Saudi Journal of Ophthalmology (2013) 27, 177186

Ocular Oncology Update

Ocular surface squamous neoplasia Review

of etio-pathogenesis and an update on clinico-pathological
diagnosis
Ruchi Mittal, MD, DNB, PDF a,; Suryasnata Rath, MS, FRCS b; Geeta Kashyap Vemuganti, MD, DNB c,d

Abstract
Ocular surface squamous neoplasia (OSSN) has a varied clinical presentation, the diagnosis of which rests on the histopathological
examination of the excised lesion. The term OSSN includes mild dysplasia on one end of the spectrum and invasive squamous cell
carcinoma on the other end. This lesion has a multi factorial aetiology with interplay of several factors like exposure to ultraviolet radiation, various chemical carcinogens and viral infections, however role of individual agents is not well understood. With the upsurge of
infection with human immunodeficiency virus, a changing trend is seen in the clinical presentation and prognosis of patients of OSSN
even in developed countries. Anterior segment optical coherence tomography (OCT) and confocal microscopy, hold promise in invivo differentiation of intraepithelial neoplasia from invasive squamous cell carcinoma. Variants of squamous cell carcinoma like
Mucoepidermoid carcinoma, spindle cell carcinoma and OSSN associated with HIV infection should be suspected in a case of aggressive clinical presentation of OSSN or with massive and recurrent tumours. Surgery, chemotherapy and immunotherapy are the various
treatment modalities which in combination show promising results in aggressive, recurrent and larger tumours.
Keywords: Ocular surface squamous neoplasia, Conjunctival intra epithelial neoplasia, Histopathology, Variants, Clinical features,
Management
2013 Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University.
http://dx.doi.org/10.1016/j.sjopt.2013.07.002

Background
Ocular surface squamous neoplasia (OSSN) is a broad
term encompassing conjunctival intraepithelial neoplastic lesions (CIN) and invasive squamous cell carcinoma (SCC) of
conjunctiva and cornea.1 CIN includes varying grades of dysplasia, ranging from mild, moderate, severe dysplasia to carcinoma in situ. When various intra epithelial lesions of
squamous epithelium of conjunctiva were identified, numer-

ous confusing terminologies such as epithelial plaque, intra

epithelial epithelioma, dyskeratosis, dysplasia, precancerous
epithelioma, Bowens disease of the conjunctiva and Bowenoid epithelioma were used to describe this lesion. The term
CIN, in vogue today was proposed by Pizarello and Jakobeic,
derived from the terminology applied to the intraepithelial
cervical malignancies.2
Advanced age, male gender, exposure to solar ultraviolet
radiation, infection with human papilloma virus (HPV), immunosuppression and infection with human immunodeficiency

Available online 6 July 2013

a

Dalmia Ophthalmic Pathology Service, L.V. Prasad Eye Institute, Bhubaneswar, India
Ophthalmic Plastic Surgery, Orbit and Ocular Oncology, L.V. Prasad Eye Institute, Bhubaneswar, India
c
Ophthalmic Pathology Services, Professor Brien Holden Eye Research Centre, L.V. Prasad Eye Institute, Hyderabad, India
d
School of Medical Sciences, University of Hyderabad, Hyderabad, India
b

Corresponding author. Address: L.V. Prasad Eye Institute, Patia, Bhubaneswar 751 024, Orissa, India. Tel.: +91 (674) 398 7999; fax: +91 (674) 398
7130.
e-mail addresses: dr.rmittal@gmail.com (R. Mittal), deanmd@uohyd.ernet.in (G.K. Vemuganti).
Peer review under responsibility
of Saudi Ophthalmological Society,
King Saud University

Production and hosting by Elsevier

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178
virus (HIV) are the factors which play an essential role in the
development of OSSN. OSSN, known as an indolent disease
of adult males, has shown changing trends with regard to its
clinical presentation and progression with upsurge of HIV
infection.3 It presents more commonly in the interpalpebral
area of perilimbal conjunctiva, and can extend across the limbus to involve the cornea. OSSN can show isolated corneal
involvement also. Atypical manifestations of OSSN like massive surface tumours and scleral necrosis after prior surgical
interventions have also been reported.4,5 Atypical clinical
manifestations of OSSN need impression cytology or incisional biopsy for definitive diagnoses for further management. While complete excision with histopathologically
proven tumour-free margins is the preferred treatment for
smaller localised lesions (<4 clock hours of limbus) alternative
modalities like chemotherapy, immunotherapy have shown
promise in recurrent and larger OSSN.6

Epidemiological aspects
The average incidence of OSSN of conjunctiva and cornea was
estimated to be 0.13/100,000 in tribal groups in Uganda by Templeton in a study published in 1967,7 and 1.9/100,000 population
per year in the Brisbane metropolitan area of Australia by Lee in
1992.8 Sun and co-workers reported an average incidence of
0.3 million per year in United States in 19979 In a recent study
published in 2012 an incidence of 37.3 per 106 was reported
for all eye cancers and 8.4 per 106 for SCC.10 Highest risk of OSSN
is seen in males, Caucasians and residents of lower latitudes (closer than 30 latitude to the equator).11 OSSN occurs predominantly in adults, average age of occurrence of OSSN is
reported as 56 years, with an age range of 4-96 years.1 Younger
age of presentation of OSSN is seen in addition to population
residing at lower latitudes, amongst patients suffering from Xeroderma pigmentosum and HIV infection.1114

Predisposing factors
Genetic injury to a proliferating cell knocks out the control of
basic cellular functions like division and differentiation and these
cells become neoplastic. Several factors are implicated in the
development of ocular surface squamous neoplasia. It has been
speculated that OSSN may arise from dysfunctional limbal stem
cells having been altered by various mutagenic agents, such as
UV radiation.15 The mutagenic factors which have been best
understood include exposure to ultraviolet B radiation, and infection with human papilloma virus. Other reported risk factors include exposure to petroleum products, heavy cigarette
smoking, chemicals such as trifluridine, arsenicals, beryllium, ocular surface injury, vitamin A deficiency, light pigmentation of the
hair and eye, defective DNA repair in Xeroderma Pigmentosum,
family origin in the British Isles, Austria, or Switzerland, infection
with HIV16,17 and other immunocompromised states.

Role of ultraviolet B rays

Various studies have shown a linear relationship between
exposure to ultraviolet radiation and development of OSSN.
Residents of lower latitudes, male sex (outdoor activity), temporal lesions being more common and more aggressive than
nasal lesions, higher incidence in fair skin individuals and history of actinic skin lesions make sunlight exposure as the

R. Mittal et al.
prime aetiological trigger. The degree of risk depends on
the type of UV rays, the intensity of exposure, total cumulative exposure and the quantity of the light-absorbing
protective mantle of melanin. The UV portion of the solar
spectrum can be divided into three wavelength ranges:
UVA (320400 nm), UVB (280320 nm), and UVC (200
280 nm). Of these, UVB is believed to be responsible for
the induction of various cutaneous and ocular surface cancers. Exposure to UVB light leads to the formation of pyrimidine dimers in DNA and also causes damage to the
nucleotide excision repair pathway which plays a key role in
repairing DNA damage caused by UV-B exposure. Unrepaired alterations in the DNA are the first essential step in
the process of initiation These alterations become heritable
when these altered and injured DNA undergoes one cycle
of proliferation, this stimulus of proliferation could be provided by the UV rays themselves or could be provided by
virus such as HPV or some chemical stimulus. In a study published in 2008 the role of matrix metalloproteinases (MMP)
and tissue inhibitors of matrix metalloproteinases in OSSN
has been hypothesised with an altered pattern of expression
of MMP-1 and MMP-3, following ultraviolet B radiation is
implicated in the pathogenesis of OSSN.18
Xeroderma pigmentosum (XP) is an autosomal recessive
disorder with defective DNA repair mechanism which also
predisposes to OSSN and other mucosal and cutaneous cancers with aggressive clinical presentation at a younger age.
OSSN has been reported as early as 3 years of age in a patient of XP.19 In the largest study with 87 participants of XP
conducted at National Eye Institute, published in 2013, 10%
of the patients of XP had ocular surface cancers,20 age range
of these patients was 528 years.

Human papilloma virus and OSSN

HPV is a nonencapsulated, icosahedral, non-lipid containing DNA virus that replicates in the nuclei of infected cell.
There are several genetically distinct types of HPV, some
types (e.g., 1, 2, 4, and 7) cause benign squamous lesions
in humans and high-risk HPVs (e.g., types 16 and 18) have
been implicated in the genesis of several cancers, particularly
squamous cell carcinoma of the cervix, anogenital region,
oropharyngeal region and ocular surface. Integration of the
viral genetic material into the host genome is a critical event
in the malignant transformation of the cell. Integration consistently interrupts the viral DNA within the E1/E2 open reading frame, leading to failure or loss of transcription of late E2
genes which functions as viral repressor proteins with absence of viral repressor proteins uncontrolled transcription
of E6 and E7 gene occurs. This type of infection is called as
non productive infection since life cycle of virus is interrupted
and complete virions are not produced. E6 and E7 genes of
high risk HPV types have a higher affinity of binding to various growth-regulating proteins encoded by proto-oncogenes and tumour suppressor genes.21 However, infection
with HPV itself is not sufficient for carcinogenesis. In addition
to genetic co-factors, HPV in all likelihood also acts in concert
with other environmental factors. Evidence of the role of HPV
16 and 18 in the development of OSSN has been established
by several studies, in contrast, our group reported that there
is no association of high risk HPV in patients with OSSN at a
tertiary eye care centres, as detected by in-situ hybridisa-

Ocular surface squamous neoplasia

179

tion.22 There are other compelling studies which suggest that

HPV does not play a role in the pathogenesis of OSSN.23,24 In
a study conducted by Scott and colleagues, published in
2001, HPV 16 or 18 DNA and mRNA corresponding to the
E6 region were detected in all 10 CIN specimens examined
using the reverse-transcriptase polymerase chain reaction.25
Chauhan and associates in their study published in 2013, reported detection of HPV16 in 11% of their OSSN cases with a
positivity of 9% in SCC patients and 15% in dysplastic cases
using multiplex PCR with PGMY09/11 primer on fresh tumour
tissues from OSSN cases. Authors also reported a better
overall survival in patients with HPV infection.26

HIV infection and OSSN

An increase in the incidence of OSSN, since the HIV pandemic, has suggested that HIV infection increases the risk for
OSSN. In Africa, OSSN has been recognised to be strongly
associated with HIV, the mean age at which the patients present with invasive squamous cell carcinoma ranges from 32 to
37 years, and the proportion of female patients ranges from
55% to 70%.27 HIV infection is now established as a risk factor
for the development of squamous cell neoplasia of the conjunctiva based on studies from Rwanda, Malawi, and
Uganda.28,29 A significant increase in the incidence of OSSN
is also reported in patients with HIV/AIDS in the United
States.30 There are several studies which have reported OSSN
as the first clinical presentation of HIV in young patients.29,31
OSSN occurring in HIV patients are more aggressive and invasive requiring enucleation or even exenteration.32

Figure 1. Varied clinical presentation of OSSN (A). Slit lamp photograph

under diffuse illumination shows papillary ocular surface tumour with
prominent feeder (B). Figure shows a globular pink-coloured lesion
arising with large feeder vessels. The lesion seems to be overlying a
pterygium and was clinically mistaken to be a pyogenic granuloma (C).
Figure shows a pigmented OSSN with feeder vessels (D). Slit lamp
photograph under diffuse illumination showing large leukoplakic lesions
with abnormal vessels.

Clinical features
Clinically OSSN has myriad presentations. It usually appears as
a sessile, fleshy, elevated lesion adjacent to the limbus in the inter-palpebral region. Contrary to general perception the thickness of the lesion is not always an indication of invasive SCC.
Even reasonably thick tumours tend to be confined within the
epithelium. The presentation of CIN and invasive SCC is very similar thus making clinical differentiation difficult. Usually the tumour presents as a circumscribed, gelatin-like, sessile,
papillomatous lesion with variable degrees of leukoplakia
(Fig. 1AD). One often finds dilated conjunctival blood vessels
feeding and draining the lesion. SCC is locally invasive and metastasis is seen in <2% of cases. It can invade intraocular tissues and
orbit. Some lesions can be diffuse, flat, and poorly-demarcated
without an obvious tumour making early diagnosis difficult. Massive tumours infiltrating the deeper corneal stroma and covering
the entire ocular surface are also seen (Fig. 2AF). Infiltrative variants of OSSN masquerading as necrotizing scleritis may pose a
challenge in early diagnosis (Fig. 3 AD).33 Rarely pigmented
variants of OSSN may be seen making differentiation from
conjunctival melanoma difficult (Fig. 1C).34
Aggressive variants of OSSN are less commonly seen but
deserve mention. Mucoepidermoid carcinoma is seen in elderly individuals and has a propensity for intraocular and
orbital invasion. Mucin producing cells give it a yellow cystic
appearance. Spindle cell carcinoma is an aggressive variant
with a tendency to metastasize. These are generally managed surgically with wider margins.

Figure 2. (A) Slit lamp photograph of the left eye under diffuse
illumination shows a large overhanging conjunctivo-corneal mass with
surface keratin, large intrinsic and feeder vessels, involving more than half
of the corneal surface with invasion into deeper stroma (B). Schematic
diagram showing cross-sectional view of the left eye of the patient and
large tumour with deep stromal invasion of the cornea. Surgical plane of
dissection is shown as a dotted line (C). Scanner view of the main limbal
mass shows an invasive tumour involving conjunctival lamina propria and
corneal stroma. The tumour is composed of nests and cords of tumour
cells that invaded the conjunctival lamina propria and corneal stroma
(Haematoxylin-eosin, X 20) (D). Microphotograph shows the tumour cells
with marked dysplasia and prominent mitotic figures (Haematoxylineosin, X400) (E). Microphotograph shows the tumour invading the deeper
corneal stroma but not reaching up to the Descemets (Haematoxylineosin, X 100) (F). Slit lamp photograph of the left eye under diffuse
illumination shows the scleral corneal graft twelve months after treatment. The corneal graft shows mild stromal haze.

180

Figure 3. (A) Slit lamp picture of the right eye under diffuse illumination
shows scleral thinning and perforation from 70 clock to 110 clock on the
temporal quadrant away from the limbus (B). Section of the eye after
modified enucleation. Note the epibulbar nodular mass involving the
peripheral cornea, limbus and sclera (C). Sections show squamous cell
carcinoma with sheets of anaplastic tumour cells with focal keratinisation.
(Haematoxylin-seosin X400) (D). Histopathology of the mass showing full
thickness infiltration of sclera and involvement of choroidal tissue. There
was focal retinal detachment and sub retinal exudates (Haematoxylineosin X100).

Diagnosis
The gold standard for the diagnosis of OSSN is the histopathological evaluation of the lesion after an incisional or
excisional biopsy. However there are several occasions when
the clinician may opt to do diagnostic tests to corroborate
the clinical suspicion of OSSN. In 1980 Gelender reported
that cytological features can be seen using a cytobrush to obtain a specimen for fixation and Papanicolaou staining.35
Impression cytology on cellulose acetate paper as described
by Nolan et al had a reasonably high predictability rate of
77% (55/71) in diagnosing moderate dysplasia to microinvasive carcinoma.36 Diagnosis is based on the presence of the
universal cytological criteria which included nuclear enlargement, hyperchromasia, irregular nuclear outline, coarse nuclear chromatin, and prominent nucleoli.37 That impression
cytology is less sensitive in diagnosing invasive sqaumous cell
carcinoma has been often highlighted in the literature. Interestingly, Nolan et al noted that the presence of keratin,
inflammatory cells, and fewer diagnostic cells on impression
cytology should alert the clinician about possibility of the disease at the severe end of the spectrum.36 It is advised that in
cases of hyperkeratotic lesions with negative impression
cytology, surgical incision biopsy be done to rule out
OSSN.36 Bio pore membrane used for impression cytology
was reported to accurately correlate with histological diagnosis in 80% (20/25) by Tole et al. More significantly Bio pore
device is easy and rapid to use in routine clinical practice
compared to longer preparation and transport time in
impression cytology with cellulose acetate paper.37 Finally,
clinicians need to keep in mind that despite its advantages

R. Mittal et al.
in early diagnosis of OSSN impression cytology has its limitations in differentiating carcinoma-in-situ from infiltrating
carcinoma.
Anterior segment optical coherence tomography (OCT)
allows morphologic and even histological characteristics of
the tissue to be examined in vivo. The recent introduction
of anterior segment OCT has enabled the assessment of
the conjunctiva and cornea with high axial resolution of tissue
planes. With the help of technological advances from timedomain to spectral-domain and ultra-high resolution (UHR)
OCT, axial resolutions of 23 microns allow an optical biopsy
of ocular surface tissue. A recent report by Kieval et al evaluated UHR OCT as a non-invasive diagnostic tool in differentiating OSSN from pterygia in 34 eyes.38 Apart from a good
correlation between histopathology and UHR OCT findings
in the OSSN group (17 eyes), a severely thickened hyperreflective epithelium with an abrupt transition from abnormal
to normal tissue were significant findings suggestive of
OSSN. Significant omissions by UHR OCT which were picked
on histopathology included poor delineation of the cleavage
plane owing to shadow artefacts in a few lesions and a falsenegative result in one case of muco-epidermoid SCC.38 The
authors of this study also derived a cut-off thickness of
142 microns as differentiating OSSN from pterygia with
94% sensitivity and 100% specificity. Superficial cytological
analysis enabled by confocal microscopy is a simple, safe
and effective tool for early diagnosis of OSSN.38 Xu et al evaluated the efficacy of in-vivo confocal microscopy in diagnosing OSSN type in addition to performing anterior segment
OCT and confirmation with histopathology in five cases.39
Cellular anisocytosis, anisonucleosis and altered nuclear-cytoplasmic ratio were seen on confocal microscopy in three
cases diagnosed as CIN. In addition nests formed by isolated
keratinised mitotic cells extending beyond the basement
membrane helped diagnose invasive SCC.39

Epigenetics
One of the challenges in OSSN is to predict the recurrences and the invasiveness of the lesion. Similar to cervical
carcinoma, our group made an attempt to see if epigenetic
markers could differentiate the intra-epithelial vs. invasive tumours. In a pilot study of five cases, we noted that hypomethylation of the promoter region of DML epigenetic changes
could possible differentiate the intraepithelial lesion from
invasive lesion. This however warrants confirmation by a larger study.40

Histopathology
Complete pictorial documentation of the ocular surface
with the lesion should be made on the Whatmans filter paper
No. 16, with a mention of the laterality and position of the lesion. Excised lesion, mucosal surface facing up, should be
placed on the filter paper with diagram with or without separate margins (Fig. 4A). Excised lesion mounted on the filter
paper in the operating room should be allowed to dry adequately (approx. 23 min) on the filter paper which causes
adhesion of the tissue on the filter paper. This tissue on the
filter paper is then submitted in 10% buffered formal saline
to histopathology laboratory. Margins when not sent separately by the surgeon should be submitted by the grossing

Ocular surface squamous neoplasia

Figure 4. (A) Excised ocular surface squamous lesion placed on the filter
paper. Exact laterality and position of the lesion can be made out with this
pictorial documentation (B). Margins from the excised tissue are placed
on separate filter papers and submitted in different cassettes.

pathologist as superior/inferior/medial and/or lateral in separate filter papers submitted in separate cassettes (Fig. 4B).
Main lesion which is seen as a greyish white plaque, nodule
or thickening should be excised into two and submitted for
edge wise processing.
Microscopic examination of the excised lesion with safe
margins shows an abrupt transition of the epithelial lesion
from the adjacent uninvolved conjunctiva (Fig. 5). Lesion
should be studied for architectural and cytological atypia.
Margins and base of the lesion should also be studied for atypia. Abnormalities in a dysplastic lesion reflect the deranged
cellular proliferation that is the abnormal/injured mitotic cells
do not fully differentiate as they rise in the epithelium (disordered proliferation with incomplete/altered differentiation).
Depending on the level and thickness of epithelial involvement varying grades of dysplasia are classified. When lower
one third and lower two thirds of the epithelium shows
abnormal transformation the lesion is termed as mild and
moderate dysplasia respectively. When the abnormality in-

Figure 5. The conjunctival epithelium is markedly thickened with an

abrupt transition noted between the involved conjunctiva and the
adjacent normal appearing conjunctival epithelium (arrow marked). Base
of the excision biopsy is free of tumour involvement (Periodic Acid Schiffs
stain, X200).

181
volves more than 2/3rds of the epithelial thickness, however
surface maturation is preserved, the lesion is termed as severe dysplasia. Involvement of full thickness of epithelium,
however with retained integrity of epithelial basement membrane is termed as carcinoma in situ (Fig. 6AD). As the lesion
progresses from mild to severe dysplasia, the cells differentiate less and less, gradually losing their squamous features until eventually the full thickness of epithelium is made of
undifferentiated/immature atypical cells which can even have
basaloid like appearance. Cytologically the dysplastic cells
show an increase in the size of nuclei, irregular nuclear membrane, hyperchromasia and fine to coarse chromatin. Degree
of nuclear atypia, irrespective of level of epithelial thickness
involved can also cause up gradation or down gradation of
severity of dysplasia. Hyperkeratosis and dyskeratosis (single
cell keratinisation) with the formation of squamous pearls is
not a discrete feature of intra epithelial lesions. An increased
mitosis with the presence of abnormal mitoses is observed,
scattered throughout the lesion, depending on the thickness
displaying abnormal maturation. Mild to moderate chronic
lymphomononuclear cell infiltration may be observed and
could cause inflammatory destruction of epithelial basement
membrane. This should not be confused with invasive squamous cell carcinoma, especially in cases of carcinoma in situ.
Lesions associated with HPV would show cytopathic effect
in some cells, resulting in the formation of a halo cell, known
as the Koilocyte.41 Koilocytes, though not sensitive for diagnoses of HPV infection, are pathognomonic of HPV infection
if strict diagnostic criteria are used to identify them. Koilocyte
is a mature squamous cell with a characteristic halo surrounding the nucleus. Halo is distinct, surrounded by dense eosinophilic cytoplasm. Nucleus of the Koilocyte looks enlarged

Figure 6. (A) Moderate dysplasia-squamous intra epithelial lesion,

abnormal transformation of epithelium involving more than 2/3rds of
epithelial thickness, however the degree of cytological atypia is not
sufficient to term this lesion as severe dysplasia (B). Severe dysplasiathere is almost full thickness replacement by abnormal epithelium, surface
maturation is noted with keratinisation. Basement membrane is intact.
(C). Carcinoma- in-situ- there is full thickness replacement by abnormal
epithelium with marked nuclear pleomorphism. Basement membrane is
intact, (arrow marked) (Haematoxylin-eosin, X 400) (D). Invasive Squamous cell carcinoma-invasion of stroma is seen as tumour nests and broad
expansive tumour masses. Tumour is well differentiated with horn pearls
and abundant keratinisation (Haematoxylin-eosin X 100).

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R. Mittal et al.

with wrinkled nuclear membrane, dense chromatin and

inconspicuous nucleoli. There can be frequent binucleation,
although there could be virus present in the nucleus, but
there is neither intranuclear nor intracytoplasmic viral inclusion seen with light microscopy. The formation of koilocytes
decreases with increasing severity of dysplasia, and they are
rarely seen in invasive lesions.
Reactive, regenerative or reparative squamous epithelium
(for example in response to trauma, inflammation or infection) may manifest atypical cytology. Excised margins of ocular surface lesion could also display reparative/inflammatory
atypia. Such changes should be studied with caution and distinguished from CIN.
In a reparative/regenerative/inflammatory lesion, a disparity is seen between the abnormal appearing, pleomorphic
nuclei with prominent nucleoli versus the preserved orderliness of the cells with bland and pale chromatin. Normal mitotic figures can be seen, however there would be absence of
abnormal mitotic figures. Clinical history is also important in
such cases.
Conjunctival intraepithelial neoplasia can progress to invasive squamous cell carcinoma with destruction of the epithelial basement membrane and extension into the underlying
stromal tissue. Invading tumour is seen as cords, strands
and clusters of malignant cells in the stroma (infiltrative pattern), but can also be seen as broad pushing fronds (expansive pattern). Dense collagenous scleral tissue in cases of
conjunctival OSSN and Bowmans membrane in corneal
OSSN (Fig. 7) attempt to limit the infiltration.42 As the cells
become infiltrative they accumulate dense, acidophilic cytoplasm with cytoplasmic accumulation of actin and myosin
which like keratin filaments appear acidophilic. These serve
as machinery for invasion of the cell (Apparent keratinisation).
They also redifferentiate from the undifferentiated stage of
carcinoma in situ to larger differentiated cells with a low N:
C ratio. Individual squamous cells in an invasive lesion (cytological features) could be large polygonal, small to spindle
in shape. The more the degree of maturation, the dense,
eosinophilic and copious is the cytoplasm, the pyknotic is
the nucleus. There could be single cell keratinisation or formation of squamous pearl. Differentiation of squamous cell
carcinoma is in terms of degree of keratinisation termed as
well-differentiated, moderately differentiated and poorly dif-

ferentiated carcinoma. Keratinisation is more in well and

moderately differentiated tumours, and these tumours cytologically display less nuclear pleomorphism. Poorly differentiated tumours have predominance of immature cells with
higher nuclear-cytoplasmic ratio, more pleomorphic nuclei,
increased typical and atypical mitoses and minimal
keratinisation.
Invasive squamous cell carcinoma, clinically and histologically needs differentiation form pseudoepitheliomatous
hyperplasia. Histologically pseudoepitheliomatous hyperplasia resembles well differentiated or moderately differentiated
carcinoma with irregular invasion, horn pearl formation and
numerous mitotic figures. Disparity between architectural
and cytological abnormality is noted with minimal or absent
nuclear hyperchromasia, hyperplasia and pleomorphism,
which helps in differentiating from a true malignant process43,44 (Fig. 8).
Other ocular surface lesions which can clinically mimic
OSSN such as actinic keratosis, pterygium, pinguecula and
actinic granuloma can be easily distinguished from OSSN
by studying the morphology. Our study reported three cases
in young women which clinically presented as OSSN and histopathological evaluation of the excised tissue confirmed
those lesions as actinic granuloma.45 OSSN can uncommonly
coexist with pterygium, 46 therefore vigilant study of pterygium specimens should be executed to exclude dysplastic
changes.
Clear cell change/hydropic change of the cytoplasm may
be seen in squamous cell carcinoma which should be observed with caution as it could mimic an aggressive disease
such as pagetoid extension in a sebaceous gland carcinoma,
Mucoepidermoid carcinoma, or even metastatic renal cell
carcinoma. Special stains, immunohistochemical work up with
clinical history and radiological correlation may be warranted
in difficult cases. Only two cases of Clear cell carcinoma, a
very rare variant of squamous cell carcinoma have been reported in the literature.47,48 Frequent local recurrences are
known, however local or distant metastasis is not reported.
Special stains for mucin, lipid and glycogen exclude Mucoepidermoid carcinoma, sebaceous gland carcinoma and metastatic renal cell carcinoma.49
Variants of Invasive Squamous cell carcinoma include
Mucoepidermoid carcinoma, Spindle cell carcinoma, papil-

Figure 7. (A) Corneal OSSN-slit lamp photograph under diffuse illumination shows minimally elevated lesion involving 3=4 of the cornea-scleral
limbus. The corneal surface is covered by a greyish membrane with
abnormal vessels (B). Atypical epithelium of the cornea, infiltration of
corneal stroma is limited by intact bowmans membrane (arrow marked).
An inflamed fibrovascular membrane is seen above the corneal stroma
(Haematoxylin-eosin X 400).

Figure 8. Pseudo epitheliomatous hyperplasia-section shows an abnormally thickened epithelium with surface keratinisation and stromal
invasion as epithelial cords displaying irregular, jagged edges. There is
minimal presence of nuclear hyperplasia, hyperchromasia with absence of
nuclear pleomorphism (Haematoxylin-eosin X 200).

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Ocular surface squamous neoplasia

lary squamous cell carcinoma and Acantholytic/Adenoid
squamous cell carcinoma.
Mucoepidermoid carcinoma (MEC) is a mucinproducing
squamous cell carcinoma of conjunctiva and is a rare neoplasm, unlike the commonly encountered Mucoepidermoid
carcinoma of salivary glands. In a large series of 287 cases of
squamous cell carcinoma of conjunctiva published by Cervantes and associates in 2002, there was only one case of Mucoepidermoid carcinoma of conjunctiva50 Only 21 cases of MEC
have been reported in the English literature till 2006.51 A series
of 71 cases of OSSN published by Alves and associates in 2011
included only one case of MEC. These tumours have the
appearance of squamous cell carcinoma with variable number
of mucin producing cells. Intermediate cells are also noted.
Mucin producing cells are large, pale, stain positively with periodic acid Schiffs stain and with mucicarmine stain which is
resistant to hyaluronidase but sensitive to sialidase (epithelial
sialo-mucin). MEC is a locally aggressive neoplasm which can
have similar clinical presentation like classic squamous cell carcinoma, histopathology plays a key role in diagnosis of this rare
and locally aggressive disease. MEC has a high rate of recurrence, ranging from 84.6% to 100% in different published
data,52 however local and distant metastases are uncommon.
Regional lymph node metastasis in MEC has been reported
in a single case by Hwang et al and associates.52
Spindle cell carcinoma is another rare and locally more
aggressive variant of squamous cell carcinoma of conjunctiva
with only few case reports in the literature. In a clinical series
of 1643 conjunctival tumours seen in an ocular oncology service, Shields and associates had 219 patients with epithelial
tumours, none of which were spindle cell carcinoma.53 Cervantes and associates in their large series of 287 cases of
squamous cell carcinoma have reported only two cases of
spindle cell squamous cell carcinoma.50 Spindle cell carci-

Figure 9. (A) Extended enucleation in a massive ocular surface tumourextended enucleation specimen with a massive ocular surface tumour,
enucleated eyeball is sectioned into one central and two peripheral
calottes (B). Conjunctival margins are sent separately mounted on filter
paper (C). Low magnification photomicrograph of the lesion altered
scleral collagen, angle structures (arrow marked) and iris tissue. Densely
cohesive spindle cell tumour is noted involving anterior one third of
scleral fibres (Haematoxylin-eosin X100) (D). High magnification photomicrograph shows malignant spindle cells. Atypical mitotic figures are
noted (arrow marked) (Haematoxylin-eosin, X 400).

noma/Sarcomatoid carcinoma is characterised by a biphasic

pattern of squamous cell carcinoma with a generally much
larger component of malignant spindle cells (divergent differentiation) reminiscent of a sarcoma. The squamous component may be scanty or even inapparent on light microscopy
(Fig. 9AD). In the latter circumstance, immunohistochemical
and electron microscopic evidence of squamous differentiation is required for diagnosis. By immunohistochemistry, sarcomatous component is characteristically vimentin positive,
may be positive for actin and desmin, and often shows only
limited or absent staining for traditional epithelial markers
such as cytokeratin or epithelial membrane antigen. In such
challenging cases, immunostaining for p63 is another useful
marker for the identification of epithelial differentiation.54
Spindle cell carcinoma on ultrastructural studies displays features of epithelial differentiation in spindle cells, such as desmosomes and tonofilaments.55 Spindle cell carcinoma is
much more likely to extend through the sclera and cornea
into the interior of the globe.56 Differential diagnoses of spindle cell carcinoma call for exclusion of malignant spindle cell
lesions such as fibrosarcoma, leiomyosarcoma, malignant fibrous histiocytoma and amelanotic malignant melanoma.
However in conjunctiva sarcomas are even rarer and spindle
cell carcinoma is still more likely.
Papillary squamous cell carcinoma is an exophytic squamous cell carcinoma with a papillary configuration composed
of tumour surrounding fibrovascular core (Fig. 10AC). There
are controversial reports regarding prognosis of head and
neck and they are generally believed to have a better prognosis.57 In our experience we have come across a case of
papillary SCC squamous cell carcinoma with a massive ocular
surface tumour (Fig. 10AC). CT scan showed evidence of
orbital invasion along the lateral rectus muscle.
Adenoid squamous cell carcinoma or Acantholytic squamous cell carcinoma is another rare variant of SCC. Mauriello
and associates had conducted a review of 12 years of cases of
SCC on the file at the AFIP and these revealed only 14 cases
of Adenoid Squamous cell carcinoma.58 This neoplasm is
composed of SCC, but characterised by acantholysis of tumour cells, leading to the formation of pseudolumina which
imparts a false glandular like appearance or sometimes even
confused with angiosarcoma. Pseudo lumina contain acantholytic cells, dyskeratotic cells and debris material. Histochemical stains, immune profiling and electron microscopy
help to exclude adeno squamous carcinoma and adenoid
cystic carcinoma. Special stains for mucin would be negative,
tumour cells would be positive for cytokeratin and EMA. They
would express hemidesmosomes and attached tonofilaments. This tumour is locally aggressive, can recur and even
metastasise and should, therefore, be histopathologically differentiated from the less aggressive conventional squamous
cell carcinoma. In the largest series of 14 cases published in
1997, 5/14 cases recurred and 1/14 cases showed brain
metastasis, despite aggressive therapy.58,59 Regular follow
up of this variant of SCC is recommended.

Management
Management modalities in OSSN range from complete
excision in well delineated tumours to chemotherapy in diffuse unresectable lesions.

184

R. Mittal et al.

Chemotherapy
Medical alternatives in the form of topical applications 5
Fluorouracil (5FU) and mitomycin C (MMC) have been extensively reported in the literature. Primary treatment with chemotherapeutic agents for OSSN is largely limited to
localised OSSN. Both MMC and 5FU have also been used
as adjuvant therapy for recurrent lesions. Extensive OSSN
with a mean diameter of 40 mm have shown 57% reduction
in tumour base after chemoreduction with MMC. However
the cumulative and delayed toxicity of MMC on the ocular
surface make these agents less preferred in the treatment
of OSSN.61,62

Immunotherapy

Figure 10. (A) Papillary variant of squamous cell carcinoma. Slit lamp
photograph under diffuse illumination shows a massive papillary variant
of invasive squamous carcinoma invading into the orbit along the lateral
rectus muscle (B). Scanner photomicrograph showing an exophytic
squamous cell lesion with papillary pattern (Haematoxylin-eosin X 40)
(C). Low magnification photomicrograph shows tumour cells with marked
cytological atypia surrounding central fibrovascular core. (Haematoxylineosin X 100).

Surgery
Complete excision with adequate margins is the treatmentof-choice for most localised lesions. Alcohol assisted keratoepitheliectomy and lamellar sclerokeratoconjunctivectomy
are indicated for the corneal and infiltrative components
respectively. There seems to be a consensus on the beneficial
role of double-freeze cryotherapy to the resected margins and
base of the lesion amongst most clinicians. Complete extirpation
is confirmed by histopathological examination of conjunctival
margins which are sent separately. Negative surgical margin is
the most important predictor for tumour recurrence. Recurrence
rates are reported to range from 5% to 33% after negative margins to as high as 56% in those where margins were found to be
positive.59 The residual defect after excision may be covered by
amniotic membrane transplant or buccal mucous membrane
graft.6 Rare reports exist in the literature describing massive
corneal OSSN infiltrating deeper stromal layers where globe
and vision were salvaged by penetrating sclerokeratoplasty
(Fig. 2AF).60 The availability of noninvasive techniques like
UHR, OCT and ultrasound biomicroscopy has made it possible
to evaluate the extent of corneoscleral invasion in OSSN.38,39
In cases with suspected intraocular invasion by OSSN
there may be cells in the anterior chamber simulating uveitis associated with raised intraocular pressure. These cases
need local eyewall resection or modified enucleation to extirpate the tumour. Treatment in OSSN with orbital invasion
may range from local resection and/or irradiation to eyelid
sparing orbital exenteration.

In 1994 Maskin was the first to report to report the use of

topical interferon (IFNa2b) in a multi-focal limbal OSSN.63
Karp reported complete response in five cases of OSSN measuring <8 mm with IFNa2b.64 Over the past decade several
authors have reported on the beneficial effects of IFNa2b
in the treatment of OSSN. Owing to a better toxicity profile,
IFNa2b currently seems to be the treatment of choice for
wider and extensive OSSN involving >4 clock hours of the
limbus.60 Overall topical IFNa2b is preferred for OSSN which
are relatively thinner for complete tumour control (immunotherapy) while combination therapy with topical and injection
IFNa2b is reserved for partial reduction of thicker and extensive OSSN (immunoreduction). Occasional flu-like symptoms
and ocular surface irritation are sometimes seen in patients
after treatment with IFNa2b. Cost of IFNa2b remains to be
a major disadvantage of IFNa2b therapy especially in the
developing world.34

Prognosis
The overall prognosis in OSSN is good. Modern treatment
strategies are effective with local recurrence rates reported
to be 5% and regional lymph node metastasis at <2%.
Aggressive variants like muco-epidermoid and spindle cell
carcinoma and OSSN in immunocompromised patients have
a worse prognosis.

Conclusion
Histopathology is the gold standard in the diagnoses of
various grades and types of OSSN, and gives a fair
understanding of disease prognosis. Conjunctival impression
cytology could be a diagnostic aid or to confirm flat corneal
limbal lesions.
Future studies are needed to understand the pathogenesis of OSSN and the role of various carcinogens specifically
HPV and HIV in varied manifestations of the disease process
and their role in prognosis of disease. Further work is required in the re diagnoses of OSSN with the aid of UHR,
OCT and confocal microscopy. While complete excision with
cryotherapy gives excellent results with localised lesions,
newer modalities like immunotherapy hold a promise in the
larger, unresectable and recurrent lesions.

Ocular surface squamous neoplasia

Authors contributions
Dr. RM designed the manuscript, wrote the etio-pathogenesis, pathological diagnoses, and compiled the pictures.
Dr. SR wrote the clinical diagnoses, management and prognosis, and contributed the clinical pictures. Dr. GKV designed
the manuscript, contributed in writing the etio-pathogenesis,
pathological diagnosis and contributed to the histopathology
pictures and approved the final picture composites.

Conflict of interest
The authors declared that there is no conflict of interest.

Acknowledgements
Authors would like to thank Pravin Ku. Balne for helping in
compiling the references and Chhotan Dey for helping in the
preparation of composites of the clinical and histopathology
pictures.

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