The Epidemiology of Eye Cancer, Eyelid Cancer, and Ophthalmic Lymphoma in a Chinese Population in Hong Kong: A Population-Based Registry Study 2005–2018

Abstract

Purpose: To investigate the incidence rate, histopathological types, and time trends of primary eye cancer, eyelid cancer, and ophthalmic lymphoma among the Chinese population.

Methods: The records of patients diagnosed with primary eye and eyelid cancers from 2005 to 2018 in Hong Kong were retrieved from the Hong Kong Cancer Registry. Patient demographics, cancer sites, and histology were recorded. Population-level age-standardized incidences and trends were analyzed by age and sex and compared with existing literature. International Classification of Diseases, Ninth Edition (ICD-9) codes were converted to ICD-10 codes. Eye cancer was defined as malignancy involving the eyeball, intraocular structures, lacrimal system, and orbit.

Results: A total of 442 eye cancers and 1103 eyelid cancers were included. Among these cancers, 295 cases were ophthalmic lymphoma. The age-standardized annual incidence rate was 4.04 per 1,000,000 population for eye cancer, 6.30 for eyelid cancer, and 1.89 for ophthalmic lymphoma. The incidence rates increased with age (P < 0.001), but there were no sex differences. The incidence rate of eyelid cancer and ophthalmic lymphoma showed an increasing trend, with annual percent changes of 2.8% and 2%, respectively. In eye cancers, the most common histological type was lymphoma (58.1%), and the most common site was orbit (35.5%). The most common histology for eyelid cancer was basal cell carcinoma, and for ophthalmic lymphoma it was extranodal marginal zone B cell lymphoma.

Conclusions: In the Chinese population, the incidence of eye cancer has remained stable, whereas eyelid cancer and ophthalmic lymphoma are increasing. Lymphoma has been the most common histological type in recent years, in contrast to findings in Western populations.

Cancers of the eye and eyelid arise from a broad variety of anatomical structures and represent a diverse group of tumors with distinctive histological and clinical features. Although rare, they can present with significant diagnostic and therapeutic challenges and result in significant morbidity and mortality among affected individuals.^1,2 However, only a limited number of population-level epidemiological studies have offered comprehensive understanding on the incidence rates and trends of eye cancers recently.^3–5 Despite more available studies on eyelid cancers, most of the research in the past decade has been conducted in Western countries and therefore does not fully capture the diversity of global populations.^6–11 

Ophthalmic lymphomas are an important histological subtype of eye and eyelid cancers. They are primary lymphoproliferative neoplasms localized in the eye and ocular adnexa, including the eyelid, conjunctiva, lacrimal gland and drainage system, and orbit. Ophthalmic lymphoma has been identified as the most common histological type of eye cancers, and increasing incidence rates have been reported in the United States, Canada, and Denmark.^4,12–14 However, the incidence rates and temporal trends in other parts of the world remain largely unknown, highlighting the need for further research. 

Accordingly, the aim of our study was to enhance our understanding of the recent epidemiological trends in eye cancer, eyelid cancer, and ophthalmic lymphoma by examining their incidences, histopathology, and time trends in a Chinese population in Hong Kong. This is of particular importance in view of the notable variations observed across different geographical locations. We also sought to provide updated data that accurately reflect the current landscape of these malignancies, can inform healthcare professionals on clinical decision making, and introduce new insights into the underlying factors accounting for the epidemiological patterns. 

Methods

Study Population

Hong Kong is a city located on the southern coast of China. It has a population of 7.4 million, and the vast majority of Hong Kong's population is ethnic Han Chinese (91.6%).¹⁵ Ours is a population-based epidemiological study analyzing cancer registry data. The Hong Kong Cancer Registry (“Registry”) is the only population-based cancer registry that collects data from all new cancer cases diagnosed in residents of Hong Kong.¹⁶ It only collects data on primary cancers and continuously collects data from public and private oncology facilities, pathology laboratories, death registries, and voluntary notifications. The Registry validates data on diagnosis and histology and consolidates clinical data by cross-referencing all clinical notes available. It is a member of and follows quality control measures of the International Association of Cancer Registries. For every new case, data regarding the patient’s age group (5-year), sex, anatomical site, histology, and stage are collected. Study approval was obtained from the Hong Kong Cancer Registry, the Institutional Review Board of the University of Hong Kong, and the Hong Kong West Cluster. 

All primary eye and eyelid cancers diagnosed between January 1, 2005, and December 31, 2018, were retrieved from the Registry's database. This period was selected because the database of the cancer registry was fully established only after 2005. A reporting lag time was around 2 years due to strict quality control procedures adopted by the Registry. The Ninth Revision of the International Classification of Diseases (ICD-9) was used in coding of the cases. Malignant neoplasms of the eye were retrieved using the ICD-9 codes 190.0 to 190.9, which included the eyeball excluding the conjunctiva, cornea, retina, and choroid (190.0); the orbit (190.1); lacrimal gland and lacrimal duct (190.2 and 190.7); conjunctiva (190.3); cornea (190.4); retina (190.5); choroid (190.6); other specified part of the eye (190.8); and other unspecified parts of the eye (190.9).¹⁷ Eyelid cancers were a distinct entity classified as malignant neoplasm of skin under codes 172.1 (malignant melanoma of skin of eyelid, including canthus) and 173.1 (unspecified malignant neoplasm of eyelid, including canthus). Lymphomas of the eye were searched using codes 200 to 202 (Hodgkin and non-Hodgkin lymphoma). Additional searches for tumor locations were done using the following keywords: conjunctiva, cornea, iris, ciliary body, choroid, uvea, sclera, lacrimal, orbit, and eyelid. The ICD-9 codes were converted to ICD-10 codes based on published literature.^18,19 The cut-off for pediatric patients was 15 years old, as quinquennial age groups were used, consistent with prior studies.^20,21 Ophthalmic lymphoma was classified by histology according to the fifth edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and coded by the International Classification of Diseases for Oncology, Third Edition.^22,23 

Statistical Analysis

The incidence rate ratio and corresponding 95% confidence intervals (CIs) were estimated following the methodological framework of Rothman et al.²⁴ Incidence rate was calculated as the number of eye cancer cases per 1,000,000 population. The numerator was the number of cases diagnosed during the study period, and the denominator was the total person-years at risk. Hong Kong mid-year population data, stratified by sex and 5-year age groups from 2005 to 2018, were extracted from the Government of Hong Kong's Census and Statistics Department.¹⁵ The incidence rate ratio was calculated to compare the incidence rates between different demographic groups including sex and age groups. Based on the characteristics of our data, we used negative binomial regression as the appropriate statistical method to determine the incidence rate ratio by age and sex. Model diagnostics were performed to ensure that model assumptions were met (see Supplementary Materials). 

We analyzed the trends in the incidence rates of eye cancers using Joinpoint regression analysis with the Joinpoint 4.9.1.0.²⁵ The program identifies time points where there are significant changes in a trend, referred to as joinpoints. To determine the optimal number of joinpoints, we used the grid search method and permutation test. The program indicated that the best model for our data had zero joinpoints, suggesting there were no significant changes in the trend over the study period. As a result, we utilized a simple linear model to estimate the annual percent change for each cancer type. 

The age-standardized incidence rate was calculated using the direct standardization method.²⁶ The WHO 2000 World Standard Population was used as the reference population.²⁶ To allow for comparison with studies worldwide, we also used the Segi world population, European Standard Population 2013, age distribution of whites in the United States in 1990, and the 2000 U.S. population to calculate age-standardized incidence rates.^27–31 Statistical significance was set at the 0.05 level. All statistical analyses were conducted in R 4.4.2 (R Foundation for Statistical Computing, Vienna, Austria). 

Results

During the study period from 2005 to 2018, a total of 442 eye cancers and 1103 eyelid cancers were identified. The ratios of males to females were 1.25:1 and 0.85:1 for eye cancer and eyelid cancer, respectively. Diagnoses by histopathology were 98.4% and 99.8% for eye and eyelid cancers, respectively. The remaining were clinically diagnosed. None was diagnosed with death certificate only. 

Eye Cancer

The incidence of eye cancer is summarized in Table 1. The overall average annual incidence rate of eye cancers was 4.44 per 1,000,000 population (95% CI, 4.02–4.85) The rate for males was 5.26 per 1,000,000 population (95% CI, 4.61–5.92), and the rate for females was 3.71 per 1,000,000 population (95% CI, 3.19–4.23), with no statistically significant difference (P = 0.206). Adjusted to the WHO 2000 World Standard Population, the overall age-standardized annual incidence rate for eye cancers was 4.04 per 1,000,000 standard population, 4.75 per 1,000,000 standard population for males and 3.33 per 1,000,000 standard population for females. 

Table 1.

 

Incidence Rates of Eye Cancer, Eyelid Cancer, and Ophthalmic Lymphoma by Sex in Hong Kong 2005–2018

 

Part (a) of the Figure shows the age-specific incidence rates by sex for eye cancers during the study period. A bimodal age distribution was observed, with the first peak in the pediatric population occurring before the age of 5 years. The incidence in adults increased significantly after the age of 40 years and peaked after 75 years (P < 0.001). The incidence rate was higher in males than females in the age group of 80 to 84 years (P < 0.001). There was no significant temporal trend observed during the study period. 

Figure.

 

Age-specific incidence rates for (a) eye cancer, (b) eyelid cancer and (c) ophthalmic lymphoma by sex in Hong Kong from 2005 to 2018.

The anatomical sites of eye cancers according to ICD-10 codes and the frequency of histological types in the corresponding sites are summarized in Table 2. The most common sites of eye cancers were orbit (35.5%), conjunctiva (17.9%), and lacrimal gland and lacrimal duct (14.0%). The most common histological types were lymphoma (58.1%), melanoma (14.5%), and retinoblastoma (12.4%), as shown in Table 3. The frequency of histological types of eye cancer was further analyzed by age group. In the pediatric group (younger than 15 years old), the most common diagnoses were retinoblastoma (88.7%), sarcoma (6.45%), and melanoma (1.61%), whereas in the ≥15 years age group, the most common were lymphoma (67.6%), melanoma (16.6%), and squamous cell carcinoma (3.42%). 

Table 2.

 

Anatomical Sites (ICD-10) and Frequency of Histological Types of Eye Cancer in Hong Kong, 2005–2018 (N = 442)

 

Table 3.

 

Histology of Eye Cancers by Age Group in Hong Kong 2005–2018 (N = 442)

 

Eyelid Cancers

In eyelid cancers, the overall average annual incidence rate was 11.07 per 1,000,000 population (95% CI, 10.42–11.72), 10.87 for males (95% CI, 9.93–11.82) and 11.42 for females (95% CI, 10.34–12.14), as shown in Table 1. There were no significant sex differences (P > 0.05). The age-standardized incidence rates for eyelid cancers were 6.30 per 1,000,000 population overall, 6.37 for males, and 6.24 for females. 

Eyelid cancers showed a different pattern of age distribution from eye cancers by being exceedingly rare in childhood and young adulthood. The incidence rates began to rise after 40 years, with a strong predilection for older age, as shown in part (b) of the Figure. Compared with the young age group (5 to 39 years old), the incidence rate in the 40 to 74 years age group was 37 times higher (P < 0.001), and that for the age group 75 years and above was 198 times higher (P < 0.001). An increasing trend in eyelid cancer incidence was found with an annual percent change of 2.8% (95% CI, 1.6–4.0). Among eyelid cancers, the most common histologies were basal cell carcinoma (76%), sebaceous cell carcinoma (9.6%), and squamous cell carcinoma (6.3%). The frequency of eyelid cancers by histology is presented in Table 4. 

Table 4.

 

Frequency of Histological Types of Eyelid Cancers in Hong Kong 2005–2018 (N = 1103)

 

Ophthalmic Lymphoma

A total of 295 cases of ophthalmic lymphoma were identified. The overall average annual incidence rate was 2.96 per 1,000,000 population (95% CI, 2.64–3.32), 3.35 for males (95% CI, 2.83–3.89), and 2.62 for females (95% CI, 2.18–3.05). There was no significant difference between males and females (P = 0.433). The age-standardized incidence rate for ophthalmic lymphoma was overall 1.89 per 1,000,000 population, 2.07 per 1,000,000 population for males, and 1.71 per 1,000,000 population for females. The incidence rates of ophthalmic lymphoma are summarized in Table 1. 

Part (c) of the Figure shows the age-specific incidence rate by sex for ophthalmic lymphoma. The incidence rates began to rise at young adulthood and increased with age (P < 0.001). In the age group of 80 to 84 years, a higher rate in males than females was observed (P < 0.001). An increasing trend in the incidence of ophthalmic lymphoma was observed during the study period, with an annual percent change of 2% (95% CI, 0.8–3.1). 

The most common site for ophthalmic lymphoma was the orbit (44.1%), followed by conjunctiva (21%), eyelid (12.5%), and lacrimal gland (12.5%). There was only one case of documented intraocular lymphoma, and the exact tumor location was not documented in 9.5% of the cases. Ocular adnexal lymphoma, defined as lymphoma affecting the orbit, conjunctiva, eyelids, and lacrimal gland, constituted 90% of all ophthalmic lymphoma. Table 5 summarizes ophthalmic lymphoma by histopathology. Over 90% of cases were B-cell lymphoma. The most common histological subtypes were extranodal marginal zone B-cell lymphoma (69.2%), diffuse large B-cell lymphoma (11.9%), and follicular lymphoma (4.1%). 

Table 5.

 

Ophthalmic Lymphoma by Histology Based on WHO Classification of Hematopoietic and Lymphoid Neoplasms (N = 295)

 

Discussion

To our knowledge, this population-based epidemiological study is the first over the past 2 decades to examine the incidence rates, histopathology distribution, and temporal trends of primary eye cancer, eyelid cancer, and ophthalmic lymphoma in the Chinese population in Hong Kong. From 2005 to 2018, the age-standardized annual incidence rates were 4.04 per 1,000,000 population for eye cancer, 6.30 for eyelid cancer, and 1.89 for ophthalmic lymphoma. During the study period, the incidence rates of eyelid cancer and ophthalmic lymphoma increased. There was no sex predilection observed in any of the malignancies. A bimodal age distribution were seen in eye cancers, and the incidence increased with age in all three groups. The most common histologies were lymphoma for eye cancer and basal cell carcinoma for eyelid cancer. The most common histological subtype of ophthalmic lymphoma was extranodal marginal zone B-cell lymphoma. 

Comparing global cancer incidence rates across populations is complicated by the different local reporting practices, study time periods, and demographics in each study. Nonetheless, to allow for meaning comparison with existing and future studies, we adopted the WHO 2000 World Standard Population for age standardization, as it matches population projections for the period of 2000 to 2025, offers an age extension to 100 years, and includes more adults ≥ 70 years of age.²⁶ These features are compatible with Hong Kong's population structure, which features a high proportion of elderly with world-leading longevity.³² In addition, we further adjusted our incidence rates to multiple standard populations that were used in published reports, as summarized in Table 6. 

Table 6.

 

Age-Standardized Incidence Rate in Different Population-Based Studies

 

The incidence of eye cancer in our study appeared to be higher than in previous studies in Asia (Table 6).^20,21 However, the studies by Cheng et al.²⁰ from Taiwan and by Lee et al.²¹ from Singapore covered the periods from 1979 to 1996 and 1968 to 1995, respectively. These periods are over 2 decades apart from our study. Cancer classification systems and practices in diagnosis and case reporting may have changed significantly over the years. Huang et al.³ reported on various countries across Asia, each of which may utilize different methods for registering cancer cases. Notably, underreporting of eye cancers may occur in developing countries due to inadequate infrastructure and mechanisms for cancer screening and reporting. Therefore, all of these factors may preclude direct comparisons. 

Compared with Western populations, our incidence rate of eye cancer was much lower (Table 6). This difference can be attributed to genetic and/or environmental factors that influence the development of specific types of eye cancers. The most common eye cancer histological types are compared across different studies and time periods in Table 7. In Asian populations, the most common type of eye cancer was lymphoma (56.9%–58.1%), whereas in the West it was predominantly melanoma (70%). It has been reported that the incidence of uveal melanoma in whites is nearly 16 times that of Asians, suggesting that the lighter iris color might exhibit an etiologic synergism with ultraviolet light exposure in development of melanoma.^33,34 A much lower rate of eyelid cancer was also observed in our study in comparison with Western literature (Table 6). Although basal cell carcinoma has been the predominant histology in eyelid cancers across studies and regions (Table 8), its strong association with fair skin color has been well demonstrated by meta-analyses.³⁵ Therefore, it is not surprising that a higher incidence rate has been observed in Western countries with a larger proportion of at-risk white individuals. 

Table 7.

 

Comparison of the Three Most Common Eyes Cancers in Studies From Different Geographical Locations

 

Table 8.

 

Top Three Most Common Histological Types of Eyelid Cancers in Population-Based Studies of Different Geographical Locations

 

In ophthalmic lymphoma, the incidence rates in our study were comparable to those from the Western world, except Canada, for which a lower incidence was reported (Table 6). We observed a small average annual increase of 2% in incidence rate. This increase is consistent with various reports in the literature. Moslehi et al.¹⁴ found an annual increase of 6% in the United States from 1975 to 2001, Sjo et al.¹³ found an increase of 3.5% in Denmark from 1980 to 2005, and Darwich et al.¹² reported an increase of 4.5% from 1992 to 2010. Our percentage of increase was smaller, which can be explained by a later study period. Indeed, Alfaar et al.³⁶ reported, in a more recent study period from 2004 to 2018, an annual decrease in incidence rate of 0.7%. Age is one known risk factor for ophthalmic lymphoma, and this is consistent in our study. The overall increase can be due to adoption of new lymphoma classification systems or infections associated with pathogenesis of lymphoma, yet the exact cause remains to be fully elucidated by more studies. 

The strengths of our study include its population-based design that minimized selection bias and enabled a comprehensive examination of the entire region. Our study focused on an ethnically homogeneous population and allowed for a targeted analysis of eye cancer epidemiology among the Chinese population. Another strength of our study is the well-established and reliable reporting system utilized. The Hong Kong Cancer Registry is run by the Hong Kong Hospital Authority, the only public system in the territory that manages both in- and outpatient oncology services. The Registry thus has direct access to cancer cases. All cases underwent stringent validation and cross-referencing. Our study attained a very high rate of morphologically verified cases (98.4%) that compares favorably with other cancer registries around the globe. Additionally, age standardization was performed for different world populations in order to account for methodology differences between studies and to facilitate meaningful comparisons of incidence rates across regions. 

Our study does have certain limitations. First, there could be potential underestimation of incidence rate due to underreporting. Individuals with undiagnosed eye cancers would not be captured in the registry. As eye and eyelid cancers are symptomatic and would prompt the patient to seek medical attention, undiagnosed cases should be minimal, and our incidence rates are not low compared with neighboring Asian populations. Our findings could also be susceptible to the “salmon bias,” an effect where migrants returning to their homeland to die are thus not counted in the mortality statistics of their host region.³⁷ However, this may be less applicable in the current context than during the study period, as few migrants die outside of Hong Kong due to the city's universally accessible and well-established health services, compared with elsewhere in the country.³² Another weakness is inadequate data in the initial reporting, thus making classification difficult. We reported one intraocular lymphoma, but there were over 20 cases of lymphoma labeled “eye” without a specific site. Nevertheless, intraocular lymphoma has been known to be extremely rare, with a reported incidence of 0.047 per 100,000.³⁸ 

In conclusion, this population-based epidemiological study comprehensively examined the incidence rate, histopathology, and trends of eye cancer, eyelid cancer, and ophthalmic lymphoma in a Chinese population in Hong Kong. It provides an updated analysis of cancer epidemiology and facilitates meaningful comparisons with similar studies worldwide. It also helps address an important knowledge gap and establish a wider understanding of the epidemiology of ophthalmic malignancies, which could subsequently inform the development of more effective preventive and therapeutic strategies. 

Acknowledgments

The authors thank the Hong Kong Cancer Registry for providing data and Yanyan Ni, PhD, for statistical advice. 

This study was partly supported by the Enhanced New Staff Start-up Research Grant, the University of Hong Kong. 

Disclosure: A. Lee, None; D.T.W. Law, None; A.H.S. Kan, None; F.F.P. Cruz, None; V. Jhanji, None; H.K.L. Yuen, None; M.Y. Ni, None