Influence of Post-radiation Ocular Surface Disorder on Ocular Surgery: A Case Report and Review of the Literature.

BACKGROUND: Ocular surface disorder after ocular radiation therapy, even though commonly reported, is often overlooked. Any delay in diagnosis may lead to complications that threaten vision. The presented case highlights the clinical outcome of a severe post-radiation disorder of the ocular surface, the importance of intensive therapy, and the limitations of further surgical interventions. CASE PRESENTATION: A 34-year-old woman was referred for a second opinion due to a years-long history of pain and redness in her right eye (OD) after proton beam therapy for recurrent iris melanoma. The patient then developed post-radiation retinopathy with macula edema, secondary glaucoma, cataract, as well as a severe ocular surface disorder with corneal decompensation and band keratopathy. Several surgical treatments have been attempted, including phacoemulsification with IOL implantation and trabeculectomy with mitomycin C. Due to refractory glaucoma, Baerveldt glaucoma drainage was then necessary. Given the worsening clinical presentation of post-radiation ocular surface disorder with progressing band keratopathy, the possibility of penetrating keratoplasty (PKP) was discussed. CONCLUSION: The continuous worsening of clinical symptoms of the disorder of the ocular surface after proton beam radiotherapy can be the result of a post-radiation syndrome. Gradual expansion of ischemia, vasculitis, and inflammatory mediators compresses the retinal tissue, leading to recurrent macular edema as well as to secondary glaucoma and corneal decompensation. Band keratopathy is occasionally noted and seems to result from severe post-radiation disorder of the ocular surface. However, PKP would typically be indicated in cases of corneal perforation, uncontrolled infectious keratitis, or for improving vision in the presence of corneal opacification, none of which applied to our patient. Furthermore, post-radiation keratopathy implies compromised corneal stromal lymphogenesis and angiogenesis, both of which are now considered essential conditions for allograft rejection. Moreover, a previously performed Baerveldt glaucoma drainage surgery can affect the survival rate of the endothelial cells of the recipient cornea. Therefore, a penetrating or endothelial keratoplasty should be viewed as a high-risk procedure. In this instance, the rigorous treatment of the severe ocular surface disorder was crucial. We managed our patient's complex situation by following the latest guidelines set by the Tear Film & Ocular Surface Society and aimed to alleviate the symptoms as effectively as possible. In conclusion, careful decision-making regarding surgical treatment options should be considered, taking into account the complexities and potential risks involved.

Side Effects of Proton Beam Radiotherapy Treatment on Iris Melanoma.

PURPOSE: This study evaluated the functional outcome and ocular side effects of patients receiving proton beam radiotherapy (PBR) for the treatment of iris melanoma (IM). DESIGN: This retrospective study analyzed prospectively collected data. PARTICIPANTS: Patients with IM who underwent PBR as a primary treatment. METHODS: Treatment was given in the form of whole PBR (wPBR: n = 51) or segmental PBR (sPBR: n = 98). MAIN OUTCOME MEASURES: Visual acuity (VA) and side effects were divided into ocular surface disease (OSD), secondary glaucoma, or cataract development. RESULTS: A total of 149 eyes of 149 patients with a mean age of 53.9 ± 16.0 years were included. Tumor recurrence developed in 3 patients (wPBR: 1/51; sPBR: 2/98). Ocular surface disease was observed in 78.4% of the wPBR group (40/51) and 25.5% of the sPBR group (25/98) (P < 0.001) after 0.7 ± 1.2 years and 1.1 ± 0.9 years, respectively. The main side effect was dry eye syndrome in both groups, but severe side effects such as limbal stem cell failure were found only in the wPBR group (4/51; 7.8%). Secondary glaucoma developed in 31.4% of the wPBR group (16/51) compared with 1.0% in the sPBR group (1/98; P < 0.001). Glaucoma control was generally achieved with eye drops, whereas surgery was necessary in 5 patients (wPBR: 4/51, 7.8%; sPBR: 1/98, 1%). Cataract surgery was performed in 47.9% of the wPBR group (23/48) and 19.8% of the sPBR group (19/96) (P < 0.001). Before treatment, VA was 0.14 ± 0.27 logarithm of the minimum angle of resolution (logMAR) in the wPBR group and 0.04 ± 0.19 logMAR in the sPBR group. A worsening was seen in the wPBR group (0.55 ± 0.16 logMAR; P < 0.001) 6 months after radiotherapy, which normalized after 12 months (0.15 ± 0.30 logMAR; P = 0.17). In the sPBR group, no such decrease in VA was observed (6 months: 0.03 ± 0.22 logMAR, P = 0.54; 12 months: 0.04 ± 0.21 logMAR, P = 0.98). CONCLUSIONS: Our results demonstrate that PBR is a very successful treatment option for patients with IM, showing a high tumor control rate and relatively low complication profile. Tumor recurrence was a rare event, and secondary enucleation was not necessary in any patient. Side effects are commonly seen, but severe side effects such as limbal stem cell failure or secondary glaucoma mainly developed after wPBR. These results are important for clinical decision making and discussion with the patient regarding this form of radiotherapy. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Topography and clinical features of iris melanoma.

BACKGROUND: To characterise the topographical and clinical features of primary iris melanoma and to visualise the patterns of tumour extent in the iris. METHODS: Clinical characteristics of iris melanomas were analysed, and data on their size, shape, and location were converted into a database of two-dimensional iris charts by means of computer-drawing software. The geometric centre of each tumour was entered into corresponding sectors of the chart. The extent of the melanomas was computationally visualised by merging the iris drawings and displaying the number of overlapping tumours on colour-coded iris maps. RESULTS: Twenty-nine patients (18 females and 11 males) with a mean age of 52 years met the inclusion criteria. The mean largest tumour diameter was 6.1 mm (range, 1.8-11.0 mm). Five tumours (17%) involved the pupillary margin, 10 (34%) involved the iris root, and 10 (34%) involved both sites. The hemispheric location of the tumour centroid was superior in 3 eyes (11%) and inferior in 25 (89%) (p < 0.0001), and the distribution between the temporal and nasal hemispheres was 17 (61%) and 11 (39%), respectively (p = 0.26). In females, the iris melanomas were located more temporally (p  =  0.02) and had more often originated from a pre-existing naevus (p = 0.03), than in males. There was also shift towards more temporally located melanomas in younger patients. CONCLUSIONS: The lower temporal iris quadrant is the preferential area of melanoma occurrence and growth. Iris melanoma tends to be more temporally located in females, who compared with males also have a higher proportion of melanomas arising from a pre-existing naevus.

Case Series: Different Presentations of Iris Melanoma-Potential Masquerade of Benign and Malignant.

SIGNIFICANCE: Iris melanoma and iris nevi can be challenging to distinguish clinically. This case series provides unique insight into the rare condition and variable clinical presentations of iris melanoma. PURPOSE: This study aimed to highlight the varying clinical presentations of iris melanoma and to demonstrate the overlapping features of melanoma and nevi. CASE REPORTS: This case series includes five patients of varying age and sex who presented to clinic with pigmented iris lesions. These five patients have differing timeline to presentation and very different clinical presentations of their lesions. Clinical evaluation was based around the established "ABDCEF" guide for the assessment of malignant risk in iris lesions. The presentation of each lesion is discussed in relation to this guide and the experienced clinician's clinical suspicion of malignancy. When comparing the clinical suspicion with histological analysis, after biopsy, the result may be unexpected. Notably, initially benign nevi may transform into melanoma over time. These five cases were managed on an individual basis because the management and prognosis of iris melanomas vary significantly. Importantly, iris melanotic lesions have variable metastatic risk based on cytology and genetic predisposition. Informed consent was obtained from all the patients, institutional approval was obtained, and no identifiable health information is included in this case series. CONCLUSIONS: When presented with a pigmented iris lesion, clinicians must be vigilant with regular monitoring and have a low threshold for biopsy in pigmented lesions of high clinical suspicion.

Usefulness of PAX8 Immunohistochemistry in Adult Intraocular Tumor Diagnosis.

PURPOSE: To evaluate the distribution of the PAX8 transcription factor protein in ocular tissues and to investigate if immunohistochemical stains for this biomarker are useful in the diagnosis of intraocular tumors. DESIGN: Observational case series. PARTICIPANTS: Excision and cytologic analysis specimens of 6 ciliary body epithelial neoplasms, 2 iris epithelial neoplasms, 3 retinal pigment epithelial neoplasms, 3 intraocular medulloepitheliomas, 15 uveal melanomas, and 5 uveal melanocytomas. METHODS: Hematoxylin-eosin and PAX8 immunohistochemical stains were performed on all specimens. In appropriate cases, bleached preparations and other immunohistochemical stains, including AE1/AE3 cytokeratin, Lin28A, and CD45, were performed. MAIN OUTCOME MEASURES: Distribution of PAX8 expression in normal and neoplastic tissue. RESULTS: Strong nuclear PAX8 expression was observed in the normal corneal epithelium, iris sphincter pupillae muscle, iris pigment epithelium and dilator muscle complex, nonpigmented and pigmented epithelia of the ciliary body, lens epithelium, and a subset of retinal neurons. The normal retinal pigment epithelium and uveal melanocytes did not stain for PAX8. The ciliary body epithelial and neuroepithelial tumors (adenoma, adenocarcinoma, and medulloepithelioma) showed uniform strong nuclear PAX8 immunoreactivity. All melanocytic tumors (iris melanoma, ciliary-choroidal melanoma, and melanocytoma) and retinal pigment epithelial neoplasms showed negative results for PAX8. A subset of tumor-associated lymphocytes, most prominent in uveal melanoma, showed positive results for PAX8. The uniformity of the PAX8 staining was superior to the variable cytokeratin staining in the ciliary epithelial neoplasms and the variable Lin28A staining in malignant medulloepithelioma. The veracity of PAX8 staining was equally as robust on cytologic analysis and open-flap biopsy specimens of ciliary epithelial and iris epithelial neoplasms, melanocytoma, and melanoma. CONCLUSIONS: PAX8 has proven to be a very useful diagnostic marker in a select group of adult intraocular tumors, and we highly recommend its inclusion in diagnostic antibody panels of morphologically challenging intraocular neoplasms.

No differences in the long-term prognosis of iris and choroidal melanomas when adjusting for tumor thickness and diameter.

OBJECTIVE: To assess the long-term prognosis for patients with iris melanomas and compare it with the prognosis for small choroidal melanomas. DESIGN: Retrospective observational case series. METHODS: All patients treated for iris melanomas at a single referral institution between January 1st 1986 and January 1st 2016 were included. Patients treated for small choroidal melanomas during the same period were included for comparison. The cumulative incidence of melanoma-related mortality was calculated. Patient and tumor characteristics and size-adjusted hazard ratio (HR) for melanoma-related mortality were compared between iris and small choroidal melanomas. RESULTS: Forty-five iris melanomas and 268 small choroidal melanomas were included. Twenty-four iris melanomas (53%) had been treated with local resection, 12 (27%) with Ruthenium-106 brachytherapy, 7 (16%) with enucleation and 2 (4%) with proton beam irradiation. Twenty-one (68%), 7 (16%) and 2 (4%) of the iris melanomas were of the spindle, mixed and epithelioid cell types, respectively. Twenty-three patients had deceased before the end of follow-up. Median follow-up for the 22 survivors was 13.3 years (SD 9.4). Patients with iris melanomas were more often asymptomatic at presentation and had a trend towards significantly lower age (59 versus 63 years, Student's T-tests p = 0.057). Further, iris melanomas had significantly smaller basal diameter (5.8 versus 8.0 mm, p < 0.0001) and tumor volume (79 mm3 versus 93 mm mm3, p < 0.0001) but greater thickness (3.0 versus 2.5 mm, p < 0.0001). The cumulative incidence of iris melanoma-related mortality was 5% at 5 years after diagnosis, and 8% at 10, 15 and 20 years. The incidence was not significantly different to small choroidal melanomas (Wilcoxon p = 0.46). In multivariate Cox regression with tumor diameter and thickness as covariates, patients with choroidal melanomas did not have increased HR for melanoma-related mortality (HR 2.2, 95% CI 0.5-9.6, p = 0.29). Similarly, there were no significant survival differences in matched subgroups (Wilcoxon p = 0.82). CONCLUSIONS: There are no survival differences between iris and choroidal melanomas when adjusting for tumor size. The reason for the relatively favorable prognosis of iris melanomas compared to melanomas of the choroid and ciliary body is likely that they are diagnosed at a smaller size.

Ectopic thyroid tissue in the iris: a case report.

BACKGROUND: Ectopic thyroid tissue in the iris, also known as a thyroid glandular epithelial choristoma of the iris, has only been described twice in the literature. In both cases it remained asymptomatic. CASE PRESENTATION: A 67-year-old female patient presented for the first time in mid-2017 with corneal endothelial decompensation, with a history of complicated cataract surgery and IStent® implantation. Slit lamp microscopy showed endothelial decompensation, pseudophakia, anterior synechiae and a whitish iris tumour adhering to the endothelium. The latter had existed since childhood. Given these findings, reduced visual acuity of hand movement perception and an intraocular pressure of 23 mmHg, we performed a keratoplasty combined with an en bloc resection of the iris tumour at 9 o'clock and sector iridectomy at the end of 2019. Histological and immunohistological examination of the iris tumour unexpectedly revealed thyroid tissue. After the procedure described above, the patient had an increase in visual acuity while the graft stayed clear and the eye showed no evidence of tumour recurrence or other complications. CONCLUSIONS: We report a third case of ectopic thyroid tissue in the iris. Both previous cases remained asymptomatic, whereas in our case, size and location of the ectopic thyroid tissue contributed to a more complex cataract surgery resulting in endothelial decompensation. Therefore, in such cases appropriate patient information should be provided prior to cataract surgery. Furthermore, careful histological examination and examination of the thyroid is important to exclude malignant diagnoses such as a metastasis of a follicular thyroid carcinoma.

Iris melanoma with ciliary body infiltration presenting as a presumed chronic unilateral inflammatory glaucoma. The challenges of iris tumor biopsy assessment.

Uveal melanoma is the most common primary malignancy of the eye in adults. It may involve the choroid and ciliary body, and in only 2-3% of cases it involves the iris. We present a case of a 56-year-old patient with a 6-year history of unilateral, inflammatory, refractory glaucoma of the right eye. Due to acquired heterochromia and heterogeneous thickness of the iris, iris melanoma was suspected, but the incisional biopsy did not confirm the diagnosis. In the next months, the lesion enlarged and the eye globe was enucleated. Histopathological examination revealed an iridociliary melanoma with annular growth pattern.

Case Report: Tapioca Iris Melanoma: An Uncommon Presentation of an Uncommon Tumor.

SIGNIFICANCE: Iris tumors are rare conditions, and there is a relative paucity of recent published data on its broad clinical spectrum. Tapioca iris melanoma is a rarer yet devastating form with wide and challenging differential diagnoses because of its amelanotic nodular appearance. PURPOSE: This study aimed to report the challenging presentation of an uncommon iris melanoma, describing the clinical and histological findings and comparing them with the existing published data. CASE REPORT: An uncommon clinicopathological report on the tumor unusual localization, patient age, absence of elevated IOP and heterochromia, and negative S-100 stain that caused diagnostic uncertainty is presented. The patient remains free of metastatic disease 7 years after a complete tumor full-thickness excision. CONCLUSIONS: Tapioca iris melanomas are uncommon tumors with a presentation/surgical management that differs from other malignant tumors. Ophthalmologists should consider it among the vast differential diagnoses when observing amelanotic lesions, even without the hallmark signs being evident.

Iris biopsy to investigate feline iris hyperpigmentation.

OBJECTIVE: To evaluate the benefit of iris biopsy in cats with iris hyperpigmentation to differentiate melanosis from early feline diffuse iris melanoma (FDIM). METHODS: The medical records of cats with unilateral iris hyperpigmentation that had undergone iris biopsy between February 2013 and September 2016 at Willows Veterinary Centre & Referral Service were reviewed. RESULTS: Seven cats with unilateral iris hyperpigmentation were included in this retrospective study. The biopsy procedure was performed under general anesthesia (n = 7) with neuromuscular blockade (n = 6) following pre-operative topical miotic therapy (n = 5). One to six biopsy samples per eye were harvested from areas of hyperpigmentation. The samples were partial thickness (n = 4 eyes) and full thickness (n = 3 eyes). Complications were minor: mild intra-operative hemorrhage (n = 4), fibrin clot (n = 2), corneal ulcer (n = 1), post-operative ocular hypertension (n = 1), dyscoria (n = 1), and pseudopolycoria (n = 2). The first biopsy was diagnostic in six cats; a repeat biopsy was necessary in one cat. Histopathology was consistent with melanosis in five cats and with early FDIM in two cats. Screening for signs of metastatic disease (thoracic computed tomography and abdominal ultrasonography) was negative in the two cats with a preliminary diagnosis of early FDIM. Subsequent enucleation and histopathology confirmed the initial diagnosis in both cases. CONCLUSIONS: Iris biopsy in cats with iris hyperpigmentation can be beneficial to differentiate melanosis from early FDIM and thereby help to justify the decision for early enucleation.

Surgical excision of iridociliary tumors using a postero-anterior cyclo-iridectomy and thermocautery in two dogs.

OBJECTIVE: To report the surgical excision of an iridociliary adenoma and iridal melanocytoma using a postero-anterior cyclo-iridectomy in two dogs. PROCEDURE: A 7 year old neutered male English springer spaniel (case 1) and a 7 year old neutered male Labrador mix (case 2) were presented for evaluation of an intrairidal mass OS. RESULTS: Complete ophthalmic examination revealed a large, dorsonasal, well-demarcated, intrairidal mass OS. A tan to pink intrairidal mass extending into the iridocorneal angle (case 1) and a pigmented intrairidal mass (case 2) were present. B-mode ultrasonography showed a focal, soft tissue, homogenous mass within the uvea adjacent to and contacting the lens. Neither pars plana involvement nor vitreal extension was present. A postero-anterior cyclo-iridectomy was performed through a polyhedral scleral flap. Thermocautery was used to complete the cyclo-iridectomy (case 1) and partial iridectomy (case 2) to excise the mass en bloc. Histopathology revealed a completely excised iridociliary adenoma (case 1) and iris melanocytoma (case 2). The surgery sites healed without complication. Mild uveitis (cases 1 and 2), scant vitreal hemorrhage (case 1), and mild hyphema (case 2) were present three days postoperatively but had resolved ten days postoperatively. The patients remain visual twenty-two months (case 1) and seven months (case 2) postoperatively with a normal intraocular examination other than an iridal defect and mild dorsonasal lens capsular opacities. CONCLUSIONS: The surgical approach described in these cases is utilized in physician-based medicine. This approach and the use of thermocautery provide a viable surgical option for excision of large iridociliary tumors in dogs.

Conservative management of suspicious melanocytic lesions of the iris.

PURPOSE: The diagnosis of iris melanoma can be difficult, with no established diagnostic criteria currently available. Careful monitoring of patients with suspicious iris lesions is one approach to managing these tumors. We determined the risk of malignant transformation and melanoma-related mortality in patients under observation to evaluate the validity of this management approach. METHODS: This was a retrospective chart review of patients with suspicious iris lesions diagnosed at Massachusetts Eye and Ear Infirmary (MEE) between 1975 and 2014. All patients with an initial diagnosis of suspicious iris lesion followed and/or treated after malignant transformation at the MEE in this 39-year period were included in the cohort. Rates of malignant transformation and melanoma-related mortality were calculated. Treatment outcomes after proton beam irradiation were evaluated in patients who developed iris melanomas during observation. RESULTS: Two hundred thirty-four patients had a diagnosis of suspicious iris lesion (median follow-up, 5.8 years). Malignant transformation occurred in 16 (6.8%) patients with suspicious lesions during the observation period (median follow-up, 9.9 years). All patients diagnosed with iris melanomas were treated with proton beam irradiation (PBI). Complications after treatment included cataract (18.8%), secondary glaucoma (6.3%), and neovascular glaucoma (12.5%). Two of 16 patients (12.5%) who developed iris melanomas died of metastatic melanoma 32.6 months and 10 years after treatment with PBI. Both cases had been followed regularly to monitor for malignant transformation of their suspicious lesions (8.2 years and 3.2 years before melanoma diagnosis, respectively). CONCLUSIONS: These data suggest that suspicious iris lesions have low malignant potential, and a conservative approach to the management of these lesions is appropriate. Survival does not appear to be compromised with an observational approach, and there is potential for preservation of good visual function because vision-threatening treatments can be avoided.

Proton Beam Therapy for Iris Melanomas in 107 Patients.

PURPOSE: To report on the clinical characteristics and outcomes for patients with iris melanoma using proton therapy. DESIGN: Retrospective study. PARTICIPANTS: One hundred seven patients with iris melanoma from 3 regional ophthalmologic centers. METHODS: A retrospective study was conducted for iris melanoma patients from 3 regional ophthalmologic centers referred to and treated at a single proton therapy facility between 1996 and 2015. MAIN OUTCOME MEASURES: At each follow-up visit, examinations included measurement of best-corrected VA, slit-lamp, examination, indirect ophthalmoscopy, and ultrasound biomicroscopy. RESULTS: With a median follow-up of 49.5 months, 5 of 107 patients experienced a local relapse within a median of 36.3 months. The cumulative incidence of relapse was 7.5% at 5 years. All 5 patients showed involvement of the iridocorneal angle (P = 0.056). Diffuse iris melanoma showed a higher risk of relapse (P = 0.044). Four patients showed out-of-field relapse and 1 showed angular relapse. Three patients were retreated with proton therapy, whereas 2 other patients, one with T1b disease and another with diffuse T3 disease, underwent secondary enucleation. None of the patients experienced metastases nor died of iris melanoma. Vision improved in 59.4% of patients (n = 60/101). However, cataracts occurred in 57.4% of the 54 patients (n = 31) without cataract or implant at diagnosis. Secondary glaucoma was reported in 7.6% of the patients (n = 8), uveitis in 4.7% (n = 5), and hyphema in 3.7% (n = 4). All but 5 cases of complications were mild, transient, and not sight limiting after treatment. Five cases of glaucoma, including 1 with uveitis, were severe and associated with visual deterioration. CONCLUSIONS: Proton therapy showed efficacy and limited morbidity in iris melanomas.

Iris Melanoma Outcomes Based on the American Joint Committee on Cancer Classification (Eighth Edition) in 432 Patients.

PURPOSE: The American Joint Committee on Cancer (AJCC) classification was updated to the eighth edition in January 2017, providing staging for iris melanoma. This study evaluated outcomes of iris melanoma per the AJCC classification, eighth edition. DESIGN: Retrospective case series. PARTICIPANTS: Four hundred thirty-two patients with iris melanoma. METHODS: Management including tumor resection, plaque radiotherapy, or enucleation. MAIN OUTCOME MEASURES: Local tumor recurrence, melanoma-related systemic metastasis, and melanoma-related death. RESULTS: Of 432 patients with iris melanoma, AJCC classification was category T1 (n = 324 [75%]), T2 (n = 83 [19%]), T3 (n = 2 [<1%]), and T4 (n = 23 [5%]). There was no difference in age, race, gender, eye, or iris color among T categories. Overall, Kaplan-Meier analysis of outcomes (at 5 and 10 years) revealed visual acuity reduction by 3 lines or more (42% and 54%, respectively), secondary glaucoma (29% and 33%, respectively), local recurrence (8% and 17%, respectively), secondary enucleation (12% and 19%, respectively), lymph node metastasis (1% and 1%, respectively), melanoma-related systemic metastasis (5% and 10%, respectively), and melanoma-related death (3% and 4%, respectively). Compared with T1 category, the hazard ratio (HR) for local recurrence in nonenucleated eyes was 1.31 for T2, not evaluable (NE) for T3 (because of small cohort), and 6.61 for T4; the HR for metastasis was 3.41 for T2, NE for T3 (because of small cohort), and 25.6 for T4; the HR for death was 7.51 for T2, NE for T3 (because of small cohort), and 26.5 for T4; and the odds ratio for enucleation was 1.23 for T2, 3.63 for T3, and 4.72 for T4. Features predictive of melanoma-related metastasis (multivariate analysis) included secondary glaucoma (P < 0.001; HR, 4.51), T2 category (vs. T1; P = 0.01; HR, 4.09), and T4 category (vs. T1; P < 0.001; HR, 30.8). Features predictive of melanoma-related death (multivariate analysis) included older age (P = 0.008; HR, 2.16 per 10-year increase), T2 category (vs. T1; P = 0.005; HR, 8.07), and T4 category (vs. T1; P < 0.001; HR, 20.3). CONCLUSIONS: The AJCC eighth edition classification provides prognostic stratification of iris melanoma. By multivariate analysis, the ratio for melanoma-related metastasis was 4 times greater in category T2 and 31 times greater in T4 compared with T1. The ratio for melanoma-related death was 8 times greater in category T2 and 20 times greater in T4 compared with T1. The cohort size for T3 was too small to provide useful information.

Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential.

PURPOSE: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi. DESIGN: Multicenter, retrospective case series. PARTICIPANTS: Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment. METHODS: Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53, and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples. MAIN OUTCOME MEASURES: Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis. RESULTS: In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11. Furthermore, 13 of 30 BAP1, 5 of 30 EIF1AX, and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3 BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT, and TP53 were detected in 6 iris melanomas and 4 iris nevi. CONCLUSIONS: Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential.

Iris pigmented lesions as a marker of cutaneous melanoma risk: an Australian case-control study.

BACKGROUND: Iris naevi and iris freckles have a frequency of 4% and 50% in the European population, respectively. They are associated with dysplastic naevi, but few studies have examined their link to cutaneous melanoma. OBJECTIVES: To assess whether iris pigmented lesions are a predictive indicator for cutaneous melanoma. METHODS: This is a melanoma case-control study of 1254 European-background Australians. Sun exposure and melanoma history, a saliva sample for DNA analysis and eye photographs taken with a digital camera were collected from 1117 participants. Iris images were assessed by up to four trained observers for the number of iris pigmented lesions. The data were analysed for correlations between iris pigmented lesions and melanoma history. RESULTS: Case participants over the age of 40 had similar numbers of iris pigmented lesions to age matched controls (mean 5·7 vs. 5·2, P = 0·02), but in younger case and control participants there was a greater difference (mean 3·96 vs. 2·19, P = 0·004). A logistic regression adjusted for age, sex, skin, hair and eye colour, skin freckling and naevus count found that the presence of three or more iris pigmented lesions increases the melanoma risk 1·45-fold [95% confidence interval (CI) 1·07-1·95]. HERC2/OCA2 rs12913832 and IRF4 rs12203592 influenced both eye colour and the number of iris pigmented lesions. On the HERC2/OCA2 A/A and A/G genotype background there was an increasing proportion of blue eye colour when carrying the IRF4 T allele (P = 3 × 10-4 ) and a higher number of iris pigmented lesions with the IRF4 T/T homozygote (P = 3 × 10-9 ). CONCLUSIONS: Iris pigmented lesion count provides additional predictive information for melanoma risk above that from conventional risk factors.

Salvage proton beam therapy for recurrent iris melanoma: outcome and side effects.

PURPOSE: This study aims to analyze the effect of salvage proton beam therapy for the treatment of recurrent iris melanoma. METHOD: In this clinical case series, we retrospectively analyzed the data of eight patients who underwent proton beam therapy of the whole anterior segment as salvage therapy between 2000 and 2016 for recurrent iris melanoma after resection, ruthenium brachytherapy, or sector proton beam therapy. Two patients received salvage proton beam therapy for repeated tumor relapse. All patients were observed and prepared for proton beam therapy at the Charité and irradiated at the Helmholtz-Zentrum Berlin where they received 50 cobalt Gray equivalents (CGE) in four daily fractions. We investigated survival rates and ocular outcome. RESULTS: Median follow-up after salvage proton beam therapy was 39 months. No local recurrence was detected during follow-up. One patient died from hepatic metastases 5.5 years after salvage therapy. Secondary glaucoma occurred in seven out of eight patients during follow-up. Two patients had chronic corneal erosion and two other patients presented with corneal decompensation, necessitating Descemet membrane endothelial keratoplasty (DMEK), and perforating keratoplasty. Median visual acuity was 0.2 logMAR before salvage proton beam therapy and 0.7 logMAR at the end of follow-up. CONCLUSION: Whole anterior segment salvage proton beam therapy has effectively controlled recurrent iris melanoma in our patients, but has been associated with a high incidence of radiation-induced corneal impairment and secondary glaucoma requiring extensive secondary treatment.