Bilateral ocular surface squamous neoplasia: A study of 25 patients and review of literature

Abstract

Purpose:

To describe the risk factors, clinical presentation, management, and outcomes of patients with bilateral ocular surface squamous neoplasia (OSSN).

Methods:

Retrospective case series.

Results:

Of the 25 patients with bilateral OSSN, the mean age at diagnosis of OSSN was 31 years (median, 24 years; range, 2–60 years). Risk factors for bilateral OSSN included xeroderma pigmentosum (n = 15, 60%), human immunodeficiency virus infection (n = 3, 12%), conjunctival xerosis (n = 1, 4%), and topical steroid use (n = 1, 4%). There were no identifiable ocular or systemic risk factors in 7 (28%) patients. Presentation was synchronous in 14 (56%) and metachronous in 11 (44%) patients. Tumor morphology was bilaterally similar in 12 (48%) patients. Histopathological examination (n = 36) revealed conjunctival intraepithelial neoplasia (CIN) grade 1 in 4 (8%); grade 2 in 7 (14%); carcinoma in situ in 5 (10%), and invasive carcinoma in 20 (40%). Primary management of OSSN (n = 49) included excisional biopsy (n = 31, 62%), topical immunotherapy (IFN α2B) (n = 11; 22%), topical Mitomycin C (MMC) (n = 3, 6%), enucleation (n = 1, 2%), orbital exenteration (n = 2, 4%), and plaque brachytherapy (PBT) (n = 1, 2%). One patient was lost to follow-up after detection of tumor in the second eye. Recurrent tumors were noted in 16 (32%) eyes and binocular globe salvage was achieved in 16 (64%) patients at a mean follow up of 41 months (median 30 months; range, 1–164 months).

Conclusion:

OSSN occurrence can be synchronous or metachronous. Meticulous examination of the fellow eye is important for an early diagnosis of OSSN.

Keywords

Eye tumor ocular surface squamous neoplasia OSSN bilateral OSSN xeroderma pigmentosum human immunodeficiency virus

Introduction

Ocular surface squamous neoplasia (OSSN) is an umbrella terminology which refers to the spectrum of dysplastic and neoplastic changes in the squamous epithelium of the ocular surface.¹ Known risk factors for OSSN include systemic factors such as advancing age, male gender, smoking, xeroderma pigmentosum (XP), immune suppression from human immunodeficiency virus (HIV) infection, organ transplantation or ocular factors such exposure to UV light and human papilloma virus (HPV) infection.^2,3 Other reported factors include exposure to chemicals, heavy metals, and vitamin A deficiency.³ Despite the fact that all these factors are likely to affect both the eyes in common, bilateral OSSN (bOSSN) is rare for reasons unknown.

The incidence of bOSSN is as low as 0.3% to 4% in those with no known systemic or local risk factors to as high as 11% to 15% in immunocompromised patients and 44% in XP patients.^4–9 Isolated case reports on bOSSN demonstrate association with HIV, XP, HPV infection, hereditary factors, atopic conjunctivitis, chronic wood dust exposure, ocular cicatricial pemphigoid, neurodermatitis and epidermo-dysplasia verruciformis, and other systemic cancers (Table 1).^10–24 However, literature pertaining to clinical presentation and outcomes of bOSSN is sparse.^10–24 This retrospective series of 25 patients aims to determine the incidence and prevalence, describe the risk factors, clinical presentation, management, and outcomes of bOSSN.

Table 1.

Literature review of bilateral ocular surface squamous neoplasia.

Author	Age/sex	Ethnicity	Risk factors and systemic history	Syn/meta (interval, months)	Morphology	Histopathology	Management	Outcome	Follow up (months, from presentation)
Odrich et al.¹¹	42/F	Caucasian	HPV+	Syn	OD papillary	OD iSCC	OD exenteration	OD tumor free	9
	42/F	Caucasian	HPV+	Syn	OS placoid	OS CIS	OD exenteration	OS stable	9
	56/M	Caucasian	Facial rosacea	Syn	OU papillary	OU iSCC	OU excisional biopsy	OU persistent tumor	6
	56/M	Caucasian	HPV+	Syn	OU papillary	OU iSCC	OU excisional biopsy	OU persistent tumor	6
Tritten et al.¹²	46/M	Caucasian	Multiple cutaneous papillomata; HPV+	Syn	OU papillary	OU papilloma with CIN	OU excisional biopsy	OU tumor free	#
Usui et al.¹⁴	86/F	Caucasian	H/o mastectomy	Syn	OD diffuse	OU CIS	Topical MMC	OD recurrence	13
Usui et al.¹⁴	86/F	Caucasian	HPV+	Syn	OS nodular	OU CIS	Topical MMC	OS tumor free	13
Grueb et al.¹⁵	75/F	German	Wood dust exposure	Syn	#	OU iSCC	OU excisional biopsy	OU tumor free	20
Grueb et al.¹⁵	75/F	German	H/o prostate cancer	Syn	#	OU iSCC	OS tumor recurrence managed with excisional biopsy	OU tumor free	20
Gericke et al.¹⁶	41/#	German	Chronic atopic conjunctivitis	Syn	OU papillary	OS well differentiated iSCC	OU IFN α2B	OD tumor free	60
			Neuro-dermatitis				OS 2 recurrences managed with excision biopsy → third recurrence: MMC	OS persistent recurrent on treatment
			Smoker					OS persistent recurrent on treatment
	60/#	German	Ocular cicatricial pemphigoid	Syn	OU papillary	OU severe dysplasia	OU MMC	OU tumor free	6
			Neuro-dermatitis				OS excision biopsy
			Smoker
			HPV 16+
Masanganise et al.¹⁷	63/M	African	HIV+	Meta (24)	#	OU iSCC	OS enucleation	Died from extensive spread of tumor	36
	63/M	African	HIV+	Meta (24)	#	OU iSCC	OD exenteration	Died from extensive spread of tumor	36
	27/M	African	HIV+	Meta (18)	#	OU iSCC	OD enucleation	Died from extensive spread of tumor	24
	27/M	African	HIV+	Meta (18)	#	OU iSCC	OS exenteration	Died from extensive spread of tumor	24
	32/M	African	HIV+	Meta (12)	#	OU iSCC	OS enucleation	Died from extensive spread of tumor	18
	32/M	African	HIV+	Meta (12)	#	OU iSCC	OD exenteration	Died from extensive spread of tumor	18
	30/F	African	HIV+	Syn	#	OU iSCC	OD enucleation	OU free of tumor	24
	30/F	African	HIV+	Syn	#	OU iSCC	OS excision	OU free of tumor	24
Arora et al.¹⁸	17/M	Asian Indian	Epidermo-dysplasia verruciformis	Syn	OD nodular	OU mild dysplasia	OD MMC → excision biopsy → MMC	OU free of tumor	48
Arora et al.¹⁸	17/M	Asian Indian	Epidermo-dysplasia verruciformis	Syn	OS gelatinous	OU mild dysplasia	OS MMC	OU free of tumor	48
Kalamkar et al.¹⁹	12/M	Asian Indian	XP	Syn	OD diffuse	OS iSCC	OD MMC	OU persistent disease	4
Kalamkar et al.¹⁹	12/M	Asian Indian	OS nodular	Syn	OS debulking + MMC	OS iSCC	Eyelid melanoma	OU persistent disease	4
Agarwal et al.²⁰	9/M	Asian Indian	XP	Syn	OD gelatinous	OD poorly differentiated iSCC	OD exenteration	OU tumor free	7
Agarwal et al.²⁰	9/M	Asian Indian	XP	Syn	OS wide local excision	OD poorly differentiated iSCC	OS nodular	OU tumor free	7
Shah et al.²¹	73/M	Caucasian	Atopic conjunctivitis	Syn	OU papillary	OD iSCC	OD exenteration	OD tumor free	9
Shah et al.²¹	73/M	Caucasian	Atopic conjunctivitis	Syn	OU papillary	OS CIS	OS IFN α2B	OS recurrent tumor	9
Iovieno et al.²²	55/F	Caucasian	OD HPV 39+	Meta (12)	OS placoid	OD moderately differentiated iSCC	OD excision biopsy	OU tumor free	23
			OS HPV 16 and 31+			OS mild dysplasia	OS IFN α2B → MMC
			Cervical cancer: HPV 39+			OS mild dysplasia	OS IFN α2B → MMC
George et al.²³	45/F	Caucasian	HPV 16+	Meta (24)	OU papillary	OS CIS	OD IFN α2B	OS persistent tumor	24
George et al.²³	45/F	Caucasian	HPV 16+	Meta (24)	OU papillary	OS CIS	OS excision biopsy	OS persistent tumor	24
Belgadi et al.²⁴	80/M	African	Bilateral ear SCC with and metastasis	Syn	OU nodular	OU iSCC		OU persistent tumor	LFU
Present study (n = 25)	Age^c: 31 (24, 2–60)	Asian-Indian	XP: 15	Syn: 14	Nodular: 15	CIN grade 1: 4	MMC: 3^a + 2^b	OU tumor free: 20	41 (30, 1–30)^c
	Age^c: 31 (24, 2–60)		HIV: 3	Meta: 11	Nodulo-ulcerative: 2	CIN grade 2: 7	IFN: 11^a + 4^b	OU eye salvaged: 16
	M: 17		None: 7		Papillary: 7	CIS: 5	Excision: 31^a + 5^b	OU vision salvaged: 14
	F: 8				Placoid: 26	iSCC: 20	Enucleation: 1^a + 1^b	OD/OS persistent disease: 5
						No biopsy: 14	Exenteration: 2^a	LFU: 3
							PBT: 1^a + 1^b

Syn: synchronous; meta: metachronous; OD: oculus dexter; OS: oculus sinister; OU: oculus universus; CIN: conjunctival intraepithelial neoplasia; CIS: carcinoma in situ; iSCC: invasive squamous cell carcinoma; MMC: mitomycin C; IFN: interferon; HIV: human immunodeficiency virus; XP: xeroderma pigmentosum; HPV: human papilloma virus; PBT: plaque brachytherapy; EBRT: external beam radiotherapy; LFU: lost to follow up.

Primary management.

Secondary management.

Data expressed in mean (median, range).

Not mentioned.

Methods

This was a retrospective cross-sectional study conducted at the Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, India. Approval from Institutional Review Board was obtained and the study adhered with the tenets of Declaration of Helsinki. Electronic medical records of patients with OSSN from January 2016 to February 2020 were reviewed to identify patients of bOSSN during this period. Demographic parameters such as age, gender, history of smoking, occupation were reviewed along with a detailed history of symptoms, immune status, and other systemic illnesses. Clinical examination details and photographs of both eyes were scrutinized in all cases from the first presentation till the last follow up. Tumor details such as quadrantic location, extent of ocular surface involved, epicenter, dimensions, presence of surface keratin, pigmentation, intrinsic vascularity, feeder vessels, cystic spaces, and scleral fixity were noted in both the eyes. Other ancillary investigations such as anterior segment optical coherence tomography (AS-OCT), ultrasound biomicroscopy (UBM), computed tomography scans were assessed where appropriate. All patients underwent HIV screening.

Management of the ocular surface tumors including primary and adjuvant treatment modalities, histopathological diagnosis, and presence of residual tumor were noted. Topical and subconjunctival immunotherapy was administered in the form of IFN α2B as a sterile subconjunctival injection (5 MIU/ml) or sterile eye drops (1 MIU/ml). Topical chemotherapy was administered as MMC eye drops (0.04%) instilled 4 days a week for 4 weeks followed by 2 weeks off regimen. Shields’ “no-touch technique”²⁵ was adopted for surgical excision of tumors. Ruthenium-106 plaques were utilized for plaque brachytherapy, enucleation was performed by myoconjunctival technique²⁶ and eyelid-sparing exenteration²⁷ were performed for advanced tumors. Final outcomes including tumor recurrence, locoregional or systemic metastasis, or death were noted.

Results

Demographics and history

Of the 764 patients of OSSN treated at our center from 2016 to 2020, 25 patients had bOSSN. The prevalence and incidence of bOSSN from this study is 3% and 17 per 1000 cases of OSSN in 5 years respectively.

Mean age at diagnosis of first tumor was 31 years (median, 24 years; range, 2–60 years). Amongst them, 17 (68%) were males and 8 (32%) were females. Outdoor occupation was noted in 7 (28%) patients. Systemic risk factors were present in 18 (72%) patients including XP (n = 15; 60%) and HIV (n = 3; 12%). HIV infection was detected on routine testing in two patients (8%). History of smoking was noted in 2 (8%) patients. Two patients with XP had additional risk factors for OSSN in the form of conjunctival xerosis (n = 1, 4%) and chronic steroid use (n = 1, 4%). None of the patients had other ocular risk factors such as Bitot’s spots or ocular cicatricial pemphigoid, or atopic conjunctivitis (Table 2). Four patients with XP developed other cancers in the periocular region and face in the form of basal cell carcinoma (n = 2) and squamous cell carcinoma (n = 2). There was no significant family history in any patient.

Table 2.

Clinical features in patients with bilateral ocular surface squamous neoplasia.

Feature	All	Systemic risk factors present	No systemic risk factors	OU synchronous presentation	OU metachronous presentation
Feature	n = 50 eyes of 25 patients n (%)	n = 36 eyes of 18 patients n (%)	n = 14 eyes of seven patients n (%)	n = 28 eyes of 14 patients n (%)	n = 22 eyes of 11 patients n (%)
Demographics
Age^a (years)	31 (24, 2–60)	24 (23, 2–60)	47 (51, 20–60)	30 (23, 2–60)	32 (24, 13–60)
Gender					7 (63)
Male	17 (68)	12 (67)	5 (71)	10 (71)
Female	8 (32)	6 (33)	2 (29)	4 (29)	4 (37)
Risk factors
Outdoor occupation	7 (28)	4 (22)	3 (43)	4 (28)	3 (27)
Smoking	2 (8)	1 (6)	1 (14)	2 (14)	0 (0)
XP	15 (60)	15 (83)	0 (0)	8 (57)	7 (63)
HIV	3 (12)	3 (17)	0 (0)	1 (7)	2 (18)
Steroid use	1 (4)	1 (6)	0 (0)	1 (7)	0 (0)
Conjunctival xerosis	1 (4)	1 (6)	0 (0)	1 (7)	0 (0)
Clinical features
Morphology
Nodular	15 (30)	13 (36)	2 (14)	9 (32)	6 (27)
Papillary	7 (14)	3 (8)	4 (29)	3 (11)	4 (18)
Placoid	26 (52)	19 (53)	7 (50)	14 (50)	12 (55)
Noduloulcerative	2 (4)	1 (3)	1 (7)	2 (7)	0 (0)
Location
Nasal	17 (34)	13 (36)	4 (29)	7 (25)	10 (46)
Inferior	2 (4)	2 (6)	0	1 (4)	1 (4)
Temporal	23 (46)	16 (44)	7 (50)	16 (57)	7 (32)
Diffuse	6 (12)	3 (8)	3 (21)	4 (14)	2 (9)
Corneal	2 (4)	2 (6)	0 (0)	0 (0)	2 (9)
Disease extent
Largest diameter^a (mm)	8 (6, 1–15)	6 (5, 1–25)	11 (11, 5–20)	9 (6, 2–25)	6 (5, 1–14)
% Ocular surface involved^a	14 (10, 2–60)	10 (5, 2–60)	22 (18, 5–60)	16 (10, 2–60)	12 (10, 5–50)
Scleral involvement	4 (8)	3 (8)	1 (7)	4 (14)	0 (0)
Intraocular invasion	1 (2)	0 (0)	0 (0)	0 (0)	1 (4)
Orbital invasion	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Classification based on AJCC eighth edition
T
Tis	30 (60)	20 (56)	10 (71)	18 (64)	12 (54)
T1	7 (14)	7 (19)	0 (0)	3 (11)	4 (18)
T2	10 (20)	7 (19)	3 (22)	5 (18)	5 (23)
T3	3 (6)	2 (6)	1 (7)	2 (7)	1 (5)
T4	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
N
N0	50 (100)	36 (100)	14 (100)	28 (100)	22 (100)
N1	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
M
M0	50 (100)	36 (100)	14 (100)	28 (100)	22 (100)
M1	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)

OU: oculus universus; XP: xeroderma pigmentosum; HIV: human immunodeficiency virus; AJCC: American Joint Committee for Cancer.

Data expressed in mean (median, range).

Clinical features

Most common symptom was the presence of a mass in 33 (66%) eyes. Synchronous presentation of bOSSN was seen in 14 (56%) patients, while 11 (44%) had metachronous presentation (Figure 1). The second eye was affected after a mean interval of 34 months (median, 24 months; range, 4–108 months) since diagnosis of OSSN in the contralateral eye. Amongst patients with synchronous presentation, eight patients (57%) had XP and one patient was seropositive for HIV. Amongst patients with metachronous presentation, seven patients (63%) had XP and two patients (18%) had HIV. The tumor morphology between the two eyes of an individual was similar in 12 (48%) patients. Tumor morphology was placoid (n = 26; 52%), nodular (n = 15; 30%), papillary (n = 7; 14%), or nodulo-ulcerative (n = 2; 4%).

Limbus was the most common tumor epicenter (n = 37 eyes; 74%). With respect to quadrantic location, temporal location (n = 23; 46%) was the most common. A mean of 14% (median, 10%; range, 2%–60%) of ocular surface was involved by the tumor with a mean tumor diameter of 8 mm (median, 6 mm; range, 1–15 mm). Scleral involvement was seen in 4 (8%) eyes and intraocular tumor invasion was noted in 1 (2%) eye.

Management and outcomes

Primary management (n = 49) was excisional biopsy in 31 (62%), topical immunotherapy with IFN α2B in 11 (22%), topical MMC in 3 (6%), enucleation in 1 (2%) eye with intraocular extension of tumor, orbital exenteration in 2 (4%) eyes (one patient with noduloulcerative OSSN and diffuse involvement of ocular surface; one patient with diffuse ocular surface lesion with inferior forniceal and tarsal conjunctival involvement) and PBT in 1 (2%). One patient (2%) refused treatment and was lost to follow-up after detection of tumor in the second eye. Histopathological examination (n = 36) after primary intervention (n = 34) or secondary intervention (n = 2) revealed conjunctival intraepithelial neoplasia (CIN) grade 1 in 4 (8%), grade 2 in 7 (14%), carcinoma in situ in 5 (10%), and invasive carcinoma in 20 (40%).

Adjuvant treatment included topical IFN α2B (n = 2; 4%), and PBT (n = 6, 12%). Recurrent tumors were noted in 16 (32%) eyes including one eye in 8 (16%) and both eyes in 4 (8%). Recurrent tumors were managed with excisional biopsy (n = 8; 16%), IFN α2B (n = 1; 2%), MMC (n = 2; 4%), plaque brachytherapy (n = 3; 6%), and enucleation (n = 1; 2%). Multiple recurrences were noted in four eyes of three XP patients.

At a mean follow-up period of 41 months (median, 30 months; range, 1–164 months), of the 25 patients, 20 (80%) were tumor free bilaterally (36 eyes and 4 anophthalmic sockets). Five (20%) patients had persistent tumor in one eye, of which 2 (8%) were still on treatment and 3 (12%) refused treatment. Of these 25 patients with bilateral OSSN, globe salvage of at least one eye was achieved in 20 (80%) patients, binocular globe salvage in 16 (64%) patients, and binocular vision salvage was achieved in 14 (56%) patients.

Overall, of the 50 eyes with OSSN, 5 (10%) eyes had persistent disease and 45 (90%) orbits were tumor-free with globe salvage in 41 (82%), enucleation in 2 (4%) and orbital exenteration in 2 (4%). Vision loss seen in two eyes resulted from corneal scarring (n = 1) and microbial keratitis (n = 1). Other treatment related complications included pseudopterygium (n = 2), radiation induced cataract (n = 1), microbial keratitis (n = 1) and conjunctival granuloma (n = 1), all of which had a good final visual outcome. Final outcomes were assessed at mean follow up of 41 months (median 30, range 1–164 months) from presentation.

Discussion

First reported case of bilateral conjunctival tumor then termed “epithelioma” dates back to 1975 by Olurin.¹⁰ Subsequently, Odrich et al.¹¹ reported the first two cases of bOSSN associated with HPV infection. Various case series report variable prevalence of bOSSN with highest being in the immune suppressed and patients afflicted with xeroderma pigmentosum.^4–9 In this study, the prevalence and incidence of bOSSN, irrespective of presence or absence of systemic risk factors was derived to be 3% and 17 per 1000 cases of OSSN in 5 years respectively. In addition to XP and HIV,^7–9 various other risk factors have been identified for bOSSN.^10–24 Conjunctival xerosis, a manifestation of altered Vitamin A and retinoic acid metabolism affecting both eyes, has been implicated in etiopathogenesis of OSSN.²⁸ Ramasubramanian et al.²⁹ attributed occurrence of corneal OSSN after keratoplasty to local immunosuppression due to chronic use of topical steroids.

Risk factors identified in this study were XP and HIV which were seen in 60% and 12% cases respectively. No systemic features of cutaneous or genital HPV were present in any patient but tumor specimens were not processed for detection of HPV. Other factors such as outdoor activity, smoking, conjunctival xerosis and steroid use were present in 8%, 4%, and 4% respectively.

Seven patients (28%) with bOSSN in this study had no identifiable risk factors. This emphasizes the need for meticulous clinical examination and follow-up irrespective of identifiable risk factors. Mean age at presentation was two decades less in patients of bOSSN with systemic risk factors than those without systemic risk factors. Synchronous presentation of bOSSN has been more commonly reported in literature than metachronous lesions (Table 1).^11–24 However, a near-equal distribution was seen in the present series with 56% showing synchronous presentation and 44% showing metachronous presentation. Of these, in 25% (n = 7) of eyes with synchronous presentation and 41% (n = 9) of eyes with metachronous presentation, there were no presenting symptoms. Thus, the lesion in the contralateral eye was diagnosed only on routine ocular examination. No significant differences in age, gender, risk factors or clinical features were noted between synchronous and metachronous presentations.

Mean interval of detection of the tumor in the contralateral eye in patients with metachronous presentation was 34 months (median 24, range 4–108 months) which warrants follow-up and sensitization of patients regarding rare possibility of development of disease in the other eye. This is especially important in one-eyed patients, as noted by Masanganise et al. wherein the fear of any intervention for the only eye in patients of bOSSN was one of the factors responsible for delay in seeking treatment. Appropriate patient education regarding the same can result in early diagnosis and necessary intervention. Further, any suspicious lesion should be carefully monitored with AS-OCT wherever feasible to detect early disease. AS-OCT greatly aids in diagnosis of early disease as well as differentiating it from benign lesions.^30,31

On histopathology, invasive squamous cell carcinoma was the most common subtype within the spectrum of OSSN, consistent with reports in literature.^10–24 Treatment options in synchronous bOSSN depend on the extent of disease in both eyes and patient’s compliance to therapy. Management of metachronous tumors further depends on the status of contralateral eye as well. None of the patients in this series, including those with systemic risk factors had bilateral advanced disease, allowing salvage of at least one eye (80%).

Novelty of this study lies in estimation of the prevalence and incidence of bOSSN in a tertiary eye care center and documentation of bOSSN in patients without any identifiable systemic risk factors. In addition, it a gives an estimate of time frame for development of OSSN in the contralateral eye, outcomes of bOSSN in terms of tumor free survival, globe salvage, and vision salvage. Limitations of the study include a relatively small data set and lack of data on HPV infection of the ocular surface.

In conclusion, bOSSN is rare. XP and HIV are risk factors but stringent follow-up and education of the patients is mandatory even without any identifiable risk factor. Presentation can be synchronous or metachronous with morphology being similar or variable between the two eyes. Despite the presence of bilateral tumors, outcomes of vision, globe salvage and survival are promising if appropriately managed.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Support provided by The Operation Eyesight Universal Institute for Eye Cancer (SK) and Hyderabad Eye Research Foundation (SK), Hyderabad, India. The funders had no role in the preparation, review or approval of the manuscript.

ORCID iD

Swathi Kaliki

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