Abstract
PURPOSE:
The purpose of the study was to review the demographic profile, risk factors, clinical presentations, and treatment outcomes in patients with ocular surface squamous neoplasia (OSSN) at government cornea centers in Malaysia.
MATERIALS AND METHODS:
This is a retrospective cohort study of patients with proven histopathological reports of either corneal/conjunctival intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC) from January 2016 to December 2021, who were recruited. The patients’ demography, histopathology, and treatment outcomes were reviewed.
RESULTS:
A total of 62 eyes involving 59 patients with proven OSSN were studied. The majority of the cases were male (76.3%), with a mean age of 65.2 ± 11.81 years, and approximately 32.2% worked as farmers. Sun exposure and smoking are the predominant risk factors observed in this study. Histopathological examination revealed that 69.4% were CIN, while 30.6% were SCC. The majority of the cases were treated surgically with adjunctive cryotherapy and topical mitomycin C (MMC) postoperatively. Five cases (3 CIN, 2 SCC) recurred after surgery. Two recurrent cases were treated with topical MMC and resolved completely. Another three cases required surgical excision after chemo reduction with topical MMC. Tumor pigmentation was shown to be a significant risk factor for recurrence (odds ratio 10.7; 95% confidence interval: 1.5–75.8; P = 0.026).
CONCLUSION:
CIN is more common than SCC, predominantly affecting the male population in Malaysia with a background history of sun exposure and smoking. MMC is a good adjunct to surgical excision, both for primary and recurrent cases. Tumor pigmentation is a predicting factor for OSSN recurrence.
Keywords: Conjunctival neoplasms, cornea, Malaysia, squamous cell carcinoma, squamous cell neoplasm
Introduction
Ocular surface squamous neoplasia (OSSN) is a spectrum of lesions ranging from different grades of dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC) involving the cornea and/or conjunctiva.[1] The term “ocular surface” denotes conjunctival or corneal involvement; squamous excludes other epithelial cells such as basal cells and melanocytes, while neoplasia includes both dysplastic and carcinomatous tumors.[1] OSSN is the most common acquired nonpigmented tumor of the ocular surface, and the third most common ocular tumor after retinoblastoma and melanoma.[2]
The incidence varies regionally between 0.03 and 3.5 cases/year/per 100,000 individuals.[3,4] The incidence in Africa is 9–10 times higher than in Europe and North America.[5] OSSN occurs worldwide but is prevalent in countries closer to the equator and in those with continuous sunlight exposure.[6] In temperate countries, OSSN predominantly affects males, while in Africa, both sexes are equally affected.[5]
Risk factors associated with the development Of OSSN include age, male sex, ultraviolet (UV) light exposure, photoimmunosuppression, cigarette smoking, exposure to petroleum products, human immunodeficiency virus (HIV), human papilloma virus (HPV), immunodeficiency, prior ocular surface surgery or trauma, previous history of mass on the affected eye, vitamin A deficiency and xeroderma pigmentosum.[2,7,8,9] In HIV endemic countries, OSSN has been found to be the presenting feature of HIV infection in 50%–86% of patients.[10] Its presentation in HIV patients is more aggressive, with a greater likelihood of bilaterality, worse prognosis, and higher recurrence rates.[10,11,12]
OSSN is considered a low-grade malignancy. Early detection and prompt treatment are essential to reduce metastasis and recurrence. While various surgical and nonsurgical options exist, there is no consensus on management.[13,14] Shield et al. described an excisional biopsy method with a no-touch technique to avoid the potential risk of tumor seeding, followed by a double freeze-slow thaw cryotherapy.[11] Although surgical excision was the mainstay treatment of OSSN, the postoperative recurrence rates are as high as 15%–56%.[1,12] A wide surgical excision with adjunctive cryotherapy had lower recurrence rates compared to surgical excision alone.[11] Cryotherapy destroys the cells using thermal effects, obliterating microcirculation, leading to ischemic infarction.[15,16]
Surgical excision may not completely eradicate the microscopic tumor cells at or beyond the edge of the surgical margin, increasing the risk of recurrence. Over the past 20 years, several alternative therapies have been proposed, including topical mitomycin C (MMC), 5-fluorouracil, and interferon-alpha 2b (IFNα2b).[17,18,19,20] MMC is typically chosen due to its affordability, fewer adverse effects, and better patient tolerance, at a concentration of 0.02% or 0.04%.[21,22,23,24] The recommended course of treatment is topical chemotherapy, either as a primary monotherapy, in conjunction with surgical excision as a preoperative chemo-adjuvant, or as a postoperative adjunctive treatment to prevent recurrence.[21,22,23,24,25]
Literature on OSSN in Malaysia is limited, with the most recent Asian study conducted in neighboring Thailand.[24] This retrospective study aims to review the clinical demographic profile, histopathological findings, and outcomes of OSSN cases in government cornea centers in Malaysia.
Materials and Methods
This is a retrospective cohort study involving patients with proven histopathological reports of either corneal-conjunctival intraepithelial neoplasia (CIN) or SCC at two tertiary eye centers in Malaysia. The study was conducted for 5 years, from January 1, 2016 to December 31, 2021. The inclusion criteria are patients with clinically suspected OSSN who had undergone wide excisional biopsy with confirmed OSSN on histopathological examination (HPE) and completed at least 1 year postoperative follow-up. Patients with clinical signs of OSSN but who did not undergo surgery or whose histological results were not OSSN were excluded. Patients who did not continue at least 1 year postoperative follow-up were excluded. The study protocol was approved by the research and ethics committee from both study centers, and the methods adhered to the tenets of the Declaration of Helsinki. The ethical approval code: NMRR ID 22-00716-RPY. The patient consent is waived by IRB.
Patients
The medical records of patients with histopathologically proven OSSN were reviewed. Demographic data, including age, gender, race, occupation, and risk factors, were collected. Evaluated parameters include demographic data, clinical history of the presenting symptoms and duration, and known OSSN risk factors. Missing data were supplemented via phone interviews with patients or their next of kin. Available blood tests for infectious screenings (HIV, Hepatitis B, Hepatitis C, Syphilis, and HPV) were also included.
Seventy-one clinically suspected OSSN cases were identified and underwent excisional biopsy with HPE, but only 62 cases were confirmed as OSSN by HPE and included in this study and analyzed. Nine cases were excluded as the HPE showed pterygium (3), squamous papilloma (3), conjunctival naevus (2), and chronic inflammation (1). The clinical examination included a visual acuity test and a detailed slit lamp examination to document tumor features. The mass was described based on the location, extension, laterality, size, number of clock hours of limbal involvement, morphology (leukoplakic, papilliform, gelatinous, fungating, and ulcerative), growth pattern (nodular/sessile/diffuse), presence of feeder vessels, pigmentation, and any associated pterygium or pinguecula. Mass recurrence after excision was also evaluated. The mass was classified as small (<5 mm basal diameter or <3 clock hours of limbal involvement), medium (6 mm to 15 mm in basal diameter or 3 clock hours to 6 clock hours of limbal involvement), or large (>15 mm in basal diameter, fornix or eyelid involvement, or >6 clock hours of limbal involvement).[25] The categorization of continuous variables such as visual acuity and lesion size was done to enhance clinical interpretability and allow comparison with prior literature. Any systemic examination or lymph node assessment done was also documented.
The surgical technique employed was wide excisional biopsy with adjunctive cryotherapy.[11] Tumors were excised 4 mm from the clinically uninvolved conjunctival margin using a no-touch technique.[11] For masses with corneal involvement, 2 mm clear corneal margins with alcohol epitheliectomy were done.[11] Cryotherapy was performed using the double freeze-slow thaw method on the conjunctival edges of the excised area within 8 s. Any remaining conjunctival defect of <3 clock hours in diameter following excision was closed primarily with a conjunctival graft. Larger defects were closed with amniotic membrane transplantation. Temporary bandage contact lens was used to promote epithelial healing. The excised tumors were tagged, placed into buffered formalin, and sent for HPE.
Based on the histopathological classification of OSSN by Basti and Macsai, CIN was graded as mild dysplasia, moderate dysplasia, or severe dysplasia (carcinoma in situ).[13] Mild dysplasia (CIN I) denotes atypical cells in <25% of the epithelial thickness, moderate dysplasia (CIN II) involves 25%–75%, and severe dysplasia (CIN III), or carcinoma in situ, affects >75% or the entire epithelium. SCC occurs when the epithelial basement membrane is breached.[13]
At one of the two centres involved in this study, topical MMC 0.02% was given for chemo reduction for extensive tumors or those extending >4 clock hours prior to surgical excision prior to surgical excision, a strategy suggested by Shield et al.[14] The regimen was topical MMC 0.02% 4 times daily (QID) for three cycles, where each cycle lasts for 1 week followed by a 1-week drug holiday.[2] The regimen was also used postoperatively at both centres for preinvasive or invasive dysplasia, based on HPE.[2,23,24] Topical MMC was started after the postoperative corneal epithelium had healed. Patients were instructed to close their eyes with punctal occlusion for 5 min after instilling the topical MMC, along with topical steroids, topical antibiotics, and topical lubricants throughout the entire period to reduce drug toxicity. Patients were monitored for recurrence.
Treatment outcomes were assessed by recurrence at 1-year postexcisional biopsy. Recurrence was defined as a new tumor at the previous surgical excision site or at another location on the same eye, after complete tumor resolution from the previous primary treatment.[26] A positive surgical margin was defined as tumor presence at any edge of the specimen.[26] Recurrence was treated with adjunctive MMC at a higher dose of 0.04% QID for three cycles. Surgical excision was done if there was no regression after topical MMC.
Statistical analysis
Proportions were presented as numbers and percentages. Continuous data were presented as the mean and standard deviation (SD) in normally distributed data or the median and interquartile range (IQR) in non-normally distributed data. The Fisher’s exact test and Mann–Whitney test were used to evaluate factors influencing recurrence. P < 0.05 was considered statistically significant. Data were analyzed by using the Statistical Package for the Social Sciences (SPSS) program version 26.0 (SPSS Inc., Chicago, IL, USA).
Results
Sociodemographic data
A total of 62 eyes from 59 patients with HPE proven OSSN were reviewed, including 3 bilateral involvement. There were 45 (76.3%) males and 14 (23.7%) females, with a mean ± SD age of 65.2 ± 11.81 years (range 24–87). The majority worked as farmers (19, 32.2%), followed by daily laborers (12, 20.3%) and lorry drivers (9,15.3%). Seven (11.9%) were housewives, 6 (10.2%) were civil servants, along with 4 (6.8%) hawkers and 2 (3.3%) businessmen [Table 1].
Table 1.
Sociodemographic data
| Patients’ demographic (n=59 patients) | n (%) |
|---|---|
| Age (year) | |
| Mean±SD | 65.2±11.81 |
| Range | 24–87 |
| Gender, n (%) | |
| Male | 45 (76.3) |
| Female | 14 (23.7) |
| Occupation, n (%) | |
| Farmer | 19 (32.2) |
| Daily laborer | 12 (20.3) |
| Lorry driver | 9 (15.3) |
| Housewife | 7 (11.9) |
| Civil servant | 6 (10.2) |
| Hawker | 4 (6.8) |
| Businessman | 2 (3.3) |
SD=Standard deviation
Clinical presentation
The most common presenting symptom was a mass on the eye (21, 33.9%), then mass with eye irritation/pain (20, 32.3%), followed by eye irritation and redness (12, 19.4%), and visual impairment (6, 9.6%) [Table 2]. The median symptom duration was 12 months (IQR 9), ranging between 1 month and 60 months. In this study, visual acuity was arbitrarily divided into two categories: good visual acuity (corrected vision of 6/12 or better) and poor visual acuity (corrected vision worse than 6/12). Forty-one cases (66.1%) had poor visual acuity, while 21 (33.9%) had good visual acuity at presentation. The reasons for poor visual acuity in these patients, aside due to the tumor alone, included cataracts (n = 30), preexisting corneal scars (n = 5), glaucoma (n = 1), and macular scar (n = 1). Thirty-three tumors were on the left eye, and 29 on the right eye. No lymph node involvement was found in physical examinations.
Table 2.
Clinical presentation
| Patients’ clinical presentation (n=62 eyes, where 3 patients have bilateral involvement) | n (%) |
|---|---|
| Presenting symptoms, n (%) | |
| Mass only | 21 (33.9) |
| Mass with irritation/pain | 20 (32.3) |
| Eye irritation/redness | 12 (19.4) |
| Visual impairment | 6 (9.6) |
| Asymptomatic | 3 (4.8) |
| Duration of symptoms (months) (IQR) | |
| Median (IQR) | 12.0 (9) |
| Range | 1–60 |
| Visual acuity, n (%) | |
| 6/12 or better | 21 (33.9) |
| Worse than 6/12 | 41 (66.1) |
| Laterality, n (%) | |
| Right eye | 29 (46.8) |
| Left eye | 33 (53.2) |
IQR=Interquartile range
Risk factors of surface squamous neoplasia
The risk variables for OSSN are shown in Table 3, with more than two risk variables for each respondent. In this study, sun exposure is the main risk factor (45, 48.9%), followed by smoking (24, 26.1%). Available blood tests revealed infections in three patients: one positive for Hepatitis C antibody, one for Hepatitis B antigen, and one for HIV antibody, but further details on the clinical course and outcome of these infections were incomplete or unavailable. Meanwhile, 9 (9.7%) had a history of pterygium surgery, 8 (8.7%) had previous growth on the affected eye, and 3 (3.3%) had ocular trauma. None had xeroderma pigmentosum.
Table 3.
Risk factors of patients with ocular surface squamous neoplasia
| Risk factors (n=total numbers of each risk factors present in the 59 patients involved) | n (%) |
|---|---|
| Sun exposure | 45 (48.9) |
| Smoking | 24 (26.1) |
| Previous pterygium surgery | 9 (9.7) |
| Previous history of growth (affected eye) | 8 (8.7) |
| Previous history of ocular trauma | 3 (3.3) |
| Infection (HIV/Hep B/Hep C) | 3 (3.3) |
| Xeroderma pigmentosum | 0 |
*Each patient has multiple risk factors. HIV=Human immunodeficiency virus
Clinical morphology of ocular surface squamous neoplasia
As shown in Table 4, a gelatinous mass was the most common presentation, seen in 20 eyes (32.3%). Nineteen eyes (30.6%) had a combined gelatinous and papilliform morphology. Fourteen (22.6%) cases had papilliform morphology. Six (9.7%) eyes presented with leukoplakia, and three eyes (4.8%) had diffuse or fungating masses.
Table 4.
Clinical morphology of ocular surface squamous neoplasia
| Clinical morphology in each eye (n=62 eyes) | n (%) |
|---|---|
| Gelatinous | 20 (32.3) |
| Combination (gelatinous and papilliform) | 19 (30.6) |
| Papilliform | 14 (22.6) |
| Leukoplakia | 6 (9.7) |
| Diffuse/fungating | 3 (4.8) |
Site and extent of ocular surface squamous neoplasia involvement
Nineteen eyes (30.6%) had cornea-conjunctiva-limbal involvement, 17 (27.4%) involved both limbus and conjunctiva, 13 (21.0%) at the limbus only, and 9 (14.5%) on the bulbar conjunctiva [Table 5]. Three eyes had purely corneal involvement (4.9%), and one eye (1.6%) had extensive involvement of the whole globe, orbit, and eyelids. The temporal (30, 48.4%) and nasal (22, 35.4%) sides of the eyes were the most common locations of the tumor, followed by the superior quadrant (3, 4.9%), all four quadrants involvement (3, 4.9%), superotemporal (2, 3.2%) and superonasal (2, 3.2%). In terms of size, more than half were within 6 mm–15 mm (36, 58.0%), 14 (22.6%) were 5 mm or smaller, and 12 (19.4) were larger than 15 mm. As for limbal involvement, 32 (51.6%) were moderate with a range of 3–6 clock hours, 15 (24.4%) were mild involving <3 clock hours, and the other 15 (24.4%) tumors were extensive, involving >6 clock hours.
Table 5.
Site of ocular surface squamous neoplasia involvement (n=62 eyes)
| n (%) | |
|---|---|
| Site of involvement | |
| Cornea-conjunctiva-limbus | 19 (30.6) |
| Limbus and conjunctiva | 17 (27.4) |
| Limbus | 13 (21.0) |
| Bulbar conjunctiva | 9 (14.5) |
| Cornea | 3 (4.9) |
| Whole globe, orbit, and eyelids | 1 (1.6) |
| Tumor location | |
| Temporal | 30 (48.4) |
| Nasal | 22 (35.4) |
| Superior | 3 (4.9) |
| All quadrants | 3 (4.9) |
| Superior temporal | 2 (3.2) |
| Superior nasal | 2 (3.2) |
| Size of the tumors (basal diameter) (mm) | |
| Small (5 or smaller) | 14 (22.6) |
| Medium (6–15) | 36 (58.0) |
| Large (Larger than 15) | 12 (19.4) |
| Extension of the tumors with limbal involvement (h) | |
| Small (<3 clock) | 15 (24.2) |
| Medium (3–6 clock) | 32 (51.6) |
| Large (>6 clock) | 15 (24.2) |
Ocular surface squamous neoplasia with associated findings
Feeder vessels were found in 52 (83.9%) tumors, and 10 tumors (16.1%) were pigmented. Local intraorbital spread occurred in one case (1.6%) [Table 6].
Table 6.
Ocular surface squamous neoplasia with associated findings (n=62 eyes)
| n (%) | |
|---|---|
| Feeder vessels | |
| Yes | 52 (83.9) |
| No | 10 (16.1) |
| Tumor pigmentation | |
| Yes | 10 (16.1) |
| No | 52 (83.9) |
| Local spreada | |
| Yes | 1 (1.6) |
| No | 61 (98.4) |
aLocal spread=Intraocular or orbital invasion
Management of ocular surface squamous neoplasia
Wide excisional biopsy was performed in all 62 cases. Six cases (9.7%) from one study centre were started on chemo reduction with topical MMC 0.02% QID for two cycles prior to surgery. These 6 cases had extensive tumor with > 6 clock limbal involvement or basal diameter of 6 mm or more.
Histopathological findings
HPE of the 62 eyes revealed 43 eyes (69.4%) had CIN and 19 eyes (30.6%) had SCC. Out of 43 CINs, 19 (30.6%) were high-grade dysplasia, 12 (19.4%) were mild, and 12 (19.4%) were moderate dysplasia [Table 7]. Out of 19 SCC cases, 9 (47.3%) were well differentiated, 8 (42.1%) were moderately differentiated, while 2 (10.5%) were poorly differentiated. Free margins were found in 46 cases (74.2%), whereas 16 cases (25.8%) had tumor-positive surgical margins, with the commonest site of positive margin being the deep margin (7, 43.8%).
Table 7.
Histopathological Examination findings (n=62 eyes)
| HPE findings | n (%) |
|---|---|
| CIN | n=43; 69.4% |
| Mild dysplasia/CIN I | 12 (19.4) |
| Moderate dysplasia/CIN II | 12 (19.4) |
| Severe dysplasia/Carcinoma in situ/CIN III | 19 (30.6) |
| SCC | n=19; 30.6% |
| Well differentiated | 9 (47.3) |
| Moderately differentiated | 8 (42.2) |
| Poorly differentiated | 2 (10.5) |
| Surgical margin | |
| Negative margin | 46 (74.2) |
| Positive margin | 16 (25.8) |
| Site of positive margin (n=16) | |
| Superior | 3 (18.7) |
| Inferior | 2 (12.5) |
| Temporal | 2 (12.5) |
| Medial | 2 (12.5) |
| Deep margin | 7 (43.8) |
CIN=Conjunctival intraepithelial neoplasia, SCC=Squamous cell carcinoma, HPE=Histopathological Examination
Postoperative topical mitomycin C
Sixty-one (96.7%) OSSN cases received 3 cycles of topical MMC 0.02% QID as postoperative adjuvant, except for one patient who refused further treatment [Table 8]. Among the 61 patients who received topical MMC, only two did not complete the treatment due to persistent epithelial defects. Most patients had no side effects (56, 91.8%). Two (3.3%) had ocular irritation, two (3.3%) had persistent epithelial defect while on the treatment, and one patient developed a pyogenic granuloma after completing the first cycle of MMC, which was successfully treated conservatively with topical steroids. This patient later resumed his topical MMC after the granuloma fully regressed. None developed punctal stenosis.
Table 8.
Postoperative topical mitomycin C (n=62 eyes)
| n (%) | |
|---|---|
| Topical MMC treatment | |
| Received | 61 (98.3) |
| Not received | 1 (1.7) |
| Completion treatment of MMC | |
| Completed (3 cycles) | 59 (95.2) |
| Partial completed | 2 (3.2) |
| Lost to follow up | 1 (1.6) |
| Side effects of MMC | |
| No side effects | 56 (91.8) |
| Ocular irritation/redness | 2 (3.3) |
| Persistent epithelial defect | 2 (3.3) |
| Pyogenic granuloma | 1 (1.6) |
| Punctal stenosis | 0 |
MMC=Mitomycin C
Treatment outcome
OSSN recurred in 5 cases (8.1%); three CIN and two SCC cases. Three had tumor-positive surgical margins. The mean postoperative follow-up duration for the entire cohort was 19.3 months, ranging from 12 to 84 months. Recurrence occurred in 2 patients within 7–12 months postoperatively, two cases after 1 year, and one at 2 years. Two patients were treated with topical MMC 0.04% QID for three cycles and had complete tumor resolution without surgery. Meanwhile, three patients had chemo reduction with topical MMC 0.02% QID for three cycles followed by repeat surgical excision [Table 9]. A summary of patients with recurrence is shown in Table 10.
Table 9.
Treatment outcome (n=5 recurrent cases)
| n (%) | |
|---|---|
| Total of recurrence (n=5/62;8.1) | |
| CIN | 3 (4.8) |
| SCC | 2 (3.3) |
| Duration of recurrence (n=5 eyes) (months) | |
| 7–12 | 2 (40) |
| >12 | 3 (60) |
| Management of recurrence (n=5 eyes) | |
| Chemoadjuvant with G. MMC 0.04% QID ×3 cycles | 2 (40) |
| Chemoreduction and wide excision biopsy and cryotherapy | 3 (60) |
CIN=Conjunctival intraepithelial neoplasia, SCC=Squamous cell carcinoma, MMC=Mitomycin C, QID=Four times daily, G. MMC=Gutt mitomycin C
Table 10.
Recurrence of ocular surface squamous neoplasia in 5 patients after excisional biopsy and adjunctive cryotherapy
| HPE | Age | Sex | Eye | Tumor size | Involvement | Characteristic | Surgical margin | Time to recur | Treatment for recurrence | Final outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| CIN II | 63 | Male | Right | Medium | Cornea | Diffuse | Negative | 1 year | G. MMC 0.02% QID ×3 cycles then repeat surgical excision | No recurrence at 6 months |
| CIN II | 73 | Right | Medium | Conjunctiva and limbus | Papilliform | Positive | 1 year | G.MMC 0.04% QID ×3 cycles | Complete resolution | |
| CIN I | 72 | Left | Medium | Bulbar conjunctiva | Gelatinous | Negative | 10 months | G.MMC 0.04% QID ×3 cycles | Complete resolution | |
| SCC | 69 | Left | Medium | Bulbar conjunctiva | Papilliform | Positive | 7 months | G. MMC 0.02% QID ×3 cycles then repeat surgical excision | No recurrence at 24 months | |
| SCC | 70 | Left | Medium | Limbus and cornea | Gelatinous | Positive | 2 years | No recurrence at 15 months |
CIN=Corneal/conjunctival intraepithelial neoplasia, SCC=Squamous cell carcinoma, G=Guttae (drops), MMC=Mitomycin C, QID=Quater in die (four times a day), HPE=Histopathological Examination
Table 11 shows the predicting factors of OSSN recurrence. Tumor pigmentation was the only significant predictive risk factor for recurrence (P = 0.026). No association was found between OSSN recurrence and sex, previous history of OSSN, tumor size or grade, surgical margin, or treatment completion with MMC [Table 11].
Table 11.
Predicting factors that influence the recurrence of ocular surface squamous neoplasia (n=62 eyes)
| Variable | Recurrence | P a | |
|---|---|---|---|
|
| |||
| Yes (n=5), n (%) | No (n=57), n (%) | ||
| Age, median (IQR) | 69.0 (15.0) | 67.0 (15.0) | 0.979b |
| Gender | >0.995 | ||
| Male | 4 (8.9) | 41 (91.1) | |
| Female | 1 (7.1) | 13 (92.9) | |
| Previous history of OSSN | 0.511 | ||
| Yes | 1 (12.5) | 7 (87.5) | |
| No | 4 (7.4) | 50 (92.6) | |
| Size of tumor (h) | 0.586 | ||
| <3 clock | 1 (6.7) | 14 (93.3) | |
| 3–6 clock | 5 (12.5) | 28 (87.5) | |
| >6 clock | 0 | 15 (100.0) | |
| OSSN grade | 0.747 | ||
| CIN I | 1 (8.3) | 11 (91.7) | |
| CIN II | 2 (16.7) | 10 (83.3) | |
| CIN III | 1 (5.3) | 18 (94.7) | |
| SCC | 1 (5.3) | 18 (94.7) | |
| Tumor pigmentation | 0.026 OR: 10.71 95% CI: 1.5–75.8 | ||
| Yes | 3 (30.0) | 7 (70.0) | |
| No | 2 (3.8) | 50 (96.2) | |
| Surgical margin | >0.995 | ||
| Positive | 3 (6.3) | 15 (93.8) | |
| Negative | 2 (4.5) | 42 (95.5) | |
| Treatment with MMC | >0.995 | ||
| Complete | 5 (8.6) | 53 (91.4) | |
| Incomplete | 0 | 2 (100.0) | |
aFisher’s exact test, bMann–Whitney test. CIN=Corneal/conjunctival intraepithelial neoplasia, SCC=Squamous cell carcinoma, OR=Odds ratio, CI=Confidence interval, MMC=Mitomycin C, OSSN=Ocular surface squamous neoplasia, IQR=Interquartile range
Discussion
This study found that OSSN in Malaysia was prevalent in males, with an average age of 65.2 years (24 years to 87 years), consistent with previous studies.[5,27,28] Earlier research also revealed that men over 55 years old were afflicted 2–4 times more frequently than women, likely due to greater sunlight exposure from outdoor work.[29,30] In contrast, OSSN in African countries affects younger individuals and tends to be more aggressive, with both sexes equally impacted, possibly due to HIV and HPV infections.[5,31,32]
The majority of our study participants were farmers. Gebremariam et al. found that farmers and males have higher UV solar radiation exposure, a major etiological factor in the pathology of OSSN.[32,33] In this study, sun exposure (48.9%) and smoking (26.1%) were the primary risk factors. Spending more than 50% of the time outdoors daily within 6 years, living within 30° of the equator, and having fair skin have been shown to be risk factors for UVB-induced OSSN.[1] UV-B radiation causes DNA damage, forming abnormal pyrimidine dimers which distort DNA structure and block DNA synthesis.[7] While previous studies found no association between smoking and OSSN,[1,12,34] our findings align with Napora et al., who found an association between cigarette smoking and OSSN.[8] Smoking induces carcinogenesis via DNA damage and gene mutation.[35]
This study found that the main presenting symptom was the presence of a mass, followed by eye irritation and visual impairment. For laterality, the left eye is more affected in CIN, whereas both sides are equally affected in SCC. Most tumors were located in the limbal region, which harbors stem cells with unlimited regenerative capacities, consistent with previous studies.[7] The temporal (46.7%) and nasal (33.9%) bulbar conjunctiva were the most affected areas, likely due to increased UV exposure. The temporal limbus receives direct sunlight exposure, and depending on the angle of incidence (θ) and the corneal central radius of curvature (r0), the light is then focused onto the nasal limbus with up to a 20-fold increase in intensity.[7] In our study, the most common clinical finding of OSSN was a gelatinous mass (32.3%), consistent with studies in the Middle Eastern and Indian populations.[26,28,36,37] The diffuse form (4.8%) was the least common. Ten (16.1%) eyes had pigmented tumors, similar to findings in Indian and Asian populations, where up to 9% of tumors showed hyperpigmentation, possibly related to the racial skin pigmentation in these populations.[23,36,38]
A wide excisional biopsy with HPE is the gold standard to treat and diagnose OSSN, and differentiate benign, preinvasive, and invasive tumors.[24] Although wide excisional biopsy with adjuncts has traditionally been used to treat OSSN, recent trends favor surgical excision as monotherapy.[16,19,39] In our study, most cases were treated with surgical excision, though extensive tumors were first reduced with preoperative topical MMC 0.02% QID for three cycles. Topical MMC 0.02% QID was used as the first-line chemotherapeutic treatment in 98.3% of the cases, preferred over IFNα2b because of its availability, cost-effectiveness, and low rates of recurrence and complications.[40,41,42] In our study, 91.8% of participants experienced no side effects from topical MMC. MMC targets rapidly dividing cells and has significant anti-tumor activity.[24] Since 1994, MMC has been used to treat both primary and recurrent OSSN, with Shield et al. reporting its safety and effectiveness, including for extensive recurrent tumors.[41,42]
Although OSSN is a low-grade malignancy, one patient with SCC (1.6%) in this study had local intraorbital spread, detected via computed tomography scan. The patient refused exenteration and external beam radiotherapy and was lost to follow-up. Previous studies have reported that intraocular and orbital invasion in 2%–13% and 12%–16% of invasive cases, respectively.[26,43] Distant metastasis is also uncommon, with 0%–16% of SCC cases having metastasis to regional lymph nodes.[25,43] In the present study, none of our patients had distant metastasis.
The recurrence rate of OSSN after surgical excision varies widely, from 10% to 56% during follow-up of 1–6.5 years.[1,2,12,26,30,37,44,45] Recurrence was consistently higher if the tumor was incompletely removed and was much lower with adjuncts such as cryotherapy and chemotherapy.[24] In our study, the recurrence rate was 8.1%, with all recurrences occurring more than 7 months postoperatively. This is consistent with Li et al.’s study, which found a recurrence rate of 7.1% at 1, 2, and 5 years after excision and cryotherapy.[45] All patients in our study received postoperative topical MMC, regardless of surgical margin status. Birkholz et al. showed that MMC reduced recurrence from 55.6% to 12.5% in eyes with positive margins, and from 83.3% to 0% in eyes with negative margins.[46] Chen et al. also reported zero recurrence in patients who received postoperative topical MMC, supporting its effectiveness to prevent OSSN recurrence.[23]
Previous studies have reported that risk factors for tumor recurrence after treatment included tumor size based on staging, local invasion, positive surgical margins, postoperative use of topical chemotherapy,[45,47,48,49] higher pathologic grade, and corneal location.[47,48,49] In our study, tumor pigmentation was the only significant risk factor associated with recurrence (P = 0.026), with an odds ratio of 10.71 (95% confidence interval: 1.5–75.8). This differs from Tananuvat et al., who reported no such association (P = 0.462).[24] Shields et al. postulated that intratumoral dendritic melanocytes in some pigmented tumors may actually be a manifestation of SCC, making it probable that the tumor is of a higher grade or the invasive type.[47] It is important to avoid overinterpreting the association of recurrence with tumor pigmentation in this study, as the statistical significance of P = 0.026 is borderline and derived from a small sample (n = 5 recurrent cases).
This study has several limitations. First, it is a retrospective cohort study with a 5-year review of OSSN cases, and some data were missing due to the retrospective design. In addition, the study was conducted during the COVID-19 pandemic, and some patients may have missed follow-up or diagnosis due to the movement control orders. Second, the number of recurrence cases in this study might not reflect the actual number of recurrent cases since recurrent cases was observed at least up to 1 year posttreatment. A study with a longer minimum postoperative follow-up may show more recurrent cases. Third, only univariate statistical tests (Fisher’s exact and Mann–Whitney) are presented. A full multivariate regression is not feasible due to the small recurrence numbers. Future studies with larger samples might explore the relationship between recurrence with the grade of OSSN, as well as the margin status, which this study found no significant association. Further studies with longer follow-up periods and more samples are needed to assess the recurrence rate more accurately. The strength of this study lies in its distinction as the first large-scale cohort analysis from two leading tertiary cornea centers in Malaysia, providing invaluable data on OSSN. Furthermore, it demonstrates the efficacy of topical MMC in managing OSSN, yielding satisfactory outcomes.
Conclusion
CIN is more common than SCC, predominantly affects the male population in Malaysia with a history of regular sun exposure and smoking. Topical MMC plays a crucial role as an adjunct in reducing the recurrence rate of OSSN. Tumor pigmentation was found to be a significant risk factor associated with recurrence. Our study enhances the understanding of OSSN in the Malaysian population, with the goal of minimizing the associated ocular morbidity and mortality.
Data availability statement
The datasets generated during and/or analyzed during the current study are not publicly available to maintain the participating patients’ confidentiality and are kept at their respective treatment centers, but are available from the corresponding author on reasonable request.
Conflicts of interest
The authors declare that there are no conflicts of interests of this paper.
Acknowledgments
The authors thank Nur Akmal Bahar and Nadiah Sa’at for consultation on statistical analyses.
Funding Statement
Nil.
References
- 1.Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol. 1995;39:429–50. doi: 10.1016/s0039-6257(05)80054-2. [DOI] [PubMed] [Google Scholar]
- 2.Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49:3–24. doi: 10.1016/j.survophthal.2003.10.008. [DOI] [PubMed] [Google Scholar]
- 3.Lee GA, Hirst LW. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Arch Ophthalmol. 1992;110:525–7. doi: 10.1001/archopht.1992.01080160103042. [DOI] [PubMed] [Google Scholar]
- 4.Sun EC, Fears TR, Goedert JJ. Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:73–7. [PubMed] [Google Scholar]
- 5.Gichuhi S, Sagoo MS, Weiss HA, Burton MJ. Epidemiology of ocular surface squamous neoplasia in Africa. Trop Med Int Health. 2013;18:1424–43. doi: 10.1111/tmi.12203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Pe’er J. Ocular surface squamous neoplasia. Ophthalmol Clin North Am. 2005;18:1–13, vii. doi: 10.1016/j.ohc.2004.08.001. [DOI] [PubMed] [Google Scholar]
- 7.Gichuhi S, Ohnuma S, Sagoo MS, Burton MJ. Pathophysiology of ocular surface squamous neoplasia. Exp Eye Res. 2014;129:172–82. doi: 10.1016/j.exer.2014.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Napora C, Cohen EJ, Genvert GI, Presson AC, Arentsen JJ, Eagle RC, et al. Factors associated with conjunctival intraepithelial neoplasia: A case control study. Ophthalmic Surg. 1990;21:27–30. [PubMed] [Google Scholar]
- 9.Mittal R, Rath S, Vemuganti GK. Ocular surface squamous neoplasia –Review of etio-pathogenesis and an update on clinico-pathological diagnosis. Saudi J Ophthalmol. 2013;27:177–86. doi: 10.1016/j.sjopt.2013.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lee GA, Hirst LW. Retrospective study of ocular surface squamous neoplasia. Aust N Z J Ophthalmol. 1997;25:269–76. doi: 10.1111/j.1442-9071.1997.tb01514.x. [DOI] [PubMed] [Google Scholar]
- 11.Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol. 1997;115:808–15. doi: 10.1001/archopht.1997.01100150810025. [DOI] [PubMed] [Google Scholar]
- 12.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;104:485–92. doi: 10.1016/s0161-6420(97)30287-5. [DOI] [PubMed] [Google Scholar]
- 13.Basti S, Macsai MS. Ocular surface squamous neoplasia: A review. Cornea. 2003;22:687–704. doi: 10.1097/00003226-200310000-00015. [DOI] [PubMed] [Google Scholar]
- 14.Shields CL, Demirci H, Marr BP, Masheyekhi A, Materin M, Shields JA. Chemoreduction with topical mitomycin C prior to resection of extensive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol. 2005;123:109–13. doi: 10.1001/archopht.123.1.109. [DOI] [PubMed] [Google Scholar]
- 15.Wilkes TD, Fraunfelder FT. Principles of cryosurgery. Ophthalmic Surg. 1979;10:21–30. [PubMed] [Google Scholar]
- 16.Peksayar G, Soytürk MK, Demiryont M. Long-term results of cryotherapy on malignant epithelial tumors of the conjunctiva. Am J Ophthalmol. 1989;107:337–40. doi: 10.1016/0002-9394(89)90655-7. [DOI] [PubMed] [Google Scholar]
- 17.Adler E, Turner JR, Stone DU. Ocular surface squamous neoplasia: A survey of changes in the standard of care from 2003 to 2012. Cornea. 2013;32:1558–61. doi: 10.1097/ICO.0b013e3182a6ea6c. [DOI] [PubMed] [Google Scholar]
- 18.Nanji AA, Moon CS, Galor A, Sein J, Oellers P, Karp CL. Surgical versus medical treatment of ocular surface squamous neoplasia: A comparison of recurrences and complications. Ophthalmology. 2014;121:994–1000. doi: 10.1016/j.ophtha.2013.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Stone DU, Butt AL, Chodosh J. Ocular surface squamous neoplasia: A standard of care survey. Cornea. 2005;24:297–300. doi: 10.1097/01.ico.0000138834.42489.ba. [DOI] [PubMed] [Google Scholar]
- 20.Cicinelli MV, Marchese A, Bandello F, Modorati G. Clinical management of ocular surface squamous neoplasia: A review of the current evidence. Ophthalmol Ther. 2018;7:247–62. doi: 10.1007/s40123-018-0140-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Rahimi F, Alipour F, Ghazizadeh Hashemi H, Hashemian MN, Mehrdad R. Topical mitomycin-C for treatment of partially-excised ocular surface squamous neoplasia. Arch Iran Med. 2009;12:55–9. [PubMed] [Google Scholar]
- 22.Heigle TJ, Stulting RD, Palay DA. Treatment of recurrent conjunctival epithelial neoplasia with topical mitomycin C. Am J Ophthalmol. 1997;124:397–9. doi: 10.1016/s0002-9394(14)70834-7. [DOI] [PubMed] [Google Scholar]
- 23.Chen C, Louis D, Dodd T, Muecke J. Mitomycin C as an adjunct in the treatment of localised ocular surface squamous neoplasia. Br J Ophthalmol. 2004;88:17–8. doi: 10.1136/bjo.88.1.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Tananuvat N, Niparugs M, Wiwatwongwana D, Lertprasertsuk N, Mahanupap P. Ocular surface squamous neoplasia in Northern Thailand: A 16-year review. BMC Ophthalmol. 2022;22:121. doi: 10.1186/s12886-022-02340-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Meel R, Dhiman R. Proposal for a new classification for ocular surface squamous neoplasia. Eye (Lond) 2018;32:1284–5. doi: 10.1038/s41433-018-0058-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Tunc M, Char DH, Crawford B, Miller T. Intraepithelial and invasive squamous cell carcinoma of the conjunctiva: Analysis of 60 cases. Br J Ophthalmol. 1999;83:98–103. doi: 10.1136/bjo.83.1.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Dandala PP, Malladi P, Kavitha Ocular surface squamous neoplasia (OSSN): A retrospective study. J Clin Diagn Res. 2015;9:C10–3. doi: 10.7860/JCDR/2015/16207.6791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Asadi-Amoli F, Ghanadan A. Survey of 274 patients with conjunctival neoplastic tumors in Farabi Eye Hospital, Tehran 2006–2012. J Curr Ophthalmol. 2015;27:37–40. doi: 10.1016/j.joco.2015.09.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Gichuhi S, Macharia E, Kabiru J, Zindamoyen AM, Rono H, Ollando E, et al. Risk factors for ocular surface squamous neoplasia in Kenya: A case-control study. Trop Med Int Health. 2016;21:1522–30. doi: 10.1111/tmi.12792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Kim BH, Kim MK, Wee WR, Oh JY. Clinical and pathological characteristics of ocular surface squamous neoplasia in an Asian population. Graefes Arch Clin Exp Ophthalmol. 2013;251:2569–73. doi: 10.1007/s00417-013-2450-0. [DOI] [PubMed] [Google Scholar]
- 31.Höllhumer R, Williams S, Michelow P. Observational study of ocular surface squamous neoplasia: Risk factors, diagnosis, management and outcomes at a tertiary eye hospital in South Africa. PLoS One. 2020;15:e0237453. doi: 10.1371/journal.pone.0237453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gebremariam TH, Wolde YA, Alemu DS, Alemu BA, Legesse K. Clinical and histopathological characteristics of ocular surface squamous neoplasia: Evidence from a tertiary eye care centre, Northwest Ethiopia. Trends Med. 2018;18:1–4. [Google Scholar]
- 33.Newton R, Ferlay J, Reeves G, Beral V, Parkin DM. Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye. Lancet. 1996;347:1450–1. doi: 10.1016/s0140-6736(96)91685-2. [DOI] [PubMed] [Google Scholar]
- 34.Early AD, Adelson S, Miller CJ, Mauger TF. Lack of relationship between cigarette smoking and alcohol use with dysplasia grade in ocular surface squamous neoplasia. Clin Ophthalmol. 2018;12:1901–4. doi: 10.2147/OPTH.S165968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Chen RJ, Chang LW, Lin P, Wang YJ. Epigenetic effects and molecular mechanisms of tumorigenesis induced by cigarette smoke: An overview. J Oncol. 2011;2011:654931. doi: 10.1155/2011/654931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Meel R, Dhiman R, Vanathi M, Pushker N, Tandon R, Devi S. Clinicodemographic profile and treatment outcome in patients of ocular surface squamous neoplasia. Indian J Ophthalmol. 2017;65:936–41. doi: 10.4103/ijo.IJO_251_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Chauhan S, Sen S, Sharma A, Tandon R, Kashyap S, Pushker N, et al. American joint committee on cancer staging and clinicopathological high-risk predictors of ocular surface squamous neoplasia: A study from a tertiary eye center in India. Arch Pathol Lab Med. 2014;138:1488–94. doi: 10.5858/arpa.2013-0353-OA. [DOI] [PubMed] [Google Scholar]
- 38.Yousef YA, Finger PT. Squamous carcinoma and dysplasia of the conjunctiva and cornea: An analysis of 101 cases. Ophthalmology. 2012;119:233–40. doi: 10.1016/j.ophtha.2011.08.005. [DOI] [PubMed] [Google Scholar]
- 39.Sayed-Ahmed IO, Palioura S, Galor A, Karp CL. Diagnosis and medical management of ocular surface squamous neoplasia. Expert Rev Ophthalmol. 2017;12:11–9. doi: 10.1080/17469899.2017.1263567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Majmudar PA, Epstein RJ. Antimetabolites in ocular surface neoplasia. Curr Opin Ophthalmol. 1998;9:35–9. doi: 10.1097/00055735-199808000-00006. [DOI] [PubMed] [Google Scholar]
- 41.Shields CL, Naseripour M, Shileds JA. Topical MMC for extensive, recurrent conjunctival-corneal squamous cell carcinoma. Am J Ophthalmol. 2002;133:601–6. doi: 10.1016/s0002-9394(02)01400-9. [DOI] [PubMed] [Google Scholar]
- 42.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 Ophthal. 2019;94:1316–21. doi: 10.1136/bjo.2009.176099. [DOI] [PubMed] [Google Scholar]
- 43.Iliff WJ, Marback R, Green WR. Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol. 1975;93:119–22. doi: 10.1001/archopht.1975.01010020125005. [DOI] [PubMed] [Google Scholar]
- 44.Ma IH, Hu FR, Wang IJ, Chen WL, Hsu YJ, Chu HS, et al. Clinicopathologic correlation of ocular surface squamous neoplasia from a university hospital in North Taiwan 1994 to 2014. J Formos Med Assoc. 2019;118:776–82. doi: 10.1016/j.jfma.2018.09.001. [DOI] [PubMed] [Google Scholar]
- 45.Li AS, Shih CY, Rosen L, Steiner A, Milman T, Udell IJ. Recurrence of ocular surface squamous neoplasia treated with excisional biopsy and cryotherapy. Am J Ophthalmol. 2015;160:213–9.e1. doi: 10.1016/j.ajo.2015.04.027. [DOI] [PubMed] [Google Scholar]
- 46.Birkholz ES, Goins KM, Sutphin JE, Kitzmann AS, Wagoner MD. Treatment of ocular surface squamous cell intraepithelial neoplasia with and without mitomycin C. Cornea. 2011;30:37–41. doi: 10.1097/ICO.0b013e3181dee560. [DOI] [PubMed] [Google Scholar]
- 47.Shields CL, Manchandia A, Subbiah R, Eagle RC, Jr, Shields JA. Pigmented squamous cell carcinoma in situ of the conjunctiva in 5 cases. Ophthalmology. 2008;115:1673–8. doi: 10.1016/j.ophtha.2008.01.020. [DOI] [PubMed] [Google Scholar]
- 48.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;119:1974–81. doi: 10.1016/j.ophtha.2012.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Mirzayev I, Gündüz AK, Özalp AteşFS, Özcan G, Işık MU. Factors affecting recurrence after surgical treatment in cases with ocular surface squamous neoplasia. Int J Ophthalmol. 2019;12:1426–31. doi: 10.18240/ijo.2019.09.09. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are not publicly available to maintain the participating patients’ confidentiality and are kept at their respective treatment centers, but are available from the corresponding author on reasonable request.