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Keywords:

  • ocular surface squamous neoplasia;
  • conjunctival intraepithelial neoplasia;
  • conjunctival intraepithelial dysplasia;
  • ocular surface epithelial dysplasia;
  • conjunctival squamous cell carcinoma;
  • risk factors;
  • incidence

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References

Objectives

To describe the epidemiology and an aetiological model of ocular surface squamous neoplasia (OSSN) in Africa.

Methods

Systematic and non-systematic review methods were used. Incidence was obtained from the International Agency for Research on Cancer. We searched PubMed, EMBASE, Web of Science and the reference lists of articles retrieved. Meta-analyses were conducted using a fixed-effects model for HIV and cigarette smoking and random effects for human papilloma virus (HPV).

Results

The incidence of OSSN is highest in the Southern Hemisphere (16° South), with the highest age-standardised rate (ASR) reported from Zimbabwe (3.4 and 3.0 cases/year/100 000 population for males and females, respectively). The mean ASR worldwide is 0.18 and 0.08 cases/year/100 000 among males and females, respectively. The risk increases with exposure to direct daylight (2–4 h, OR = 1.7, 95% CI: 1.2–2.4 and ≥5 h OR = 1.8, 95% CI: 1.1–3.1) and outdoor occupations (OR = 1.7, 95% CI: 1.1–2.6). Meta-analysis also shows a strong association with HIV (6 studies: OR = 6.17, 95% CI: 4.83–7.89) and HPV (7 studies: OR = 2.64, 95% CI: 1.27–5.49) but not cigarette smoking (2 studies: OR = 1.40, 95% CI: 0.94–2.09). The effect of atopy, xeroderma pigmentosa and vitamin A deficiency is unclear.

Conclusions

Africa has the highest incidence of OSSN in the world, where males and females are equally affected, unlike other continents where male disease predominates. African women probably have increased risk due to their higher prevalence of HIV and HPV infections. As the survival of HIV-infected people increases, and given no evidence that anti-retroviral therapy (ART) reduces the risk of OSSN, the incidence of OSSN may increase in coming years.

Objectifs

Décrire l’épidémiologie et un modèle étiologique de la néoplasie squameuse de la surface oculaire (NSSO) en Afrique.

Méthodologie

Des méthodes d'analyse systématique et non systématique ont été utilisées. L'incidence a été obtenue auprès de l'Agence Internationale de Recherche sur le Cancer. Nous avons cherché dans PubMed, Embase, Web of Science et les listes de référence des articles trouvés. Des méta-analyses ont été effectuées en utilisant un modèle à effets fixes pour le VIH et le tabagisme et à effets aléatoires pour le VPH.

Résultats

L'incidence de la NSSO est la plus élevée dans l'hémisphère sud (160 sud), avec le taux le plus élevé normalisé selon l’âge (ASR) rapporté au Zimbabwe (3.4 et 3.0 cas/an/100.000 habitants chez les hommes et les femmes, respectivement). La moyenne ASR dans le monde entier est de 0.18 et 0.08 cas/an/100.000 chez les hommes et les femmes, respectivement. Le risque augmente avec l'exposition directe à la lumière du jour (2 à 4 heures, OR = 1.7; IC 95%: 1.2–2.4; et ≥ 5 heures OR = 1.8; IC 95%; 1.1–3.1) et le travail à l'extérieur (OR = 1.7; IC 95%: 1.1–2.6). La méta-analyse montre également une forte association avec le VIH (6 études: OR = 6.17; IC 95%: 4.83 à 7.89) et le VPH (7 études: OR = 2.64; IC 95%: 1.27 – 5.49) mais pas avec la cigarette (2 études: OR = 1.40, IC 95%: 0.94 à 2.09). L'effet de l'atopie, de la xérodermie pigmentaire et de la carence en vitamine A n'est pas clair.

Conclusions

L'Afrique a la plus forte incidence de NSSO dans le monde, où les hommes et les femmes sont équitablement touchés, contrairement à d'autres continents où la maladie masculine prédomine. Les femmes africaines ont probablement un risque accru en raison de la prévalence plus élevée des infections VIH et VPH chez elles. Comme la survie des personnes infectées par le VIH augmente et étant donné qu'aucune preuve n'existe sur la réduction du risque de NSSO par la thérapie antirétrovirale (ART), l'incidence de la NSSO pourrait augmenter dans les années à venir.

Objetivos

Describir la epidemiología y un modelo etiológico de neoplasia escamosa de la superficie ocular (NESS) en África.

Métodos

Se utilizaron métodos de revisión sistemáticos y no sistemáticos. La incidencia se obtuvo de la Agencia Internacional para la Investigación del Cáncer. Hemos buscado en PubMed, EMBASE, Web of Science y las listas de referencia de los artículos encontrados. Los meta-análisis se realizaron utilizando un modelo de efectos fijos para VIH y el fumar cigarillos y de efectos aleatorios para VPH.

Resultados

La incidencia de NESS es mayor en el hemisferio sur (160 Sur), con la mayor tasa estandarizada por edad (TEE) reportada para Zimbabwe (3.4 y 3.0 casos/año/100 000 habitantes para hombres y mujeres, respectivamente). La media de la TEE a nivel mundial es de 0.18 y 0.08 casos/año/100 000 entre hombres y mujeres, respectivamente. El riesgo aumenta con la exposición directa a la luz del sol (2–4 horas, OR = 1.7, IC 95%; 1.2–2.4 y ≥5 horas OR = 1.8, IC 95%; 1.1–3.1) y con realizar trabajos en el exterior (OR = 1.7, IC 95%; 1.1–2.6). El meta análisis también mostró una fuerte asociación con el VIH (6 estudios: OR = 6.17, IC 95%; 4.83–7.89) y el VPH (7 estudios: OR = 2.64, IC 95%; 1.27–5.49), pero no con el fumar cigarrillos (2 estudios: OR = 1.40, IC 95%; 0.94–2.09). El efecto de la atopia, la xeroderma pigmentosa y la deficiencia de vitamina A no están claros.

Conclusiones

África tiene la mayor incidencia de NESS en el mundo, donde hombres y mujeres están igualmente afectados, a diferencia de otros continentes en donde predomina la enfermedad en hombres. Las mujeres Africanas probablemente tienen un riesgo aumentado debido a la alta prevalencia de las infecciones con VIH y VPH. A medida que aumenta la supervivencia de personas infectadas con VIH, y sin evidencia de que la terapia antirretroviral (TAR) reduzca el riesgo de NESS, la incidencia de NESS podría aumentar en los próximos años.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References

Ocular surface squamous neoplasia (OSSN) is the most common ocular surface tumour (Grossniklaus et al. 1987). Other synonymous terms include ‘conjunctival epithelial neoplasia’, ‘ocular surface epithelial dysplasia’ and ‘conjunctival squamous cell neoplasia’ (Lee & Hirst 1992; McDonnell et al. 1992; Tulvatana 2003). OSSN covers a spectrum of disease ranging from non-invasive intra-epithelial dysplasia of the conjunctiva and cornea (CCIN) to invasive squamous cell carcinoma (Lee & Hirst 1995).

Clinical features

The disease may present with irritation, red eye, raised gelatinous mass and leucoplakia (Tunc et al. 1999). In Africans, it is often pigmented brown (Figure 1). OSSN is usually unilateral (Chisi et al. 2006) and arises at the limbus – the junction between the cornea and conjunctiva (Lee & Hirst 1997). Most lesions occur within the exposed part of the eyeball between the lids (Ateenyi-Agaba 1995; McKelvie 2002; Waddell et al. 2006). Up to 31.2% of cases seen are recurrent lesions (Chisi et al. 2006). Late stages present with a large fungating oculo-orbital mass (Ogun et al. 2009). Early lesions resemble benign growths such as pterygia and pingueculae. OSSN can be the first manifestation of HIV infection in about 50% of cases in HIV-endemic settings (Porges & Groisman 2003; Spitzer et al. 2008).

image

Figure 1. A range of clinical presentations of ocular surface squamous neoplasia (OSSN) in East Africa. (a) Small lesion with leukoplakia; (b) Medium sized lesion with pigmentation; (c) Large lesion with corneal extension but not involving the fornices; (d) Very large lesion extending into the orbit.

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Histopathology

Histologically, OSSN may be classified into 3 forms: benign, pre-invasive and invasive (Table 1; Basti & Macsai 2003). The term OSSN usually excludes the benign forms. The term ‘invasive’ indicates infiltration through the basement membrane of the conjunctival epithelium into the underlying stroma (Basti & Macsai 2003; Shields & Shields 2004).

Table 1. Histopathological classification of ocular surface squamous neoplasia (OSSN), Basti & Macsai (2003) and American Joint Committee on Cancer (2010)
  1. a

    The American Joint Committee on Cancer (AJCC) staging manual 2010 classifies CIS under CIN.

Benign
Squamous papilloma
Pseudoepitheliomatous hyperplasia
Benign hereditary intraepithelial dyskeratosis
Pre-invasive
Conjunctival intraepithelial neoplasia (CIN)
CIN I (mild dysplasia) – confined to the basal third of the conjunctival epithelium
CIN II (moderate dysplasia) – extends into the middle third of the conjunctival epithelium
CIN III (severe dysplasia) – extends into the superficial third of the conjunctival epithelium
CIS (carcinoma-in-situ) – full thickness dysplasiaa
Invasive
Squamous cell carcinoma
GX – grade cannot be defined
G1 – Well differentiated
G2 – Moderately differentiated
G3 – Poorly differentiated
G4 – undifferentiated
Mucoepidermoid carcinoma

Epidemiology overview

Two disease patterns of OSSN are recognised: older, predominantly male in temperate climates, not associated with HIV or human papilloma virus (HPV); and younger men and women, in tropical climates, associated with HIV and HPV. The latter represents a public health challenge in Africa in relation to the HIV pandemic and late presentation of large tumours (Ukponmwan et al. 2002; Chisi et al. 2006; Ogun et al. 2009), diagnostic difficulties (Furahini & Lewallen 2010), malignant transformation and high recurrence rates after treatment (1-year recurrence of 16.6% reported in Tanzania; Makupa et al. 2012). Experienced surgeons report lower recurrences (3.2%) after excision (Waddell et al. 2006). Trial data to guide management in this context are lacking (Gichuhi & Irlam 2013). For the temperate pattern of disease, one randomised controlled crossover trial in Australia compared mitomycin-C with placebo in participants whose average age was 67 years (Hirst 2007). There was a significant treatment effect on clinically assessed complete resolution of lesions (P = 0.0005), but no effect on histologically assessed complete resolution (P = 0.49).

Incidence rates and geographical variation

Incidence estimates for OSSN are difficult to ascertain and vary regionally (Table 2). The first paper to examine this used cancer registry data from International Agency for Research on Cancer (IARC; Newton et al. 1996). A subset of these data were used in a subsequent publication looking at variation in incidence across the USA (Emmanuel et al. 2012). However, published results need to be interpreted with caution – firstly, all eye cancers are classified together by the International Classification of Diseases for Oncology (ICD-O-3 C.69) while other databases classify squamous cell carcinoma of the conjunctiva (SCCC) with head and neck cancers (Lee et al. 2000; Curado et al. 2007; Parkin et al. 2010). OSSN is not recognised as a separate entity. Squamous cell carcinomas that are site-coded for the eye (C69) probably include some cancers that originate in the eyelid skin (WHO 2000, 2010; Curado et al. 2007). Secondly, the availability of histopathology services to confirm OSSN diagnosis is often limited in low- and middle-income countries (Furahini & Lewallen 2010). Thirdly, health information systems tend to capture invasive squamous cell carcinoma (SCC) but not earlier stages. Countries reporting higher rates of SCC (mostly in Africa) only started sending cancer registry data to IARC in the mid-1980s (Curado et al. 2007). Completeness of the current IARC database is hampered in that only data from 80 countries were submitted, of which 75% was of acceptable quality, and not all countries had data on squamous cell carcinoma in the eye under code C69. Africa had the lowest level of acceptable quality of data (36%). Fourthly, crude incidence rates can be influenced by population structure, a problem often addressed by reporting age-standardised incidence rates. Finally, in areas with limited health facilities for cancer treatment where a large number of patients are treated outside the reference area, incidence may be underestimated. Moreover, in defining incidence from different sources, it may be difficult to distinguish between recurrence or extension of an existing cancer on one hand and the development of a new primary on the other. Analysis of incidence time trends is also difficult if geographical coverage, ICD revisions and disease definitions in a registry change.

Table 2. Age-standardized incidence rates of squamous cell carcinoma in the eye (ICD-O-3 C.69) by continent for the period 1998–2002 (Curado et al. 2007)
RegionAge-standardized incidence rate (cases/year/100 000 pop)P-value
Males mean (95% CI)Females mean (95% CI)
  1. CI = confidence interval.

Africa1.38 (−1.00 to 3.75)1.18 (−1.08 to 3.43)0.853
Central & South America0.48 (0.33 to 0.62)0.21 (0.10 to 0.33)0.005
Oceania0.28 (0.14 to 0.41)0.05 (0.01 to 0.10)0.002
North America0.08 (0.06 to 0.10)0.00 (0.00 to 0.01)<0.001
Asia0.08 (0.01 to 0.14)0.05 (0.00 to 0.09)0.416
Europe0.05 (0.02 to 0.08)0.01 (0.00 to 0.03)0.033
Southern Hemisphere0.61 (0.14 to 1.09)0.33 (−0.12 to 0.78)0.355
Northern Hemisphere0.10 (0.06 to 0.14)0.05 (0.00 to 0.08)0.045
Worldwide estimate0.18 (0.09 to 0.26)0.08 (0.01 to 0.15)0.091

Methods for this review

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References

Systematic and non-systematic review methods were used. No a priori systematic review protocol had been published. Incidence data were obtained from the current IARC report (9th Volume) covering the period 1998–2002. The IARC collates data from cancer registries worldwide. The report uses ICD codes to show the age-standardised incidence per 100 000 population stratified by sex and histological type. Under code C.69 where eye cancers are reported, the four main groups are retinoblastoma, malignant melanoma, carcinomas (11.4% of all eye cancers), sarcoma and other unspecified tumours. Under carcinomas, there are three subgroups – SCC (principally tumours of the conjunctiva and cornea, comprising 70% of the carcinoma subgroup), other specified carcinoma (adenocarcinomas of the lacrimal gland and lacrimal duct) and unspecified carcinomas. We extracted data from the SCC subgroup. The coordinates locating each registry were obtained from http://itouchmap.com/latlong.html.

We searched PubMed, EMBASE and Web of Science for systematic reviews, meta-analysis and case–control studies using ‘OSSN’, ‘conjunctival squamous cell carcinoma’, ‘risk factors’ and their synonyms as key words with no language restrictions. Abstracts were assessed and studies were selected if they reported analysis of known or suspected risk factors. The search was conducted on 2 January 2013 and updated on 31 May 2013. Data were extracted from the full texts of articles and additional articles obtained from their reference lists. Meta-analyses were conducted where appropriate. A fixed-effects model was used for HIV and cigarette smoking. A random-effects model was chosen for HPV after investigation of heterogeneity.

Results and discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References

Africa has the highest age-standardised incidence rate of ocular SCC followed by Central and South America then Oceania (Australia, New Zealand and Hawaii), respectively (Table 2 and Figure 2). The rate in Africa is about 9–10 times higher than in Europe and North America. The highest incidence rate is 3.4 cases/year/100 000 among males and 3.0 cases/year/100 000 among females in Zimbabwe (Curado et al. 2007). Uganda follows with 1.6 cases/year/100 000 for males and females. Australia comes third with 0.3–0.5 cases/year/100 000 in parts of that country. Other countries have rates between 0 and 0.1 cases/year/100 000. The rates have a right-skewed bell-shaped distribution peaking at latitude 16° South (Figure 3). Incidence rates are higher in the Southern Hemisphere than the Northern Hemisphere, with male ASR = 0.61 cases/year/100 000 (95% CI: 0.14–1.09) and female ASR = 0.33 (95% CI: −0.12 to 0.78) in the Southern Hemisphere, compared with male ASR = 0.10 (95% CI: 0.06–0.14) and female ASR = 0.05 (95% CI: 0.00–0.08) in the Northern Hemisphere.

image

Figure 2. Worldwide mapping of the age-standardized incidence rates (ASR) of squamous cell carcinoma of the eye (ICD-O-3 C.69) for the period 1998–2002 (Curado et al. 2007). Key: Dot size is directly proportional to incidence. Males are shown in blue and females in red. Overlaps between males and females appear purple in colour.

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image

Figure 3. The age-standardized incidence rates (ASR) of squamous cell carcinoma of the eye (ICD-O-3 C.69) for the period 1998–2002 (Curado et al. 2007).

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The high rates in Africa are consistent with other estimates from the region. A Tanzanian study estimated the incidence of suspected OSSN from 2006 to 2008 using operating theatre records across the country. Although there was no histological confirmation in all cases, the incidence was found to be 2.2 cases/year/100 000 (Furahini & Lewallen 2010). Uganda reported a peak incidence of 3.5 cases/year/100 000 in 1992 (Ateenyi-Agaba 1995). More recent data from the Kampala Cancer Registry also show a marked increase, although it is reported as ocular cancer, rather than specifically as OSSN (Wabinga et al. 2000).

Cancer registry data in two African countries show that OSSN has become more prevalent with time. In Zimbabwe, the age-adjusted annual incidence rates of SCCC underwent a more than 10-fold increase from 0.17 to 1.8/100 000 between 1990 and 1999 (Masanganise et al. 2008) while the prevalence of OSSN among ocular surface tumour biopsy specimens increased from 33% in 1996 to 58% by 2000 (Pola et al. 2003).

OSSN is the most common indication for orbital exenteration performed in adults in Africa (Table 3). This surgical procedure to excise all the orbital tissue including stripping the periosteum from the orbital walls is performed in cases with advanced disease. More than half (≥57%) the exenterations performed in Africa are for OSSN compared with 32% in Australia and 9–15% in Europe and India. Although available data does not clearly distinguish those performed for primary eyelid disease from conjunctival disease, SCC still emerges as an important cause in Africa. Eyelid SCC is uncommon in Africa (Templeton 1967, 1973).

Table 3. The proportion of orbital exenterations performed due to ocular squamous cell carcinoma in different regions of the world
Year (ref.)CountryNo. of exenterations (N)No. due to SCCC (n)Proportion (n/N) (%)
  1. a

    Included children.

  2. b

    Mainly elderly patients.

2011 (Ackuaku-Dogbe 2011)Ghana251976
2001 (Masanganise & Magava 2001)Zimbabwe231357
2007 (Nemet et al. 2007)Australia381232
2004 (Pushker et al. 2004)India26315
2008 (Croce et al. 2008)Italya6113
2005 (Rahman et al. 2005)UKb6969

Incidence of OSSN by age and sex

In temperate countries, OSSN remains a rare, slow-growing tumour of elderly males (70–80% are males with a mean age of about 60 years; Lee & Hirst 1997; Tunc et al. 1999). In contrast, in tropical countries, particularly in Eastern and Southern Africa, the prevalence is highest among young people in their 30s and among women (50–70%; Table 4; Poole 1999; Pola et al. 2003; Chisi et al. 2006; Furahini & Lewallen 2010). Within East Africa, the pattern of SCCC in the 1960s differed to that seen today. In 1967, the average age of affected patients was 48 years, and males were four times more frequently affected than females (Templeton 1967).

Table 4. The age and sex of patients affected by ocular surface squamous neoplasia (OSSN)
Year (ref.)CountryMean age (years)Male (%)Female (%)Male:Female ratio
1995 (Ateenyi-Agaba 1995)Uganda3352481:2.3
2008 (Spitzer et al. 2008)Malawi3342581:2.1
2010 (Simbiri et al. 2010)Botswana3939611:1.6
2003 (Pola et al. 2003)Zimbabwe3530701:1.4
2002 (Mahomed & Chetty 2002)S. Africa3750501:1.3
2006 (Chisi et al. 2006)Kenya3850501:1
2012 (Makupa et al. 2012)Tanzania3932681:1
2009 (Ogun et al. 2009)Nigeria5443571:0.9
1999 (Tunc et al. 1999)USA6470301:0.4
2002 (McKelvie 2002)Australia6977231:0.3

Worldwide, IARC data show that the overall incidence is higher in males than females but the difference is not statistically significant (Figure 3 and Table 2). The mean male ASR worldwide is 0.18 cases/year/100 000 (95% CI: 0.09–0.26) and 0.08 (95% CI: 0.01–0.15) among females (P = 0.09). Incidence is significantly higher in males than females except in Africa and Asia where both sexes are equally affected (Table 2). Prevalence in Africa is higher in females than males (Table 4). This may be related to Africa having the highest prevalence of both HIV and HPV, which may increase the risk of OSSN in women and gender differences in mortality of HIV-infected adults. In South Africa, HIV-infected females have a longer life expectancy than HIV-infected males (Cornell et al. 2012; Johnson et al. 2013; Maskew et al. 2013). Men present in later stages of HIV/AIDS for antiretroviral therapy (ART) and possibly have poorer adherence to ART (Taylor-Smith et al. 2010). This has also been observed in Latin America, China and Lao (Dou et al. 2011; Gonzalez et al. 2011; Bastard et al. 2013). In Europe, the response to ART and mortality is similar for both sexes (Perez-Molina et al. 2012; Thorsteinsson et al. 2012).

Variation in disease severity

There may be variation in disease stage at presentation, with more advanced disease present at time of surgery in East Africa, compared with other regions (Table 5; Chisi et al. 2006; Waddell et al. 2010; Kao et al. 2012; Makupa et al. 2012). This may reflect delayed presentation to ophthalmic services in this region, leading to more advanced pathology by the time of surgery. Histopathological reporting is also subjective, and pathologists may not always grade tumours the same way (Margo et al. 2002). Alternatively, the disease may be intrinsically more aggressive in the East African region or HIV worsens disease progression.

Table 5. Stages of ocular surface squamous neoplasia (OSSN) seen at presentation in Africa and USA
Country year (ref.)Stage of OSSN, n (%)
Mild dysplasia (CIN I)Moderate dysplasia (CIN II)Severe dysplasia (CIN III)Carcinoma in situ (CIS)Well differentiated SCCModerately differentiated SCCPoorly differentiated SCC
Kenya 2006 (Chisi et al. 2006)7 (21.9)   1 (3.1)9 (28.1)15 (46.9)
Uganda 2008 (de Koning et al. 2008)17 (21.0)18 (22.2)22 (27.2)0 (0)24 (29.6)  
Uganda 2010 (Ateenyi-Agaba et al. 2010)39 (29.3)   94 (70.7)  
Uganda 2010 (Waddell et al. 2010)48 (15.1)66 (20.8)81 (25.5)0 (0)123 (38.7)  
Tanzania 2012 (Makupa et al. 2012)28 (21.2) 73 (55.3)0 (0)31 (23.5)  
Malawi 2013 (Tiong et al. 2013)1 (2.0)5 (10.2)9 (18.4)17 (34.7)17 (34.7)  
USA 2012 (Kao et al. 2012)48 (8.1)98 (16.4)59 (9.9)322 (54.0)69 (11.6)  

Risk factors

Various factors are thought to influence the causation of OSSN, but it is not clear how they interact or which is the most potent. The rising incidence of OSSN in recent decades may be driven by increased prevalence of these factors. We found no systematic reviews of risk factors for OSSN after the literature search. Of the case–control studies found, two in Uganda and Australia examined the association with solar exposure; six in Africa examined the association with HIV; sixteen examined the association with HPV; seven in Africa, five in Asia, one in Brazil, two in USA and one in Australia. Two studies examined cigarette smoking in Uganda.

Ultraviolet solar radiation

Several cutaneous malignancies, including melanoma and SCC, have a strong association with solar radiation. It was first noted in the 1960s that SCCC was relatively common in East Africa, and this apparent excess risk was attributed to higher exposure to sunlight (Templeton 1967). There is a strong relationship between the incidence of SCCC and increasing Ultraviolet (UV) levels (Newton et al. 1996). Using IARC data and published measurements of ambient solar ultraviolet light, the incidence of SCCC was found to reduce by 49% for every 10° increase in latitude from 1.2 cases/year/100 000 (Table 7) in Uganda (latitude 0.3°) to <0.02/year/100 000 in the UK (latitude > 50°). More recently, the National Institutes of Health/American Association of Retired Persons (NIH-AARP) Diet and Health Study in the USA found a slightly lower risk of SCCC in those who lived >35° compared with ≤35° from the equator, although this was not statistically significant (adjusted Hazard Ratio = 0.92, 95% CI: 0.49–1.71; Emmanuel et al. 2012). The USA has comparatively lower HIV prevalence, solar irradiance and incidence of OSSN than Africa, which is bisected by the equator. The high incidence of ocular SCC near the equator may be related to high solar irradiance (the amount of solar radiant energy incident on a surface per unit area and per unit time) in the world (World Energy Council 2007).

A case–control study in Uganda adjusted for age, sex, residential district, and HIV serostatus demonstrated that the risk of OSSN was higher with increasing time spent in daylight (Waddell et al. 2010). Compared with those who reported spending up to 1 h a day in direct sunlight, the odds ratio (OR) for those who spent 2–4 h was 1.7 (95% CI: 1.2–2.4), and for those who spent 5 or more hours a day, it was 1.8 (95% CI: 1.1–3.1). A case–control study in Australia reported that the strongest risk factor was a past history of skin cancer (OR = 15, 95% CI: 2.0–113.6), although other factors, including outdoor activity, pale skin and irides and propensity to burn, were also important (Lee et al. 1994).

More direct evidence for UV radiation induced damage in the pathophysiology of SCCC was described in another case–control study in Uganda in which 52% of the cases had mutations in the tumour suppressor gene TP53 compared with 14% of controls (Ateenyi-Agaba et al. 2004a). The mutations were mainly of the CC TT type, consistent with UV-induced mutagenesis. This gene also downregulates the replication of HPV type 16 via the viral E2 protein, suggesting that its mutation may allow replication of HPV particles (Brown et al. 2008). Further, exposure to UV radiation is associated with altered expression of matrix metalloproteinases (MMPs) and the tissue inhibitors of these metalloproteinases (TIMPs), molecules that may be responsible for tissue invasion and metastasis of tumours (Ng et al. 2008).

In addition, OSSN lesions occur more often at the limbus. A study in Uganda demonstrated that tumours almost always occur in sun-exposed areas of the eye (Waddell et al. 2006). It is thought that the human eye is more exposed laterally, making this a large collecting zone of peripheral sunlight, which, depending on the incident angle and radius of curvature of the cornea, is focused on the limbus, lens and lid margin, which are the main foci of sun-related eye diseases such as pterygium, OSSN, cataract and lid malignancies (Maloof et al. 1994). Low doses of ambient sunlight received on every day exposure inhibit immunity in the skin and internal organs (Halliday et al. 2012).

HIV

There is strong evidence that HIV is a major risk factor for OSSN. Uganda, which had a cancer registry since 1951, was the first country to report a dramatic increase in the annual incidence of SCCC shortly after the outbreak of HIV/AIDS. There was a sixfold increase from 0.6 cases/year/100 000 between 1970 and 1988 to 3.5/year/100 000 by 1992 (Figure 4; Ateenyi-Agaba 1995). A marked rise was also observed in the USA with the onset of the HIV pandemic (Guech-Ongey et al. 2008). At the same time, a US study observed a strong association in an HIV-infected cohort (OR = 13.0, 95% CI: 4–34; Goedert & Cote 1995). In Tanzania, regional incidence rates were significantly correlated with regional HIV prevalence (Pearson's r = 0.53, P = 0.03; Furahini & Lewallen 2010). The majority of patients (60–77%) with OSSN seen in Africa are HIV-infected (Table 6). A meta-analysis of 6 case–control studies (Table 7) in Uganda, Rwanda and Zimbabwe shows a strong association with HIV infection (pooled OR = 6.17, 95% CI: 4.83–7.89; Figure 5).

image

Figure 4. Sudden rise in the annual incidence rates of conjunctival SCCC in Kampala with the onset of the HIV pandemic – number of cases shown (Ateenyi-Agaba 1995).

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image

Figure 5. Meta-analysis of case-control studies of HIV infection in ocular surface squamous neoplasia (OSSN) in Africa (fixed effect).

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Table 6. Prevalence of HIV infection in cases of squamous cell carcinoma of the conjunctiva in Africa
Year (ref.)CountryStudy periodHIV prevalence in SCCC cases (%)
2012 (Makupa et al. 2012)Tanzania2005–200860
2011 (Osahon et al. 2011)Nigeria1999–200975
2002 (Mahomed & Chetty 2002)South Africa1995–199771
1995 (Ateenyi-Agaba 1995)Uganda1990–199175
1996 (Waddell et al. 1996)Uganda1993–199471
2003 (Porges & Groisman 2003)Zimbabwe1993–199591
2001 (Newton et al. 2001)Uganda1994–199877

The association with HIV suggests that immunosuppression plays a role in OSSN; however, a linear association between the CD4 lymphocyte count and OSSN has not been confirmed. A cross-sectional study conducted in Tanzania found a median CD4 cell count of 71 cells/μl among HIV-infected individuals with OSSN (Makupa et al. 2012). HIV-infected cases tended to have larger lesions: 71% had lesions >5 mm in diameter vs. 27% among HIV-negative individuals (OR = 3.13, 95% CI: 1.5–6.5). HIV-infected cases were also more likely to develop recurrent tumours within a year of excision (82% vs. 18%; OR = 3.54, 95% CI: 1.12–11.2). However, there was no significant trend found between CD4 count and the grade of OSSN (P = 0.94). In a Ugandan study, among 112 HIV-infected cases of CIN and invasive SCC, the median CD4 count at diagnosis was 111 cells/μL (IQR; 62–221; Waddell et al. 2006). Excess risks standardised incidence ratio (SIR = 19.5, 95% CI: 6.3–45.5) have also been observed among a cohort of kidney transplant recipients in Australia suggesting that immune suppression from other causes may play a role (Vajdic et al. 2007).

HAART does not reduce the incidence of SCCC according to data from the US HIV/AIDS Cancer Match (HACM) Study (Guech-Ongey et al. 2008) which compared SIRs in the pre-HAART and HAART eras among 491 048 adults aged ≥15 years with HIV/AIDS diagnosed from 1980 to 2004. The SIRs here estimate the excess risk of SCCC attributable to HIV/AIDS compared with a population with negligible HIV/AIDS prevalence and were similar at 12.0 (95% CI: 5.5–22.8) and 12.6 (95% CI: 4.6–27.4) in the pre- and post-HAART eras, respectively (P = 0.79). There is, however, a case report of ART causing tumour regression in an otherwise inoperable case (Holkar et al. 2005).

Human papilloma virus

The relationship between human papilloma virus (HPV) and OSSN is rather controversial with variable results. (Tulvatana 2003; Moubayed et al. 2004; Sen et al. 2007; de Koning et al. 2008; Guthoff et al. 2009; Simbiri et al. 2010; Yu et al. 2010). A review of 12 case series and 17 case–control studies concluded that there was no causal association between mucosal HPV types and OSSN while the role of cutaneous types was uncertain (de Koning et al. 2008). The studies included used different methods for testing of HPV (including PCR and serology), and different HPV types were examined. Conversely, a random-effects meta-analysis of various case–control studies shows that OSSN is associated with HPV infection in sub-Saharan Africa (pooled OR = 2.64, 95% CI: 1.27–5.49) and worldwide (pooled OR = 4.00, 95% CI: 2.11–7.57; Figure 6). The prevalence of HPV in OSSN ranges from 0% to 100% depending on geographical region with subtypes HPV18 and HPV16 being the most common (Table 8; di Girolamo 2012). Most African studies report prevalence of 75–85% (Ateenyi-Agaba et al. 2004b; Simbiri et al. 2010; Yu et al. 2010). HPV is more commonly isolated in OSSN than pterygium – on average, considering studies from different regions of the world, 33.8% of OSSN lesions and 18.6% of pterygia are HPV positive (di Girolamo 2012). There may be a true geographical variation in the prevalence of HPV in OSSN.

image

Figure 6. Meta-analysis of case-control studies of human papilloma virus (HPV) infection in ocular surface squamous neoplasia (OSSN) (random effects).

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Table 7. Characteristics of case–control studies included in the meta-analysis of HIV as a risk factor of ocular surface squamous neoplasia (OSSN)
Study period (ref.), CountryCasesControls
1989–1990 (Kestelyn et al. 1990), Rwanda11 patients with clinical evidence of conjunctival dysplasia or malignancy seen at Centre Hospitalier de Kigali22 controls. 2 controls per case from the same area matched for age and sex within 5 years. Referrals from elsewhere were excluded
1990–1991 (Ateenyi-Agaba 1995), Uganda48 patients with conjunctival growths who presented to the eye clinic at Mulago Hospital, Kampala48 patients matched for age and sex attending the same eye clinic with other eye diseases
1993–1994 (Waddell et al. 1996), Uganda38 patients in seven countrywide eye clinics including New Mulago Hospital, Kampala who had suspicious conjunctival lesions had excision biopsy of the lesion76 controls. 2 controls per case matched for age and sex. 16 Controls were patients in the eye clinic without neoplasia or clinical features of HIV disease; the remainder were general (non-eye clinic) anonymous outpatients at the same health units
1993–1995 (Porges & Groisman 2003), Zimbabwe13 cases from patients who underwent excisional biopsy for conjunctival lesions at Bindura Provincial Hospital (Mashonaland Central, Zimbabwe)7 controls. Patients were from the same group as cases but had benign lesions on histology
1994–1998 (Newton et al. 2001), Uganda22 cases. Patients aged >15 years with a provisional diagnosis of cancer from all wards and out-patient clinics of the 4 main hospitals in Kampala: Mulago, Nsambya, Mengo and Rubaga112 controls. 93 patients with tumours not suspected to be of infectious aetiology and 19 with non-malignant conditions
2001–2005 (Waddell et al. 2010), Uganda318 cases recruited from country-wide ophthalmology clinics in Uganda. Anyone with a suspected OSSN was offered surgical treatment and histology, together with enrolment into a case-control study762 controls were recruited from 2 sources. The first group comprised patients attending the ophthalmology clinics with concerns or conditions other than OSSN. This group also included those individuals who were originally recruited as cases, but where histology subsequently revealed another diagnosis. The second group comprised people who were recruited through the voluntary HIV counselling and testing (VCT) service
Table 8. Studies on the prevalence and subtypes of human papilloma virus (HPV) in ocular surface squamous neoplasia (OSSN)
Lead author (ref.)YearCountryDisease includedSample sizeDiagnostic methodHPV prevalence (%)HPV subtypes foundTissue used
  1. ? – means unclear or not mentioned.

  2. a

    The 21 subtypes were HPV types 1, 3, 7, 11, 13, 16, 18, 29, 39, 40, 43, 45, 59, 61, 68, 70, 77, 85, 89, 91, 97.

Africa
Ateenyi-Agaba (Ateenyi-Agaba et al. 2004a)2004UgandaSCC21PCR8614, 27, 37, 38Fresh frozen tissue shipped to France
Simbiri (Simbiri et al. 2010)2010BotswanaOSSN30PCR726, 11, 16, 18, 31, 33Fresh tissue shipped in tissue transport medium to USA
DNA sequencing10021 subtypesa
IHC72?
ISH61?
Waddell (Waddell et al. 2003)2003UgandaCIN I–III254anti-HPV antibodies1516Plasma shipped in dry ice to France
Newton (Newton et al. 2002)2002UgandaSCC39anti-HPV antibodies3616, 18, 45Serum shipped in dry ice to France
de Koning (de Koning et al. 2008)2008UgandaCIN I17PCR4735% gen, 29% cutFormalin-fixed paraffin-embedded tissue shipped overseas
CIN II185650% gen, 28% cut
CIN III224527% gen, 23% cut
SCC242242% gen, 13% cut
Ateenyi-Agaba (Ateenyi-Agaba et al. 2010)2010UgandaSCC94PCR456.4% muc, 44.7% cutFresh frozen biopsies shipped to the Netherlands
Dysplasia39417.7% muc, 41% cut
Tornesello (Tornesello et al. 2006)2006UgandaCIN I16PCR3120, CJ198, indeterm?
CIN II183318, 38, 100, DL473, PPHLIFR
CIN III231318, 100
SCC29314, 20,CJ198
North America
Scott (Scott et al. 2002)2002USADysplasia10PCR10016, 18Formalin-fixed paraffin-embedded tissue
Odrich (Odrich et al. 1991)1991USASCC3PCR10016?
McDonnell (McDonnell et al. 1992)1992USAOSSN42PCR/DB8816Formalin-fixed paraffin-embedded tissue
Lauer (Lauer et al. 1990)1990USAOSSN5PCR8016, 18?
Dushku (Dushku et al. 1999)1999USAOSSN8PCR0Nil detectedFresh tissue
Asia
Kuo (Kuo et al. 2006)2006TaiwanDysplasia9PCR1006, 11, 16, 18, 33, 58, 72Formalin-fixed paraffin-embedded tissue
Karcioglu (Karcioglu & Issa 1997)1997Saudi ArabiaCIS/SCC45PCR5616, 18Formalin-fixed paraffin-embedded tissue
Nakamura (Nakamura et al. 1997)1997JapanOSSN8PCR/IHC5016, 18Formalin-fixed paraffin-embedded tissue
Saegusa (Saegusa et al. 1995)1995JapanOSSN8PCR/ISH3816Formalin-fixed paraffin-embedded tissue
Toth (Toth et al. 2000)2000Saudi ArabiaSCC16PCR2516Formalin-fixed paraffin-embedded tissue
Manderwad (Manderwad et al. 2009)2009IndiaOSSN48PCR/ISH-CARD0Nil detectedFormalin-fixed paraffin-embedded tissue supplemented with 7 fresh tissues
Eng (Eng et al. 2002)2002TaiwanOSSN20PCR0Nil detectedFormalin-fixed paraffin-embedded tissue
Tulvatana (Tulvatana 2003)2003ThailandOSSN30PCR/DB0Nil detectedFormalin-fixed paraffin-embedded tissue
Sen (Sen et al. 2007)2007IndiaOSSN30IHC0Nil detectedFormalin-fixed, paraffin-embedded tissue
Oceania
Tabrizi (Tabrizi et al. 1997)1997AustraliaOSSN88PCR396, 11, 13, 16, 18Formalin-fixed paraffin-embedded tissue
Europe
Auw-Haedrich (Auw-Haedrich et al. 2006)2008GermanyDysplasia12PCR1716Freshly prepared formalin-fixed paraffin-embedded tissue
Toth (Toth et al. 2000)2000HungarySCC7PCR1418Formalin-fixed paraffin-embedded tissue
Reszec(Reszec & Sulkowski 2005)2005PolandSCC11 916, 18?
Guthoff (Guthoff et al. 2009)2009GermanyOSSN31PCR/IHC0Nil detectedFormalin-fixed paraffin-embedded tissue
Tuppurainen (Tuppurainen et al. 1992)1992FinlandCIS/SCC4PCR0Nil detected?

Differences in HPV prevalence in OSSN may be influenced by patient selection, sample handling in the operating theatre, preparation, storage, overseas shipping and the detection method. Variations may also be due to different testing methodology and the specific HPV types tested for. Most existing molecular diagnostic tests applied in OSSN testing for HPV were developed for cervical tissue testing. The sensitivity and specificity of various polymerase chain reaction (PCR) tests varies and may be influenced by various factors including the PCR design (nested, broad spectrum or type-specific), size of amplified product and choice of polymerase used (Munoz et al. 2012; Mesher et al. 2013). Detection of E6/E7 mRNA transcripts by quantitative reverse transcriptase–PCR (qRT-PCR) has been proposed as the gold standard for HPV testing (Smeets et al. 2007). However, RNA is unstable limiting this test to fresh frozen tissue (Kim et al. 2013). Testing for HPV DNA by PCR from paraffin-embedded archived tumour blocks may be complicated by contamination between samples at the time of initial tissue sectioning for DNA harvest (Boyd et al. 1996; Iftner & Villa 2003).

Generally, only a limited subset of HPV types has been investigated among OSSN cases. There are 170 genotypes of HPV described to date, which are broadly subdivided into cutaneous and mucosal types (de Villiers 2013). There are conflicting reports on which of these two are more commonly associated with OSSN. One study conducted in Uganda reported that among OSSN cases, the prevalence of mucosal types was higher than cutaneous types (38% vs. 22%) while from another study in the same population, the prevalence of cutaneous types was higher than mucosal types (43.6% vs. 6.8%; Table 8; de Koning et al. 2008; Ateenyi-Agaba et al. 2010). Multiple HPV types have been found in individual patients with OSSN tumours. One Ugandan study reported multiple HPV types in 57.1% of SCCC and 75% of dysplasia cases by PCR (Ateenyi-Agaba et al. 2010). In Botswana, multiple HPV types were identified in all OSSN and all pterygium specimens by DNA sequencing (Simbiri et al. 2010). The HPV types found by sequencing ranged from 4 to 21 types per sample. The same study also described co-infection with multiple other viral types per individual in 17 of 18 (94%) histologically proven OSSN specimens by PCR; 83% were positive for Epstein–Barr virus (EBV), 72% were HPV positive, 67% were Kaposi's sarcoma-associated herpesvirus (KSHV) positive, 67% were herpes simplex virus (HSV-1/2) positive and 56% were cytomegalovirus (CMV) positive. All the pterygium specimens from that study similarly had multiple viruses; 75% were positive for each of EBV, KSHV, CMV and HSV while 50% were HPV positive. The proportion of HPV infection in this series was much higher than any other studies in the region have reported raising the question whether this could be due to the methodology used.

The mechanism by which HPV is associated with OSSN is unknown. HPV is associated with causation of metaplasia in squamocolumnar epithelial transition zones such as the corneoscleral limbus and eyelid skin of the eye, the cervix and anus where there is active cell turnover and continuous cell division to replace desquamated cells (Chow et al. 2010). HPV also promotes degradation of the p53 gene (Scheffner et al. 1990).

The epidemiology of OSSN is closely related to that of cervical cancer with respect to high incidence in Africa and the association with HIV and HPV mainly types 18 and 16 (Sun et al. 1997; Clifford et al. 2003; Stanley 2010). A meta-analysis of HPV prevalence reports worldwide shows that Africa has the highest adjusted prevalence (22.1%; 95% CI: 20.9–23.4%) among women with cytologically normal cervical pap smears using PCR-based or high-risk Hybrid Capture 2 (HC-2) technology to detect HPV DNA (de Sanjose et al. 2007). Whether vaccination against HPV may help to reduce the incidence of OSSN remains to be seen (Hughes et al. 2008).

Occupation

Outdoor occupations have been associated with OSSN, probably related to UV solar radiation exposure. In Uganda, those with outdoor occupations had an OR of 1.7 (95% CI: 1.1–2.6) compared to those with indoor occupations (Waddell et al. 2010). Another in Uganda reported that 74% of 133 patients with SCCC or dysplasia had outdoor occupations (Ateenyi-Agaba et al. 2010). In Japan, exposure to petroleum products was also described as a risk factor for conjunctival intraepithelial neoplasia (synonym of OSSN) in a small age–sex-matched case–control study (Napora et al. 1990). Exposure to smoke from burning wood in the kitchen was described as a risk factor for cervical cancer among HPV-infected women in Honduras (Velema et al. 2002).

Cigarette smoking

Cigarette smoking is implicated in other squamous cell cancers (Haverkos 2004). There is, however, evidence of no effect from smoking on OSSN in Africa. In Uganda, two case–control studies showed that current smokers were not at a significantly higher risk for OSSN than non-smokers (Waddell et al. 2010; Ateenyi-Agaba et al. 2010; pooled OR = 1.40; 95% CI: 0.94–2.09; Figure 7). In a Nigerian series of 37 SCCC cases, only two patients (5.4%) had a history of cigarette smoking (Ogun et al. 2009) while in a series from Australia, 5 of 11 cases of SCCC (45%) were smokers (McKelvie 2002).

image

Figure 7. Meta-analysis of case-control studies in Uganda on cigarette smoking and ocular surface squamous neoplasia (OSSN) in Africa (fixed effect).

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Allergy

There is little evidence that allergic conjunctivitis is a risk factor. Among 215 SCCC cases in Tanzania, 1.9% had allergic conjunctivitis (Poole 1999). In Rwanda, allergic conjunctivitis was found in 4% of children and was responsible for 3–6% of hospital visits of all ages (de Smedt et al. 2013). In a case–control study in Uganda, none of the cases of OSSN had a history of allergic eye disease (Waddell et al. 2010). However, a case series of SCCC from Germany reported that 6/10 cases had atopic eczema, so this may be of more importance in temperate climates (Heinz et al. 2003).

Xeroderma pigmentosum

Xeroderma pigmentosum (XP), a rare, inherited skin disease characterised by high sensitivity to UV damage is associated with a high prevalence (40%) of specific mutations of the TP53 tumour suppressor gene (Dumaz et al. 1993). Over a 25-year period in Zimbabwe, in a series of 12 cases, 2 had SCCC while the rest had SCC of the skin, lip or tongue (Chidzonga et al. 2009). From a series of 7 XP cases in India, 6 of the 14 eyes (42.9%) had invasive SCC and eight eyes (57.1%) had CIN (Gupta et al. 2011). A larger series of 32 cases in France found that 59% of them had ocular and periocular malignancies (Touzri et al. 2008).

Vitamin A deficiency

The importance of vitamin A in maintaining the health of the ocular surface is well known, but the role of vitamin A deficiency in OSSN has not been established. Deficiency of vitamin A induces keratinisation of the ocular surface (Beitch 1970; Pfister & Renner 1978). Keratinisation is commonly observed as leucoplakia in OSSN lesions (Figure 1). There is a synergistic interaction between vitamin A and zinc in maintenance of the corneal and conjunctival epithelium (Kanazawa et al. 2002). In South Africa, it was shown that 54% of HIV-infected adults are deficient in vitamin A (plasma retinol <1.05 μm) and 33% deficient in zinc (<10.7 μm; Visser et al. 2003). In Ethiopia, 53% of HIV-infected adults were deficient in vitamin A (Fufa et al. 2009). As most patients with OSSN are also HIV-infected, it is plausible that vitamin A deficiency contributes to the aetiology.

Other risk factors

There is limited evidence of a role for exposure to dust, ocular trauma and pre-existing benign conjunctival lesions such as pterygia and pingueculae (Templeton 1967; Margo & Groden 1986; Waddell et al. 2010).

Protective factors

One of the Ugandan case–control studies found that some factors are associated with a lower risk for SCCC such as higher personal income (adjusted OR = 0.4, 95% CI: 0.3–0.7) and decreasing age at leaving home (P = 0.05), perhaps reflecting less exposure to sunlight consequent to rural-to-urban migration (Newton et al. 2002).

Aetiological model of OSSN

Various models have been proposed to simultaneously address the role of two or more risk factors in cancer causation within hierarchical levels (Victora et al. 1997). Most such models focus on social and environmental hypothesis but do not incorporate biological factors. A recently proposed framework called Multi-level Biological And Social Integrative Construct (MBASIC) includes biological factors together with macro-environmental and individual level factors (Lynch & Rebbeck 2013). Using the existing evidence reviewed in this article, we propose an aetiological model that might explain how the risk factors discussed may be involved development of OSSN (Figure 8).

image

Figure 8. An aetiological model illustrating how ocular surface squamous neoplasia (OSSN) might develop. MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases.

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Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References

OSSN is a disease of increasing importance in Africa. A triad of ultraviolet solar radiation, HIV and HPV form the major risk factors and this may explain the high incidence rates in Africa. There is evidence from case–control studies that exposure to UV radiation, outdoor occupations – perhaps due to exposure to sunlight, HIV and HPV infection are associated with a higher risk for OSSN. These studies also show no evidence of effect of cigarette smoking. Dust, ocular trauma and pre-existing benign conjunctival tumours may play a role. Although mentioned in the literature, the effect of atopy and xeroderma pigmentosa is unclear. The effect of vitamin A deficiency has not been examined in case–control studies.

The highest incidence of OSSN is found in Africa, where males and females are equally affected, unlike other continents where male disease predominates. This probably reflects that African women have increased risk due to their higher prevalence of HIV and HPV infections. As people with HIV are living longer, and given no evidence that ART reduces risk of OSSN, one could expect incidence of OSSN to increase in Africa in coming years.

Currently, the best available options for OSSN control remain early detection and effective treatment. However, there are no early non-invasive diagnostic methods in use and no trial evidence to guide treatment. OSSN is currently largely neglected by both eye and HIV care programmes. Eye care programmes prioritise preventable blindness while OSSN often in early stages does not affect vision. OSSN may, however, lead to facial disfigurement and death in late stages. In Africa, a key research question is whether scale-up of ART and HPV vaccination will impact on OSSN.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References

SG received funding from the British Council for Prevention of Blindness (BCPB) to conduct this study. MJB is supported by The Wellcome Trust (Grant Number 098481/Z/12/Z). We acknowledge Benjamin D. Hennig from the University of Oxford (http://www.viewsoftheworld.net) for help with preparing the incidence map (Figure 2).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods for this review
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  • Ackuaku-Dogbe E (2011) Review of orbital exenterations in Korle-Bu teaching hospital. Ghana Medical Journal 45, 4549.
  • American Joint Committee on Cancer 2010. Carcinoma of the conjunctiva. In: Cancer Staging Handbook, 7th edn (eds SB Edge, DR Byrd, CC Compton, AG Fritz, FL Greene & A Trotti) Springer, New York, 597.
  • Ateenyi-Agaba C (1995) Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda. Lancet 345, 695696.
  • Ateenyi-Agaba C, Dai M, le Calvez F et al. (2004a) TP53 mutations in squamous-cell carcinomas of the conjunctiva: evidence for UV-induced mutagenesis. Mutagenesis 19, 399401.
  • Ateenyi-Agaba C, Weiderpass E, Smet A et al. (2004b) Epidermodysplasia verruciformis human papillomavirus types and carcinoma of the conjunctiva: a pilot study. British Journal of Cancer 90, 17771779.
  • Ateenyi-Agaba C, Franceschi S, Wabwire-Mangen F et al. (2010) Human papillomavirus infection and squamous cell carcinoma of the conjunctiva. British Journal of Cancer, 102, 262267.
  • Auw-Haedrich C, Sundmacher R, Freudenberg N et al. (2006) Expression of p63 in conjunctival intraepithelial neoplasia and squamous cell carcinoma. Graefes Archive for Clinical and Experimental Ophthalmology 244, 96103.
  • Bastard M, Soulinphumy K, Phimmasone P et al. (2013) Women experience a better long- term immune recovery and a better survival on HAART in Lao People's Democratic Republic. BMC Infectious Diseases 13, 27.
  • Basti S & Macsai MS (2003) Ocular surface squamous neoplasia: a review. Cornea 22, 687704.
  • Beitch I (1970) The induction of keratinization in the corneal epithelium. A comparison of the “dry” and vitamin A-deficient eyes. Investigative Ophthalmology 9, 827843.
  • Boyd AS, Annarella M, Rapini RP, Adler-Storthz K & Duvic M (1996) False-positive polymerase chain reaction results for human papillomavirus in lichen planus. Potential laboratory pitfalls of this procedure. Journal of the American Academy of Dermatology 35, 4246.
  • Brown C, Kowalczyk AM, Taylor ER, Morgan IM & Gaston K (2008) P53 represses human papillomavirus type 16 DNA replication via the viral E2 protein. Virology Journal 5, 5.
  • Chidzonga MM, Mahomva L, Makunike-Mutasa R & Masanganise R (2009) Xeroderma pigmentosum: a retrospective case series in Zimbabwe. Journal of Oral and Maxillofacial Surgery 67, 2231.
  • Chisi SK, Kollmann MK & Karimurio J (2006) Conjunctival squamous cell carcinoma in patients with human immunodeficiency virus infection seen at two hospitals in Kenya. East African Medical Journal 83, 267270.
  • Chow LT, Broker TR & Steinberg BM (2010) The natural history of human papillomavirus infections of the mucosal epithelia. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica 118, 422449.
  • Clifford GM, Smith JS, Plummer M, Munoz N & Franceschi S (2003) Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. British Journal of Cancer 88, 6373.
  • Cornell M, Schomaker M, Garone DB et al. (2012) Gender differences in survival among adult patients starting antiretroviral therapy in South Africa: a multicentre cohort study. PLoS Medicine 9, e1001304.
  • Croce A, Moretti A, D'agostino L & Zingariello P (2008) Orbital exenteration in elderly patients: personal experience. Acta Otorhinolaryngologica Italica 28, 193199.
  • Curado MP, Edwards B, Shin HR et al. (eds.) (2007). Cancer incidence in Five Continents. International Agency for Research on Cancer, Lyon, France.
  • de Koning MN, Waddell K, Magyezi J et al. (2008) Genital and cutaneous human papillomavirus (HPV) types in relation to conjunctival squamous cell neoplasia: a case- control study in Uganda. Infectious Agents and Cancer 3, 12.
  • de Sanjose S, Diaz M, Castellsague X et al. (2007) Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. The Lancet Infectious Diseases 7, 453459.
  • de Smedt S, Wildner G & Kestelyn P (2013) Vernal keratoconjunctivitis: an update. British Journal of Ophthalmology 97, 914.
  • de Villiers EM (2013). Cross-roads in the classification of papillomaviruses. Virology.
  • di Girolamo N (2012) Association of human papilloma virus with pterygia and ocular-surface squamous neoplasia. Eye (London, England) 26, 202211.
  • Dou Z, Xu J, Jiao JH et al. (2011) Gender difference in 2-year mortality and immunological response to ART in an HIV-infected Chinese population 2006–2008. PLoS One 6, e22707.
  • Dumaz N, Drougard C, Sarasin A & Daya-Grosjean L (1993) Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proceedings of the National Academy of Sciences, USA 90, 1052910533.
  • Dushku N, Hatcher SL, Albert DM & Reid TW (1999) p53 expression and relation to human papillomavirus infection in pingueculae, pterygia, and limbal tumors. Archives of Ophthalmology 117, 15931599.
  • Emmanuel B, Ruder E, Lin SW, Abnet C, Hollenbeck A & Mbulaiteye S (2012) Incidence of squamous-cell carcinoma of the conjunctiva and other eye cancers in the NIH-AARP Diet and Health Study. Ecancermedicalscience 6, 254.
  • Eng HL, Lin TM, Chen SY, Wu SM & Chen WJ (2002) Failure to detect human papillomavirus DNA in malignant epithelial neoplasms of conjunctiva by polymerase chain reaction. American Journal of Clinical Pathology 117, 429436.
  • Fufa H, Umeta M, Taffesse S, Mokhtar N & Aguenaou H (2009) Nutritional and immunological status and their associations among HIV-infected adults in Addis Ababa, Ethiopia. Food and Nutrition Bulletin 30, 227232.
  • Furahini G & Lewallen S (2010) Epidemiology and management of ocular surface squamous neoplasia in Tanzania. Ophthalmic Epidemiology 17, 171176.
  • Gichuhi S & Irlam JH (2013) Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals. Cochrane Database Systematic Review, 2, CD005643.
  • Goedert JJ & Cote TR (1995) Conjunctival malignant disease with AIDS in USA. Lancet 346, 257258.
  • Gonzalez MA, Martin L, Munoz S & Jacobson JO (2011) Patterns, trends and sex differences in HIV/AIDS reported mortality in Latin American countries: 1996–2007. BMC Public Health 11, 605.
  • Grossniklaus HE, Green WR, Luckenbach M & Chan CC (1987) Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 6, 78116.
  • Guech-Ongey M, Engels EA, Goedert JJ, Biggar RJ & Mbulaiteye SM (2008) Elevated risk for squamous cell carcinoma of the conjunctiva among adults with AIDS in the United States. International Journal of Cancer 122, 25902593.
  • Gupta N, Sachdev R & Tandon R (2011) Ocular surface squamous neoplasia in xeroderma pigmentosum: clinical spectrum and outcome. Graefes Archive for Clinical and Experimental Ophthalmology 249, 12171221.
  • Guthoff R, Marx A & Stroebel P (2009) No evidence for a pathogenic role of human papillomavirus infection in ocular surface squamous neoplasia in Germany. Current Eye Research 34, 666671.
  • Halliday GM, Damian DL, Rana S & Byrne SN (2012) The suppressive effects of ultraviolet radiation on immunity in the skin and internal organs: implications for autoimmunity. Journal of Dermatological Science 66, 176182.
  • Haverkos HW (2004) Viruses, chemicals and co-carcinogenesis. Oncogene 23, 64926499.
  • Heinz C, Fanihagh F & Steuhl KP (2003) Squamous cell carcinoma of the conjunctiva in patients with atopic eczema. Cornea 22, 135137.
  • Hirst LW (2007) Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology 114, 976982.
  • Holkar S, Mudhar HS, Jain A et al. (2005) Regression of invasive conjunctival squamous carcinoma in an HIV-positive patient on antiretroviral therapy. International Journal of STD and AIDS 16, 782783.
  • Hughes DS, Powell N & Fiander AN (2008) Will vaccination against human papillomavirus prevent eye disease? A review of the evidence. British Journal of Ophthalmology 92, 460465.
  • Iftner T & Villa LL (2003) Chapter 12: Human papillomavirus technologies. Journal of the National Cancer Institute, Monographs 31, 8088.
  • Johnson LF, Mossong J, Dorrington RE et al. (2013) Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies. PLoS Medicine 10, e1001418.
  • Kanazawa S, Kitaoka T, Ueda Y, Gong H & Amemiya T (2002) Interaction of zinc and vitamin A on the ocular surface. Graefes Archive for Clinical and Experimental Ophthalmology 240, 10111021.
  • Kao AA, Galor A, Karp CL, Abdelaziz A, Feuer WJ & Dubovy SR (2012) Clinicopathologic correlation of ocular surface squamous neoplasms at bascom palmer eye institute: 2001 to 2010. Ophthalmology 119, 17731776.
  • Karcioglu ZA & Issa TM (1997) Human papilloma virus in neoplastic and non-neoplastic conditions of the external eye. British Journal of Ophthalmology 81, 595598.
  • Kestelyn P, Stevens AM, Ndayambaje A, Hanssens M & van de Perre P (1990) HIV and conjunctival malignancies. Lancet 336, 5152.
  • Kim Y, Choi KR, Chae MJ et al. (2013) Stability of DNA, RNA, cytomorphology, and immunoantigenicity in Residual ThinPrep Specimens. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavicadoi: 10.1111/apm.12082[Epub ahead of print].
  • Kuo KT, Chang HC, Hsiao CH & Lin MC (2006) Increased Ki-67 proliferative index and absence of P16INK4 in CIN-HPV related pathogenic pathways different from cervical squamous intraepithelial lesion. British Journal of Ophthalmology 90, 894899.
  • Lauer SA, Malter JS & Meier JR (1990) Human papillomavirus type 18 in conjunctival intraepithelial neoplasia. American Journal of Ophthalmology 110, 2327.
  • Lee GA & Hirst LW (1992) Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey. Archives of Ophthalmology 110, 525527.
  • Lee GA & Hirst LW (1995) Ocular surface squamous neoplasia. Survey of Ophthalmology 39, 429450.
  • Lee GA & Hirst LW (1997) Retrospective study of ocular surface squamous neoplasia. Australian and New Zealand Journal of Ophthalmology 25, 269276.
  • Lee GA, Williams G, Hirst LW & Green AC (1994) Risk factors in the development of ocular surface epithelial dysplasia. Ophthalmology 101, 360364.
  • Lee SB, Au Eong KG, Saw SM, Chan TK & Lee HP (2000) Eye cancer incidence in Singapore. British Journal of Ophthalmology, 84, 767770.
  • Lynch SM & Rebbeck TR (2013) Bridging the gap between biologic, individual, and macroenvironmental factors in cancer: a multilevel approach. Cancer Epidemiology Biomarkers & Prevention 22, 485495.
  • Mahomed A & Chetty R (2002) Human immunodeficiency virus infection, Bcl-2, p53 protein, and Ki-67 analysis in ocular surface squamous neoplasia. Archives of Ophthalmology 120, 554558.
  • Makupa II, Swai B, Makupa WU, White VA & Lewallen S (2012) Clinical factors associated with malignancy and HIV status in patients with ocular surface squamous neoplasia at Kilimanjaro Christian Medical Centre, Tanzania. British Journal of Ophthalmology, 96, 482484.
  • Maloof AJ, Ho A & Coroneo MT (1994) Influence of corneal shape on limbal light focusing. Investigative Ophthalmology & Visual Science 35, 25922598.
  • Manderwad GP, Kannabiran C, Honavar SG & Vemuganti GK (2009) Lack of association of high-risk human papillomavirus in ocular surface squamous neoplasia in India. Archives of Pathology and Laboratory Medicine 133, 12461250.
  • Margo CE & Groden LR (1986) Squamous cell carcinoma of the cornea and conjunctiva following a thermal burn of the eye. Cornea 5, 185188.
  • Margo CE, Harman LE & Mulla ZD (2002) The reliability of clinical methods in ophthalmology. Survey of Ophthalmology 47, 375386.
  • Masanganise R & Magava A (2001) Orbital exenterations and squamous cell carcinoma of the conjunctiva at Sekuru Kaguvi Eye Unit, Zimbabwe. Central African Journal of Medicine 47, 196199.
  • Masanganise R, Rusakaniko S, Makunike R et al. (2008) A historical perspective of registered cases of malignant ocular tumors in Zimbabwe (1990 to 1999). Is HIV infection a factor? Central African Journal of Medicine 54, 2832.
  • Maskew M, Brennan AT, Westreich D, McNamara L, Macphail AP & Fox MP (2013) Gender differences in mortality and CD4 count response among virally suppressed HIV- positive patients. Journal of Women's Health (2002) 22, 113120.
  • McDonnell JM, McDonnell PJ & Sun YY (1992) Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia. Investigative Ophthalmology & Visual Science 33, 184189.
  • McKelvie PA (2002) Squamous cell carcinoma of the conjunctiva: a series of 26 cases. British Journal of Ophthalmology 86, 168173.
  • Mesher D, Szarewski A, Cadman L et al. (2013) Comparison of human papillomavirus testing strategies for triage of women referred with low-grade cytological abnormalities. European Journal of Cancer 49, 21792186.
  • Moubayed P, Mwakyoma H & Schneider DT (2004) High Frequency of Human Papillomavirus 6/11, 16, and 18 Infections in Precancerous Lesions and Squamous Cell Carcinoma of the Conjunctiva in Subtropical Tanzania. American Journal of Clinical Pathology 122, 938943.
  • Munoz M, Camargo M, Soto-De Leon SC et al. (2012) The diagnostic performance of classical molecular tests used for detecting human papillomavirus. Journal of Virological Methods, 185, 3238.
  • Nakamura Y, Mashima Y, Kameyama K, Mukai M & Oguchi Y (1997) Detection of human papillomavirus infection in squamous tumours of the conjunctiva and lacrimal sac by immunohistochemistry, in situ hybridisation, and polymerase chain reaction. British Journal of Ophthalmology 81, 308313.
  • Napora C, Cohen EJ, Genvert GI et al. (1990) Factors associated with conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surgery 21, 2730.
  • Nemet AY, Martin P, Benger R et al. (2007) Orbital exenteration: a 15-year study of 38 cases. Ophthalmic Plastic and Reconstructive Surgery 23, 468472.
  • Newton R, Ferlay J, Reeves G, Beral V & Parkin DM (1996) Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye. Lancet 347, 14501451.
  • Newton R, Ziegler J, Beral V et al. (2001) A case-control study of human immunodeficiency virus infection and cancer in adults and children residing in Kampala, Uganda. International Journal of Cancer 92, 622627.
  • Newton R, Ziegler J, Ateenyi-Agaba C et al. (2002) The epidemiology of conjunctival squamous cell carcinoma in Uganda. British Journal of Cancer 87, 301308.
  • Ng J, Coroneo MT, Wakefield D & di Girolamo N (2008) Ultraviolet radiation and the role of matrix metalloproteinases in the pathogenesis of ocular surface squamous neoplasia. Investigative Ophthalmology & Visual Science 49, 52955306.
  • Odrich MG, Jakobiec FA, Lancaster WD et al. (1991) A spectrum of bilateral squamous conjunctival tumors associated with human papillomavirus type 16. Ophthalmology, 98, 628635.
  • Ogun GO, Ogun OA, Bekibele CO & Akang EE (2009) Intraepithelial and invasive squamous neoplasms of the conjunctiva in Ibadan, Nigeria: a clinicopathological study of 46 cases. International Ophthalmology 29, 401409.
  • Osahon AI, Ukponmwan CU & Uhunmwangho OM (2011) Prevalence of HIV seropositivity among patients with squamous cell carcinoma of the conjunctiva. Asian Pacific Journal of Tropical Biomedicine 1, 150153.
  • Parkin DM, Nambooze S, Wabwire-Mangen F & Wabinga HR (2010) Changing cancer incidence in Kampala, Uganda 1991–2006. International Journal of Cancer 126, 11871195.
  • Perez-Molina JA, Mora Rillo M, Suarez-Lozano I et al. (2012) Response to combined antiretroviral therapy according to gender and origin in a cohort of naive HIV-infected patients: GESIDA- 5808 study. HIV Clinical Trials, 13, 131141.
  • Pfister RR & Renner ME (1978) The corneal and conjunctival surface in vitamin A deficiency: a scanning electron microscopy study. Investigative Ophthalmology & Visual Science 17, 874883.
  • Pola EC, Masanganise R & Rusakaniko S (2003) The trend of ocular surface squamous neoplasia among ocular surface tumour biopsies submitted for histology from Sekuru Kaguvi Eye Unit, Harare between 1996 and 2000. Central African Journal of Medicine 49, 14.
  • Poole TR (1999) Conjunctival squamous cell carcinoma in Tanzania. British Journal of Ophthalmology 83, 177179.
  • Porges Y & Groisman GM (2003) Prevalence of HIV with conjunctival squamous cell neoplasia in an African provincial hospital. Cornea 22, 14.
  • Pushker N, Kashyap S, Balasubramanya R et al. (2004) Pattern of orbital exenteration in a tertiary eye care centre in India. Clinical & Experimental Ophthalmology 32, 5154.
  • Rahman I, Cook AE & Leatherbarrow B (2005) Orbital exenteration: a 13 year Manchester experience. British Journal of Ophthalmology 89, 13351340.
  • Reszec J & Sulkowski S (2005) The expression of P53 protein and infection of human papilloma virus in conjunctival and eyelid neoplasms. International Journal of Molecular Medicine 16, 559564.
  • Saegusa M, Takano Y, Hashimura M, Okayasu I & Shiga J (1995) HPV type 16 in conjunctival and junctional papilloma, dysplasia, and squamous cell carcinoma. Journal of Clinical Pathology 48, 11061110.
  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ & Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 11291136.
  • Scott IU, Karp CL & Nuovo GJ (2002) Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia. Ophthalmology 109(542–7), 39.
  • Sen S, Sharma A & Panda A (2007) Immunohistochemical localization of human papilloma virus in conjunctival neoplasias: a retrospective study. Indian Journal of Ophthalmology 55, 361363.
  • Shields CL & Shields JA (2004) Tumors of the conjunctiva and cornea. Survey of Ophthalmology 49, 324.
  • Simbiri KO, Murakami M, Feldman M et al. (2010) Multiple oncogenic viruses identified in Ocular surface squamous neoplasia in HIV-1 patients. Infectious Agents and Cancer 5, 6.
  • Smeets SJ, Hesselink AT, Speel EJ et al. (2007) A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. International Journal of Cancer 121, 24652472.
  • Spitzer MS, Batumba NH, Chirambo T et al. (2008) Ocular surface squamous neoplasia as the first apparent manifestation of HIV infection in Malawi. Clinical & Experimental Ophthalmology 36, 422425.
  • Stanley M (2010) Pathology and epidemiology of HPV infection in females. Gynecologic Oncology 117, S510.
  • Sun EC, Fears TR & Goedert JJ (1997) Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiology Biomarkers & Prevention 6, 7377.
  • Tabrizi SN, McCurrach FE, Drewe RH, Borg AJ, Garland SM & Taylor HR (1997) Human papillomavirus in corneal and conjunctival carcinoma. Australian and New Zealand Journal of Ophthalmology 25, 211215.
  • Taylor-Smith K, Tweya H, Harries A, Schoutene E & Jahn A (2010) Gender differences in retention and survival on antiretroviral therapy of HIV-1 infected adults in Malawi. Malawi Medical Journal 22, 4956.
  • Templeton AC (1967) Tumors of the eye and adnexa in Africans of Uganda. Cancer 20, 16891698.
  • Templeton AC (1973) Tumours of the eye and adnexa. Recent Results in Cancer Research, 41(20), 314.
  • Thorsteinsson K, Ladelund S, Jensen-Fangel S et al. (2012) Impact of gender on the risk of AIDS-defining illnesses and mortality in Danish HIV-1-infected patients: a nationwide cohort study. Scandinavian Journal of Infectious Diseases 44, 766775.
  • Tiong T, Borooah S, Msosa J et al. (2013) Clinicopathological review of ocular surface squamous neoplasia in Malawi. British Journal of Ophthalmology 97, 961964.
  • Tornesello ML, Duraturo ML, Waddell KM et al. (2006) Evaluating the role of human papillomaviruses in conjunctival neoplasia. British Journal of Cancer 94, 446449.
  • Toth J, Karcioglu ZA, Moshfeghi AA, Issa TM, Al-Ma'ani JR & Patel KV (2000) The relationship between human papillomavirus and p53 gene in conjunctival squamous cell carcinoma. Cornea 19, 159162.
  • Touzri RA, Mohamed Z, Khalil E et al. (2008) Ocular malignancies of xeroderma pigmentosum: clinical and therapeutic features. Annales de Dermatologie et de Venereologie 135, 99104.
  • Tulvatana W (2003) Risk factors for conjunctival squamous cell neoplasia: a matched case-control study. British Journal of Ophthalmology 87, 396398.
  • Tunc M, Char DH, Crawford B & Miller T (1999) Intraepithelial and invasive squamous cell carcinoma of the conjunctiva: analysis of 60 cases. British Journal of Ophthalmology 83, 98103.
  • Tuppurainen K, Raninen A, Kosunen O et al. (1992) Squamous cell carcinoma of the conjunctiva. Failure to demonstrate HPV DNA by in situ hybridization and polymerase chain reaction. Acta Ophthalmologica 70, 248254.
  • Ukponmwan CU, Igbokwe UO & Aligbe JU (2002) Squamous cell carcinoma of the conjunctiva in Benin City Nigeria. Nigerian Journal of Medical Practice 5, 143147.
  • Vajdic CM, van Leeuwen MT, McDonald SP et al. (2007) Increased incidence of squamous cell carcinoma of eye after kidney transplantation. Journal of the National Cancer Institute 99, 13401342.
  • Velema JP, Ferrera A, Figueroa M et al. (2002) Burning wood in the kitchen increases the risk of cervical neoplasia in HPV-infected women in Honduras. International Journal of Cancer 97, 536541.
  • Victora CG, Huttly SR, Fuchs SC & Olinto MT (1997) The role of conceptual frameworks in epidemiological analysis: a hierarchical approach. International Journal of Epidemiology 26, 224227.
  • Visser ME, Maartens G, Kossew G & Hussey GD (2003) Plasma vitamin A and zinc levels in HIV-infected adults in Cape Town, South Africa. British Journal of Nutrition 89, 475482.
  • Wabinga HR, Parkin DM, Wabwire-Mangen F & Nambooze S (2000) Trends in cancer incidence in Kyadondo County, Uganda 1960–1997. British Journal of Cancer 82, 15851592.
  • Waddell KM, Lewallen S, Lucas SB, Atenyi-Agaba C, Herrington CS & Liomba G (1996) Carcinoma of the conjunctiva and HIV infection in Uganda and Malawi. British Journal of Ophthalmology 80, 503508.
  • Waddell K, Magyezi J, Bousarghin L et al. (2003) Antibodies against human papillomavirus type 16 (HPV-16) and conjunctival squamous cell neoplasia in Uganda. British Journal of Cancer 88, 20022003.
  • Waddell KM, Downing RG, Lucas SB & Newton R (2006) Corneo-conjunctival carcinoma in Uganda. Eye (London, England) 20, 893899.
  • Waddell K, Kwehangana J, Johnston WT, Lucas S & Newton R (2010) A case-control study of ocular surface squamous neoplasia (OSSN) in Uganda. International Journal of Cancer 127, 427432.
  • WHO (2000) International Classification of Diseases for Oncology (ICD-O-3) [Online]. Available: http://www.who.int/classifications/icd/adaptations/oncology/en/index.html [Accessed 14th March 2013.
  • WHO (2010) International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) [Online]. Available: http://apps.who.int/classifications/icd10/browse/2010/en [Accessed 4th January 2013].
  • World Energy Council (2007) Survey of Energy Resources [Online]. Available: http://www.worldenergy.org/documents/fig_solar_10_2.gif [Accessed 4th March 2013].
  • Yu JJ, Fu P, Pink JJ et al. (2010) HPV infection and EGFR activation/alteration in HIV-infected East African patients with conjunctival carcinoma. PLoS One 5, e10477.