohistochemistry
CK7

Mucoepidermoid carcinoma of the conjunctiva
(MECC) is a rare but ominous condition3,7,14,31
histopathologically similar to mucoepidermoid car-
cinoma of the major and minor salivary glands,
where it is the most common malignancy. Cytoarch-
itectural grading is well correlated with prognosis in
these structures.6 Mucoepidermoid carcinoma has
also been reported in the nasal cavity, paranasal
sinuses, thyroid, bronchus, breast, skin, lacrimal
gland, and lacrimal sac,9,12,18,20,30,38 and even in
a dacryops19 or after an incomplete excision of
a squamous papilloma of the lacrimal sac.18 Al-
though MECC is anatomically, histopathologically,
and histogenetically closely related to conventional
conjunctival squamous cell carcinoma (CSCC), the
latter has a much slower clinical course and a more
favorable outcome after appropriate surgery (less
than 5% recurrence rate compared with 85% for

337
Ó 2012 by Elsevier Inc. 0039-6257/$ - see front matter
All rights reserved. doi:10.1016/j.survophthal.2011.12.002
338 Surv Ophthalmol 57 (4) July--August 2012
MECC).31 We review the salient differences between
MECC and CSCC and highlight the clinical and
histopathologic features that may enhance the
earliest possible diagnosis and lead to a well planned
and timely strategy for ablative surgery, helping to
avert the frequent complications of MECC with
intraocular and intraorbital invasion.
Case Report
A 63-year-old Hispanic woman presented with left
eye pain. Her ocular history was notable for
a ‘‘pterygium’’ excision from her left eye two years
prior to presentation, followed by recurrent epi-
sodes of left eye pain and vascular injection thought
to represent a scleritis. The pterygium specimen had
not been sent for pathological analysis. At the time
of the pterygium excision, however, a biopsy was
performed on another ‘‘tan’’ conjunctival lesion on
the left eye that was interpreted as a nevus. We were
unable to obtain the slides for review. She had
rheumatoid arthritis, insulin-dependent diabetes
mellitus, and underwent a liver transplant for
primary biliary cirrhosis 2 years before presentation.
Her medications included mycophenolate mofetil,
tacrolimus, indomethacin, gabapentin, and insulin.
Slit lamp examination revealed a 4-mm sclerocor-
neal perforation at the inferonasal limbus with pro-
lapsed, elevated uveal tissue containing bubbles
(Fig. 1A). Also observed were a bordering arc of
thickened limbal epithelium inferiorly and 2þ cells
and flare in the anterior chamber. She was taken to the
operating room for an urgent open-globe repair.
Under the operating microscope, the sclera surround-
ing the perforation was noted to be diffusely thinned,
and the medial rectus muscle appeared encased in
fibrotic scar tissue. Several scleral biopsies were
performed along the edges of the perforation, and
a sclera patch graft of irradiated freeze-dried cornea
was placed over the thinned and perforated sclera from
the insertion of the medial rectus onto the peripheral
cornea extending approximately 3 clock hours. A
biopsy of the prolapsed iris tissue and multiple scleral
biopsies were sent for pathological evaluation.
Microscopic evaluation of the excised scleral
specimen revealed that the surface epithelium,
present in one of the samples, was disorganized
and replaced by a full thickness proliferation of
atypical cells showing mild atypia with small nucleoli
and no inflammation in the underlying stroma
(Fig. 1B). Several fragments of sclera were infiltrated
by islands of mildly atypical squamous carcinoma
cells without accompanying inflammation (Fig. 1C).
Neither individual dyskeratotic cells nor squamous
pearls were identified. Mitoses were present at all
levels of the surface dysplastic epithelium; within the
RANKIN ET AL
infiltrating islands there was an average of one
mitosis per 5 high power microscopic fields.
Microscopic examination of the biopsied prolapsed
intraocular tissue revealed a sheet of squamous
carcinoma cells extending onto the iris surface and
infiltrating the ciliary body and its processes
(Fig. 1D). Although not initially diagnosed as
a MECC, but rather as a CSCC, subsequent sections
at deeper levels of the blocks were stained for Alcian
blue and mucicarmine-positive material and un-
covered parsimonious mucus production in the
neoplastic cells confirmatory of MECC (Fig. 1E, left
and right panels). These studies were conducted
after the histopathologic results derived from the
enucleated globe became available.
The patient was referred to an oculoplastic
surgeon for evaluation. Visual acuity was 20/30 in
the right eye and counting fingers at 4 feet in the
left eye. There was a left relative afferent pupillary
defect. Slit lamp examination of the left eye revealed
a large injected conjunctival/episcleral vessel over-
lying thinned, bluish sclera unassociated with
diffuse conjunctival erythema, an intact scleral
patch graft, and synechiae between the iris and the
lens. There was a poor fundus view. The decision
was made to enucleate the left eye because of the
diagnosis of invasive squamous cell carcinoma
involving the sclera and the iris. In the operating
room biopsies were also obtained from the superior,
medial, inferior, and lateral conjunctiva, as well as
from the superior and inferior palpebral conjuncti-
val surfaces. The enucleated globe measured 25 mm
horizontally, 23.5 mm vertically, and 25 mm ante-
rior--posteriorly. The tectonic graft seen on gross
examination covered the nasal sclera and peripheral
cornea. Where not thickened by invasive tumor, the
iris and ciliary body were atrophic, with several
anterior and posterior synechiae present.
Microscopic examination of the globe revealed
neoplastic squamous cells invading along the in-
terface between the scleral patch graft and the
corneal stroma, extending into the uvea, and
occupying the anterior chamber (Figs. 1F, 2A).
The graft was totally acellular whereas the adjacent
cornea contained keratocytes. There was posterior
extension of tumor within the sclera and uvea.
Neoplastic squamous cells also lined the cavity
formed by the episcleral surface and the undersur-
face of the tectonic graft (Fig. 2B), with a small
contribution of non-neoplastic squamous cells to
the lining. The tumor gained access to the deep
stroma of the peripheral cornea, the chamber angle,
and the iris surface (Fig. 2A). The ciliary body and
anterior and posterior uvea were invaded through
the face of the ciliary body and via direct perme-
ation through the thinned anterior scleral tissue.
CONJUNCTIVAL MUCOEPIDERMOID CARCINOMA
The tumor cells elicited remarkably little inflamma-
tory microcystic response (Figs. 2A, 2B).
In the pars plana and choroid variably sized cysts
(micro- and macro- types) were discovered with
lumens delimited by one to three layers of cells
(Figs. 2C, 2D). The peripapillary choroid was spared.
These cysts in all likelihood interconnected in three
dimensions, creating a honeycombed or catacomb
system accompanied by extensive secondary choroi-
dal fibrosis (Fig. 2C). A minimal number of small
lymphocytes were identified in the cortical vitreous
bordering the pars plana (Fig. 2B). The posterior
scleral tunic was intact. There was infrequent focal
invasion of the innermost scleral lamellae by the
neoplastic cells. Two extrascleral nodules of tumor
were found sequestered in a fibrous capsule (Fig. 2C).
The meninges and optic nerve were spared. The six
conjunctival biopsies obtained during the enucle-
ation were all negative for tumor.
Periodic acid--Schiff, Alcian blue (Fig. 2D), and
mucicarmine staining (Fig. 2D, inset) disclosed
mucous substance in the cystic formations within
the choroid, but not in the invasive squamous
corneoscleral and ciliary body components, nor in
the tumor cells that had spread as a solid mass into
the anterior chamber angle or as a sheet along the
iris surface. Goblet cells engorged with intracellular
mucin were surprisingly few in number among the
choroidal neoplastic cysts (Fig. 2D). Cytokeratin
AE1/AE3 (Fig. 2E), EMA, and Ki-67 were all positive
in the tumor cells forming cysts wherever they were
located in the eye, whereas carcinoembryonic
antigen (CEA) was only faintly positive. CK7 was
positive in the innermost cells lining the micro- and
macrocysts. Review of the conjunctival portion of
the epibulbar biopsies after immunostaining with
CK7 disclosed the presence of a few positive
scattered intraepithelial cells (Fig. 2F). The Ki-67
index was high (40%) in the purely squamous solid
ciliary body and iris surface components and in the
lining of the epibulbar graft space, but very low
(!5%) in the uveal neoplastic cysts. These immu-
nohistochemical findings provided additional sup-
port for the diagnosis of MECC.
Discussion
CSCC is the most common conjunctival malig-
nancy in the world4,36 yet it is diagnosed accurately
preoperatively in only 40% of cases.4 With an
incidence that varies geographically from 0.02 to
3.5 per 100,000, it occurs preferentially at the limbus
in older white men (86% with an average age of 63
years) with a history of sun exposure.4,25,36,43 As
a low-grade malignancy, treatment usually consists of
339
wide excision with the application of multiple
freeze--thaw adjunctive cryotherapy to the surgical
bed and surrounding conjunctival epithelium.
Topical antimetabolite therapy with mitomycin C
has been employed for incomplete excisions or
recurrent lesions.36 In Western countries there are
only rare reported cases of intraocular invasion and
metastases. CSCC appears to be more aggressive in
individuals with human immunodeficiency virus
(HIV), xeroderma pigmentosa, or medical immu-
nosuppression.11,28,34,39 Orbital invasion and
regional metastases have been reported more
frequently in series from tropical and subtropical
countries, which may be related to genetic factors,
ultraviolet exposure, chronic irritation, delay in
diagnosis, and inadequate excision. In a series of
30 consecutive patients from Saudi Arabia who had
secondary squamous cell carcinomas of the orbit, 28
originated in the conjunctiva.16
MECC is a rare variant of CSCC and accounts for
only 0.3% of all premalignant and malignant
squamous lesions.4 In the aforementioned Saudi
Arabian series, only 2 of the 28 conjunctival
squamous tumors responsible for orbital invasion
were MECCs.16 Originally described in the conjunc-
tiva by Rao and Font in a series of five cases in
1976,29 all of which recurred within 6 months,
MECC is characterized by a mixture of epidermoid
(synonymous with squamous cells exhibiting prom-
inent eosinophilic cytoplasm) and mucin-producing
cells in various proportions. The mucin-producing
cells may have a classic signet ring (eccentrically
displaced nucleus by a large cytoplasmic vacuole) or
bloated columnar (goblet cell) character, but in
many cases of epibulbar MECC, Alcian blue or
mucicarmine stains in histopathologic evaluation
are required to identify minute amounts of
intracellular mucin, as in the current lesion.
Extracellular mucus pools can frequently be circum-
scribed by adjacent tumor cells, a distinctive feature
in salivary gland tumors6 but usually absent in
conjunctiva-derived lesions. Because the normal
conjunctiva is composed of stratified squamous
epithelial cells with scattered mucus-producing
goblet cells, Rao and Font29 theorized that MECC
develops neoplastic differentiation along both di-
rections. Intermediate cells (basaloid-type cells that
are smaller than epidermoid cells) observed in
salivary gland tumors are not a typical or prominent
finding in MECC.6 In conjunctival lesions the
malignant epidermoid cells have ample eosinophilic
cytoplasm, but rarely form keratin pearls or show
the dyskeratosis emblematic of many CSCCs.
Although mucoepidermoid carcinoma is the most
common malignant tumor of the salivary glands,6 it
is much rarer in the conjunctiva, constituting a small
340 Surv Ophthalmol 57 (4) July--August 2012 RANKIN ET AL

Fig. 1. A: The eye of a 63-year old Hispanic woman who had undergone a ‘‘pterygium’’ excision 2 years earlier. She
subsequently developed bluish scleral thinning (arrow) with an inferonasal elevated, limbal uveal prolapse (UP)
accompanied by adjacent conjunctival air bubbles (B) signifying a perforation. Juxtalimbal opalescent, neoplastic tissue is
present inferiorly (crossed arrows). B: A disorganized and thickened carcinoma-in-situ without dyskeratosis or keratin
pearls has artifactiously separated from the underlying stroma (ST). C: Infiltrating islands of minimally atypical squamous
cells are separated by the dense fibrous tissue of the sclera that lacks inflammation. Goblet cells are not discernible.
Neither individual cell dyskeratosis nor keratin pearls are present and mitotic figures are not identifiable in this field. D:
The prolapsed intraocular tissue is lined by invasive tumor which includes the iris (arrows) with its sclerotic stromal vessels
(crossed arrows). A solid epidermoid tumor component (T) infiltrates the ciliary body and its processes (CP). Special stains
failed to disclose the presence of mucin in this region. E: After the diagnosis of mucoepidermoid carcinoma was
established from microscopic examination of the enucleated globe, multiple deeper levels of the initial epibulbar invasive
CONJUNCTIVAL MUCOEPIDERMOID CARCINOMA 341

subset (0.3%) of all premalignant and malignant
epibulbar squamous/epidermoid tumors. Some-
what more than 20 cases of MECC have now
appeared in the English ophthalmic litera-
ture.3,8,13,14,16,24,29,31,39,40 Compared with CSCC,
MECC is much more locally aggressive. In some
regards MECC resembles the exceptional conjunc-
tival spindle cell SCC, which offers a whitish or
discolored polypoidal clinical appearance and also
can invade the globe, but generally does not
metastasize.37 Positive cytokeratin staining and the
ultrastructural demonstration of desmosomes estab-
lish this rare diagnosis and separate the entity from
spindle cell melanomas and sarcomas. In a report
from Mexico of 287 secondary squamous cell
carcinomas of the orbit, two originating in the
conjunctiva were spindle cell carcinomas.4 Other
epithelial subtypes were a mucoepidermoid carci-
noma and three previously uncharacterized lym-
phoepitheliomas (malignant squamous cells
enveloped in a lymphoid stroma), both types again
having arisen from the conjunctiva. The latter
tumor was reminiscent of nasopharyngeal carcino-
mas originating in the fossa of Rosenmuller (pre-
viously termed Schminke and Regaud variants of
poorly differentiated squamous cell carcinoma).42
Nearly all cases of MECC recur within 4--6 months
after initial excision, with the looming prospect of
intraocular and intraorbital invasion. Metastases,
however, are rare, with regional lymph node in-
volvement without fatality reported in two cases.14,16
The tumor is also capable of causing sinus in-
volvement.24 Whereas both CSCC and MECC usually
occur in older men, the latter tumor may also
develop in the fourth and fifth decades.14,24,31,39
Clinically, MECC cannot be distinguished from
CSCC unless it offers an unusual soft and fleshy
appearance because of the abundant presence of
intracystic and interstitial mucus, an exceptional
feature in epibulbar tumors. Although juxtalimbal
lesions are the most common owing to the
presence of stem cells at this site, forniceal,
caruncular, and eyelid lesions developing from
the palpebral conjunctiva are also encountered.
Not yet found to originate in the eyelid skin,
authentic mucoepidermoid carcinoma has been
described elsewhere in the integument.30 Both
CSCC and MECC are easily overlooked because
they may grow as inconspicuous juxtalimbal lesions
without appreciable tumefaction.8,21,32 Probably
the most reliable tip-off to this rare type of placoid
lesion is the coexistence of a skein of corkscrew or
hairpin vessels betokening an underlying stromal
sessile papillary architecture that supplies the
dysplastic epithelium.22,39 The involved epithelium
may also be subtly opalescent and show punctate
staining with supravital dyes. MECC, in contrast to
CSCC, is thus almost always misdiagnosed clinically
on initial presentation. In the current case as in
others, it is possible that a ‘‘pterygium’’ excision
performed earlier was actually a MECC. Unfortu-
nately, the excised tissue from our patient was not
submitted for microscopic examination. Cases of
MECC originally misdiagnosed as a pterygium are
well documented.32,39
Pain and irritation may accompany
MECC.8,10,29,32 Patients with CSCC have been di-
agnosed with ‘‘nodular scleritis’’ and perforation of
the globe.21 Our patient is the first with MECC who
truly had an underlying rheumatoid scleromalacia
that promoted scleral perforation by the super-
imposed invading tumor. MECC has been well
documented to arise in patients with systemic
immune and autoimmune diseases besides rheuma-
toid arthritis, such as HIV, ocular cicatricial pem-
phigoid, and multiple sclerosis.14,31,39 An aggressive
CSCC was described in a man with sclerosing
cholangitis who was immunosuppressed after a liver
transplantation.34 In the present case, the patient
had multiple factors working to diminish host
resistance: autoimmune sclerosing cholangitis, rheu-
matoid arthritis, diabetes, and protracted immuno-
suppression with tacrolimus and mycophenolate
mofetil to prevent a liver transplant rejection.
MECC may even be missed histopathologically,
especially if stains for mucin are not routinely used
to thoroughly evaluate the microscopic slides pre-
pared from biopsies of the initial or recurrent
tumors of any behaviorally suspicious squamous
epibulbar cell lesion. In a series published in 2001 of
three squamous cell carcinomas that invaded the
globe, no stains were employed to determine if
epithelial mucin was present.21 In our case conjunc-
tival and scleral biopsies had only faint mucin

tumor were obtained and stained with Alcian blue (illustrated here) and mucicarmine. In these two panels representing
widely separated fields note the intracellular blue mucus deposits (arrows) and associated slit-like lumens (L). F: Anterior
segment of the enucleated globe displays that the tectonic scleral graft (TG) present nasally is separated from the
patient’s sclera by an elongated cavity (C). The chamber angle is occluded by solid tumor (arrow). The insert
demonstrates tumor cells at the interface between the acellular graft (above) and the cellular sclera (below) of the
patient; neoplastic cells (NC) line the anterior rounded portion of the cystic cavity. The crossed arrow indicates the
emergence of microcysts in the anterior uvea. (B, C, D: hematoxylin and eosin 100, 200, 100; E: Alcian blue, left and
right panels, 200.)
342 Surv Ophthalmol 57 (4) July--August 2012 RANKIN ET AL

Fig. 2. A: The nasal chamber angle is plugged with solid, neoplastic, eosinophilic squamous cells bereft of goblet cells on
Alcian blue staining (not shown). The tumor cells spread out as a multiple layered covering on the iris stromal surface
(arrow). There is tumor invasion of the deepest peripheral corneal stromal lamellae (crossed arrow) and of the ciliary body
(T). B: Neoplastic squamous epithelium lacking goblet cells (arrows) lines the episcleral surface of the interface cavity
above and displays a focus of microinvasion into the sclera (crossed arrow). Deeper invasion of the sclera by small
neoplastic cysts (C) is shown along with light inflammation of the uveal tissue (UT) of the pars plana region. There is also
a mild lymphocytic dispersion in the adjacent cortical vitreous (V). C: Strikingly large macrocystic spaces (MC) were
predominant post-equatorially but did not reach the peripapillary choroid. The arrow indicates an episcleral tumor cell
nodule completely surrounded by fibrosis that probably extended along an intrascleral emissary channel. D: Only very
rare goblet cells (arrows) stained here with Alcian blue were identified in association with the cyst formations (C).
S 5 sclera, PPE 5 pars plana neuroepithelium. The inset displays reddish mucicarmine positivity in a cyst (C) lumen.
CONJUNCTIVAL MUCOEPIDERMOID CARCINOMA 343

production, which was not appreciated initially on
hematoxylin and eosin stained sections, and no
special stains were ordered. Small intracellular
Alcian blue and mucicarmine-positive deposits of
mucin, however, were detected in rare cells, but only
on multiple deeper levels of the specimen.
Several investigations have reported a topographic
diphasic morphology. Some tumors have lacked
mucin production in the epibulbar, conjunctival, or
invasive corneal components, which differentiation
appeared only after intraocular invasion occurred
and vice versa.2,3,32 Rao and Font reported that
among their five cases, all the recurrences showed
more epidermoid differentiation than the original
tumor.29 In their case 4, the original conjunctival
lesion, but not the epibulbar recurrence, stained
positively for mucin—although the intraocular
component showed a re-expression of mucus-
production. Explanations for this phenomenon
have included propitious intraocular environmental
influences on tumor differentiation or clonal shifts
in the tumor’s composition.10,32 The high Ki-67
proliferation index found in the solid anterior
segment epidermoid component and the low index
present in the uveal cystic spaces lends indirect
support, beyond the presence of focal mucus
synthesis, for the presence of multiple clonalities.
Our strong recommendation, therefore, is that all
aggressive or rapidly recurrent epibulbar ‘‘squa-
mous’’ dysplastic lesions should be re-evaluated with
Alcian blue and mucicarmine stains, with attention
paid to differential cytologic and staining properties
in the various components of the tumor at different
levels of sectioning. Exiguous amounts of mucin
that are not discernible in hematoxylin and eosin
stained sections can be discovered with this
approach.
To our knowledge, this is the second report of
a MECC with intraocular invasion where epibulbar
recurrence was not recognized before intraocular
invasion occurred, with the proviso that our
patient’s excised pterygium was not in fact
a MECC.39 It also uniquely displayed a range of
micro- and macrocysts throughout extensive por-
tions of the anterior uvea and posterior choroid.
This cystic feature, which is common in salivary
gland mucoepidermoid carcinomas,6 was present in
only one of the five first reported cases of epibulbar
MECCs29 and has been noted only several times
since then in the epibulbar and intraocular compo-
nents of other lesions,2,10,32,39 but not as dominant
a feature as in our case. It was not observed in the
epibulbar tumor in our case, although a few small
microscopic slit-like lumens were found on recuts at
deeper levels. One of the reports of a MECC that
invaded the globe displayed many epibulbar small
cystic spaces in the substantia propria with minimal
nuclear atypia closely resembling the appearance of
an inverted mucoepidermoid papilloma.39 The
latter, however, does not invade beyond the con-
junctival substantia propria.15 MECC must also be
separated from florid proliferation of pseudoglands
of Henle (pseudoadenomatous hyperplasia of the
conjunctiva) which is goblet-cell rich.23 A lumen-
forming, tubular variant of MECC at the eyelid
margin that arose from the palpebral conjunctiva
has also been described.13 There is a highly in-
triguing and pertinent case of MECC that exhibited
an elevated single cystic cavity situated in the
choroid that was lined by neoplastic epidermoid
(squamous) cells without any goblet cells or mucus
production, which had been detected in the original
epibulbar lesion.10 If our patient’s tumor had not
been proved to have derived from a primary
epibulbar lesion with anterior scleral invasion, the
uveal appearance would have been consistent with
a metastatic carcinoma, in which case either a lung
or breast primary tumor would have to be consid-
ered and appropriate immunohistochemical studies
performed to establish the source.
For prognostic purposes, studies based on salivary
gland tumors have divided mucoepidermoid
carcinoma into three categories: low grade lesions
(92 to 100% 5-year survival), intermediate grade
(62 to 92%), and high grade (0 to 43%).6 Criteria
for classification include the degree of mucus
production, the presence of cyst formation, the
level of mitotic activity, and the presence or absence
of necrosis and anaplasia.6,33 A chromosomal trans-
location has been found (METCT1-MAML2) in
a subset of salivary gland mucoepidermoid carcino-
mas that is associated with low grade histopathologic
features and a favorable clinical prognosis, but a test
for this was not available to us.27 As already

Surviving melanocytes (arrows) are present in the choroid below the cyst. E: Cytokeratin AE1/AE3 (shown here in the
main panel) vividly immunostains the cystic space (CS) between the tectonic scleral graft (TG) and the patient’s sclera
(PS). Positive staining of the solid tumor in the anterior chamber angle (CA) and in the cells forming the neoplastic cysts
(arrows) is also highlighted. CB 5 uninvolved area of ciliary body smooth musculature; CP 5 ciliary processes. The inset
discloses CK7 positivity of the innermost cells of the cysts (C and arrow). F: CK7 positivity of scattered cells present in the
epibulbar biopsy intimates potential for mucoepidermoid differentiation. ST 5 underlying stroma of conjunctiva. (A, B,
and C: hematoxylin and eosin 200, 200, 100; D: Alcian blue 200, inset: mucicarmine 200; E and F:
immunoperoxidase reaction with diaminobenzidine chromogen counterstained with toluidine blue 100, 200.)
344 Surv Ophthalmol 57 (4) July--August 2012
mentioned, MECC has been established only in
several cases to have produced cervical lymph node
metastases,14 but death attributable to the tumor has
yet to be reported. This departs from the behavior of
salivary gland mucoepidermoid carcinomas, which
have a decided propensity to metastasize and
a significant mortality rate.6 In applying the salivary
gland histopathologic grading system to MECC, it is
interesting to note that the latter paradoxically
frequently exhibits a higher grade cytologic appear-
ance (less differentiation) as a result of the minimal
number of mucus-producing cells and cystic spaces
that are present. Although it has a more favorable
prognosis regarding survival in comparison with
salivary gland lesions, MECC is still highly threaten-
ing from an ophthalmologic point of view, because
its recurrences can culminate in enucleation for
intraocular invasion or exenteration for somewhat
less frequent orbital invasion.2,3,8,14,24,31,32 Despite
invasion of the globe or orbit, it must be emphasized
that in such deeply invasive conjunctival tumors, in
comparison with the typical salivary gland mucoepi-
dermoid carcinoma, the total lesional volume is
small, which confers a better overall prognosis.
Furthermore, the general absence of lymphatic
channels within the posterior globe and orbital
tissues are local differences that could be expected
to discourage metastases. Lymphatics, however, are
present in the lacrimal gland and have recently
allegedly been detected in the human ciliary body.44
Some points that can serve as aids to earlier
diagnosis are that all previous excisions for ‘‘pter-
ygia’’ should have their pathology critically reviewed,
and if Alcian blue or mucicarmine stains had not
been originally obtained, then these should be
performed. If there is clinical confusion about
whether scleral thinning or perforation is the result
of accompanying rheumatoid scleral disease or deep
corneoscleral neoplastic invasion, a judicious scleral
biopsy with multiple surrounding conjunctival bi-
opsies should be performed to establish the correct
diagnosis and its extent in order to plan for
definitive surgery (be it wide local excision with or
without a tectonic scleral graft, or enucleation or
exenteration). In our case subtle signs that a neo-
plasm was the primary problem were the absence of
diffuse vascular episcleral engorgement (There was
a solitary large vessel arcing over the thinned bluish
sclera.) and a translucent thickening of the inferior
limbal epithelium.
Epibulbar ‘‘squamous’’ malignancies that recur or
ulcerate within months, or are associated with
‘‘scleritis’’ or anterior segment ‘‘inflammation’’
(actually tumor cells floating in the aqueous
humor), should immediately arouse suspicion,
because these signs are present in over half of cases
RANKIN ET AL
of MECC.31 Fixation of an epibulbar lesion to the
sclera, persistence of epibulbar inflammation in the
wake of surgical healing, and corneoscleral thinning
or perforation should automatically raise a diagnos-
tic alarm. At the time of definitive surgery, multiple
surrounding conjunctival map biopsies should be
taken to determine adequacy of excision because of
the capacity of MECC to involve apparently bland
conjunctiva beyond the epicenter of the lesion; such
easily undetected involvement can serve as a basis
for recurrence. In view of the vagaries of mucus
synthesis, multiple deeper levels evaluated in con-
junction with special stains for highlighting in-
tracellular mucus must be performed initially in all
suspicious cases. Among a group of mucosubstan-
ces, MUC 19 appears to be preferentially expressed
in mucoepidermoid carcinoma.35 Immunohisto-
chemical stains can also be potentially helpful:
MECC is CK7þ and epithelial membrane antigen
(EMA)-positive and can be faintly CEA-posi-
tive.1,5,6,26,31 As expected, in our patient’s tumor
the markers were CK7þ/EMAþ/CEA faintly posi-
tive. Of additional importance is that immunostain-
ing for CK7 reactivity of the conjunctival biopsy
demonstrated scattered intraepithelial positive cells
within the carcinoma-in-situ portion. In our experi-
ence, the normal conjunctival epithelium expresses
CK7 positivity while conjunctival squamous cell
carcinomas are usually CK7-negative. The phenom-
enon of scattered CK7-positive cells suggests the
persistence of some cells that are not fully epider-
moid and should provoke further scrutiny of the
slides for minimal mucoid differentiation of a sub-
population of cells.
B-scan ultrasonography, not performed on our
patient, might have disclosed diffuse choroidal
thickening and cystic formation from the infiltrating
tumor cells and accompanying choroidal fibrosis.
Ultrasonic biomicroscopic evaluation could also
have revealed evidence of anterior segment involve-
ment. Predisposing conditions that facilitate invasion
of the globe or orbit include earlier ‘‘pterygium’’
surgery,8,39 patch grafts, systemic autoimmune dis-
ease,14 local autoimmune disease like conjunctival
cicatricial pemphigoid,31 and immunosuppres-
sion.39 Our patient’s tectonic scleral graft provided
additional tissues planes for tumor extension and led
to a neoplastic cellular lining of the cavity originating
at the interface of the graft and the patient’s own
sclera. The extensive scleral and uveal tumor in-
filtration undoubtedly substantially pre-dated the
graft surgery and was facilitated by the thinned sclera
brought about by her rheumatoid arthritis. Her
prolonged systemic immunotherapy following liver
transplantation necessitated by sclerosing cholangi-
tis represents the first time that MECC is
CONJUNCTIVAL MUCOEPIDERMOID CARCINOMA
documented in such a setting. There is, however,
a report of a patient who developed what was
diagnosed as CSCC and orbital invasion who was
immunosuppressed for the same reason34 where
special stains for the discovery of mucus production
were not used.
Once faced with the diagnosis of MECC, the
surgeon must undertake a wide local excision with
a superficial or deep sclerectomy. Frozen-section
monitoring of the tumor margins is difficult and
generally unreliable with small conjunctival or scleral
specimens. Conjunctiva that looks clinically unin-
volved may nonetheless show microscopic tumor.8
Therefore, surrounding conjunctival map biopsies,
as well as the excision of additional sclera at the deep
surgical margin, should be performed. Attention to
the deep margin is obligatory if the lesion is fixed to
the sclera. For movable in situ MECC or lesions with
only superficial invasion, adjuvant cryotherapy or
topical interferon or mitomycin can be utilized, with
follow-up biopsies taken at regular intervals to
establish the adequacy of therapy.36 Carbon dioxide
laser therapy, brachyradiotherapy, and external beam
radiotherapy have been disappointing.8,14,24,31,41 A
heroic anterior segment transplantation resulted in
failure in the case of an allegedly conventional
squamous cell carcinoma with intraocular spread.21
A similar result would also be anticipated with more
aggressive MECC, which displays intraocular spread
much more frequently. Perilesional subconjunctival
injections of interferon for conjunctival squamous
cell carcinoma in situ have recently showed promis-
ing results, but have not yet been employed for in situ
or invasive MECC.17 Patients deserve close clinical
follow-ups every 3 months for 12--18 months. The
persistence or rapid emergence of any of the
suspicious clinical features mentioned earlier should
lead to immediate rebiopsy of multiple sites, followed
by a wider and deeper local en-bloc surgical pro-
cedure executed by an experienced corneal surgeon
in an effort to forestall intraocular or orbital invasion.
Conclusion
There is persistent difficulty in distinguishing
MECC from conventional CSCC on clinical
grounds. A low level of suspicion among many
ophthalmologists and ophthalmic pathologists un-
derlines the need to follow a diagnostic schema to
improve early diagnosis of this rare and highly
aggressive tumor. Rapid growth or regrowth coupled
with inflammatory signs should trigger concern for
MECC. The often minimal production of mucin in
epibulbar lesions often compounds diagnostic
difficulties. Diagnosis could be improved by the
development of more sensitive and specific
345
immunohistochemical stains for cell surface and
cytoplasmic antigens or, better still, genetic markers,
such as the MECT1-MAML2 translocation or related
mutations already identified in salivary gland mu-
coepidermoid carcinoma. Presently CK7 focal pos-
itivity can be a valuable adjunct pointing to the need
to search for sparse amounts of intracellular mucin
demonstrable with Alcian blue and mucicarmine
staining. Heightened awareness of subtle clinical
and pathologic findings and more rigorous sequen-
tial treatment strategies should assist clinicians and
surgeons experienced in the treatment of MECC to
achieve improved outcomes.
Method of Literature Search
A PubMed search was performed using various
combinations of the following search terms: mucoe-
pidermoid carcinoma, conjunctiva, salivary glands, goblet
cells, mucus, intraocular invasion, Alcian blue, mucicar-
mine, immunohistochemistry, CK7, squamous cell carci-
noma, and spindle cell carcinoma. There was no
restriction on date of publication but the earliest
article used was published in 1976. Non-English
articles were evaluated for pertinence and their
content of new information, but none were cited in
this article.
Disclosure
The authors reported no proprietary or commer-
cial in any product mentioned or any concept
discussed in the article.
References
1. Azevedo RS, de Almeida OP, Kowalski LP, et al. Comparative
cytokeratin expression in the different cell types of salivary
gland mucoepidermoid carcinoma. Head Neck Pathol.
2008;2:257--64
2. Brownstein S. Mucoepidermoid carcinoma of the conjunc-
tiva with intraocular invasion. Ophthalmology. 1981;88:
1226--30
3. Carrau RL, Stillman E, Canaan RE. Mucoepidermoid
carcinoma of the conjunctiva. Ophthal Plast Reconstr Surg.
1994;10:163--8
4. Cervantes G, Rodriguez AA Jr, Leal AG. Squamous cell
carcinoma of the conjunctiva: clinicopathological features in
287 cases. Can J Ophthalmol. 2002;37:14--9, discussion 9--20.
5. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20
expression in epithelial neoplasms: a survey of 435 cases.
Mod Pathol. 2000;13:962--72
6. Ellis G, Auclair P. umors of the salivary glands, in Ellis G,
Auclair P (eds). AFIP Atlas of Tumor Pathology. Washington,
DC, American Registry of Pathology; 2008, pp 173--93
7. Font RL, Croxatto JO, Rao NA. umors of the eye and ocular
adenexa, in Ellis G, Auclair P (eds). AFIP Atlas of Tumor
Pathology. Washington, DC, American Registry of Pathology;
2006, pp 12--4, 237--8, 55--57.
8. Gamel JW, Eiferman RA, Guibor P. Mucoepidermoid carci-
noma of the conjunctiva. Arch Ophthalmol. 1984;102:730--1
346 Surv Ophthalmol 57 (4) July--August 2012
9. Gore HL, Corin SM, Klussmann KG, et al. Mucoepidermoid
carcinoma presenting as an orbital apex syndrome.
Ophthalmic Surg. 1992;23:59--61
10. Gunduz K, Shields CL, Shields JA, et al. Intraocular
neoplastic cyst from mucoepidermoid carcinoma of the
conjunctiva. Arch Ophthalmol. 1998;116:1521--3
11. Gupta N, Sachdev R, Tandon R. Ocular surface squamous
neoplasia in xeroderma pigmentosum: clinical spectrum
and outcome. Graefes Arch Clin Exp Ophthalmol. 2011;249:
1217--21
12. Harach HR. A study on the relationship between solid cell
nests and mucoepidermoid carcinoma of the thyroid.
Histopathology. 1985;9:195--207
13. Herschorn BJ, Jakobiec FA, Hornblass A, et al. Mucoepider-
moid carcinoma of the palpebral mucocutaneous junction. A
clinical, light microscopic and electron microscopic study of
an unusual tubular variant. Ophthalmology. 1983;90:1437--46
14. Hwang IP, Jordan DR, Brownstein S, et al. Mucoepidermoid
carcinoma of the conjunctiva: a series of three cases.
Ophthalmology. 2000;107:801--5
15. Jakobiec FA, Harrison W, Aronian D. Inverted mucoepider-
moid papillomas of the epibulbar conjunctiva. Ophthalmol-
ogy. 1987;94:283--7
16. Johnson TE, Tabbara KF, Weatherhead RG, et al. Secondary
squamous cell carcinoma of the orbit. Arch Ophthalmol.
1997;115:75--8
17. Karp CL, Galor A, Chhabra S, et al. Subconjunctival/perile-
sional recombinant interferon alpha2b for ocular surface
squamous neoplasia: a 10-year review. Ophthalmology. 2010;
117:2241--6
18. Lee SB, Kim KN, Lee SR, et al. Mucoepidermoid carcinoma
of the lacrimal sac after dacryocystectomy for squamous
papilloma. Ophthal Plast Reconstr Surg. 2011;27:e44--6
19. Levin LA, Popham J, To K, et al. Mucoepidermoid
carcinoma of the lacrimal gland. Report of a case with
oncocytic features arising in a patient with chronic dacryops.
Ophthalmology. 1991;98:1551--5
20. Luna MA. Salivary mucoepidermoid carcinoma: revisited.
Adv Anat Pathol. 2006;13:293--307
21. Mahmood MA, Al-Rajhi A, Riley F, et al. Sclerokeratitis: an
unusual presentation of squamous cell carcinoma of the
conjunctiva. Ophthalmology. 2001;108:553--8
22. Margo CE, Groden LR. Intraepithelial neoplasia of the
conjunctiva with mucoepidermoid differentiation. Am J
Ophthalmol. 1989;108:600--1
23. Margo CE, Grossniklaus HE. Pseudoadenomatous hyperpla-
sia of the conjunctiva. Ophthalmology. 2001;108:135--8
24. Margo CE, Weitzenkorn DE. Mucoepidermoid carcinoma of
the conjunctiva: report of a case in a 36-year-old with
paranasal sinus invasion. Ophthalmic Surg. 1986;17:151--4
25. McKelvie PA, Daniell M, McNab A, et al. Squamous cell
carcinoma of the conjunctiva: a series of 26 cases. Br J
Ophthalmol. 2002;86:168--73
26. Nikitakis NG, Tosios KI, Papanikolaou VS, et al. Immuno-
histochemical expression of cytokeratins 7 and 20 in
malignant salivary gland tumors. Mod Pathol. 2004;17:
407--15
RANKIN ET AL
27. Okabe M, Miyabe S, Nagatsuka H, et al. MECT1-MAML2
fusion transcript defines a favorable subset of mucoepider-
moid carcinoma. Clin Cancer Res. 2006;12:3902--7
28. Poole TR. Conjunctival squamous cell carcinoma in
Tanzania. Br J Ophthalmol. 1999;83:177--9
29. Rao NA, Font RL. Mucoepidermoid carcinoma of the
conjunctiva: a clinicopathologic study of five cases. Cancer.
1976;38:1699--709
30. Riedlinger WF, Hurley MY, Dehner LP, et al. Mucoepider-
moid carcinoma of the skin: a distinct entity from
adenosquamous carcinoma: a case study with a review of
the literature. Am J Surg Pathol. 2005;29:131--5
31. Robinson JW, Brownstein S, Jordan DR, et al. Conjunctival
mucoepidermoid carcinoma in a patient with ocular
cicatricial pemphigoid and a review of the literature. Surv
Ophthalmol. 2006;51:513--9
32. Searl SS, Krigstein HJ, Albert DM, et al. Invasive squamous
cell carcinoma with intraocular mucoepidermoid features.
Conjunctival carcinoma with intraocular invasion and di-
phasic morphology. Arch Ophthalmol. 1982;100:109--11
33. Seethala RR. An update on grading of salivary gland
carcinomas. Head Neck Pathol. 2009;3:69--77
34. Shelil AE, Shields CL, Shields JA, et al. Aggressive
conjunctival squamous cell carcinoma in a patient following
liver transplantation. Arch Ophthalmol. 2003;121:280--2
35. Shemirani N, Osipov V, Kolker A, et al. Expression of mucin
(MUC) genes in mucoepidermoid carcinoma. Laryngo-
scope. 2011;121:167--70
36. Shields CL, Shields JA. Tumors of the conjunctiva and
cornea. Surv Ophthalmol. 2004;49:3--24
37. Slusker-Shternfeld I, Syed NA, Sires BA. Invasive spindle cell
carcinoma of the conjunctiva. Arch Ophthalmol. 1997;115:
288--9
38. Sofinski SJ, Brown BZ, Rao N, et al. Mucoepidermoid
carcinoma of the lacrimal gland. Case report and review of
the literature. Ophthal Plast Reconstr Surg. 1986;2:147--51
39. Soong HK, Feil SH, Elner VM, et al. Conjunctival
mucoepidermoid carcinoma in a young HIV-infected man.
Am J Ophthalmol. 1999;128:640--3
40. Soysal HG. Orbital exenteration: a 10-year experience of
a general oncology hospital. Orbit. 2010;29:135--9
41. Ullman S, Augsburger JJ, Brady LW. Fractionated epibulbar
I-125 plaque radiotherapy for recurrent mucoepidermoid
carcinoma of the bulbar conjunctiva. Am J Ophthalmol.
1995;119:102--3
42. Wenig BM. Atlas of Head and Neck Pathology, 2nd ed.
Philadelphia, PA, Saunders; 2008, pp 330--40
43. Yang J, Foster CS. Squamous cell carcinoma of the
conjunctiva. Int Ophthalmol Clin. 1997;37:73--85
44. Yucel YH, Johnston MG, Ly T, Patel M, et al. Identification of
lymphatics in the ciliary body of the human eye: a novel
‘‘uveolymphatic’’ outflow pathway. Exp Eye Res. 2009;89:810--9
Reprint address: Frederick A. Jakobiec, MD, DSc, Massachusetts
Eye and Ear Infirmary, Suite 32, 243 Charles Street, Boston,
MA 02114. e-mail: Fred_Jakobiec@MEEI.Harvard.edu.