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BMC Ophthalmol
BMC Ophthalmol
BMC Ophthalmology
1471-2415
BioMed Central London

3657
10.1186/s12886-024-03657-6
Research
Treatment of ocular surface squamous neoplasia in an Indian rural facility: a study of 38 eyes
Agarwal Ayushi 1
Ghose Neha 1
Rathi Varsha 2
Khanna Rohit 2
Kaliki Swathi kalikiswathi@yahoo.com

1
1 https://ror.org/01w8z9742 grid.417748.9 0000 0004 1767 1636 The Operation Eyesight Universal Institute for Eye Cancer (AA, LV Prasad Eye Institute, Hyderabad, 500034 NG, SK, Telangana India
2 Gullapalli Pratibha Rao International Center for Advancement of Rural Eye Care (VR, RK), Hyderabad, 500030 Telangana India
3 9 2024
3 9 2024
2024
24 38919 1 2024
23 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Purpose

To report the demographic profile, clinical presentation, and management outcomes of ocular surface squamous neoplasia (OSSN) treated with primary topical chemotherapy in a limited resource secondary eye care facility in rural parts of South India.

Methods

Retrospective interventional study of 38 eyes of 37 patients with OSSN treated with topical 1% 5-Fluorouracil (5FU), over a period of two years.

Results

The median age at presentation with OSSN was 44 years (mean, 46 years; range 13 to 74 years). Majority (76%) were males. The most common morphological variant was placoid OSSN (18, 47%). Limbus was the most common epicenter (31, 82%). Corneal OSSN was the most initially misdiagnosed variant (n = 3). Of the 38 eyes receiving one week on and 3-weeks off cycles of 5FU regimen, complete tumor resolution was achieved in 36 (95%) eyes. The median number of topical 5FU cycles for tumor resolution was 2 (mean, 2; range, 1 to 4). Over a median follow-up period of 5 months (mean, 6 months; range, 1 to 27 months), tumor recurrence was noted in 3 eyes (8%), of which one case had xeroderma pigmentosum with bilateral multifocal recurrence. Complication rate was 5% (n = 2), which included transient conjunctival hyperemia (n = 1), and bacterial keratitis (n = 1) which resolved with fortified antibiotics.

Conclusion

Primary chemotherapy with topical 1% 5FU is a safe and effective management modality for OSSN at limited resource settings in rural India.

Keywords

Eye
Tumor
OSSN
Ocular surface squamous neoplasia
5FU
5-fluorouracil
Hyderabad Eye Research Foundationissue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Ocular surface squamous neoplasia (OSSN) represents a wide spectrum of neoplastic squamous lesions involving the conjunctiva, limbus, or cornea. Overall, OSSN is the most common conjunctival ocular malignancy, and the most common malignant ocular tumor in > 10 years’ age group in the Indian subcontinent [1]. Occurrence of OSSN is multifactorial, the major risk factors being ultraviolet B (UV-B) radiation exposure, human immunodeficiency virus (HIV), human papilloma virus (HPV), ocular surface injury, vitamin A deficiency, and heavy cigarette smoking [2]. Increased outdoor time (> 50%) in the initial six years of life while residing within thirty degrees latitude to the equator is associated with a higher risk of developing OSSN [3].

Over the past two decades, with the advent of topical chemo and immunotherapeutic agents and anterior segment optical coherence tomography (AS-OCT), management of OSSN has experienced a paradigm shift from surgical excision to primary medical management [4, 5]. Majority of the studies on OSSN, however, hail either from developed countries or from urban tertiary centers of developing countries [6–8]. While almost 70% of the population in India resides in rural areas where majority are engaged in outdoor activities, literature describing clinical profile and management challenges of OSSN in these limited resource settings is scarce [9]. Herein, we report the demographic details, clinical features, and management outcomes of OSSN at a limited resource rural facility, and also propose guidelines for referral to a tertiary eyecare center.

Materials and methods

Ethical clearance was obtained from the Institutional Review Board of LV Prasad Eye Institute (LEC – BHR – R – 03–23 – 1024) and the study adhered to the guidelines of Declaration of Helsinki. Informed consent has been obtained from the patients/parents/legal guardian for study participation and publication.

A retrospective interventional study was conducted at a limited resource secondary eyecare facility in Southern India, affiliated with L V Prasad Eye Institute. Inclusion criteria were cases of OSSN diagnosed based on clinical and AS-OCT (Primus 200, Carl Zeiss Meditec, Dublin, CA) characteristics, by ocular oncology trainees (NG, AA) in the rural facility, treated with topical Fluorouracil 1% (5FU), and had a follow-up after completion of medical treatment as prescribed. The study period was between February 2021 to March 2023. Cases of OSSN who were lost to follow-up during or before completion of medical treatment with 5FU were excluded from the study.

Diffuse OSSN was defined as lesion extending beyond 6 clock hours of the limbus. The AS-OCT features suggestive of OSSN included hyper-reflective thickened epithelium with abrupt transition from normal to abnormal epithelium, with or without back-shadowing or an underlying cleavage plane. Patients requiring further investigations or advanced care such as cases with inconclusive diagnosis of OSSN or those needing excisional biopsy of OSSN were referred to the nearest associated tertiary eye centre, a referral system based on the unique pyramid eye model developed by LV Prasad Eye Institute [10].

A cyclical regimen of topical 1% 5FU four times/day for a week with 3 weeks of drug holiday was initiated upon diagnosis of OSSN. All affected eyes were prescribed adjuvant topical lubricants, carboxymethylcellulose 0.5%, four times/day for a month. Tumor response was graded as ‘good’ if there was no tumor residue, ‘moderate’ if tumor responded with > 50% reduction, ‘poor’ if there was < 50% reduction, and ‘nil’ if there was no change in tumor size. Successful outcome was defined as complete tumor resolution based on clinical findings and confirmed on AS-OCT.

Statistical analysis

Data was managed in the Excel sheet (Microsoft Corporation, Redmond, WA, USA) and analysis was performed using Stata 17.0 (StataCorp LLC, Texas, USA) software. The mean, median, and interquartile ranges were calculated for continuous variables. For categorical variables, results were expressed in terms of either frequency or percentage. A p-value of < 0.05 was considered significant.

Results

A total of 45 OSSN cases were seen at the secondary eyecare facility during the study period. Of these, 38 eyes of 37 patients (82%) were included in this study based on the defined inclusion criteria. Nine eyes of 8 patients (18%) were excluded due to inadequate follow-up (n = 8) or referral to tertiary eyecare facility due to concomitant microbial keratitis (n = 1). The median age at presentation of OSSN was 44 years (mean, 46 years; range, 13 to 74 years). Of the 37 patients, 28 (76%) were males, and 9 were females (24%). Majority (31, 82%) had outdoor occupation. One (3%) patient with xeroderma pigmentosum (XP) had bilateral presentation. OSSN was an incidental finding in 3 cases (8%). A summary of demographic details is provided in Table 1.

Table 1 Ocular surface squamous neoplasia in a rural setting: demographics and clinical history

Feature	n (%)	
Age at presentation (years)

Mean (median, range)

	46 (44, 13 to 74)	
Gender	n = 37	
Male	28 (76)	
Female	9 (24)	
Occupation	n = 37	
Indoor	6 (16)	
Outdoor	31 (84)	
Significant systemic disease	n = 37	
HIV infection	0 (0)	
Systemic cancer	0 (0)	
Xeroderma pigmentosum	1 (3)	
Symptoms*	n = 38	
Asymptomatic	4 (11)	
Ocular surface mass	22 (58)	
Watering	11 (29)	
Foreign body sensation	17 (45)	
Duration of symptoms (months)

Mean (median, range)

	3 (< 1, < 1 to 24)	
HIV = human immunodeficiency virus; *Few patients had more than one symptoms

Four cases of OSSN were initially misdiagnosed, which included 3 cases of corneal OSSN and one case of noduloulcerative OSSN. Corneal OSSN was initially diagnosed as interstitial keratitis (n = 1), viral epithelial keratitis (n = 1), and limbal stem cell deficiency (n = 1) and noduloulcerative variant of OSSN was misdiagnosed as pseudoepithelomatous hyperplasia, by a comprehensive ophthalmologist.

While the cornea was the epicenter in 3 eyes (8%), corneal involvement was noted in 19 (50%) cases. OSSN was multifocal, involving nasal and temporal quadrants bilaterally in case of XP. Nasal quadrant was involved in 20 eyes (53%), temporal in 18 (47%), and inferior in 1 (3%) eye. OSSN had varied morphological variants in our cohort, the most common being the placoid type (n = 18, 47%). Typical appearance of corneal OSSN in the form of greyish opalescent layer with fimbriated edges was identified in 2 cases (5%). Clinical features are summarized in Table 2.

Table 2 Ocular surface squamous neoplasia in a rural setting: tumor features and outcomes

Feature	n (%)
n = 38 eyes of 37 cases	
Tumor epicenter		
Limbus	31 (82)	
Cornea	3 (8)	
Bulbar conjunctiva	4 (11)	
Forniceal conjunctiva	0 (0)	
Tarsal conjunctiva	0 (0)	
Quadrantic tumor location		
Nasal	20 (53)	
Inferior	1 (3)	
Temporal	18 (47)	
Superior	0 (0)	
Diffuse	0 (0)	
Tissues involved*		
Cornea	19 (50)	
Limbus	34 (89)	
Bulbar conjunctiva	34 (89)	
Forniceal conjunctiva	0 (0)	
Tarsal conjunctiva	0 (0)	
Intraocular tumor extension	0 (0)	
Orbital tumor extension	0 (0)	
Number of clock hours of tumor involvement		
Conjunctiva

Mean (median, range)

	2 (2, < 1 to 6)	
Limbus

Mean (median, range)

	1.8 (, < 1 to 6)	
Cornea

Mean (median, range)

	1 (0, < 1 to 6)	
Tumor basal diameter (in millimeters)

Mean (median, range)

	5 (4, 1 to 15)	
Tumor thickness (in millimeters)

Mean (median, range)

	1 (1, < 1 to 10)	
Tumor morphology		
Nodular	13 (34)	
Papillary	6 (16)	
Placoid	18 (47)	
Noduloulcerative	1 (3)	
Tumor pigmentation	22 (58)	
% of tumor pigmentation

Mean (median, range)

	29 (20, 5 to 100)	
Area of tumor pigmentation*		
Corneal	2 (5)	
Limbal	7 (18)	
Conjunctival	21 (55)	
Associated features		
Keratin	31 (82)	
Feeder vessels	32 (84.)	
Intrinsic vascularity	34 (89)	
Scleral fixity of the tumor	1 (3)	
AS-OCT features		
Epithelial thickening	38 (100)	
Back-shadowing	31 (82)	
Abrupt transition from normal to abnormal thickened epithelium	38 (100)	
Intralesional cavitations	1 (3)	
Subepithelial hyperreflectivity	10 (26)	
Visibility of posterior tumor limit	7 (18)	
Outcomes		
Complete tumor resolution	36 (95)	
Tumor recurrence	3 (8)	
Systemic metastasis	0 (0)	
*More than one area was involved; AS-OCT = anterior segment optical coherence tomography

Topical 1% 5FU chemotherapy cyclical regimen was successfully administered in all 38 eyes. Of these, good tumor response was achieved in 36 (95%) eyes (Fig. 1), and no response in 2 eyes (Table 2). The median number of cycles until complete tumor resolution were 2 (mean 2; range, 1 to 4). Complications with topical 5FU included transient conjunctival hyperemia (n = 1), and development of microbial keratitis during the second cycle of 5FU therapy (n = 1).

Fig. 1 Ocular surface squamous neoplasia treated with topical 5-fluorouracil monotherapy. (A) Clinical photograph of a patient with ocular surface squamous neoplasia (OSSN) in the inferonasal quadrant of the left eye (B) Anterior segment optical coherence tomography (AS-OCT) showing hyper-reflective thickened epithelium with abrupt transition from normal to abnormal epithelium (arrow) and an underlying cleavage plane (asterisk)(C) Post-treatment clinical photograph following 1 cycle of 5-fluorouracil (5FU) showing resolution of keratin plaque with residual pigmentation (D) Corresponding AS-OCT showing normal epithelial thickness with subepithelial hyper-reflectivity (E) Clinical photograph of left nasal OSSN overlying a pterygium (F) Corresponding AS-OCT showing hyper-reflective thickened epithelium (asterisk) with backshadowing and abrupt transition from normal to abnormal epithelium (arrow)(G) Clinical photograph following 2 cycles of 5FU showing pterygium with no tumor residue (H) Corresponding post-treatment AS-OCT showing normal overlying epithelium with subepithelial hyper-reflectivity corresponding to pterygium

Over a mean follow-up period of 17 months (median 16 months; range, 5 to 39 months), tumor recurrence was noted in 3 eyes (8%) after complete tumor resolution. The median interval between tumor resolution and tumor recurrence was 6 months (mean, 4 months; range, 1 to 6 months).

Discussion

A significant proportion of the Indian subcontinent belong to the underserved rural areas. Firstly, there is a lack of proper medical infrastructure and social awareness regarding ocular tumors in this section of society. Secondly, evidence reveals an underutilization of already well-established eyecare services in these areas [11]. Although the exact incidence of ocular surface tumors in India is unknown, the reported incidence from an Electronic medical record (EMR)-based data from a tertiary eyecare center is < 1%.1 This study was undertaken to recognize the demographic distribution, clinical presentation, management outcomes, and the referral patterns of OSSN reporting to a limited resource secondary eyecare unit in rural India.

Males comprised 76% of all cases in our cohort, which is similar to the reported average of 68 to 70% [8, 12] Although one may argue that males are more likely to involve in outdoor occupations leading to higher exposure to UV radiation, in rural areas there is considerable outdoor exposure to women as well. The male predominance can be attributed to the notion that males being the predominant breadwinners of the society, are twice as likely to seek health care than females in rural areas [11].

Though surgical excision is the gold standard treatment for OSSN, wide excisional biopsy with cryotherapy to surgical margins and ocular surface reconstruction with amniotic membrane graft (AMG) is challenging in a limited resource healthcare setup in rural India. Also, pathology centers for processing of excised specimens do not exist in most parts of rural India. With the availability of AS-OCT which provides optical biopsy confirming the diagnosis of OSSN, medical treatment of OSSN with topical medications is an emerging trend. Amongst the topical medications, Interferon alfa 2b (IFN-a2b) has shown to be effective against OSSN and is known to be associated with least complications compared to Mitomycin-C (MMC) and 5FU [13]. However, utilization of IFN-a2b in a rural setup is challenging owing to lack of availability of a refrigerator for drug storage in most rural households. In 2021, the National Family Healthy Survey (NFHS) of India, revealed a stark urban-rural divide on refrigerator ownership, with 63% urban households owning a refrigerator as opposed to only 25% ownership in rural households. These limits the utility of topical IFN-a2b in rural areas, as it requires a robust cold chain storage. Another considerable limiting factor is the difference in the cost of one vial of IFN-a2b, which is atleast three times more expensive than a vial of 5FU (250 mg/5mL) in the Indian subcontinent [14]. MMC is also effective for OSSN but has a relatively increased side-effect profile compared to IFN-a2b and also requires cold chain maintenance [15].

Due to the above-mentioned challenges, all OSSN cases were being referred to tertiary care centers for confirmation of diagnosis and further management, till 2 years ago. At our secondary eyecare facility, though trained eyecare professionals are available, surgical excision was not possible due to lack of cryotherapy, AMG, and pathology setup; IFN-a2b and MMC were not ideal due to limitations with cold chain maintenance. Based on the published literature, topical 5FU has shown encouraging results, [16] is inexpensive compared to IFN-a2b and MMC, and the drug can be stored at room temperature. These factors encouraged us to initiate the use of topical 5FU as the first line of management of OSSN in our rural setup. Also, AS-OCT was available at the rural setup at regular intervals through an advanced mobile diagnostic unit “Pashyantu”, aiding in confirmation of diagnosis of OSSN, prior to initiation of medical treatment.

The first usage of 5FU for OSSN dates back to 1986, when de Keizer et al. reported a case of intraepithelial neoplasia involving the cornea and conjunctiva, successfully managed with instillation of topical 5FU [17]. Since then, this chemotherapeutic agent has gained worldwide popularity as a primary monotherapy for OSSN. Venkateswaran et al. in their direct comparison between primary topical 5FU and IFN-a2b therapy showed comparable efficacy (96% in 5FU versus 81% in IFN-a2b group) in the primary management of OSSN. In their study, although 5FU showed superiority based on univariate analysis, multivariate regression showed no statistically significant difference between the two therapies [18]. In our study, complete tumor resolution with topical 5FU monotherapy was seen in 95% and is consistent with the published literature. The mean number of topical 5FU cycles for complete tumor resolution was 2 cycles, indicating the mean duration to tumor resolution being 2 months. This reflects the relatively quicker time to resolution when compared to the published literature reporting mean duration to resolution as 4–6 months [16, 19]. This could be related to referral bias in tertiary health care centers versus early diagnosis of smaller lesions in a rural setup.

Tumor recurrence was noted in 3 of the 36 eyes after complete tumor resolution with topical 5FU monotherapy. Two of these recurrences were noted in the youngest case (13 years) of our cohort, who had bilateral multifocal OSSN with XP, a well-established association [20]. XP was detected only when the patient had sought care at our eye center for the growing ocular surface mass. The sequential multifocal involvement and tumor recurrence despite topical 5FU and the need for genetic testing led to referral to our tertiary eyecare center. Considering the proven association of XP with ocular, periocular, head and neck malignancies, and higher recurrence rates of OSSN, awareness regarding this condition amongst the general population as well as healthcare personnel, and the need for lifelong follow-up should be highlighted [21].

Reported complications following topical 1% 5FU therapy vary in severity, ranging from transient hyperemia, pain, eyelid edema, to rare sight-threatening complications such as perforated corneal ulcer and stromal melt. Tendency for causing keratopathy and eyelid edema is significantly more, when compared to IFN-a2b [18, 22, 23]. However, recent long-term studies have shown reasonable side-effect profile of IFN-a2b with comparable rates of hyperemia between IFN-a2b and 5FU (19% versus 23%, respectively) [24]. In our series, 5FU related adverse effects were noted in 2 eyes (5%). One patient developed transient conjunctival hyperemia not warranting discontinuation of 5FU therapy, and another case developed bacterial keratitis during the last cycle of 5FU therapy, which resolved with fortified antibiotics. The authors recommend avoiding topical 5FU in cases with pre-existing dellen or compromised cornea. None of the patients in our series had eyelid edema, periocular excoriation, or pigmentation, which may be due to adequate counselling of patients on the appropriate way of instilling these eye drops, avoiding exposure of the drug to the periocular surface.

This was a retrospective case series with a small sample size and limited duration of follow-up. Though the study was in a rural set-up, there was availability of AS-OCT which was crucial in confirming the diagnosis and monitoring the treatment response. Such a facility may not be available at all rural setups. Despite these limitations, the authors strongly advocate for topical 1% 5FU as a safe and effective primary monotherapy for OSSN in limited resource settings of rural areas. However, topical chemotherapy should be judiciously used only in definitive OSSN cases. Whenever the diagnosis is uncertain, topical chemotherapy should be avoided and the patients should be referred to higher centers for an appropriate diagnosis and treatment. The authors propose the following referral guidelines for better overall success rates: (a) Diagnostic dilemma with atypical AS-OCT features, (b) Scleral fixity of OSSN, (c) No or suboptimal response beyond 3 cycles of topical 5FU, (d) Worsening of OSSN despite treatment initiation, (e) Tumor recurrence, and (f) OSSN in setting of corneal dellen, microbial keratitis, or compromised ocular surface. A closer follow-up is recommended in patients of XP and HIV.

Acknowledgements

None.

Author contributions

Ayushi Agarwal: Material preparation, data collection, data analysis, and preparation of first draft, approval of final draft Neha Ghose: Material preparation, data collection, data analysis, revision of the draft, and approval of final draftVarsha Rathi: Study design, revision of the draft, and approval of final draftRohit Khanna: Study design, revision of the draft, and approval of final draftSwathi Kaliki: Study conception and design, revision of the draft, and approval of final draft.

Funding

Support provided by The Operation Eyesight Universal Institute for Eye Cancer (Swathi Kaliki) and Hyderabad Eye Research Foundation (Swathi Kaliki), Hyderabad, India. The funders had no role in the preparation, review, or approval of the manuscript.

Data availability

The corresponding author, Dr Swathi Kaliki can be contacted at kalikiswathi@yahoo.com to obtain access to the raw data analysed in this study.

Declarations

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of LV Prasad Eye Institute (March 24, 2023/No LEC-BHR-R-03-23-1024). Informed consent was obtained from all individual participants/parents/legal guardian included in the study.

Conflict of interests

No conflicting relationship exists for any author

Consent for publication

Not applicable.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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