Update on Diagnosis and Management of Conjunctival Papilloma

Abstract

Conjunctival papilloma is an acquired benign squamous cell tumor that can present at any age, but most frequently in the third and fourth decades of life. Papillomas have been associated with human papilloma virus (HPV) infection, usually types 6 and 11. Although histopathological diagnosis remains the gold standard, the advent of newer non-invasive imaging modalities such as optical coherence tomography (OCT) is transforming the way we diagnose and treat ocular surface tumors, including conjunctival papilloma. Management of these lesions can prove a challenge to the treating physician since not all lesions respond to medical and/or surgical therapy and in fact may worsen after surgical manipulation. In this review, the epidemiology, pathophysiology, clinical characteristics, and diagnosis of conjunctival papilloma including the use of OCT are discussed. Indications, efficacy, and side effects of currently available management options are also reviewed to guide the selection of the best treatment approach.

Full text

R E V I E W Open Access
Update on Diagnosis and Management of
Conjunctival Papilloma
Despoina Theotoka
1†
, Melina I. Morkin
1†
, Anat Galor
1,2
and Carol L. Karp
1*
Abstract
Conjunctival papilloma is an acquired benign squamous cell tumor that can present at any age, but most
frequently in the third and fourth decades of life. Papillomas have been associated with human papilloma virus
(HPV) infection, usually types 6 and 11.
Although histopathological diagnosis remains the gold standard, the advent of newer non-invasive imaging
modalities such as optical coherence tomography (OCT) is transforming the way we diagnose and treat ocular
surface tumors, including conjunctival papilloma. Management of these lesions can prove a challenge to the
treating physician since not all lesions respond to medical and/or surgical therapy and in fact may worsen after
surgical manipulation.
In this review, the epidemiology, pathophysiology, clinical characteristics, and diagnosis of conjunctival papilloma
including the use of OCT are discussed. Indications, efficacy, and side effects of currently available management
options are also reviewed to guide the selection of the best treatment approach.
Keywords: Conjunctival papilloma, Squamous cell papilloma, Optical coherence tomography, Treatment, Interferon,
Mitomycin, Surgery, Cryotherapy, Human papilloma virus
Background
The first reported case of conjunctival papilloma
dates back to 1883, when Critchett and Juler de-
scribed a small reddish mass near the inner canthus
of a 14-year-old girl presenting with discomfort and
slow increase in size for 5 years [1]. Since then, as a
result of scientific advances in the understanding of
the pathophysiology and management of conjunctival
papilloma, both awareness and knowledge about the
disease have increased among ophthalmologists and
other eye care providers.
Conjunctival papilloma is an acquired benign tumor
that arises from the stratified squamous epithelium of
the conjunctiva. It can occur in both children and adults,
typically with a slow progressive course [2]. This tumor
is usually easily identified by clinical examination since
the conjunctiva is a readily visible structure, although
tarsal lesions may be missed in the absence of eyelid
eversion.
Management of conjunctival papilloma is diverse and
both medical and surgical approaches have been de-
scribed. The course of papillomas can be complicated by
multiple recurrences, especially in the pediatric popula-
tion [3]. It is essential for the ophthalmologist to be
aware of the tools available to aid in the diagnosis of
papilloma and to understand the available medical and
surgical therapeutic options.
Main text
Epidemiology
Overall, conjunctival papillomas account for 1 to 16% of
conjunctival lesions seen in adults and 1 to 10% of the
lesions seen in children and adolescents [4–12], with fre-
quencies differing by study population. Conjunctival
papillomas are more common in men and occur most
often between the ages of 21 and 40 years with a pro-
gressive decrease in incidence thereafter [2,3,5,13–16].
This age distribution is similar to that seen in genital hu-
man papilloma virus (HPV) infection in sexually active
adults [17]. The main reported risk factor for conjunc-
tival papilloma is HPV infection, with studies in the
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: ckarp@med.miami.edu
†
Despoina Theotoka and Melina I. Morkin contributed equally to this work
1
Department of Ophthalmology, Bascom Palmer Eye Institute, University of
Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136, USA
Full list of author information is available at the end of the article
Theotoka et al. Eye and Vision (2019) 6:18
https://doi.org/10.1186/s40662-019-0142-5

literature reporting HPV detection in 44 to 92% of con-
junctival papillomas [2,15,18–21].
There is currently no good evidence to support ultra-
violet (UV) light, smoking, and immunodeficiency as po-
tential risk factors. A study that took place in Iran
showed that papillomas occurred more commonly in the
group with sun-exposure < 180 days/year [12]. In regard
to human immunodeficiency virus (HIV), while studies
have found it to be a risk factor for ocular surface squa-
mous neoplasia (OSSN) [22–24], this has not been
shown for papilloma. The only weak suggestion in the
literature has been a case of an aggressive papilloma as-
sociated with HPV type 33 thought to have enhanced
growth by immunodeficiency in an HIV-positive individ-
ual [25]. Lastly, although an increased risk of develop-
ment of genital papillomas has been associated with
tobacco use [26], studies have not yet examined the rela-
tionship between smoking and conjunctival papilloma.
HPV association
HPV is a double-stranded circular DNA virus of the
papillomavirus family with epithelial tropism that
bears oncogenic potential [27]. HPV is classified in
five genera, alpha (α)-, beta (β)-, gamma (γ)-, mu (μ)-
and nu (ν)- papilloma virus (PV), of which α-PV is
typically identified in genital lesions whereas (β)-, (γ)-,
(μ)- and (ν)-PV are predominantly isolated in skin le-
sions [28]. To date, more than 150 HPV types have
been identified and classified as low or high risk ac-
cording to their epidemiological association with cer-
vical cancer [28,29].
HPV types 6 and 11 are most frequently identified in
conjunctival papillomas [2,3,15,16,18,19,21,30,31]
with a reported frequency ranging from 44.4 to 75.4%
and 4.71 to 28% from all lesions, respectively [15,20,
31]. Types 5b, 13, 16, 20, 23, 33, and 45 have also
been detected [25,31–33]. Additionally, co-infection
with different papilloma virus types has been reported
as in one study an individual had HPV types 6/11
and 16 identified in the conjunctival papilloma [30].
Low-risk HPV types 6 and 11 are mostly identified in
children and adults with conjunctival papillomas [15],
while high-risk HPV types 16 and 18 are mostly
found in adults with OSSN [34,35]. This seems to be
in agreement with the fact that the majority of con-
dyloma acuminata are associated with low-risk HPV
types while high-risk types are mainly associated with
uterine cervical intraepithelial neoplasia and cervical
cancer [29]. The mode of ocular HPV transmission is
thought to vary from vertical transmission from the
mother to the infant during delivery to inoculation
through ocular contact with contaminated surfaces or
hands [30,36,37]. Coexistent presence or history of
condyloma acuminata, cutaneous and conjunctival
papillomas have been reported, implying that HPV in-
fection can simultaneously appear at multiple sites [3,
13,38,39].ThepresenceofHPVhasindeedbeen
detected on the fingers of patients (37.5% of females,
n= 3; 69% of males, n= 9) with genital warts [40],
however the association between conjunctival and
genital/anal papillomas is not clear. In a study of 17
women with HPV-related cervical dysplasia, DNA of
HPV 16 was detected in both limbal and cervical
swabs by polymerase chain reaction (PCR) in 35% of
the patients [6], although no conjunctival papillomas
were present [41]. Another study reported that coex-
istent genital warts and conjunctival papillomas was
seen in 4% of patients (3 out of 73) [3].
Multiple groups have confirmed the presence of HPV in
squamous cell papilloma with the use of hybrid capture
and PCR assays [16]. As mentioned above, HPV has been
detected in 44 to 92% of conjunctival papillomas [2,15,
18–21]. Two of these studies identified HPV in 92 and
81% of 52 and 165 specimens, respectively [15,30].
The role of HPV in benign and malignant lesions of
the conjunctiva is not completely clear as normal con-
junctiva had been found to harbor HPV. As above, while
one study did not find HPV in normal conjunctivae
(n= 20) [15], two others did [41,42]. One detected HPV
types 16/18 in 32% of normal specimens (n=19) [42],
and the other identified HPV type 16 in 76.5% of pa-
tients with normal ocular surface (n=17) [41]. There-
fore, HPV may contribute to the development of
papilloma lesions but can also be found in normal
appearing tissue.
Development of the HPV vaccine and its use in
immunization programs are intended to reduce the
prevalence of HPV colonization [43]. In the United
States, there are 3 prophylactic HPV vaccines available:
the bivalent vaccine targets HPV 16 and 18; the quadri-
valent targets HPV 6, 11, 16, and 18; and the 9-valent
targets HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 [44].
Prior to the availability of the vaccine, the prevalence of
HPV 6, 11, 16, and 18 was 11.5 and 18.5% in females
aged 14–19 (n= 1363) and 20–24 (n= 432) years, re-
spectively [45]. Six years after vaccine availability, preva-
lence decreased by 64 and 34% in the above mentioned
age groups. The same study showed that within the vac-
cine era, the prevalence of HPV among vaccinated ver-
sus unvaccinated females aged 14–24 years was 2.1%
versus 16.9%, respectively. While the effect on conjunc-
tival papilloma is unknown, vaccination to include tar-
gets of HPV 6 and 11 may decrease the incidence of
conjunctival papilloma in the future [46,47].
Clinical findings of conjunctival papillomas
Patients can manifest with a broad range of symptoms
depending on the size and location of the tumor [3,48].
Theotoka et al. Eye and Vision (2019) 6:18 Page 2 of 17

Smaller lesions are usually asymptomatic while larger le-
sions may cause foreign body sensation and dryness due
to inadequate eyelid closure and chronic mucus produc-
tion. In addition, patients may present with conjunctival
hemorrhages and/or cosmetic disturbance [3,49]. Visual
impairment can occur with extensive papillomas and, in
children, amblyopia can develop if the visual axis is
blocked [50]. Conjunctival papillomas can rarely cause
complete obstruction of the canalicular and nasolacrimal
duct and invade the nasolacrimal sac, with resultant
epiphora, bloody tears, and epistaxis [51–53].
Morphologically, conjunctival papillomas can have an
exophytic (sessile or pedunculated), mixed, or inverted
growth pattern. They are usually characterized by nu-
merous fronds or finger-like projections of epithelium
which surrounds a core of highly vascular connective tis-
sue (Fig. 1a and b). The underlying vessels are often seen
as multiple “hair pin”vascular loops [54].
Papillomas can present unilaterally or bilaterally, and
can be solitary or multi-focal (Fig. 1a) [55]. Lesions in
children are often larger than those of adults and are
more likely to be multi-focal. These multi-focal lesions
can coalesce to form a massive papilloma [3]. In adults,
papillomas generally present as solitary, pedunculated
tumors, with an abnormal “hair pin”blood vessel pattern
[49,56]. An important way to differentiate papilloma
from OSSN is to lift the edge of the papilloma to look
for a pedicle, whose presence is almost pathognomonic
for papilloma. On the other hand, OSSN is more likely
to be part of the conjunctival epithelium, without the
ability to lift the edge of the lesion. However, overlap in
features can occur. Conjunctival papilloma can be pig-
mented in darker skinned individuals [57].
In terms of location, some groups have identified the
caruncle as the most commonly affected site in adults
(24 to 43% of lesions) [3,10,48], while others have re-
ported the bulbar (42 to 52%) [5,13] and tarsal conjunc-
tivae (38%) [2] as the most common locations. In
children and adolescents, the most common locations
are the inferior fornix (27%) [3] and the caruncle (33%)
[9]. Overall, papillomas tend to localize on the nasal and
inferior portions of the conjunctiva [2,10] perhaps ex-
plained by autoinoculation of HPV by eye rubbing and
collection of the virus medially and inferiorly due to the
natural tear flow [2,9].
Clinicopathological correlation
The exophytic pattern can be sessile or pedunculated,
and is usually covered by multi-layered, non-keratinized
squamous epithelial cells and a varying number of goblet
and acute inflammatory cells [55]. Exophytic lesions oc-
curring over the limbus tend to be sessile and to have an
acanthotic squamous epithelium.
Inverted or endophytic papillomas are made of invagi-
nated lobules of proliferating, non-keratinized squamous
epithelial cells which contain goblet cells and grow to-
wards the substantia propria of the conjunctiva [55].
The inverted growth pattern, which is quite rare with
only a few references in the literature, carries a greater
risk for malignant transformation [58]. The different
types of papilloma configuration have been identified to
co-exist in the same eye [59].
In one study, histological differences were noted by
HPV status. HPV-positive papillomas were mainly
composed of basaloid cells with intraepithelial goblet
cells, had extra-limbal location, and did not exhibit
elastosis [31]. On the other hand, HPV-negative papil-
lomas usually did not have goblet cells, exhibited a
perilimbal location, and were associated with elastosis
and epithelial keratinization. This suggests that HPV
may have a specific mechanism of pathogenicity, and
that in HPV-negative lesions, other factors such as
UV radiation could be precipitating agents. It was hy-
pothesized that perilimbal lesions were more exposed
to UV radiation compared to non-limbic areas [31],
and solar elastosis was a common finding with UV
damage [60]. Naturally, exceptions to these general
findings exist and more studies are needed. Further-
more, although koilocytosis (squamous epithelial cells
in which the hyperchromatic nucleus is displaced by
Fig. 1 Extensive tarsal conjunctival papilloma. a. Slit lamp photograph of a 50-year-old white male with a confluent papillomatous lesion seen
with eyelid eversion. b. Classic vascular fronds or finger-like projections are easily visualized under the transparent epithelium
Theotoka et al. Eye and Vision (2019) 6:18 Page 3 of 17

a large perinuclear vacuole) [61] is an important mor-
phologic finding of HPV infections of the uterine cer-
vix [62]; different authors have shown that it is not a
useful finding for HPV detection in conjunctival tis-
sue as its presence can range from 3 to 40% [2,3].
Benign papillomas may occasionally contain areas of
dysplasia which are characterized by the presence of cy-
tologic atypia, epithelial thickening, lack of goblet cells,
and mitotic figures extending beyond the basal layer
[54]. On examination, inflammation, keratinization, sym-
blepharon formation, and palpebral conjunctival involve-
ment may be seen in individuals with histologic evidence
of dysplasia [63]. In addition, sessile rather than pedun-
culated papillomas are more likely to contain foci of dys-
plasia [56]. Nevertheless, carcinoma rarely develops
from dysplastic conjunctival papilloma [2,64].
Differential diagnosis of conjunctival papilloma
Multiple conditions can resemble conjunctival papillo-
mas to some degree, including benign lesions of the sur-
face epithelium (e.g., benign epithelial hyperplasia,
epithelial inclusion cyst, keratoacanthoma, and oncocy-
toma), vascular lesions (e.g., pyogenic granuloma), ma-
lignant lesions (e.g., OSSN, sebaceous cell and
mucoepidermoid carcinoma, conjunctival lymphomas,
and amelanotic melanomas), secondary tumors, and
other ocular diseases (e.g., phlyctenular keratoconjuncti-
vitis, and internal hordeolum or chalazion) [49].
Diagnosis
Patients should be asked about history of ocular surgery
and trauma, malignancy, immunodeficiency, presence of
genital warts and risk factors for sexually transmitted
diseases, genital HPV, vaccination status, immunosup-
pression, and UV light exposure. In pediatric patients,
maternal HPV exposure should be elicited.
Clinical examination aids in tumor categorization and
should include eyelid eversion. Lesion characteristics
such as basal dimension and thickness, configuration
(exophytic, inverted, or mixed), intrinsic vascularity,
feeder vessels, presence of pigment, and tumor location
should be noted [3]. Baseline and follow-up slit lamp
photographic documentation is also helpful and recom-
mended [3,49].
Tumor palpation is performed during the slit lamp
examination using a cotton-tip applicator under topical
anesthesia. Most papillomas should be freely mobile over
the sclera with the body of the papilloma forming a
mushroom shape over a pedicle attached to the conjunc-
tiva. On the other hand, an epithelial lesion that has in-
vaded the underlying connective tissue will feel fastened
to the globe [65] and should suggest OSSN, or a sub-
epithelial process such as lymphoma and reactive lymph-
oid hyperplasia. Diffuse and poorly defined lesions
should also raise concern for a malignant process such
as sebaceous carcinoma (pagetoid spread).
Biopsy for conjunctival papilloma is controversial. On
one hand, histopathological analysis showing the previ-
ously described characteristics is the gold standard for
diagnosis. On the other hand, there is concern that cut-
ting in the area of the lesion can disseminate the virus
and lead to new lesions [48,49]. As such, excisional bi-
opsy is favored over incisional biopsy. Similarly, nonin-
vasive in vivo diagnostic techniques can help in the
management of ocular surface lesions, traditionally in-
cluding impression cytology as well as relatively newer
modalities such as anterior segment high resolution op-
tical coherence tomography (HR-OCT) and ultrasound
biomicroscopy (UBM) [66].
Impression cytology, a long-standing diagnostic
technique first described for conjunctival use in the
‘70s [67], is the non-invasive removal of ocular sur-
face epithelium by adherence to collection devices
(cellulose acetate filter paper or biopore membrane)
followed by staining with periodic acid-Schiff,
hematoxylin-eosin, and/or Papanicolaou, and cytologic
analysis [68]. The main advantages are the relatively
easy collection of epithelial samples in an outpatient
setting, usual good tolerability by patients, preserva-
tion of limbal stem cells that can be affected with
surgical methods, and the ability to identify histo-
pathological abnormalities such as dysplasia. However,
some disadvantages have made impression cytology
fall out of favor. Not all pathology laboratories
process these samples due to the need for an experi-
enced cytologist. Additionally, the superficial samples
do not allow for assessment of invasion or margin
involvement.
Impression cytology has yielded positive results in 77
to 97% of biopsy-proven OSSN [69–71]. However, the
literature is scarce for its use in the diagnosis of con-
junctival papilloma. In one study, the value of impres-
sion cytology was compared to tissue histology in the
diagnosis of ocular surface neoplasia. Unfortunately, only
one out of the 4 histologically confirmed papillomas was
positive by cytology [71]. No other studies have reported
the diagnostic applicability of this diagnostic technique
in conjunctival papilloma and, therefore, no conclusions
can be reached at this point.
As anterior segment imaging evolved with improved
image quality, easier operation, and expanded applica-
tions, non-invasive imaging diagnosis and surveillance
havebecomearealityandincreasinglyvaluableinthe
management of ocular surface tumors. While no im-
aging technique is perfect, these tools can aid in the
diagnosis and management of conditions such as
OSSN, precluding the need for excisional or incisional
biopsies [72].
Theotoka et al. Eye and Vision (2019) 6:18 Page 4 of 17

Rapid, non-contact OCT image acquisition does not
require a highly skilled operator, and images can be
interpreted by experienced as well as novice clinicians
[73]. The distinctive features of conjunctival papilloma
on HR-OCT have not been previously described. We
have found that HR-OCT findings of conjunctival
papilloma include a thickened hyperreflective epithe-
lium with or without an abrupt transition to normal
epithelium (hyporeflective) and usually displaying a
dome-shaped or lobulated configuration in cases of
exophytic growth pattern (Fig. 2a-d). The highly vas-
cularized core may also be visualized on HR-OCT
(Fig. 3a and b). However, no pathognomonic findings
have been identified and studies with larger sample
sizes that compare conjunctival papillomas to other
ocular surface lesions are needed to determine what
other key findings may be gleaned by HR-OCT.
Therapeutically, HR-OCT helps confirm tumor regres-
sion by allowing for direct tumor measurement on the
scans and comparison of serial pictures. After successful
medical therapy or surgical intervention, HR-OCT find-
ings can confirm the normalization of the epithelium
(Fig. 3a-d). By detecting subtle lesions not seen on clin-
ical examination, premature termination of treatment
may be avoided.
The limitations of HR-OCT include optical shadowing
of deeper structures that can occur with large papillo-
mas. In addition, lesions in the fornix and/or caruncle
can be difficult to image [74,75]. While morphological
and internal reflectivity changes can be identified with
HR-OCT, the resolution cannot yet identify cellular
changes of atypia at this time.
UBM is able to penetrate opaque ocular surface le-
sions, assess presence of invasion, and visualize the pos-
terior border of the tumor at the expense of axial
resolution (20 to 50 μm) [76]. As opposed to HR-OCT,
UBM requires direct contact with the eye. Additionally,
a skilled technician or provider is required to perform
the image acquisition and interpretation.
UBM has proven to be helpful in assessing tumor
depth and invasion in other ocular surface tumors
[77–79], but its utility is limited in noninvasive dis-
ease. Furthermore, no studies exist on its specific use
for conjunctival papilloma. At this time, UBM re-
mains an additional diagnostic tool to rule out other
conditions that may be part of the differential diagno-
sis of conjunctival papilloma.
Treatment
In the early twentieth century, wide surgical excision
of conjunctival papilloma with cauterization of re-
sidual conjunctiva was historically recommended as
the best treatment approach [80]. Although excision
with cryotherapy is still the most preferred treatment
by some [3,49,81], postsurgical recurrence is com-
mon and can often be dramatically worse than the
original lesion [82]. Due to the risks of recurrence
and spreading, management of conjunctival papilloma
has evolved to include non-surgical treatment
modalities in an effort to provide less invasive, more
Fig. 2 Conjunctival papilloma on high resolution optical coherence tomography (HR-OCT). a. Slit lamp photograph of a 51-year-old white male
with a sessile tarsal conjunctival papilloma. Direction and location of the HR-OCT scan (black dotted arrow). b. HR-OCT shows a well-defined
dome-shaped elevation of hyperreflective epithelium. c. Slit lamp photograph of a caruncular papilloma in a 66-year-old white male. Direction
and location of the HR-OCT scan (black dotted arrow). d. An elevated, lobulated, and thickened hyperreflective epithelium is seen on HR-OCT
Theotoka et al. Eye and Vision (2019) 6:18 Page 5 of 17

effective and sustained therapies. The advent of top-
ical chemotherapy and immunotherapy has expanded
treatment options for conjunctival papilloma, provid-
ing not only the possibility of primary non-invasive
treatment, but also combined adjuvant treatment
along with surgery.
Once the diagnosis and extent of the conjunctival pap-
illoma have been established, there are many factors to
consider before deciding on the best treatment modality.
The choice of therapy for each individual patient de-
pends on age, systemic comorbidities, location, exten-
sion and aggressiveness of the papilloma, ability to
comply with medications and/or undergo surgery, and
financial constraints.
Considering that slow spontaneous regression can
occur in a number of cases, observation and reassurance
are reasonable and in fact indicated for small asymptom-
atic conjunctival lesions [49,83]. Recurrences can occur
after surgical intervention and manipulation of tissue
may seed uninvolved areas [49].
A trial of topical steroids can be considered when an
inflammatory process (e.g., pyogenic granuloma) is sus-
pected. However, clinical examination and ancillary im-
aging can typically differentiate the two entities.
Conjunctival papilloma generally does not show tumor
regression with corticosteroids.
Serial slit lamp photographs should be obtained to
monitor for growth or changes in patients, with a
frequency of examination between 3 to 6 months de-
pending on the level of concern and progression [49].
Medical treatment options
Interferon alpha-2b
Interferon (IFN) is an endogenous immunomodulatory
glycoprotein released by various immune cells with anti-
viral, antimicrobial and antineoplastic functions [84]. Its
anti-oncogenic mechanism of action includes increased
immunogenicity by enhancement of dendritic and T-cell
function as well as a direct effect on tumor cells through
induction of cancerous cell apoptosis [85]. Used in a re-
combinant form, administration of topical IFN alpha-2b
(IFN α-2b) also leads to anti-proliferative and anti-
angiogenic effects. IFN has successfully been adminis-
tered for the treatment of other HPV-related diseases,
such as genital papilloma, cervical intraepithelial neopla-
sia, and OSSN [86,87]. Furthermore, it can be beneficial
in highly vascularized carcinomas, although these mech-
anisms of action are not well understood [88]. Addition-
ally, the therapeutic effects of IFN have also been
attributed to its antiviral properties [84].
Interferon can also be administered subcutaneously for
a systemic effect, topically or intralesionally. In terms of
systemic use, IFN use for the treatment of conjunctival
papilloma was first reported by Lass et al. in 1987 [89].
In this study, interferon alpha-N1 (IFN α-N1) was used
intramuscularly as a post-surgical adjuvant treatment in
Fig. 3 Resolution of conjunctival papilloma on high resolution optical coherence tomography (HR-OCT) with topical interferon (IFN)
treatment. a. Slit lamp photograph of a 54-year-old white male with a highly vascularized sessile bulbar conjunctival papilloma and a
corresponding feeder vessel. Direction and location of the HR-OCT scan (black dotted arrow). b. Elevated hyperreflective epithelial layer
without abrupt transition to normal epithelium is seen in this papilloma. Hyporeflective lines within the lesion likely represent shadowing
from the vessels. c. Slit lamp photograph showing complete regression of the lesion after 5 months of topical IFN (1 MIU/ml 4 times
daily). Of note, the feeder vessel significantly decreased in caliber as well. Direction and location of the HR-OCT scan (black dotted
arrow). d. The thickened hyperreflective epithelial mass is resolved on HR-OCT after treatment with IFN. Normal hyporeflective epithelium
is indicated with arrowheads
Theotoka et al. Eye and Vision (2019) 6:18 Page 6 of 17

5 patients with multiple recurrent conjunctival papillo-
mas. Intramuscular injections of IFN α-N1 5 million
international units/m
2
(MIU/m
2
) were administrated
daily for 1 month and then 2 or 3 times weekly for an-
other 5 months. Although initially suppressive, recur-
rence was seen in 3 out of 5 patients upon IFN taper or
discontinuation. de Keizer reported using systemic IFN
administered subcutaneously 3 times weekly (5 × 10
6
U)
for 6 months for conjunctival papilloma, leading to the
shrinkage but not resolution of recurrent conjunctival
papillomas in a 38-year old woman [64]. On the other
hand, another report of systemic IFN given subcutane-
ously 3 times weekly for 6 months in a 5-year-old with a
2-year history of HPV 11 PCR-positive conjunctival pap-
illoma reported lesion resolution [90]. In this case, a cu-
taneous wart appeared 6 months later on the forearm,
which was positive for HPV type 27 and was treated suc-
cessfully with excision and cryotherapy. No additional
papilloma recurrences were encountered during the 2-
year follow-up period.
Interferon can also be administered directly to the
ocular surface, topically or intralesionally, and the choice
depends on the location and size of the papilloma [64,
65,91,92]. In 2002, Schechter at al. first described the
successful use of topical IFN α-2b as primary therapy on
one HPV-positive and one HPV-negative conjunctival
papilloma [92]. IFN α-2b 1 MIU/ml drops were adminis-
tered 4 times daily until clinical resolution was achieved,
which occurred after 3 months and 6 weeks, respectively,
with no recurrence seen after 40 and 18 months of
follow-up.
Falco et al. presented another case that responded to
primary treatment with topical IFN α-2b (1 MIU/ml 4
times daily) leading to tumor regression in just 2 weeks
[65]. Lastly, topical IFN led to resolution in a case of a
recalcitrant papilloma with a 4-year history of 12 recur-
rences (treated with surgical excision, cryotherapy, 5-
fluorouracil, systemic IFN-αand CO
2
laser). However, a
new lesion appeared 22 months after the initial regres-
sion with IFN and was treated with repeat topical IFN,
leading this time to a tumor- free period of 7 years [64].
We also favor the use of topical IFN as primary
treatment (either alone or followed by surgery if ne-
cessary) with a dosage of 1 MIU/ml 4 times daily
(Fig. 4aandb).
Topical therapy can be considered for all lesions, but
larger tumors may need surgical excision after chemo-
debulking. Tumors in a location where prolonged con-
tact with topical medications is difficult (e.g., eyelid mar-
gin) generally do not respond as well to topical therapy
[91]. Poor compliance and cost concerns also need to be
considered. In such cases, as well as in cases of extensive
or recurrent papillomas or those that are poorly respon-
sive to topical treatment, intralesional IFN injections can
be tried.
In comparison with IFN drops, injections have the ad-
vantage of assured compliance. In terms of efficacy, suc-
cessful primary treatment with intralesional IFN α-2b
alone has not been reported [93] (with the exception of
pegylated IFN α-2b described below). Instead, a combin-
ational approach for recurrent and resistant papillomas
has been reported in many studies [53,91,94,95]. For
example, topical IFN eye drops used in combination
with subconjunctival and intralesional IFN (0.3 ml of 6
MIU/ml concentration) resulted in tumor regression of
a case in 2 weeks; however, the lesion recurred 6 weeks
later with treatment cessation [95]. In this case, add-
itional intralesional IFN injections and topical IFN led to
tumor regression by the 6-week follow-up. Successful
treatment with topical and intralesional injections for re-
current papillomas of the nasolacrimal system has also
been documented [53]. Lastly, treatment with IFN drops
in a 7-year-old child with 4 papillomas led to regression
of a large nasal bulbar conjunctival lesion, but not of
those tumors remaining in the lateral canthus and eye-
lids. Intralesional IFN injections of these non-
Fig. 4 Recurrent multifocal conjunctival papilloma treated with concomitant topical interferon (IFN) and cimetidine. a. Sessile (black arrowheads)
and pedunculated caruncular (white arrow) papillomas seen on the ocular surface of a 51-year-old white male. Note the spontaneous
intralesional hemorrhages in the palpebral lesion. The patient had a history of conjunctival papilloma on the same eye treated with topical IFN 6
years earlier, as well as venereal warts. b. After 6 months of topical IFN 1 MIU/ml 4 times daily and 1month of oral cimetidine 800 mg 3 times
daily, the lesion resolved with only follicles remaining (dashed white arrow)
Theotoka et al. Eye and Vision (2019) 6:18 Page 7 of 17

responding tumors led to complete resolution of 2 out
of 3 lesions [91].
Pegylated interferon (PegIFN) α-2b is more potent
than IFN α-2b in vitro, while safety and tolerance
profiles are similar [96,97]. Additionally, pegylation
of therapeutic proteins is a well-established method
for delaying clearance, leading to reduced dosing.
PegIFN α-2b injections have been described when all
other methods (including 12 surgeries and adjunct
treatments) failed in a 23-year-old woman with a con-
firmed HPV 6 associated conjunctival papilloma [98].
Weekly injections of pegIFN α-2b directly into the
papilloma resulted in resolution after 2 months, with
no recurrence or adverse effects after 2 years without
treatment. The downside of PegIFN is its higher cost
compared to IFN [99].
It is not clear why some lesions respond to IFN and
others do not. Many factors may play a role including
tumor size, location, duration, HPV status, immune sta-
tus, medication concentration, and frequency of medica-
tion administration [90,91].
In terms of side effects, along with flu-like symptoms
and myalgias, patients treated systemically may experi-
ence gastrointestinal disturbances (e.g., nausea and
vomiting), neutropenia and thrombocytopenia [84]. Fur-
thermore, systemic IFN can cause retinopathy, particu-
larly in patients with vasculopathic disease such as
diabetes [100]. Systemic IFN is generally not used in the
treatment of conjunctival papilloma given the possibility
of local administration with less side effects.
Topical IFN eyedrops are generally gentle on the
ocular surface and well tolerated, except for mild con-
junctival hyperemia, follicular conjunctivitis, and occa-
sional superficial keratitis [64,65,91,101]. This
makes topical IFN attractive in the pediatric popula-
tion and those with any ocular surface issues. Unfor-
tunately, in the United States, the cost is high, at
approximately $600 dollars per month, although it
may be much less in other countries. In addition, the
drops are used off label, and a compounding phar-
macy is required to prepare the formulations [102].
Additional issues to consider include the need for
continuous treatment, compliance, and requirement
for refrigeration.
Intralesional injections are also well tolerated but do
have more significant side effects than topical eyedrops.
These include flu-like symptoms such as myalgias and
fever seen in a third of the patients [103], which can be
ameliorated by administering an oral anti-pyretic (e.g.,
1000 mg of oral acetaminophen) at the time of injection
and every six hours thereafter. Injections however have
the advantage of being commercially available as powder
or injection ready solution and no compounding is ne-
cessary [102].
Mitomycin C
Mitomycin C (MMC) is an alkylating agent derived from
the actinobacterium Streptomyces caespitosus that ex-
erts its anti-neoplastic effect by cross-linking DNA
[104]. It has been used successfully in OSSN [86]. There
is a paucity of data in its use for benign squamous
papillomas.
The first report of topical MMC treatment for squa-
mous papilloma was in a patient with diffuse tumor re-
currence after 4 surgical excisions with cryotherapy
[105]. It was used as an adjunct to excision. Seven days
after the fifth excision, a course of MMC 0.02% drops (4
times daily for 2 weeks) was prescribed with the
intention to prevent tumor recurrence. No recurrence
was noted during a follow-up period of 24 months. Fur-
thermore, MMC has also been used as a primary treat-
ment. In one case, 4 cycles of topical MMC 0.04% (4
times daily; cycles of one week on and one week off ) led
to complete tumor resolution, and was successfully used
as an alternative in an immunocompromised patient
who did not respond to topical IFN therapy, possibly
due to concurrent tacrolimus use [93]. However, treat-
ment failure with primary topical MMC 0.04% (4 times
daily, three 1-week cycles) has also been reported [106].
MMC has a higher frequency of side effects compared
with IFN, the most common being ocular discomfort
and pain and conjunctival hyperemia [107]. Limbal stem
cell deficiency has been reported in 12 to 24% of OSSN
patients treated with MMC, particularly with longer
treatment course [108]. Other complications include re-
current corneal erosions and keratopathy, corneal per-
foration, secondary glaucoma and cataract [107] as well
as epiphora due to punctal stenosis in up to 14% of cases
[109]. Hence, we favor the use of punctal plugs during
treatment.
Given this side effect profile, topical MMC is generally
considered in cases where IFN has failed or is cost-
prohibitive. The cost of MMC is approximately $300
dollars per bottle in the United States and similar to
IFN, MMC also needs refrigeration and compounding at
a pharmacy and is administered in an off-label manner
[102]. It has also been used intraoperatively as an ad-
junct to surgery, as described below.
5-Fluorouracil
5-Fluorouracil (5-FU) is a pyrimidine analog that blocks
DNA and RNA synthesis by inhibiting thymidylate syn-
thase [110]. To our knowledge, there has only been one
article in the literature reporting the use of 5-FU as pri-
mary and adjuvant treatment of recurrent conjunctival
papilloma. They describe a 35-year old woman and a 75-
year old man [64]. In the first case, topical 5-FU 1% (4
times daily; the authors did not specify duration) was
used after the tenth recurrence of previously benign
Theotoka et al. Eye and Vision (2019) 6:18 Page 8 of 17

papillomas with new signs of dysplasia and carcinoma
in situ (CIS). However, no improvement was noted,
and treatment was discontinued due to several side
effects such as corneal and conjunctival erosions. In
the second case, post-excisional recurrence of benign
papilloma was treated with topical 5-FU 1% 4 times
daily. Ectropion and corneal erosion were noted after
4 weeks of treatment and did not resolve despite 5-
FU taper. The tumor was then excised and adjuvant
3-month topical treatment with 5-FU 1% combined
with retinoid ointment (to prevent corneal side ef-
fects) was resumed. Once more, recurrence occurred
3months later.
We have used cyclical 5-FU 1% (1 week on, 3 weeks
off) in a patient with recurrent papillomas 2 years after
resolution with topical IFN treatment. After 6 cycles of
5-FU, the tumors resolved (Fig. 5a and b). However, after
11 months, the papilloma recurred.
5-FU has relatively more side effects than IFN but is
generally well tolerated. It can sometimes cause ocular
pain, conjunctival hyperemia, eyelid edema, superficial
keratitis, filamentary keratitis and may rarely cause
superficial stromal melting [86,111,112]. These symp-
toms are typically manageable with topical preservative-
free tears, a short course of prednisolone, and petroleum
jelly on the eyelids. However, in contrast to IFN, it is
very affordable (approximately $35 per cycle in the
United States) and although it does require compound-
ing, no refrigeration is needed [102].
Cimetidine
Cimetidine is an oral histamine H
2
receptor antagon-
ist mainly used for the management of peptic ulcers.
However, at high doses, cimetidine demonstrates im-
munomodulatory effects evoked by inhibiting suppres-
sor T cell H
2
receptors and by augmenting delayed-
type hypersensitivity responses [113]. Cimetidine has
been used as an alternative and safe treatment in
pediatric patients with multiple recalcitrant cutaneous
wartsaswellasrecurrentrespiratorypapillomatosis
[114,115]. It is important to note that although three
uncontrolled studies showed successful treatment of
skin warts with cimetidine, three placebo-controlled,
double-blind trials did not validate this clinical effect.
A trend toward increased efficacy was seen in youn-
ger patients and with higher dosages [116].
In terms of conjunctival papilloma, cimetidine has
been prescribed as a primary treatment, but there is a
paucity of publications supporting its use with vari-
able and unpredictable response. One report de-
scribed dramatic tumor regression noted after 4
months of oral treatment (30 mg/kg/day) in an 11-
year old boy when previous therapeutic modalities
(excisional biopsy, cryotherapy and topical MMC
0.04%) did not lead to tumor resolution [106]. Of the
6 reported cases in another study, lesions in 2 chil-
dren did not change with cimetidine therapy, 3 le-
sions in adults had partial regression and 1 lesion in
an adult completely resolved [3]. We have used oral
cimetidine successfully (800 mg 3 times daily) alone
for tarsal conjunctival papilloma (Fig. 6aandb)and
in combination with topical IFN for extensive papillo-
mas (Fig. 4a and b). While we generally place all pa-
tients with conjunctival papillomas on oral cimetidine,
in our personal experience, only about a mere 10%
will respond.
Oral cimetidine has also been used in cases of
massive and recalcitrant conjunctival papillomas as
presurgical or post-surgical adjuvant therapy to re-
duce tumor excision burden [117]. Tumor regression
was noted after 4 months of oral treatment (30 mg/
kg/day) in a 9-year-old patient. Tumor reduction with
cimetidine decreased the need for extensive conjunc-
tival resection. This reduced the risk of post-operative
conjunctival scarring, symblepharon and ankyloble-
pharon, and limbal stem cell deficiency [117]. The
Fig. 5 Recurrent conjunctival papilloma treated with 5-fluorouracil (5-FU). a. A 78-year-old white female presented with a medially localized
recurrence of a previously biopsy-proven poorly defined papilloma covering the entire right upper tarsal conjunctiva and treated with topical
interferon 2 years earlier. Inlet: note the fine branching vascularization. b. After 4 cycles of 5-FU 1% (1 week on, 3 weeks off), the lesion significantly
improved with decreased papillomatous appearance. 2 additional cycles of 5-FU led to tumor resolution. Unfortunately, the lesion recurred
11 months later
Theotoka et al. Eye and Vision (2019) 6:18 Page 9 of 17

authors of both studies claim that no systemic or
local side effects were encountered [106,117].
Pattern scanning laser photocoagulation
Pattern scanning laser photocoagulation is a fully inte-
grated photocoagulation laser scan system that was pro-
posed for the treatment of conjunctival papilloma as an
alternative in low resource settings with limited operat-
ing room access [118].
Pattern scanning laser photocoagulation is typically
applied after topical anesthesia and toluidine blue 1% in-
stillation to stain areas of high mitotic activity, with
treatment administered to an area of 2 mm beyond the
tumor edges (20–100 ms, 600–1800 W, spot size
200 μm, 300–1400 shots depending on lesion size and
patient tolerability). Mild discomfort was noted by pa-
tients during the laser procedure which continued for
one to two days but did not require the use of analgesics.
No other side effects or complications were noted.
This therapeutic modality was used for primary treat-
ment of 7 eyes of 6 patients with conjunctival papillo-
mas, both pedunculated and sessile. Complete resolution
was noted in all 6 patients after an average of 2.3 ses-
sions (range 1 to 6, until resolution via slit lamp biomi-
croscopy). No recurrences were noted for all patients in
a follow-up period ranging from 12 to 15 months.
This technique may be more accessible and cost-
effective, however more studies are needed to establish
efficacy and cost effectiveness.
Photodynamic therapy
Photodynamic therapy is a minimally invasive treatment
which uses visible light to activate a photosensitizing
drug that can lead to tumor destruction through the ac-
tion of reactive oxygen species [119]. Photodynamic
therapy has been used for the treatment of squamous
cell carcinoma and vascular tumors [120,121] and it has
also been described by Kaliki et al. in the treatment of
one patient with conjunctival papilloma [3]. The authors
report complete regression of a caruncular papilloma
after a single photodynamic therapy session. No further
reports have been published to date.
Surgical treatment
Since its popularization by Shields et al., the “no-touch”
wide resection technique has been the traditional
method for surgical management of conjunctival lesions
with the potential to extend [122]. The procedure is usu-
ally performed under monitored anesthesia care with a
regional block. Conjunctival forceps and blunt scissors
are typically used for excision while care is taken not to
touch the tumor with the surgical instruments.
In conjunctival papilloma, surgical excision has been
associated with recurrences, which can result in papillo-
mas more severe than preoperatively due to seeding and
shedding of viral particles to the surrounding tissue [48,
82,117]. Identification of microscopic disease beyond
the clinically identified lesion is not easily appreciable
and thus incomplete excisional biopsy can occur [49].
Furthermore, subsequent surgeries can not only increase
the risk of additional recurrences but also lead to further
corneal and conjunctival cicatricial changes and even
limbal stem cell deficiency in large excisions.
Double freeze-thaw cryotherapy application to the sur-
rounding tissues is known to decrease postsurgical re-
currences seen with other ocular surface tumor
resections [123,124] and thus has potential benefit in
the treatment of papillomas, although recurrences have
been seen even after cryotherapy was added to surgical
excision of papilloma [64,82,125,126]. In-office cryo-
therapy can also be used on small lesions similar to the
treatment of warts elsewhere in the body.
We recommend a modified double-freeze thaw tech-
nique, including a first application of cryotherapy to the
entire tumor to kill papillomatous epithelial cells and
theoretically minimize viral seeding, followed by a
Fig. 6 Primary treatment of conjunctival papilloma with cimetidine. a. Sessile papilloma located on the tarsal conjunctiva of a 53-year-old white
male with history of soft contact lens use and giant papillary conjunctivitis. Note the “hair pin”vessel configuration. b. After 3 months of primary
treatment with only oral cimetidine (800 mg, 3 times daily), the tumor completely regressed. No recurrence was encountered with a follow up
of 16 months
Theotoka et al. Eye and Vision (2019) 6:18 Page 10 of 17

second application down to the tumor base for simultan-
eous excision. This second complete tumor cryotherapy
allows for traction on the lesion without forceps ma-
nipulation while excision is performed simultaneously in
its frozen state (Fig. 7a-f ) [49]. During removal, the base
is cauterized. Cryotherapy is also applied to all the con-
junctival margins [127].
After tumor removal, either conjunctival undermining
and primary closure, autograft from the fellow eye, am-
niotic membrane or even buccal mucosa transplantation
can be used for conjunctival defect coverage [49,128]. A
cultivated conjunctival cell transplant has also been used
successfully after removal of multiple conjunctival papil-
lomas in a 10-year old child. According to the authors,
this technique allows for earlier epithelization when
compared with the traditional use of amniotic mem-
branes, leading to faster healing and decreased incidence
of scar formation [129]. However, our preferred method
of closure is with cryopreserved human amniotic mem-
brane transplant (AMT), which facilitates rapid epitheli-
alization, spares the remaining conjunctiva and limbal
stem cells [130], and is widely available without the need
for pre-surgical processing (as with cultivated cell trans-
plants). Fornix deepening sutures and symblepharon
rings should be considered in procedures on forniceal
and tarsal conjunctiva to prevent fornix shortening
[131]. As described below, we favor an injection of 3
MIU/0.5 cc of IFN α-2b at the end of the surgery.
We consider surgery in individuals with large or pe-
dunculated lesions that are symptomatic and in children
Fig. 7 Surgical excision, cryotherapy, and interferon (IFN) α-2b injection for treatment of plical and multiple bulbar conjunctival papillomas. a,b.A
6-year-old black male presented with multiple papillomatous lesions affecting the caruncle/plica (a) and bulbar conjunctiva (a, b) in the left eye
since age 1. Due to the patient’s age and inability of the mother to instill topical IFN, a decision was made to treat surgically. c. Complete
cryotherapy was first applied to the papilloma with the intention to minimize viral spreading during subsequent manipulation. d. Then, a second
cycle of cryotherapy of the entire tumor down to its base was performed. While in frozen state, lifting of the frozen tumor-probe complex
allowed for tumor excision with a ‘no touch’technique and 2 mm margins without the need for forceps. This was followed by cautery and
cryotherapy at the borders of the excised conjunctiva and Tenon’s bed, as well as IFN α-2b injection (3 MIU/0.5 ml). An amniotic membrane was
sutured to close the remaining conjunctival defect. e, f. At one month after surgery, the excision sites were healing well with no visualized
papillomas. The amniotic membrane was secure with interrupted vicryl sutures on the tarsal conjunctiva
Theotoka et al. Eye and Vision (2019) 6:18 Page 11 of 17

where amblyopia is a concern [49]. Ultimately, a person-
alized approach must be taken when deciding between
medical management and surgical intervention.
Adjuvant medical therapy
MMC has also been administered intraoperatively as an
adjuvant agent after surgical excision. Its use intraopera-
tively for the treatment of conjunctival papilloma was
first reported in 1996 [82]. A 5-year-old African Ameri-
can girl experienced recurrent bulbar and palpebral con-
junctival papillomas after multiple treatments including
cryotherapy, 3 excisions plus cryotherapy, 3 excisions
with intraoperative IFN injection and postoperative top-
ical IFN (4 times daily for 2 weeks). Recurrence was
noted after each operation with papillomas growing fas-
ter and larger. She was successfully managed with a sev-
enth surgical excision and intraoperative application of
MMC (0.3 mg/ml for 3 min), which resulted in a
disease-free interval of at least 24 months, with develop-
ment of a small symblepharon as a complication.
Since then, studies have found intraoperative MMC to
be effective even in very extensive lesions [50,132]. Sur-
gical excision with cryotherapy and intraoperative MMC
successfully eradicated a diffuse papilloma of the bulbar
conjunctiva with mild nuclear atypia encroaching the
cornea and a pedunculated papilloma of the caruncle
with mild dysplasia [132]. No recurrences were noted
for a follow-up period of 10 and 3 years, respectively.
Surgical excision with intraoperative MMC were also ef-
fective in a child with extensive lesions on the bulbar
and tarsal conjunctiva covering most of the palpebral
fissure [50]. No complications were reported, and no re-
currence was seen for 10 months after surgery.
MMC is applied at concentrations of 0.2 or 0.3 mg/ml
via a cellulose sponge, which is held in the area of exci-
sion for 2 to 3 min followed by copious irrigation with
normal saline [50,82,132]. Although severe complica-
tions have been reported with the use of intraoperative
MMC such as corneal and scleral perforation and en-
dophthalmitis secondary to scleral melting [133,134],
others reported no major side effects when used for the
treatment of conjunctival papilloma or other ocular sur-
face lesions [50,82,132,135]. Potential complications
may be decreased by avoiding application of MMC dir-
ectly on the scleral bed [136]. We favor the use a flat
piece of plastic (which can be obtained from the dispos-
able packaging of multiple surgical instruments) cut to
size of the exposed bare sclera and placed as a platform
under the MMC sponges to avoid their direct contact
with sclera. This allows treatment of the conjunctival
edges with a barrier between the MMC and the sclera.
Topical and/or intraoperative adjuvant immuno- and
chemo-therapeutic agents such as IFN α-2b or MMC
are administrated in addition to excision in an attempt
to reduce the risk of recurrences, especially in resistant
and aggressive papillomas. As above, if surgery is
needed, our recommended surgical approach consists of
a combination of a ‘no-touch’surgical technique with
adjunctive double freeze-thaw cryotherapy and intrale-
sional IFN α-2b (3 MIU/0.5 ml) at the time of surgery.
However, there are no randomized control trials com-
paring the effectiveness of surgical resection with and
without adjuvant therapies, and treatment recommenda-
tions are mostly based on small or anecdotal reports. A
recent publication showed that excisional biopsy, cryo-
therapy, intralesional IFN and post-operative topical IFN
for 3 months was successful in eradicating recurrent,
multifocal papillomas in a 2-year old child who did not
respond to primary topical IFN drops [137]. No recur-
rence was noted for 14 months. Other authors also favor
a triple approach with complete tumor excision, cryo-
therapy, and adjunctive oral cimetidine (300–400 mg 3
times daily) and/or topical IFN α-2b for 3 months after
surgery [3]. In spite of the combined treatment approach
undertaken, recurrences can unfortunately still occur [3,
98,138].
Dinitrochlorobenzene
Dinitrochlorobenzene (DNCB) is a chemical first identi-
fied in the study of glutathione-S-transferases and found
to cause a type IV hypersensitivity reaction [139]. Its
protocol for conjunctival papilloma treatment involves a
single topical application of DNCB on the forearm in
order to sensitize the body [140]. After application,
sensitization is confirmed by the development of a
prominent flare at the test site. DNCB can then be ap-
plied directly to the conjunctival papilloma, both topic-
ally and intralesionally on multiple occasions.
DNCB immunotherapy has been used for the treat-
ment of conjunctival papilloma with mixed results. In
1981, DNCB immunotherapy (topical and subconjuncti-
val injections) was first reported to be successful in a 24-
year old man who suffered from a benign papilloma re-
current with atypia and resistant to electrocautery, surgi-
cal excision and cryosurgery [126]. The patient
improved after 7 applications of DNCB over 8 weeks
(50% reduction of the papilloma’s original mass). He was
however lost to follow-up and then reappeared with a le-
sion increased in size. He underwent 6 more DNCB
treatments and remained tumor free for a period of 10
months. Similar results were reported 2 years later when
DNCB was used as an adjuvant treatment after surgical
excision of recurrent papillomas in a 4-year old boy
[125]. No recurrence was noted for 8 months. However,
the third case report showed no lesion resolution with
topical application of DNCB for the treatment of recur-
rent papillomas (increasing concentrations from 0.1 to
2%) [140]. With respect to side effects, corneal scarring
Theotoka et al. Eye and Vision (2019) 6:18 Page 12 of 17

and superficial peripheral vascularity have been noted
[125]. The role of DNCB in the treatment of conjunc-
tival papilloma remains, therefore, inconclusive.
Anti-vascular endothelial growth factor (anti-VEGF)
Bevacizumab is a humanized monoclonal antibody
against vascular endothelial growth factor (VEGF) activ-
ity that inhibits angiogenesis [141].
Its use as an adjuvant off-label therapy for recurrent
conjunctival papilloma has recently been reported [142].
A 29-year-old patient with a history of 3 papilloma re-
currences after surgical excision received a single dose
of subconjunctival bevacizumab (0.2 ml, 25 mg/ml) in-
traoperatively after repeat excisional biopsy. No recur-
rence was noted after 37 months of follow-up. There are
no other reports on the use of bevacizumab for the
treatment of conjunctival papilloma in the literature.
In terms of side effects, the study above reported none.
In addition, no local or systemic side effects were en-
countered with the use of anti-VEGF agents for the
treatment of OSSN [143,144]. However, the cost of
anti-VEGF injections can limit its use [102]. Although
potentially effective and safe, larger studies on the role
of anti-VEGF in the management of conjunctival papil-
loma are needed.
Carbon dioxide (CO
2
) laser therapy
First used by otolaryngologists for tracheal and laryngeal
papillomas, this approach consists of the use of infrared
CO
2
laser that generates temperatures of around 750 de-
grees Fahrenheit. The thermal damage not only precisely
disrupts the surrounding 100 μm of tissue but is also
thought to decrease the chances of viral seeding by in-
activating HPV and sealing the lymphatic vessels [145,
146]. This treatment can provide a bloodless field of
treatment, with minimal induced damage and scarring,
which makes it well tolerated by patients [147].
The CO
2
laser therapy was used in the 1980s concur-
rently with surgical excision for treatment of highly ag-
gressive and recurrent conjunctival papillomas not
responding to prior rounds of surgical excision, cryo-
therapy, chemotherapy, and immunotherapy [145–148].
In 75 cases of recurrent conjunctival papillomas that
were vaporized with the CO
2
laser and followed up for
over 2 years, 2 recurrences were observed. Compara-
tively, the reported recurrence frequency with surgical
excision alone was 20% [146].
Follow-up
During the medical treatment period, patients should be
followed every 1 to 2 months to assess treatment re-
sponse and identify possible adverse events. Patients
treated surgically are usually seen 1 day, 1 week, 1
month, and every couple of months after surgery. Upon
resolution, follow-up every 3 months during the first
year, every 6 months during the second year, and yearly
thereafter is generally indicated to rule out recurrence.
Recurrence frequencies after all treatments range from
3 to 27% [2,3,5,48]. These rates are higher in the
pediatric and adolescent population compared to adults
[3]. In a study of 22 patients, a higher recurrence rate
was seen with surgical excision alone (50%, 4 out of 8)
when compared with surgical excision and adjuvant
therapy (cryotherapy, CO
2
laser or MMC) (7.1%, 1 out
of 14) [48]. In another study of 73 patients, recurrence
for excisional biopsy and cryotherapy was lower and
noted in only 1 of the 61 patients treated [3]. These
studies are very small to draw conclusions.
Other factors associated with higher recurrence in-
clude bulbar conjunctival location and corneal involve-
ment [48]. No association between HPV 16 and 18, the
high-risk types, and lesion recurrence after surgical exci-
sion have been noted [149]. Histopathologically, recur-
rent papillomas were found to exhibit moderate to
severe epithelial dysplasia and higher mitotic activity (in-
dicated by positive staining for Ki67 and p53) when
compared with non-recurrent papillomas [149,150].
For OSSN, it has been shown that the presence of
microscopic disease at the lesion border may increase
the risk of recurrence [123,151]. This may also apply to
papilloma; however, it has not been shown.
Conclusions
Conjunctival papilloma is a benign epithelial tumor of
the conjunctiva that can occur at any age in pediatric
and adult patients. HR-OCT is a non-invasive diagnostic
tool that can help identify lesions without the need for
biopsy and assess treatment response. Papillomas can be
managed medically, surgically, or with a combined ap-
proach depending on patient and tumor factors. Obser-
vation is also an option for small and asymptomatic
tumors. Medical management is generally preferred
given the theoretical lower risk of viral seeding. When
used before surgery, medical therapy can debulk the le-
sion and minimize tissue excision. For papillomas that
require surgical excision, a ‘no-touch’technique along
with cryotherapy and intraoperative MMC or IFN injec-
tion should be considered to reduce the risk of recur-
rences. Close surveillance is necessary to ensure timely
detection and treatment of recurrences.
Despite the benign nature of the tumor, treatment can
be challenging with the occurrence of medical treatment
failures and recurrences after medical and surgical inter-
ventions. There is a paucity of published data with the
use of topical chemotherapies as primary interventions,
and overall from our experience as well as from the lit-
erature review, it seems that lesions with a higher degree
of dysplasia tend to respond better to topical chemo-
Theotoka et al. Eye and Vision (2019) 6:18 Page 13 of 17

and immunotherapy. Lesions with no signs of dysplasia
seem to be more recalcitrant and resistant to topical
treatment. We hypothesize that this occurs due to a
higher cell turnover in lesions with more dysplastic fea-
tures, making them more susceptible to topical chemo-
and immunotherapy.
Given that conjunctival papilloma is relatively rare, the
majority of data is from reports and series, and no head-
to-head comparisons between treatment approaches are
yet available for this challenging condition. Hopefully
the future will bring effective, new therapeutic options
for patients with this condition.
Abbreviations
5-FU: 5-fluorouracil; CIS: carcinoma in situ; CO2: carbon dioxide;
DNCB: dinitrochlorobenzene; H2: histamine 2; HIV: human immunodeficiency
virus; HPV: human papilloma virus; HR-OCT: high resolution optical
coherence tomography; IFN: interferon; mm: millimeter; MMC: mitomycin C;
ms: milliseconds; OSSN: ocular surface squamous neoplasia; PCR: polymerase
chain reaction; Peg: pegylated; PV: papilloma virus; UBM: ultrasound
biomicroscopy; UV: ultraviolet
Acknowledgements
Not applicable.
Authors’contributions
DT, MIM, AG, CLK were major contributors in writing the manuscript. DT and
MIM contributed equally to this work. All authors read and approved the
final manuscript.
Funding
NIH Center Core Grant P30EY014801, RPB Unrestricted Award and Career
Development Awards, Department of Defense (DOD- Grant#W81XWH-09-1-
0675), The Dr. Ronald and Alicia Lepke Grant, The Lee and Claire Hager
Grant, The Jimmy and Gaye Bryan Grant, The H. Scott Huizenga Grant, The
Grant and Diana Stanton-Thornbrough, The Robert Baer Family Grant, The
Emilyn Page and Mark Feldberg Grant, The Jose Ferreira de Melo Grant, Rich-
ard and Kathy Lesser Grant, and the Richard Azar Family Grant (institutional
grants).
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors have no financial conflict to disclose.
Author details
1
Department of Ophthalmology, Bascom Palmer Eye Institute, University of
Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136, USA.
2
Miami Veterans Administration Medical Center, 1201 NW 16th Street, Miami
33125, FL, USA.
Received: 16 March 2019 Accepted: 24 May 2019
References
1. Ophthalmological Society. Lancet. 1883;122(3147):1090–3.
2. Sjö N, Heegaard S, Prause JU. Conjunctival papilloma. A histopathologically
based retrospective study. Acta Ophthalmol Scand 2000;78(6):663–6.
3. Kaliki S, Arepalli S, Shields CL, Klein K, Sun H, Hysenj E, et al. Conjunctival
papilloma: features and outcomes based on age at initial examination.
JAMA Ophthalmol. 2013;131(5):585–93.
4. Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643
melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology.
2004;111(9):1747–54.
5. ASH JE. Epibulbar tumors. Am J Ophthalmol. 1950;33(8):1203–19.
6. Asadi-Amoli F, Ghanadan A. Survey of 274 patients with conjunctival
neoplastic lesions in Farabi Eye Hospital, Tehran 2006-2012. J Curr
Ophthalmol. 2015;27(1–2):37–40.
7. Elsas FJ, Green WR. Epilbubar tumors in childhood. Am J Ophthalmol. 1975;
79(6):1001–7.
8. Cunha RP, Cunha MC, Shields JA. Epibulbar tumors in children: a survey of
282 biopsies. J Pediatr Ophthalmol Strabismus. 1987;24(5):249–54.
9. Shields CL, Sioufi K, Alset AE, Boal NS, Casey MG, Knapp AN, et al. Clinical
features differentiating benign from malignant conjunctival tumors in
children. JAMA Ophthalmol. 2017;135(3):215–24.
10. Shields CL, Alset AE, Boal NS, Casey MG, Knapp AN, Sugarman JA, et al.
Conjunctival tumors in 5002 cases. Comparative analysis of benign versus
malignant counterparts. The 2016 James D. Allen lecture. Am J Ophthalmol.
2017;173:106–33.
11. Reddy SC, Sarma CS, Rao VV, Banerjea S. Tumour and cysts of conjunctiva-a
study of 175 cases. Indian J Ophthalmol. 1983;31(5):658–60.
12. Amoli FA, Heidari AB. Survey of 447 patients with conjunctival neoplastic
lesions in Farabi eye hospital, Tehran, Iran. Ophthalmic Epidemiol. 2006;
13(4):275–9.
13. Furdová A, Stopková A, Kapitánová K, Kobzová D, Babál P. Conjuctival
lesions-the relationship of papillomas and squamous cell carcinoma to HPV
infection. Cesk Slov Oftalmol. 2018;74(3):92–7.
14. Grossniklaus EH, Green RW, Luckenbach CM, Chan CC. Conjunctival lesions
in adults: a clinical and histopathologic review. Cornea. 1987;6(2):78–116.
15. Sjö NC, von Buchwald C, Cassonnet P, Norrild B, Prause JU, Vinding T, et al.
Human papillomavirus in normal conjunctival tissue and in conjunctival
papilloma: types and frequencies in a large series. Br J Ophthalmol. 2007;
91(8):1014–5.
16. Takamura Y, Kubo E, Tsuzuki S, Akagi Y. Detection of human papillomavirus
in pterygium and conjunctival papilloma by hybrid capture II and PCR
assays. Eye (Lond). 2008;22(11):1442–5.
17. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al.
Prevalence of HPV infection among females in the United States. JAMA.
2007;297(8):813–9.
18. McDonnell PJ, McDonnell JM, Kessis T, Green WR, Shah KV. Detection
of human papillomavirus type 6/11 DNA in conjunctival papillomas by
in situ hybridization with radioactive probes. Hum Pathol. 1987;18(11):
1115–9.
19. Saegusa M, Takano Y, Hashimura M, Okayasu I, Shiga J. HPV type 16 in
conjunctival and junctional papilloma, dysplasia, and squamous cell
carcinoma. 1995;48(12):1106–10.
20. Nakamura Y, Mashima Y, Kameyama K, Mukai M, Oguchi Y. Detection of
human papillomavirus infection in squamous tumours of the
conjunctiva and lacrimal sac by immunohistochemistry, in situ
hybridisation, and polymerase chain reaction. Br J Ophthalmol. 1997;
81(4):308–13.
21. Eng HL, Lin TM, Chen SY, Wu SM, Chen WJ. Failure to detect human
papillomavirus DNA in malignant epithelial neoplasms of conjunctiva by
polymerase chain reaction. Am J Clin Pathol. 2002;117(3):429–36.
22. Ateenyi-Agaba C. Conjunctival squamous-cell carcinoma associated with
HIV infection in Kampala, Uganda. Lancet. 1995;345(8951):695–6.
23. Waddell KM, Lewallen S, Lucas SB, Atenyi-Agaba C, Herrington CS, Liomba
G. Carcinoma of the conjunctiva and HIV infection in Uganda and Malawi.
Br J Ophthalmol. 1996;80(6):503–8.
24. Karp CL, Scott IU, Chang TS, Pflugfelder SC. Conjunctival intraepithelial
neoplasia: a possible marker for human immunodeficiency virus infection?
Arch Ophthalmol. 1996;114(3):257–61.
25. Buggage RR, Smith JA, Shen D, Chan CC. Conjunctival papillomas caused by
human papillomavirus type 33. Arch Ophthalmol. 2002;120(2):202–4.
26. Schabath MB, Villa LL, Lazcano-Ponce E, Salmerón J, Quiterio M, Giuliano AR.
Smoking and human papillomavirus (HPV) infection in the HPV in men
(HIM) study. Cancer Epidemiol Biomark Prev. 2012;21(1):102–10.
27. zur Hausen H. Papillomavirus infections - a major cause of human cancers.
Biochim Biophys Acta. 1996;1288(2):F55–78.
28. Bernard HU, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villiers EM.
Classification of papillomaviruses (PVs) based on 189 PV types and proposal
of taxonomic amendments. Virology. 2010;401(1):70–9.
Theotoka et al. Eye and Vision (2019) 6:18 Page 14 of 17

29. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, et al. The
biology and life-cycle of human papillomaviruses. Vaccine. 2012;
30(Suppl 5):F55–70.
30. Sjö NC, Heegaard S, Prause JU, von Buchwald C, Lindeberg H. Human
papillomavirus in conjunctival papilloma. Br J Ophthalmol. 2001;85(7):785–7.
31. Mlakar J, Kocjan BJ, Hošnjak L, Pižem J, Beltram M, Gale N, et al.
Morphological characteristics of conjunctival squamous papillomas in
relation to human papillomavirus infection. Br J Ophthalmol. 2015;99(3):
431–6.
32. Benevides dos Santos PJ, Borborema dos Santos CM, Rufino Mendonça R,
Vieira do Carmo MA, Astofi-Filho S. Human papillomavirus type 13 infecting
the conjunctiva. Diagn Microbiol Infect Dis. 2005;53(1):71–3.
33. Assadoullina A, de Villiers EM, Bialasiewicz AA, Richard G. Detection of
human papillomavirus types in tumors and inflammations of the eye. Klin
Monatsbl Augenheilkd. 1999;215(1):10–8.
34. Scott IU, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18 expression in
conjunctival intraepithelial neoplasia. Ophthalmology. 2002;109(3):542–7.
35. Moyer AB, Roberts J, Olsen RJ, Chévez-Barrios P. Human papillomavirus–
driven squamous lesions: high-risk genotype found in conjunctival
papillomas, dysplasia, and carcinoma. Am J Dermatopathol. 2018;40(7):
486–90.
36. Egbert JE, Kersten RC. Female genital tract papillomavirus in conjunctival
papillomas of infancy. Am J Ophthalmol. 1997;123(4):551–2.
37. Naghashfar Z, McDonnell PJ, McDonnell JM, Green WR, Shah KV. Genital
tract papillomavirus type 6 in recurrent conjunctival papilloma. Arch
Ophthalmol. 1986;104(12):1814–5.
38. Minchiotti S, Masucci L, Serapiao Dos Santos M, Perrella E, Graffeo R,
Lambiase A, et al. Conjunctival papilloma and human papillomavirus:
identification of HPV types by PCR. Eur J Ophthalmol. 2006;16(3):473–7.
39. Fierlbeck G, Rassner G, Thiel HJ, Pfister H. Virus-induced papilloma of the
conjunctiva. Detection of HPV 6a DNA. Z Hautkr. 1990;65(5):497–9.
40. Sonnex C, Strauss S, Gray JJ. Detection of human papillomavirus DNA
on the fingers of patients with genital warts. Sex Transm Infect. 1999;
75(5):317–9.
41. McDonnell JM, Wagner D, Ng ST, Bernstein G, Sun YY. Human
papillomavirus type 16 DNA in ocular and cervical swabs of women with
genital tract condylomata. Am J Ophthalmol. 1991;112(1):61–6.
42. Karcioglu ZA, Issa TM. Human papilloma virus in neoplastic and non-
neoplastic conditions of the external eye. Br J Ophthalmol. 1997;81(7):595–8.
43. Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, et al. A 9-
valent HPV vaccine against infection and intraepithelial neoplasia in women.
N Engl J Med. 2015;372(8):711–23.
44. Markowitz LE, Dunne EF, Saraiya M, Chesson HW, Curtis CR, Gee J, et al.
Human papillomavirus vaccination: recommendations of the advisory
committee on immunization practices (ACIP). MMWR Recomm Rep. 2014;
63(RR-05):1–30.
45. Markowitz LE, Liu G, Hariri S, Steinau M, Dunne EF, Unger ER. Prevalence of
HPV after introduction of the vaccination program in the United States.
Pediatrics. 2016;137(3):e20151968.
46. Hughes DS, Powell N, Fiander AN. Will vaccination against human
papillomavirus prevent eye disease? A review of the evidence. Br J
Ophthalmol. 2008;92(4):460–5.
47. Kalogeropoulos CD, Moschos MM. Advances in diagnosis and treatment of
HPV ocular surface infections. Med Hypothesis Discov Innov Ophthalmol.
2015;4(2):31–5.
48. Huang YM, Huang YY, Yang HY, Tsai CC, Yu WK, Kao SC, et al. Conjunctival
papilloma: clinical features, outcome, and factors related to recurrence.
Taiwan J Ophthalmol. 2018;8(1):15–8.
49. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv
Ophthalmol. 2004;49(1):3–24.
50. Dawodu OA, Okeigbemen V. A severe case of conjunctival papilloma in a
five year old female. J New Front Ophthalmol. 2016;2.
51. Migliori ME, Putterman AM. Recurrent conjunctival papilloma causing
nasolacrimal duct obstruction. Am J Ophthalmol. 1990;110(1):17–22.
52. Lauer SA. Recurrent conjunctival papilloma causing nasolacrimal duct
obstruction. Am J Ophthalmol. 1990;110(5):580–1.
53. Parulekar MV, Khooshabeh R, Graham CJ. Topical and intralesional
interferon therapy for recurrent lacrimal papilloma. Eye (Lond). 2002;
16(5):649–51.
54. Eagle RC. Eye pathology: an atlas and text. 2nd ed. Philadelphia: Wolters
Kluwer Health/Lippincott Williams & Wilkins; 2011.
55. Font R, Croxatto J, Rao N. AFIP atlas of tumor pathology, fourth series,
fascicle 5: tumors of the eye and ocular adnexa. Washington DC: ARP; 2006.
56. Rosa RH, Buggage R, Harocopos G, et al. Ophthalmic pathology and
intraocular tumors. San Francisco, CA: American Academy of
Ophthalmology; 2011. p. 61–2.
57. Kremer I, Sandbank J, Weinberger D, Rotem A, Shapiro A. Pigmented
epithelial tumours of the conjunctiva. Br J Ophthalmol. 1992;76(5):294–6.
58. Lassalle S, Maschi C, Caujolle JP, Giordanengo V, Hofman P. Inverted
conjunctival papilloma: a certainly underestimated high-risk lesion for
carcinomatous transformation-a case report. Can J Ophthalmol. 2017;
52(1):e30–1.
59. Kalantzis G, Papaconstantinou D, Georgalas I, Tsitlidou A, Georgopoulos G.
Different types of conjunctival papilloma presenting in the same eye. Orbit.
2010;29(5):266–8.
60. Kligman LH. Intensification of ultraviolet-induced dermal damage by
infrared radiation. Arch Dermatol Res. 1982;272(3–4):229–38.
61. Krawczyk E, Suprynowicz FA, Liu X, Dai Y, Hartmann DP, Hanover J, et al.
Koilocytosis: a cooperative interaction between the human papillomavirus
E5 and E6 oncoproteins. Am J Pathol. 2008;173(3):682–8.
62. Koss LG. Cytologic and histologic manifestations of human papillomavirus
infection of the uterine cervix. Cancer Detect Prev. 1990;14(4):461–4.
63. Mannis MJ. Epithelial tumors of the conjunctiva. In: Holland EJ, editor.
Cornea. Fourth edition. Edinburgh, Scotland: Elsevier; 2017. p. 410–26.
64. de Keizer RJ, de Wolff-Rouendaal D. Topical alpha-interferon in recurrent
conjunctival papilloma. Acta Ophthalmol. 2003;81(2):193–6.
65. Falco LA, Gruosso PJ, Skolnick K, Bejar L. Topical interferon alpha 2 beta
therapy in the management of conjunctival papilloma. Optometry. 2007;
78(4):162–6.
66. Karp CL. Evolving technologies for lid and ocular surface neoplasias: is
optical biopsy a reality? JAMA Ophthalmol. 2017;135(8):852–3.
67. Thatcher RW, Darougar S, Jones BR. Conjunctival impression cytology. Arch
Ophthalmol. 1977;95(4):678–81.
68. Barros Jde N, Almeida SR, Lowen MS, Cunha MC, Gomes JÁ. Impression
cytology in the evaluation of ocular surface tumors: review article. Arq Bras
Oftalmol. 2015;78(2):126–32.
69. Nolan GR, Hirst LW, Wright RG, Bancroft BJ. Application of impression
cytology to the diagnosis of conjunctival neoplasms. Diagn Cytopathol.
1994;11(3):246–9.
70. Tole DM, McKelvie PA, Daniell M. Reliability of impression cytology for the
diagnosis of ocular surface squamous neoplasia employing the Biopore
membrane. Br J Ophthalmol. 2001;85(2):154–8.
71. Tananuvat N, Lertprasertsuk N, Mahanupap P, Noppanakeepong P. Role of
impression cytology in diagnosis of ocular surface neoplasia. Cornea. 2008;
27(3):269–74.
72. Thomas BJ, Galor A, Nanji AA, El Sayyad F, Wang J, Dubovy SR, et al. Ultra
high-resolution anterior segment optical coherence tomography in the
diagnosis and management of ocular surface squamous neoplasia. Ocul
Surf. 2014;12(1):46–58.
73. Yim M, Galor A, Nanji A, Joag M, Palioura S, Feuer W, et al. Ability of novice
clinicians to interpret high-resolution optical coherence tomography for
ocular surface lesions. Can J Ophthalmol. 2018;53(2):150–4.
74. Shousha MA, Karp CL, Canto AP, Hodson K, Oellers P, Kao AA, et al.
Diagnosis of ocular surface lesions using ultra–high-resolution optical
coherence tomography. Ophthalmology. 2013;120(5):883–91.
75. Nanji AA, Sayyad FE, Galor A, Dubovy S, Karp CL. High-resolution optical
coherence tomography as an adjunctive tool in the diagnosis of corneal
and conjunctival pathology. Ocul Surf. 2015;13(3):226–35.
76. Ong SS, Vora GK, Gupta PK. Anterior segment imaging in ocular surface
squamous neoplasia. J Ophthalmol. 2016;2016:5435092.
77. Bianciotto C, Shields CL, Guzman JM, Romanelli-Gobbi M, Mazzuca D Jr,
Green WR, et al. Assessment of anterior segment tumors with ultrasound
biomicroscopy versus anterior segment optical coherence tomography in
200 cases. Ophthalmology. 2011;118(7):1297–302.
78. Finger PT, Tran HV, Turbin RE, Perry HD, Abramson DH, Chin K, et al.
High-frequency ultrasonographic evaluation of conjunctival
intraepithelial neoplasia and squamous cell carcinoma. Arch
Ophthalmol. 2003;121(2):168–72.
79. Char DH, Kundert G, Bove R, Crawford JB. 20 MHz high frequency
ultrasound assessment of scleral and intraocular conjunctival squamous cell
carcinoma. Br J Ophthalmol. 2002;86(6):632–5.
80. Duke-Elder SW. Text-book of ophthalmology. South Med J. 1941;34(1):103.
Theotoka et al. Eye and Vision (2019) 6:18 Page 15 of 17

81. Warner MA, Stagner AM, Jacobiec FA. Epithelial tumors of the conjunctiva.
In: Mannis MJ, Holland EJ, editors. Cornea. Fourth ed. Edinburgh: Elsevier;
2017. p.412.
82. Hawkins AS, Yu J, Hamming NA, Rubenstein JB. Treatment of recurrent
conjunctival papillomatosis with mitomycin C. Am J Ophthalmol. 1999;
128(5):638–40.
83. Bowling B. Ocular tumors. In: Bowling B, editor. Kanski's Clinical
Ophthalmology: A Systematic Approach. Eighth ed. London: Elsevier; 2016.
p. 468.
84. Baron S, Tyring SK, Fleischmann WR Jr, Coppenhaver DH, Niesel DW, Klimpel
GR, et al. The interferons. Mechanisms of action and clinical applications.
JAMA. 1991;266(10):1375–83.
85. Ferrantini M, Capone I, Belardelli F. Interferon-alpha and cancer:
mechanisms of action and new perspectives of clinical use. Biochimie. 2007;
89(6–7):884–93.
86. Venkateswaran N, Mercado C, Galor A, Karp CL. Comparison of topical 5-
fluorouracil and interferon alfa-2b as primary treatment modalities for ocular
surface squamous neoplasia. Am J Ophthalmol. 2019;199:216–22.
87. Handley JM, Horner T, Maw RD, Lawther H, Dinsmore WW. Subcutaneous
interferon alpha 2a combined with cryotherapy vs cryotherapy alone in the
treatment of primary anogenital warts: a randomised observer blind
placebo controlled study. Genitourin Med. 1991;67(4):297–302.
88. Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, et al.
Inhibition of basic fibroblast growth factor expression, angiogenesis, and
growth of human bladder carcinoma in mice by systemic interferon-α
administration. Cancer Res. 1998;58(4):808–14.
89. Lass JH, Foster CS, Grove AS, Rubenfeld M, Lusk RP, Jenson AB, et al.
Interferon-alpha therapy of recurrent conjunctival papillomas. Am J
Ophthalmol. 1987;103(3 Pt 1):294–301.
90. Okan G, Ayan I, Karslioğlu S, Altiok E, Yenmis G, Vural G. Conjunctival
papilloma caused by human papillomavirus type 11 treated with systemic
interferon in a five-year-old boy. Turk J Pediatr. 2010;52(1):97–100.
91. Kothari M, Mody K, Chatterjee D. Resolution of recurrent conjunctival
papilloma after topical and intralesional interferon alpha2b with partial
excision in a child. J AAPOS. 2009;13(5):523–5.
92. Schechter BA, Rand WJ, Velazquez GE, Williams WD, Starasoler L. Treatment
of conjunctival papillomata with topical interferon alfa-2b. Am J
Ophthalmol. 2002;134(2):268–70.
93. Ganapathy PS, Plesec T, Singh AD. Conjunctival squamous papilloma
refractory to interferon α-2b in a patient on systemic immunosuppression
(tacrolimus). Am J Ophthalmol Case Rep. 2017;6:1–3.
94. Rodríguez-Cabrera L, García-Regil P, Velasco-Levy A, Serna-Ojeda JC.
Conjunctival papillomatosis in children treated with co-adjuvant topical
interferon alpha-2b. Arch Soc Esp Oftalmol. 2018;(18):30307–1.
95. Morgenstern KE, Givan J, Wiley LA. Long-term administration of topical
interferon alfa-2βin the treatment of conjunctival squamous papilloma.
Arch Ophthalmol. 2003;121(7):1052–3.
96. Glue P, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, et al. A dose-
ranging study of pegylated interferon alfa-2b and ribavirin in chronic
hepatitis C. the hepatitis C intervention therapy group. Hepatology. 2000;
32(3):647–53.
97. Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al. A
randomized, double-blind trial comparing pegylated interferon alfa-2b to
interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology.
2001;34(2):395–403.
98. Tseng SH. Conjunctival papilloma. Ophthalmology. 2009;116(5):1013–1013.e1.
99. Karp CL, Galor A, Lee Y, Yoo SH. Pegylated interferon alpha 2b for treatment
of ocular surface squamous neoplasia: a pilot study. Ocul Immunol Inflamm.
2010;18(4):254–60.
100. Mimura O, Iwasaki Y, Shimo-Oku M, Kawara A. Ocular myasthenic syndrome
after interferon therapy for chronic hepatitis. Neuro-Ophthalmology. 1996;
16(3):197–202.
101. Schechter BA, Koreishi AF, Karp CL, Feuer W. Long-term follow-up of
conjunctival and corneal intraepithelial neoplasia treated with topical
interferon alfa-2b. Ophthalmology. 2008;115(8):1291–6.e1.
102. Sayed-Ahmed IO, Palioura S, Galor A, Karp CL. Diagnosis and medical
management of ocular surface squamous neoplasia. Expert Rev Ophthalmol.
2017;12(1):11–9.
103. Karp CL, Galor A, Chhabra S, Barnes SD, Alfonso EC. Subconjunctival/
perilesional recombinant interferon α2b for ocular surface squamous
neoplasia: a 10-year review. Ophthalmology. 2010;117(12):2241–6.
104. Verweij J, Pinedo HM. Mitomycin C: mechanism of action, usefulness and
limitations. Anticancer Drugs. 1990;1(1):5–13.
105. Yuen HK, Yeung EF, Chan NR, Chi SC, Lam DS. The use of postoperative
topical mitomycin C in the treatment of recurrent conjunctival papilloma.
Cornea. 2002;21(8):838–9.
106. Shields CL, Lally MR, Singh AD, Shields JA, Nowinski T. Oral cimetidine
(Tagamet) for recalcitrant, diffuse conjunctival papillomatosis. Am J
Ophthalmol. 1999;128(3):362–4.
107. Rubinfeld RS, Pfister RR, Stein RM, Foster CS, Martin NF, Stoleru S, et al.
Serious complications of topical mitomycin-C after pterygium surgery.
Ophthalmology. 1992;99(11):1647–54.
108. Russell HC, Chadha V, Lockington D, Kemp EG. Topical mitomycin C
chemotherapy in the management of ocular surface neoplasia: a 10-year
review of treatment outcomes and complications. Br J Ophthalmol. 2010;
94(10):1316–21.
109. Khong JJ, Muecke J. Complications of mitomycin C therapy in 100 eyes
with ocular surface neoplasia. Br J Ophthalmol. 2006;90(7):819–22.
110. Abraham LM, Selva D, Casson R, Leibovitch I. The clinical applications of
fluorouracil in ophthalmic practice. Drugs. 2007;67(2):237–55.
111. Rudkin AK, Dempster L, Muecke JS. Management of diffuse ocular surface
squamous neoplasia: efficacy and complications of topical chemotherapy.
Clin Exp Ophthalmol. 2015;43(1):20–5.
112. Rudkin AK, Muecke JS. Adjuvant 5-fluorouracil in the treatment of localised
ocular surface squamous neoplasia. Br J Ophthalmol. 2011;95(7):947–50.
113. Sahasrabudhe DM, McCune CS, O'Donnell RW, Henshaw EC. Inhibition of
suppressor T lymphocytes (Ts) by cimetidine. J Immunol. 1987;138(9):2760–3.
114. Das BB, Anton K, Soares N, Riojas S, McDermott J, Knox L, et al. Cimetidine:
a safe treatment option for cutaneous warts in pediatric heart transplant
recipients. Med Sci (Basel). 2018;6(2):pii: E30.
115. Harcourt JP, Worley G, Leighton SE. Cimetidine treatment for recurrent
respiratory papillomatosis. Int J Pediatr Otorhinolaryngol. 1999;51(2):109–13.
116. Rogers CJ, Gibney MD, Siegfried EC, Harrison BR, Glaser DA. Cimetidine
therapy for recalcitrant warts in adults: is it any better than placebo? J Am
Acad Dermatol. 1999;41(1):123–7.
117. Chang SW, Huang ZL. Oral cimetidine adjuvant therapy for recalcitrant,
diffuse conjunctival papillomatosis. Cornea. 2006;25(6):687–90.
118. Belfort Neto R, Isenberg J, Castillejos AG, Sant'ana R, Romano AO. Novel
treatment of papillomatous conjunctival lesions using pattern scanning
laser photocoagulation: 1-year results. Ocul Surf. 2018;16(3):337–40.
119. Henderson BW, Dougherty TJ. How does photodynamic therapy work?
Photochem Photobiol. 1992;55(1):145–57.
120. Sanchez CG, Caballero Chávez YV, Plazola S. Photodynamic therapy for
palpebral and conjunctival proliferative vascular tumors: clinical case report.
Orbit. 2009;28(6):420–1.
121. Barbazetto IA, Lee TC, Abramson DH. Treatment of conjunctival squamous
cell carcinoma with photodynamic therapy. Am J Ophthalmol. 2004;138(2):
183–9.
122. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival
tumors. The 1994 Lynn B. McMahan lecture. Arch Ophthalmol. 1997;115(6):
808–15.
123. Galor A, Karp CL, Oellers P, Kao AA, Abdelaziz A, Feuer W, et al. Predictors of
ocular surface squamous neoplasia recurrence after excisional surgery.
Ophthalmology. 2012;119(10):1974–81.
124. De Potter P, Shields CL, Shields JA, Menduke H. Clinical predictive factors for
development of recurrence and metastasis in conjunctival melanoma: a
review of 68 cases. Br J Ophthalmol. 1993;77(10):624–30.
125. Burns RP, Wankum G, Giangiacomo J, Anderson PC. Dinitrochlorobenzene
and debulking therapy of conjunctival papilloma. J Pediatr Ophthalmol
Strabismus. 1983;20(6):221–6.
126. Petrelli R, Cotlier E, Robins S, Stoessel K. Dinitrochlorobenzene
immunotherapy of recurrent squamous papilloma of the conjunctiva.
Ophthalmology. 1981;88(12):1221–5.
127. Tehrani S, Fraunfelder FW. Cryotherapy in ophthalmology. Open J
Ophthalmol. 2013;3(4):103–17.
128. Chen Z, Yan J, Yang H, Wu Z, Pang Y, Ai S, et al. Amniotic membrane
transplantation for conjunctival tumor. Yan Ke Xue Bao. 2003;19(3):165–7, 145.
129. Ang LP, Tan DT. Autologous cultivated conjunctival transplantation for
recurrent viral papillomata. Am J Ophthalmol. 2005;140(1):136–8.
130. Espana EM, Prabhasawat P, Grueterich M, Solomon A, Tseng SC. Amniotic
membrane transplantation for reconstruction after excision of large ocular
surface neoplasias. Br J Ophthalmol. 2002;86(6):640–5.
Theotoka et al. Eye and Vision (2019) 6:18 Page 16 of 17

131. Klefter ON, Rasmussen MLR, Toft PB, Heegaard S. Therapeutic options for
conjunctival neoplasia. Expert Rev Ophthalmol. 2018;13(1):17–31.
132. Kalogeropoulos C, Koumpoulis I, Papadiotis E, Zioga A, Gkrepi K, Pappa C, et
al. Squamous cell papilloma of the conjunctiva due to human
papillomavirus (HPV): presentation of two cases and review of literature. Clin
Ophthalmol. 2012;6:1553–61.
133. Oram O, Gross RL, Wilhelmus KR, Hoover JA. Necrotizing keratitis following
trabeculectomy with mitomycin. Arch Ophthalmol. 1995;113(1):19–20.
134. Dougherty PJ, Hardten DR, Lindstrom RL. Corneoscleral melt after
pterygium surgery using a single intraoperative application of mitomycin-C.
Cornea. 1996;15(5):537–40.
135. Khakshoor H, Razavi ME, Daneshvar R, Shakeri MT, Ghate MF,
Ghooshkhanehi H. Preoperative subpterygeal injection vs intraoperative
mitomycin C for pterygium removal: comparison of results and
complications. Am J Ophthalmol. 2010;150(2):193–8.
136. Sarici AM, Arvas S, Pazarli H. Combined excision, cryotherapy, and
intraoperative mitomycin C (EXCRIM) for localized intraepithelial and
squamous cell carcinoma of the conjunctiva. Graefes Arch Clin Exp
Ophthalmol. 2013;251(9):2201–4.
137. Singh M, Gautam N, Gupta A, Kaur M. Interferon alfa-2b in the management
of recurrent conjunctival papillomatosis. Indian J Ophthalmol. 2016;64(10):
778–80.
138. Muralidhar R, Sudan R, Bajaj MS, Sharma V. Topical interferon alpha-2b as an
adjunctive therapy in recurrent conjunctival papilloma. Int Ophthalmol.
2009;29(1):61–2.
139. Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases. The first
enzymatic step in mercapturic acid formation. J Biol Chem. 1974;249(22):
7130–9.
140. Novick NL, Bosniak SL. The failure of immunotherapy with
dinitrochlorobenzene and Rhus extract for recurrent conjunctival squamous
papillomas. J Dermatol Surg Oncol. 1986;12(6):602–5.
141. Braghiroli MI, Sabbaga J, Hoff PM. Bevacizumab: overview of the literature.
Expert Rev Anticancer Ther. 2012;12(5):567–80.
142. Lee CY, Chen HC, Meir YJ, Ma DH, Wu WC. Subconjunctival injection of
bevacizumab for recurrent conjunctival papilloma: a case report. Can J
Ophthalmol. 2017;52(5):e156–9.
143. Asena L, Dursun Altınörs D. Topical bevacizumab for the treatment of ocular
surface squamous neoplasia. J Ocul Pharmacol Ther. 2015;31(8):487–90.
144. Faramarzi A, Feizi S. Subconjunctival bevacizumab injection for ocular
surface squamous neoplasia. Cornea. 2013;32(7):998–1001.
145. Bosniak SL, Novick NL, Sachs ME. Treatment of recurrent squamous
papillomata of the conjunctiva by carbon dioxide laser vaporization.
Ophthalmology. 1986;93(8):1078–82.
146. Jean B, Thiel HJ, Stumper K. CO2 laser vaporization of papilloma of the
conjunctiva and eyelids. Fortschr Ophthalmol. 1989;86(6):672–5.
147. Schachat A, Iliff WJ, Kashima HK. Carbon dioxide laser therapy of recurrent
squamous papilloma of the conjunctiva. Ophthalmic Surg. 1982;13(11):916–8.
148. Jackson WB, Beraja R, Codère F. Laser therapy of conjunctival papillomas.
Can J Ophthalmol. 1987;22(1):45–7.
149. Yazu H, Dogru M, Miyauchi J, Tanaka Y, Yamaguchi T, Den S, et al.
Association of epithelial atypia with recurrence after surgical excision in
conjunctival papilloma. Eye Contact Lens. 2018;44(Suppl 1):S77–81.
150. Jakobiec FA, Mendoza PR, Colby KA. Clinicopathologic and
immunohistochemical studies of conjunctival large cell acanthoma,
epidermoid dysplasia, and squamous papilloma. Am J Ophthalmol. 2013;
156(4):830–46.
151. Tabin G, Levin S, Snibson G, Loughnan M, Taylor H. Late recurrences and
the necessity for long-term follow-up in corneal and conjunctival
intraepithelial neoplasia. Ophthalmology. 1997;104(3):485–92.
Theotoka et al. Eye and Vision (2019) 6:18 Page 17 of 17