OSSN is the most common ocular surface tumour.3 It has two major patterns of presentation, an older white male, and younger black female population.3 The leading risks associated with OSSN are UVB exposure and HIV infection.4 Our study describes the demographic pattern, clinical presentation and associated risks in an urban South African population.
The traditional description of OSSN demographics has been dichotomous with HICs (previously ‘developed’ countries) describing an older white male population where UVB exposure is the main risk factor and LMICs (previously ‘developing’ countries) describing a younger female population.3 This difference has been ascribed to HIV which disproportionately affects LMICs and is a known risk factor for OSSN.3,8 Our study (from South Africa, a middle income country) found OSSN in a young population with a median age of 44 years but no particular gender predilection. Table 4 summarises the age and gender associations with OSSN that have been reported, in the literature, from around the world and relates these to the gross national income (GNI) per capita and HIV prevalence of the country (and in the year) in which the research was conducted. As can be seen, it is necessary for us to update our classification of OSSN into low, middle and high-income countries. The low income countries demonstrate the young, female demographic in OSSN prevalence, the high income the older male demographic, with middle income countries falling between the two with an intermediate age and no gender predilection. Our study’s young population can be explained by the high HIV prevalence that likely resulted in an earlier age of presentation in South Africa (as with Botswana). In common with other middle income countries our cohort did not show a gender predilection. Future studies could further investigate the relationship between income, risk factors and OSSN.
Table 4
Comparison of gross national income, HIV infection rates, and demographics in OSSN for studies conducted in low, middle and high income countries.
Country
|
GNI per capita
|
HIV Prevalence
|
Mean Age
|
Male: Female
|
Low Income Countries
|
Kenya (2015)11
|
$1300
|
2.6%
|
41 years
|
1:2
|
Kenya (2016)8
|
$1460
|
2.6%
|
42 years
|
1:2.6
|
Kenya (2017)12
|
$1510
|
2.6%
|
42 years
|
1:1.8
|
India (2015)13
|
$1600
|
0.19%
|
40 years
|
1:0.4
|
Nigeria (2021)14
|
$2100
|
1.4%
|
48 years
|
1:1
|
Nigeria (2010)15
|
$2150
|
4.6%
|
39 years
|
1:1.5
|
India (2022)16
|
$2170#
|
0.19%
|
49 years
|
1:0.5
|
Middle Income Countries
|
Botswana (2015)17
|
$6430
|
15.7%
|
38 years
|
1:1.4
|
South Africa (2022)
|
$6440#
|
13.7%
|
44 years
|
1:1.1
|
Thailand (2022)18
|
$7260#
|
0.69%
|
59 years
|
1:0.5
|
Mexico (2022)19
|
$9380#
|
0.26%
|
66 years
|
1:0.8
|
High Income Countries
|
Canada (2020)20
|
$43540
|
0.17%
|
69 years
|
1:0.3
|
New Zealand (2021)21
|
$45340
|
0.06%
|
69 years
|
1:0.3
|
USA (2012)22
|
$52790
|
0.4%
|
71 years
|
1:0.5
|
USA (2020)23
|
$64 140
|
0.4%
|
66 years
|
1:0.8
|
USA (2021)24
|
$70 430
|
0.4%
|
71 years
|
1:0.25
|
GNI: gross national income |
*GNI data from the The World Bank10, HIV data from UNAIDS (data used from closest year)25 |
#GNI data from 2021 used, as 2022 data not yet available |
OSSN can be asymptomatic or present with symptoms ranging from redness, foreign body sensation, pain, epiphora and reduced vision.1,14,26 Our cases reported a similar symptom profile between the cases and controls. Pain was however a distinguishing feature with more pain reported in cases. Reduced vision and redness were reported to a greater degree in the control group, but this was likely due to selection bias as the controls were only offered surgery if they had significant astigmatism or persistent symptoms despite medical therapy.
The epicentre of OSSN in our study was largely at the limbus and in the conjunctiva. This is in keeping with large studies and follows the pathophysiology of OSSN, which is thought to originate from the limbal stem cells.7,13,16,18,27 OSSN is also most commonly reported in the interpalpebral space, with the nasal quadrant mostly affected.16,18 This is hypothesised to be due to the amplification of UVB radiation on the nasal limbus.27 Our results were in keeping with this, where the nasal quadrant was mostly affected followed by the temporal quadrant. On clinical examination there were several features that were significantly associated with OSSN. These include a mass with feeder vessels, leukoplakia and pigmentation. The large number of pigmented lesions in our study is likely due to our predominantly black African cohort where more pigmentation has been reported than in white patients.11 Pigmentation in OSSN lesions has been reported at 1% in a white cohort, 9% in a Thai cohort, 78% in an Indian cohort, and 55% in our mostly black African cohort.16,18,24 Mild and moderate pigmentation likely represents complexion associated melanosis. With severe pigmentation, the differential diagnosis should include a naevus, melanoma and OSSN. Conjunctival melanoma is an uncommon presentation in the black South African population, and so a high index of suspicion should be maintained for OSSN.28 Morphology was a further feature distinguishing OSSN from benign lesions. A fibrovascular lesion was more likely to be benign, whereas a leukoplakic or gelatinous lesion was more likely to be OSSN. Kaliki et al16 in India and Tananuvat et al18 in Thailand found papilliform lesions to be the most common morphological type, whereas Gichuhi et al11 in Kenya found a predominance of leukoplakic lesions. This difference may be attributed to different associated risk factors such as HPV infection, which could be reviewed in further studies.
Our study had a predominance of CIN lesions, with an even distribution between CIN 1, CIN 2 and CIN 3. This was followed by SCC and CiS. This differs from other African countries where SCC was the dominant histological finding.15,17,29 Our study resembles the histological profile of developed nations.17,18,21,24,30 Our study was conducted in an urban environment where there is easy access to healthcare services. This is reflected by the short delay of 2 days between presentation to a primary care centre and referral to our ophthalmic unit. This could explain the predominance of earlier histological grades of OSSN in our cohort. OSSN has been described as an incidental finding in pterygium surgery in 10% of cases.31 Our study found OSSN in 31% of cases that were clinically suspected to be pterygia. This highlights the importance of sending all specimens for histology to rule out OSSN.
HIV has been reported as an important association with OSSN, notably in Africa where prevalence rates are high.8,11,15, 32–34 The overall prevalence of HIV in our study was 61%. The cases had a prevalence of 74% while the controls had a prevalence of 32%. This is in keeping with other studies in Africa where prevalence rates of HIV in OSSN ranged from 74–79%.8,11,26,32 In HIC this is an uncommon association with prevalence rates of 3% in the United States.23 Although this highlights the importance of HIV as an associated risk for developing OSSN, this also means that 26% of OSSN patients in our group did not have HIV as a risk factor. There was a significant association between a lower CD4 and higher viral load for OSSN, but this did not hold up with regression analysis. There was a decreasing trend of CD4 count with more advanced histology of OSSN. Gichuhi et al8 also described an association between OSSN and CD4, with an OR of 37 when comparing a CD4 of < 200 and > 500, albeit it with a large confidence interval (95% CI: 7.98–174.5).
Other associated factors reviewed in our study included reported sun exposure, ocular trauma, history of ocular inflammatory disease, exposure to petroleum products, vitamin A levels and hepatitis infections. These were not shown to be statistically different between cases and controls. Of these, sun exposure is a known risk factor for the development of pterygia which made up most of the controls.35 It would therefore be difficult to draw any conclusions on the role of sun exposure as a risk factor for the cases in our group. South Africa is situated at the edge of the 30-degree high risk UV belt at 28.2 degrees, so it may be that sun exposure is not a significant risk factor in our cohort. The other risk factors we evaluated are not known associations with pterygia and therefore are also not likely associations with OSSN in our study population.35 This brings to the fore the importance of other associated factors such as HPV infection.
There are several limitations in this study. Recruitment occurred predominantly during the course of the COVID19 pandemic and was consequently affected by waves of infection where all research activity was halted. Cases were therefore not recruited from consecutive cases that presented to the clinic. We do not think that this would have resulted in selection bias, as many patients did not present during the peak waves of infection and there was consecutive recruitment in between waves. Several components of the questionnaire were subject to recall bias, such as duration of symptoms, when the mass was first noticed, diagnosis and initiation of treatment for HIV, previous ocular history, tobacco use, and sun exposure. Sun exposure only took into account the average amount of time in the sun over the recent months. This therefore did not account for previous sun exposure in younger years. Tumour thickness was compared to the eyelid as UBM was not available during the study. This is a crude method of measurement and used as a surrogate for UBM. This is not expected to have any effect of our results. In the HIV positive patients with a known diagnosis, data were not available from the initial point of diagnosis. This would have been a useful metric to determine if the nadir CD4 and viral loads had any impact on disease presentation. The controls only had 14 patients with HIV. This limited a more in-depth analysis of the effects of CD4, viral load and the effect of anti-retro-viral therapy. This was however a large group of patients with OSSN and represents the largest study conducted in South Africa.
Our study describes an OSSN cohort of a MIC, but with a lower age due to the high prevalence of HIV. The majority of cases presented with CIN lesions, rather than SCC reported in other African countries. Severe pigmentation was present more commonly than groups with a predominantly white patient profile. In black patients OSSN should be considered before melanoma when presenting with a clinically suspicious pigmented conjunctival mass. In keeping with other studies in Africa, HIV was the leading risk factor. Future studies could investigate the role of CD4 and viral load in an HIV cohort and the role of HPV.