Corresponding Author: Alexander W. Suh, MD. Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA. Corneal melanoma (CM), first reported in 1892, is an extremely rare variation of ocular melanoma [1]. As there is limited documentation describing the origin of the disease, there are multiple proposed theories to explain the possible etiologies. One theory is that CM arises from contiguous spread of an undetectable conjunctival melanoma into corneal tissue, which lacks melanocytes [1]. Another theory, called primary acquired melanosis (PAM), suggests that melanocytes undergo malignant change and extend into the cornea [2]. PAM tumors originate from conjunctival melanocytic migration arising at the limbus [2]. Migrating melanocytes can then invade corneal stroma by way of penetrating traumas or complicated surgeries to infiltrate Bowman membrane [2]. CM is incredibly rare and has yet to be summarized beyond a case study setting. A deeper understanding of the disease pathology and prognosis is necessary to better treat future patients.
The presentation of CM usually includes gradual loss of vision, pain, discomfort, and a dense pigmentation over the cornea, subsequently interfering with vision [3]. Two case reports have described extensive evasion of tumor tissue, resulting in dense pigmentation covering the cornea and difficulty with eyelid closure [3,4]. Risk factors are poorly defined for such an extremely rare cancer and any disposition or origins of primary CM has not been fully characterized. While there is no consensus on a gold standard for diagnosis, slit-lamp examinations, ultrasound, and excisional biopsies have been used in case reports to detect and identify cases of CM [3]. Panagiotou et al. [1] noted the rules of atypia for CM mimic the rules of melanoma of the skin: “Irregular boundaries, change in shape, color, size, presence of epithelial defects or ulcers on the surface, dilated feeder blood vessels leading to the tumor, and displacement and/or infiltration of adjacent tissues.” Therapeutical modalities have also not been well-defined due to the inherently rare incidence of CM. Surgical excision, cryotherapy, and topical chemotherapy followed by steroid and antibiotic medicine have been described to have a good prognosis [4]. However, there is a need for tailored treatment approaches for specific histologic subtypes.
In this study, we conducted a Surveillance, Epidemiology, and End Results (SEER) population-based study that included 29 cases to identify possible prognostic roles of several clinicopathogical factors of CM. Our aim was to investigate the patterns, risks for development, and socioeconomic factors that may contribute to the incidence of corneal melanoma. The rarity of this subject makes characterizing the disease difficult, but the data may provide support for future facilitation of clinical predictions, prognosis, and therapeutic guidance for patients diagnosed with CM.
Materials and Methods
Study design
Cohort information for all patients was sourced from The National Cancer Institute’s SEER Program database across 18 registries (available at www.seer.cancer.gov). This database encompasses approximately 48% of the entire US population and is widely utilized in reputable tumor epidemiology research [5]. The data, extracted from the database, underwent analysis through SEER*Stat software ver. 8.4.2 (National Cancer Institute).
The following inclusion criteria was applied to the patient cohort for this study: (1) patients distinguished with primary malignancy from 1983 to 2018 were reviewed; (2) the diagnoses for all cases in the cohort were established during the patients’ lifetime, with exclusion criteria specifically omitting cases involving death certificates or autopsies; (3) morphology codes defined by the International Classification of Diseases for Oncology, 3rd Edition; (4) primary site Extent of Disease Data coded to the cornea (C691); and (5) not otherwise specified Histology Terms and Codes for Melanoma in situ (8720/2). After isolating cases matching the specified inclusion criteria, 24 malignant melanomas (not otherwise specified, NOS), 1 superficial spreading melanoma, 2 spindle cell melanomas, 1 nodular melanoma, and 1 epithelioid cell melanoma were identified.
Statistical analysis
Relevant demographic or clinicopathological variables, including sex, age at diagnosis, laterality primary tumor site, tumor size, extent of disease, treatment, medical facility, marital status, income, and residential area were brought into the analysis. The age at diagnosis was sorted based on 10-year intervals. Overall survival (OS), the time from diagnosis to death due to all possible causes, was our primary outcome measure. A Cox proportional hazards regression was used for univariate analysis of survivals. The hazard ratio (HR) and matched 95% confidence interval (CI) of OS were generated. Statistical significance was defined as p < 0.05. Cox proportional hazards regression was performed using JMP Statistical Discovery ver. JMP 17.2 (SAS Institute). The Kaplan-Meier survival analysis and log-rank tests were also performed to determine consistency with the Cox HR and reveal other significant prognostic factors. Statistical significance was defined as p < 0.05.
Results
Patient baseline characteristics
Overall, 29 patients were included in the study. The clinicopathological characteristics of CM patients are shown in Table 1. Among the patients included, 16 (55.2%) were male. The median age for the CM patients at diagnosis was 69 years old. For histological subtype, 24 (82.8%) were malignant melanoma (NOS), 1 (3.4%) was superficial spreading melanoma, 2 (6.9%) were spindle cell melanoma (NOS), 1 (3.4%) was nodular melanoma, and 1 (3.4%) was epithelioid cell melanoma. Among the overall patients, 23 (79.3%) underwent surgery, 2 (6.9%) underwent radiation, and the rest (13.8%) were unknown. The median survival time for all enrolled patients was 83 months.
Prognostic factors associated with the OS of CM
Sex, age at diagnosis, laterality primary tumor site, tumor size, extent of disease, treatment, medical facility, marital status, income, and residential area were included in the analysis. Different outcomes were observed with different histologic subtypes compared to the malignant melanoma (NOS) subtype. Spindle cell melanoma (NOS) had poorer outcomes compared to malignant melanoma (HR, 19.09; 95% CI, 1.145-318.2; p < 0.05). Nodular melanoma similarly had worse outcomes compared to malignant melanoma (HR, 27.5; 95% CI, 1.72-439.6; p < 0.05). Survival outcomes were worse for patients treated at other hospital outpatient units or surgery centers compared to those who received care at inpatient/outpatient hospitals or private medical offices (HR, 27.5; 95% CI, 1.72-439.6; p < 0.05). Our results indicated that the sex, age at diagnosis, laterality, tumor size, extent of disease, treatment, marital status, income, and residential area had no significant impact on the OS (Table 2).
After performing the Kaplan-Meier survival analysis and log-rank test (Fig. 1), the results were consistent with the previously reported Cox HR. However, due to the limited number of patients in the spindle cell melanoma, NOS, and nodular melanoma groups, the possibility of outliers affecting the results cannot be ruled out. This limitation also applies to cases reported by other hospital outpatient units or surgery centers from 2006 onwards.
The log-rank test identified additional prognostic markers. Specifically, patients aged 80 years and older have a statistically higher likelihood of dying from CM, although their advanced age may make them more susceptible to other comorbidities or complications (p < 0.05). Interestingly, patients residing in metropolitan areas with populations between 250,000 and 1,000,000 have a lower survival probability over time (p = 0.04).
The Kaplan-Meier analysis and log-rank test confirm previous findings but highlight the need for caution due to small sample sizes in certain subgroups. Additionally, age and metropolitan residency emerged as significant prognostic factors.
Discussion
This study identified 29 patients with different characteristics and outcomes from the SEER database and systematically analyzed for potential prognostic factors of CM. From this nationwide sample, we found that spindle cell melanoma and nodular melanoma patients showed significantly worse survival outcomes (p < 0.05). Most cases of CM arise from metastatic melanoma, but this primary site was not found to significantly correlate to survivability. Patients who received treatment from other hospital outpatient units or surgery centers had poorer survival outcomes in comparison to those who received care from either an inpatient/outpatient hospital or private medical office. Inpatient/outpatient hospitals and private medical offices may offer a more comprehensive range of services, including specialized treatments and a multidisciplinary approach, which could contribute to better overall patient outcomes.
Additionally, the continuity of care and follow-up provided by these settings may play a role in improving survival rates compared to more specialized or limited-care facilities. Beyond these factors, age at diagnosis, laterality, primary site, tumor size, the extent of disease, marital status, income, residential area, and treatment showed no significant prognostic factors for CM patients (p > 0.05). This was likely due to the rarity of CM and the associated challenges of obtaining robust survival data for this disease.
The simultaneous involvement of the conjunctiva, iris, uvea, or choroid in CM patients represents a complex clinical scenario requiring a comprehensive and multidisciplinary approach to diagnosis, treatment, and monitoring. Regarding extent of disease and simulataneous involvement of other eye structures such as the conjunctiva, iris, uvea, or choroid, our patient data set did not have any cases with involvement of other eye structures. This involvement indicates a more advanced and aggressive disease, necessitating vigilant management to optimize outcomes and preserve vision as much as possible.
Regarding metastatic spread, our study had 19 out of 29 patients with localized CM, while the remaining 10 were unstaged. We believe melanoma of the cornea tends to stay localized due to the cornea’s avascular nature and its dense, layered structure, which creates a physical barrier against invasive growth [5]. Additionally, the tight junctions between corneal epithelial cells and the immune-privileged status of the cornea further inhibit the spread of melanoma cells to adjacent ocular structures [5]. Early detection through routine eye exams also contributes to the higher likelihood of identifying and treating CM before it can advance [4].
In our data set, 24 of the 29 patients underwent surgical interventions after CM diagnosis confirmed with pathology. Surgical techniques for removing CM are carefully designed to ensure complete excision while preserving as much vision as possible. One common approach in our data set was a partial lamellar keratectomy, where the surgeon removes the melanoma along with a margin of healthy tissue to ensure clear boundaries [6]. In fewer cases where the melanoma is deeper, a penetrating keratoplasty, or full-thickness corneal transplant, was performed to replace the affected corneal tissue with a donor graft. Cryosurgery, which involves freezing the tumor tissue, was also employed as an adjunct to surgery to eliminate residual malignant cells [6]. Of our patients, 11 (38%) received excisional biopsy, 4 (14%) received cryosurgery, 4 (14%) received partial/total excision, and 3 (10%) received total enucleation surgery.
Advanced imaging techniques, such as intraoperative optical coherence tomography, help surgeons visualize tumor margins and ensure precise excision. Postoperative care includes the use of topical steroids and antibiotics to manage inflammation and prevent infection, with close follow-up to monitor for recurrence or complications [6]. These surgical interventions aim to achieve a balance between effective tumor removal and the preservation of corneal structure and function.
Postoperative outcomes in CM patients largely depend on the size, depth, and location of the tumor, as well as the specific surgical technique employed. Generally, successful removal of the melanoma with clear margins results in favorable outcomes, including the preservation of vision and a low recurrence rate [7]. Patients often experienced an initial period of blurred vision and discomfort, which typically improves as the eye heals [7]. The use of topical steroids and antibiotics is crucial in managing inflammation and preventing infection during the recovery period. Though our patient data set did not have the ability to assess long-term follow-up or visual prognosis, which is one of the limitations of the study using the SEER population study, long-term follow-up is essential to monitor for any signs of recurrence or complications such as graft rejection in cases of corneal transplantation. The primary goal is the complete excision of the melanoma, maintaining the patient’s visual acuity and quality of life is also a critical aspect of postoperative care. Similarly, the visual prognosis in CM patients is generally favorable if the melanoma is detected early and completely excised, but it can vary depending on the tumor’s size, depth, and the extent of surgical intervention required [8].
Survival rates are crucial in medical treatment planning as they inform the patient and care team about prognosis and potential outcomes for individuals diagnosed with life changing conditions. Based on the patient population recorded in the SEER database, we showed that those with spindle cell melanoma and nodular melanoma primary sites could benefit from treatments tailored to a specific primary site. While there was limited statistical significance, this study provides valuable insight into survival trends that are essential for clinicians and researchers to guide treatment decisions and tailor patient counseling. Patients and their families can make more informed decisions about their healthcare when they have access to survival rate and prognostic data to help weigh the potential risks and outcomes. Together, the healthcare team can assist in setting realistic expectations and facilitating shared decision making in the management of CM.
There are several limitations to note in this study. Due to the low prevalence of CM, our sample size was small, which limits the statistical power of the study. While the SEER database provides ample individual factors to consider, some additional factors that would be beneficial to consider for CM include a more detailed characterization of radiotherapy (e.g., dosage and location), treatment plans (e.g., topical chemotherapy, cryotherapy), frequency of postoperative follow-up, and visual acuity. Therapeutic management in several case studies included surgical excision [8]. In a study describing corneal PAM, recommended treatment was to do a complete excision with alcohol debridement of Bowman membrane later. After excision, adjuvant double freeze-thaw cryotherapy was performed on adjacent conjunctiva free margins. This technique yielded favorable outcomes and a close nine-year follow-up period showed no recurrence in one recorded case of CM [9]. In another case, feeder vessels were cauterized before the lesion was removed on free margins then the corneal epithelial was scraped. Post-procedural topical chemotherapy was administered (mitomycin 0.03%, 2 × 4 for 2 weeks and dexamethasone 0.1%, 2 × 4 for the following 2 weeks, followed by another cycle of mitomycin 0.03%, 2 × 4 for another 2 weeks). After 2 years, the eye was fully functional and there were no signs of local or distant recurrence [9]. Future studies should investigate diverse treatment modalities and prognosis associated with various cases of CM. Findings may provide comprehensive guidance for future cases, shedding light on the most effective treatment approaches and offering valuable insights into the expected outcomes for patients diagnosed with CM.
Drawing from a multicenter database, we investigated numerous independent prognostic factors for CM survivability and uncovered several factors—primary site and alternative care facilities—for further research. These findings can help guide researchers in designing more targeted studies to explore these factors in greater detail. Being diagnosed with a rare and potentially serious cancer like CM can be incredibly demanding physically, mentally, and socially. We emphasize the importance of providing patients with as much information as possible to support their emotional well-being and empower them with knowledge of new avenues to explore with their care team.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
Print
