Innocent ocular symptoms, including change of refractive error, dryness, or allergy, may masquerade a hidden malignancy. Moreover, such lesions can be the first sign of metastasis [14, 15]. Secondary malignancy is terminology-wise mistaken with second-primary tumors . Secondary tumors may refer to metastatic tumors or relapsing tumors of ocular or adnexal origin. Our paper focuses on the risk of developing a second malignancy in the eye or its adnexa after the incidence of a previous primary malignancy elsewhere in the body.
Improvements in the early detection and the treatment protocols have led to more cancer survivors, hence an increase in the number of patients developing subsequent cancers. We found that the overall risk of developing a second primary EOA malignancy increases significantly following a cancer diagnosis compared with the incidence of the primary EOA malignancies in general population. This is consistent with many other studies that documented the incidence of second malignancies among cancer survivors. Understanding the pattern of second malignancies is essential for planning the follow-up and screening protocols after the first cancer diagnosis.
Curtis et al. found that cancer survivors had a 14% higher risk to develop a new malignancy compared with that expected in the general population. They showed cumulative incidence of 5.0%, 8.4%, 10.8%, and 13.7% at 5, 10, 15, and 25 years, respectively . This risk may be a result of the lifestyle, genetic predisposition, environmental exposures, and/or the effects of cancer therapy .
Many studies evaluated the risk of a second malignancy in specific sites. Between 1973 and 2011, Laíns et al. followed patients diagnosed with uveal melanoma as their first malignancy. They found an 11% excess risk of a second malignancy, mainly due to a significantly increased risk of skin melanomas and kidney tumors. Radiotherapy showed no effect on this risk . Abramson et al. reported 28 third tumors developed in 211-s tumor survivors of retinoblastoma patients within a median time of 5.8 years .
The pattern of second primary malignancies in our results contradicts that in metastatic tumors where the breast followed by the lung were the most common primary sites for metastasis either for the ocular adnexa or the eye [11, 20, 21].
In our study, SIR was statistically significant in females and those between 20 and 39, and 40–59 years. Among the sites of primary cancers, the skin melanoma came first, followed by non-Hodgkin’s lymphoma (NHL). This is in agreement with different studies that did not report SPMT in the EOA region after breast cancer [4, 22, 23] and prostate .
Age pattern for second malignancies in the EOA is different from that for second malignancies elsewhere, where our results showed 58.9% of the patients developing second malignancies in the EOA are in the age range of 50–69 years at their first presentation. While the previously published relative risk of developing second malignancies was 6-fold higher for survivors of childhood cancer. This may be attributed to the effect of initial therapy, genetic susceptibility, and the age effect . Both males and females showed a significantly higher risk of a second malignancy in the EOA, which is consistent with Youlden et al. . Curtis et al. reported that females had a slightly higher relative risk than males for all subsequent cancers .
Regarding the type of first primary tumor, we found that prior NHL was associated with a significant increase in the risk of second malignancies in the lacrimal gland, ciliary body, orbit, and eyelid. NHL is associated with SPMT in different sites. In a large-scale analysis of NHL cases, the EOA region was reported to develop SPMT with a SIR of 1.73. This is in agreement with our results, while the difference in the SIR may be attributed to the combined analysis of the eye and the ocular adnexal regions in their analysis . Similarly, NHL had a pooled RR of 1.43 for SPMT in the EOA region in a meta-analysis, which included 23 studies . However, the combined analysis for the whole region may account for the lower SIR in these studies compared with ours. Nonetheless, the excess risk for SPMT after NHL is well documented and reported [25, 26].
Eyeball malignancies are not far from the orbital ones, sharing similar challenges. Ocular metastasis is well studied, being the most common intraocular malignancy, where near half of these tumors originate in the breast, followed by lung and prostate [6, 20]. SEER central quality control paid attention to differentiate between metastasis and second primaries according to IARC Guidelines. Therefore, the observed patterns in our study are different from the distribution of other common malignancies and their metastasis.
Conjunctiva is another site that possessed a significantly higher risk of SPMT after NHL with no significant influence of gender or age. Eyelid is a known site for primary as well as metastatic tumors. As well, it showed a higher risk for SPMT that was significantly higher for males, females, and all age groups in our analysis. Basal and squamous cell carcinomas were the most prevalent primary eyelid malignancies. Similarly, they were significantly detected as SPMT in the eyelid. Skin melanoma and NHL were reported as primary malignancies for SPMT in the eyelid. As well, they may be the SPMT in the eyelid in contrast to their rare primary occurrence in the eyelid [27,28,29]. The paucity of the literature of eyelid SPMT hinders comparing our results to explore matching or discrepancy.
Lacrimal gland tumors are common among the white race with an age-adjusted incidence rate of 0.6 per 1,000,000. In the USA, NHL is the most common primary lacrimal gland malignancy. In our study, the lacrimal gland did not show a significantly higher overall risk for SPMT. NHL dominated as the only significant pathological type of SPMT. Nonetheless, the lacrimal gland was not reported among SPMT after NHL elsewhere [3, 5]. Lacrimal gland secretion decreases with radioiodine in thyroid carcinoma therapy, a mechanism that may contribute to the risk of SPMT in the lacrimal gland after radiation for other malignancies .
EOA tumors are among the most challenging malignancies. Five-year survival after the exenteration for orbital tumors reached 57% . SPMTs in the EOA are not an exception for this, our study showed a significantly worse survival in the former.
Figure 1 shows different patterns in annual incidence rates of first and second primaries where first primary malignancies showed multiphasic pattern and second primary malignancies showed a steady increase. The potential causes for first primary malignancies were discussed elsewhere . Our paper presents a new pattern in second ocular and its adnexal malignancies that may not be influenced by the same factors. Such point is a potential for future further research for investigating the underlying molecular and genetic differences between the cancers especially in non-Hodgkin’s lymphoma and melanoma.
Our literature review of the most common pathological subtypes and/or sites revealed shared predisposing genes (Supplementary Table 1). We believe that such shared genetic factors may play a role for predicting the incidence of a second malignancy. Moreover, it can guide minimizing the panel used for targeting the second malignancy.
The current study has superior reliability compared with other case studies in terms of the primary sites reported and the histological type of malignancies. However, the retrospective nature of our study carries a potential risk of bias due to the misreporting of the primary malignancy for SPMT or other demographic data. Other limitations are related to the coding of cancer registries, where some anatomical regions are not represented in topographical classifications, e.g., orbital bones and minute orbital structures, e.g., ganglia.
In conclusion, we propose that second ocular and its adnexal primary malignancies are driven by a different underlying mechanism from first primaries. Moreover, a primary malignancy should raise the suspicion for screening either for metastasis or SPMT with any innocent presentation. So, it is recommended to perform a thorough ophthalmic examination with particular attention to the eyelid, the conjunctiva, and the eyeball in the follow-up of cancer cured patients. This is of paramount importance if the first primary malignancy was after the age of 20 years in white race patients. As well, a prior history of any of NHL, EOA malignancy, melanoma, and oropharyngeal malignancies should be thoroughly assessed for potential SPMT in the EOA region.