Ciliary Body Melanoma Research Articles

Characteristics of retinal and scleral infiltration in uveal melanoma

Objective: To analyze features of retinal and scleral infiltration of uveal melanoma. Methods: It was a retrospective case series study. The pathological and clinical data of 102 cases of uveal melanoma were analyzed retrospectively, which were collected between Jun. 2001 and Apr. 2013 in Beijing Tongren Hospital, Capital Medical University. The tumor shape, size, cell types, retinal and scleral invasion were recorded and analyzed. The relationship between retinal invasion and scleral invasion was analyzed by trend Chi-square test. Results: There were 44 male patients and 58 female patients with an average age of 45.6±12.4 (range from 15 to 78 years old) in 102 cases. As for tumor size, there were 68 (66.7%) large size tumors, 27 (26.5%) medium size tumors and 7(6.8%) small size tumors; As for cell types, 76 (74.5%) were spindle cell, 6 (5.9%) were epithelioid cell, 16 (15.7%) were mixed cell, and 4 (4.0%) were others; As for tumor location, there were 3 (2.94%) ciliary body melanoma, 28 (27.5%) ciliary body and anterior choroid melanoma, and 71 (69.6%) choroid melanoma. Eighty-six cases (84.3%) showed retinal invasion, in which there were 20 cases of outer nuclear layer invasion (19.6%), 12 cases of inner nuclear layer invasion (11.8%), 30 cases of ganglion cell layer invasion (29.4%), and 24 cases of inner limiting membrane invasion (23.5%). Fifty-five cases (53.9%) showed scleral invasions, in which there were 11 cases (68.8%) of no retinal invasion, 13 cases of outer nuclear layer invasion (65.0%), 5 cases of inner nuclear layer invasion (41.7%), 15 cases of ganglion cell layer invasion (50.0%) and 11 cases of inner limiting membrane invasion (45.8%). In 76 spindle cell cases, the scleral invasion rate of different retinal invasion degree were 72.7% in 8 cases of none retinal invasion, 71.4% in 10 cases of outer nuclear layer invasion, 62.5% in 5 cases of inner nuclear layer invasion, 53.9% in 14 cases of ganglion cell layer invasion and 47.1% in 8 cases of inner limiting membrane invasion. No significant relationship was found between retinal and scleral invasion (γ=-0.21, P=0.127) . Conclusion: With the increase of scleral invasion, the retinal invasion decreased. However, the correlation show no statistical significance.(Chin J Ophthalmol, 2016, 52: 749-754).

Episcleral brachytherapy of uveal melanoma: role of intraoperative echographic confirmation

PurposeTo compare the rates of tumour recurrence following episcleral brachytherapy for uveal melanoma before and after implementation of intraoperative echographic confirmation of plaque placement.Materials and methodsAll patients with primary single...

Vision Loss Following Episcleral Brachytherapy for Uveal Melanoma: Development of a Vision Prognostication Tool.

Vision loss following episcleral brachytherapy for uveal melanoma is difficult to predict for individual patients. To generate a risk calculator for vision loss following episcleral brachytherapy for uveal melanoma. A retrospective review of data was conducted at a multispecialty tertiary care center in Cleveland, Ohio. All patients with primary ciliary body or choroidal melanoma treated with iodine 125 or ruthenium 106 episcleral brachytherapy between January 1, 2004, and December 30, 2013, were included. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log-rank analyses) were used to estimate freedom from vision loss. Bootstrap resampling was performed to bias correct this estimate. Vision loss (to visual acuity [VA] worse than 20/50 and worse than 20/200). A total of 311 patients were included in the study, with a mean (SD) age of 62 (14.7) years at start of treatment and a median follow-up of 36 months (interquartile range, 18-60 months). At presentation, VA was better than or equal to 20/50 in 199 patients (64%) and better than or equal to 20/200 in 289 patients (93%). By Kaplan-Meier analysis, VA less than 20/200 at 3 years was not associated with sex, diabetes, systemic hypertension, or hypercholesterolemia but was associated with history of ocular comorbidities, type of isotope (ruthenium 106 or iodine 125), and initial VA ( >20/50 or <20/50). By multivariable analysis, age (hazard ratio [HR], 0.97; 95% CI, 0.94-1.00; P = .06), largest basal diameter (HR, 1.25; 95% CI, 1.16-1.34; P = <.001), total radiation dose to the fovea (HR, 1.03; 95% CI, 1.01-1.04; P = .001) and optic disc (HR, 1.01; 95% CI, 1.00-1.01; P = .005), and initial VA worse than 20/50 (HR, 1.85; 95% CI, 1.20-2.85; P = .005) were predictive of vision loss to a VA of less than 20/200. The concordance index for the full data set was 0.77. Using these data, an online risk calculator was developed to predict vision loss following episcleral brachytherapy. The vision prognostication tool presented herein needs to be validated by independent data sets. This tool may improve counseling for patients being evaluated for episcleral brachytherapy. At-risk individuals identified by this tool could be considered for inclusion into trials exploring prevention or treatment of radiation retinopathy and alternative therapies of uveal melanoma.

Clinical and histopathological features of adenomas of the ciliary pigment epithelium.

Adenomas of the ciliary pigment epithelium (CPE) are rare benign tumours which have mainly to be differentiated from malignant ciliary body melanomas. Here we report on a consecutive series of patients with CPE adenomas and describe their characteristics. The retrospective hospital-based case series study included all patients who were consecutively operated for CPE adenomas. Of the 110 patients treated for ciliary body tumours, five patients (4.5%) had a CPE adenoma. Mean age was 59.0±9.9years (range: 46-72years). Mean tumour apical thickness was 6.6±1.7mm. Tumour colour was mostly homogenously brown to black, and the tumour surface was smooth. The tumour masses pushed the iris tissue forward without infiltrating iris or anterior chamber angle. Sonography revealed an irregular echogram with sharp lesion borders and signs of blood flow in Color Doppler flow imaging. Ultrasonographic biomicroscopy demonstrated medium-low internal reflectivity and acoustic attenuation. In magnetic resonance imaging (MRI), the tumours as compared to brain were hyperintense on T1-weighted images and hypointense on T2-weighted images. Tumour tissue consisted of cords and nests of pigment epithelium cells separated by septa of vascularized fibrous connective tissue, leading to a pseudo-glandular appearance. The melanin granules in the cytoplasm were large and mostly spherical in shape. In four patients, the tumours were hyperpigmented. Tumour cells were large with round or oval nuclei and clearly detectable nucleoli. These clinical characteristics of CPE adenomas, such as homogenous dark brown colour, smooth surface, iris dislocation and anterior chamber angle narrowing but no iris infiltration, segmental cataract, pigment dispersion, and, as compared to brain tissue, hypointensity and, as compared to extraocular muscles or lacrimal gland, hyperintensity on T2-weighted MRI images, may be helpful for the differentiation from ciliary body malignant melanomas.

Serum adiponectin, insulin resistance, and uveal melanoma: clinicopathological correlations.

To investigate the status of insulin resistance, metabolic syndrome, dyslipidemia, and serum adiponectin levels in patients with uveal melanoma and choroidal nevus were investigated. Our study included 86 patients with uveal melanoma, 38 patients with choroidal nevus, and 86 controls. Uveal melanomas were classified as small, medium, and large on the basis of Collaborative Ocular Melanoma Study (COMS) criteria. Patients with uveal melanoma had significantly higher homeostatic model assessment scores compared with patients with choroidal nevus (P<0.001). Patients with uveal melanoma and choroidal nevus had significantly lower levels of serum adiponectin compared with controls (P<0.001). Patients with uveal melanoma who developed systemic metastases had significantly lower levels of serum adiponectin levels compared with patients with nonmetastases during follow-up (P=0.018). When the largest tumors (COMS III) were compared, ciliary body melanomas were associated with significantly lower levels of serum adiponectin than choroidal melanomas. In patients who were treated with enucleation, epitheloid predominant and mixed cell-type tumors were associated with lower levels of serum adiponectin compared with tumors with spindle cell type, but this did not reach statistical significance. By providing an antiapoptotic and proangiogenic environment, low serum adiponectin levels and insulin resistance may play a role in promoting the growth of uveal melanocytic tumors and may contribute toward a more aggressive clinical course, adversely affecting the prognosis.

Uveal melanoma: An analysis of cellular features and comparison to monosomy 3 status.

Choroidal and ciliary body melanomas divide into two approximately equal groups. Local therapy cures one group while the other metastasizes and proves lethal. Monosomy 3 strongly associates with aggressive behavior. We analyzed a series of choroidal and ciliary body melanomas to describe the cellular features and to compare them to monosomy 3 status using the latter as a surrogate for survival. One hundred eleven specimens met the study's inclusion criteria. Following ThinPrep processing, samples were analyzed for cellular features including: cell type, nuclear grade, tumor infiltrating lymphocytes, and the presence of necrosis and melanin. FISH analysis for monosomy 3 was performed on ThinPrep slides using a threshold of 20% monosomic cells per 200 melanoma cells. Seventy-two tumors (65%) had a mixed cell type while spindle cell type and epithelioid cell type occurred in 37 (33%) and 2 (1.8%), respectively. Seventy-five tumors (68%) had Grade 2 nuclear atypia. Monosomy 3 occurred in 57 tumors (51%). Significantly more tumors with Grade 3 nuclei had monosomy 3 (79% vs.43%, P = 0.002) and metastases (29% vs. 8%, P = 0.01). None of the 11 pure spindle cell tumors with Grade 1 nuclei metastasized or had monosomy 3. Uveal melanoma has a relatively consistent cellular appearance, characterized by a mixed cell pattern and no more than moderate nuclear atypia. This consistent appearance aids in the cellular diagnosis but limits prognostication using cellular features. Cellular features significantly associate with monosomy 3 status only in the minority of tumors at the extremes of the morphologic spectrum.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group

To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Retrospective, multicenter observational study. Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Commentary on Visual Acuity, Contrast Sensitivity and Color Vision Three Years after Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma

Commentary on Visual Acuity, Contrast Sensitivity and Color Vision Three Years after Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma

Local Recurrence Significantly Increases the Risk of Metastatic Uveal Melanoma

To assess of the effect of local recurrence of uveal melanoma on metastasis using a multicenter international tumor registry. Retrospective study using an online tumor registry. Patients with uveal melanoma diagnosed between 2001 and2011. A committee was formed to create uveal melanoma patient-specific data fields. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma and adequate records to allow tumor staging by American Joint Committee on Cancer (AJCC) criteria and follow-up for metastatic melanoma. Local tumor recurrence and metastatic uveal melanoma. Of 3809 total entries, 3217 patients with ciliary body and choroidal (CBC) melanoma and 160 with iris melanoma were evaluated. There was a median follow-up of 3.7 years (95% confidence interval [CI], 3.5-3.8). One hundred fifty-two patients (4.7%) with CBC melanoma experienced local recurrence, with a cumulative incidence of 11%. Kaplan-Meier point estimates for remaining free of local recurrence were 99% (95% CI, 99-99) at 1 year, 93% (95% CI, 92-94) at 5 years, and 89% (95% CI, 86-91) at 10 years. Five- and 10-year metastasis-free Kaplan-Meier estimates for the recurrence-free group were 87% (95% CI, 86-89) and 82% (95% CI, 79-84), and those for the local recurrence group were 71% (95% CI, 62-78) and 62% (95% CI, 49-72). The difference between these 2 groups was statistically significant (P < 0.001). Furthermore, local tumor recurrence increased the risk of metastasis by a hazard ratio (HR) of 6.28 (95% CI, 4.4-8.9; P < 0.001). Local recurrence was detected up to 9.8 years after treatment. Extrascleral extension also was associated with local recurrence (HR, 3.2; 95% CI, 1.5-6.7; P= 0.003), but higher AJCC T-size category was not (P= 0.63). Five patients (n= 5/161 [3.1%]) with iris melanoma demonstrated local recurrence and 1 metastasized. International multicenter data sharing was used to evaluate the effect of local tumor recurrence on metastatic rate. In that local tumor recurrence was associated with a significantly higher risk of systemic metastasis, effective initial treatment and long-term surveillance of treated uveal melanoma patients is necessary.

Expression and prognostic value of putative cancer stem cell markers CD117 and CD15 in choroidal and ciliary body melanoma

AimsThe aim of the present study was to immunohistochemically investigate the expression and prognostic significance of putative cancer stem cell markers CD117 (c-kit), CD34, CD20 and CD15 in a cohort...

Abstract 1156: Widespread deficiency of ASS1 in uveal melanoma and sensitivity to pegylated arginine deiminase

Abstract Uveal melanoma, involving the iris, choroid and ciliary body, is the commonest intraocular tumor in adults. Approximately half of these patients will develop metastasis with a high mortality despite currently available systemic therapies including immune checkpoint blockade. The urea cycle enzyme argininosuccinate synthetase 1 (ASS1), responsible for arginine synthesis, is downregulated in melanoma and other cancers and these are therefore sensitive to arginine deprivation therapy. In early phase trials of the arginine depletor pegylated arginine deiminase, ADI-PEG20, uveal melanoma, in particular, was identified with potential for further therapeutic development. Here, we tested uveal melanoma cell lines for sensitivity to ADI-PEG20 and analyzed enucleated tumors for ASS1 expression to assess the extent of ASS1 deficiency. Methods: ASS1 gene and protein expression were assessed in three uveal melanoma cell lines (OMM1, OMM2.5 and Mel270) by real-time quantitative PCR (qPCR) and western blot analysis, respectively. Sensitivity to ADI-PEG20 was performed using the cell viability MTS assay. We screened 102 enucleated choroidal and ciliary body melanomas for ASS1 protein using red chromogen for the immunohistochemistry (IHC) and selected the most positive area for scoring. Results: The uveal melanoma cell lines expressed negligible ASS1 mRNA with a complete absence of ASS1 protein. All three ASS1 negative uveal melanoma cell lines were sensitive to ADI-PEG20 by day 6 of the MTS assay, whereas an ASS1-expressing positive control cell line was resistant. There was a convincing lack of ASS1 expression (&amp;lt;5% staining) in the majority of uveal melanomas (75/102; 74%) and where ASS1 was present (5-30% staining) in the remainder (27/102; 26%) this was due to a mixture of melanoma cells and intratumoral macrophages, the latter being confirmed with CD68 (IHC) in the cases with the highest ASS1 expression. Conclusion: ASS1 is absent in the tested uveal melanoma cell lines and predisposes to arginine sensitivity with ADI-PEG20 in vitro. Most primary uveal melanomas have a marked deficiency of ASS1, representing a good target for exploring arginine deprivation further in the clinic, either alone or in combination with rationally selected agents. A trial of ADI-PEG20 combined with carboplatin and paclitaxel is planned in metastatic malignant melanoma with an expanded cohort in patients with uveal disease. Citation Format: Ramsay S. Khadeir, Melissa M. Phillips, Mandeep S. Sgoo, Amit Arora, Victoria Cohen, Caroline Thaung, Peter W. Szlosarek. Widespread deficiency of ASS1 in uveal melanoma and sensitivity to pegylated arginine deiminase. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1156. doi:10.1158/1538-7445.AM2015-1156

Outcomes of Proton Beam Radiotherapy for Large Non-Peripapillary Choroidal and Ciliary Body Melanoma at TRIUMF and the BC Cancer Agency

Background and Purpose: To report outcomes and toxicity after proton beam radiotherapy for non-peripapillary choroidal and ciliary body melanoma considered unsuitable for other eye-sparing therapies. Materials and Methods: An existing database of 77 patients with non-peripapillary tumors treated at TRIUMF, Canada, including patient, tumor, and treatment characteristics, was updated with ocular complications and follow-up status from chart reviews. Results: Most of the patients had large tumors: 61% were T3/T4 tumors (AJCC classification), while 48% were large by the Collaborative Ocular Melanoma Study classification. The median thickness was 7.1 mm, and the ciliary body was involved in 35%. After 5 and 10 years, the actuarial ocular tumor control rate was 85 and 85%, metastasis-free survival was 72 and 57%, overall survival was 77 and 63%, the enucleation rate was 22 and 22%, and complete blindness was found in 38 and 38%, respectively. On univariate analysis, patients with ciliary body involvement had significantly worse metastasis-free survival and overall survival rates compared to patients without ciliary body involvement (p < 0.001). Conclusions: Proton therapy for large anteriorly located tumors resulted in acceptable ocular tumor control and survival rates. The risk of blindness and severe toxicity requiring enucleation was low, and a substantial proportion of patients maintained useful vision.

Visual Acuity, Contrast Sensitivity and Color Vision Three Years After Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma.

Purpose : To report visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after iodine-125 brachytherapy for choroidal and ciliary body melanoma (CCM).Design : Prospective interventional case series.Participants : Thirty-seven patients (37 eyes) with CCM.Methods : Patients had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, Pelli-Robson contrast sensitivity and Hardy-Rand-Rittler color vision measurement; comprehensive ophthalmology examination; optical coherence tomography; and ultrasonography at baseline prior to, 1 year after, 2 years after and 3 years after I-125 brachytherapy.Main Outcome Measures : Visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after brachytherapy.Results :Nineteen (19) men and 18 women with mean age of 58 years (SD 13, range 30-78) prior to, 1 year after, 2 years after and 3 years after brachytherapy had mean best-corrected visual acuity of 77 letters (20/32), 65 letters (20/50), 56 letters (20/80) and 47 letters (20/125); contrast sensitivity of 30, 26, 22 and 19 letters; color vision of 26, 20, 17 and 14 test figures, respectively. Decrease in visual acuity, contrast sensitivity and color vision was statistically significant from baseline at 1 year, 2 years, and 3 years after brachytherapy. Decreased acuity at 3 years was associated with mid-choroid and macula melanoma location, ≥ 4.1 mm melanoma height, radiation maculopathy and radiation optic neuropathy.Conclusion : 1, 2 and 3 years after brachytherapy, eyes with CCM had significantly decreased visual acuity, contrast sensitivity and color vision.

Visual Acuity, Contrast Sensitivity and Color Vision Three Years After Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma

Visual Acuity, Contrast Sensitivity and Color Vision Three Years After Iodine-125 Brachytherapy for Choroidal and Ciliary Body Melanoma

Long-term Results of the UCSF-LBNL Randomized Trial: Charged Particle With Helium Ion Versus Iodine-125 Plaque Therapy for Choroidal and Ciliary Body Melanoma

Relevant clinical data are needed given the increasing national interest in charged particle radiation therapy (CPT) programs. Here we report long-term outcomes from the only randomized, stratified trial comparing CPT with iodine-125 plaque therapy for choroidal and ciliary body melanoma. From 1985 to 1991, 184 patients met eligibility criteria and were randomized to receive particle (86 patients) or plaque therapy (98 patients). Patients were stratified by tumor diameter, thickness, distance to disc/fovea, anterior extension, and visual acuity. Tumors close to the optic disc were included. Local tumor control, as well as eye preservation, metastases due to melanoma, and survival were evaluated. Median follow-up times for particle and plaque arm patients were 14.6 years and 12.3 years, respectively (P=.22), and for those alive at last follow-up, 18.5 and 16.5 years, respectively (P=.81). Local control (LC) for particle versus plaque treatment was 100% versus 84% at 5 years, and 98% versus 79% at 12 years, respectively (log rank: P=.0006). If patients with tumors close to the disc (<2 mm) were excluded, CPT still resulted in significantly improved LC: 100% versus 90% at 5 years and 98% versus 86% at 12 years, respectively (log rank: P=.048). Enucleation rate was lower after CPT: 11% versus 22% at 5 years and 17% versus 37% at 12 years, respectively (log rank: P=.01). Using Cox regression model, likelihood ratio test, treatment was the most important predictor of LC (P=.0002) and eye preservation (P=.01). CPT was a significant predictor of prolonged disease-free survival (log rank: P=.001). Particle therapy resulted in significantly improved local control, eye preservation, and disease-free survival as confirmed by long-term outcomes from the only randomized study available to date comparing radiation modalities in choroidal and ciliary body melanoma.

International Validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma.

Although an accurate uveal melanoma staging system is needed to improve research and patient care, the evaluation of eye cancer staging systems requires international multicenter data sharing to acquire a statistically significant analysis. To assess patient mortality outcomes associated with uveal melanoma staging according to the 7th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. A committee was formed to create patient-specific data fields for patients with uveal melanoma. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma from April 1, 2001, to April 1, 2011, adequate records to allow tumor staging by the AJCC criteria, and follow-up for metastatic melanoma. Primary treatments included local resection, radiation therapy, and enucleation. Metastasis after initial tumor staging with 5- and 10-year Kaplan-Meier metastasis-free point estimates, depending on AJCC prognostic stages I through IV, tumor size category, and subclassification (defined by the presence of ciliary body involvement and/or extrascleral extension). A total of 3809 patients were entered into the database. Of these, 3377 records (88.7%) were complete. Primary ciliary body and choroidal melanoma was the diagnosis for 3217, and 160 had primary iris melanoma. Tumor size categories were T1 in 1115 (34.7%) of the 3217 patients, T2 in 1128 patients (35.1%), T3 in 789 patients (24.5%), and T4 in 185 patients (5.8%). The 5- and 10-year Kaplan-Meier metastasis-free point estimates by tumor size categories were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for T1 tumors, 85% (95% CI, 82%-88%) and 80% (95% CI, 75%-84%) for T2 tumors, 77% (95% CI, 73%-80%) and 68% (95% CI, 60%-74%) for T3 tumors, and 61% (95% CI, 49%-71%) (5-year only) for T4 tumors, respectively. Increasing tumor size was consistent with increased metastasis risk (P <.001). Subclassifications were significantly associated with increased risk of metastasis (P < .001). The AJCC prognostic and anatomical groupings were as follows: stage I, 1030 (32.0%); stage IIA, 1095 (34.0%); stage IIB, 710 (22.1%); stage IIIA, 282 (8.8%); stage IIIB, 79 (2.5%); and stage IIIC, 21 (0.7%). The 5- and 10-year Kaplan-Meier metastasis-free estimates for prognostic stages were 97% (95% CI, 95%-98%) and 94% (95% CI, 91%-96%) for stage I, 89% (95% CI, 86%-91%) and 84% (95% CI, 80%-88%) for stage IIA, 79% (95% CI, 75%-83%) and 70% (95% CI, 62%-76%) for stage IIB, 67% (95% CI, 59%-73%) and 60% (95% CI, 51%-68%) for stage IIIA, 50% (95% CI, 33%-65%) and 50% (95% CI, 33%-65%) for stage IIIB, and 25% (95% CI, 4%-53%) (5-year only) for stage IIIC, respectively. The 160 iris melanomas were too few for subgroup analysis. Multicenter, worldwide, Internet-based data sharing was used to study a heterogenous patient population in ophthalmic oncology. Our results support the continued use of the 7th edition of the AJCCCancer Staging Manual for uveal melanoma.

American Joint Committee on Cancer Classification of Uveal Melanoma (Anatomic Stage) Predicts Prognosis in 7731 Patients: The 2013 Zimmerman Lecture

To analyze the clinical features and prognosis of posterior uveal melanoma based on the American Joint Committee on Cancer (AJCC) (7th edition) tumor staging. Retrospective interventional case series. A total of 7731 patients. Uveal melanoma management. Melanoma-related metastasis and death. Of 7731 patients with posterior uveal (ciliary body and choroidal) melanoma, the AJCC tumor staging was stage I in 2767 (36%), stage II in 3735 (48%), stage III in 1220 (16%), and stage IV in 9 (<1%). Based on tumor staging (I, II, III, and IV), features that showed significant increase with tumor staging included age at presentation (57, 58, 60, 60 years) (P < 0.001), tumor base (8, 12, 17, 17 mm) (P < 0.001), tumor thickness (2.9, 6.0, 10.1, 10.2 mm) (P < 0.001), distance to optic disc (3, 5, 5, 5 mm) (P < 0.001), distance to foveola (3, 5, 5, 5 mm) (P < 0.001), mushroom configuration (6%, 24%, 34%, 33%) (P < 0.001), plateau configuration (3%, 4%, 7%, 11%) (P < 0.001), tumor pigmentation (48%, 53%, 69%, 78%) (P < 0.001), and extraocular extension (0%, 1%, 11%, 22%) (P < 0.001). After therapy, Kaplan-Meier estimates of metastasis at 1, 5, 10, and 20 years were <1%, 5%, 12%, and 20% for stage I, 2%; 17%, 29%, and 44% for stage II; 6%, 44%, 61%, and 73% for stage III, and 100% by 1 year for stage IV. Kaplan-Meier estimates of death at 1, 5, 10, and 20 years were <1%, 3%, 6%, and 8% for stage I; <1%, 9%, 15%, and 24% for stage II; 3%, 27%, 39%, and 53% for stage III, and 100% by 1 year for stage IV. Compared with stage I, the hazard ratio for metastasis/death was 3.1/3.1 for stage II and 9.3/10.1 for stage III. Compared with uveal melanoma classified as AJCC stage I, the rate of metastasis/death was 3 times greater for stage II, 9 to 10 times greater for stage III, and further greater for stage IV. Early detection of posterior uveal melanoma, at a point when the tumor is small, can be lifesaving.

Classificação do melanoma uveal como fator prognóstico em 7731 pacientes

The American Joint Committee on Cancer (AJCC) classification is in its seventh edition. In addition to universal tumor staging (TNM), this classification is very relevant in the field of ocular oncology, which involves iris, ciliary body, and choroidal melanoma. It aimed to separate uveal melanoma into anatomical stages to provide information regarding the prognosis for metastasis and death. The AJCC’s classification of posterior uveal melanoma involves melanoma categorization and staging. Categorization includes measurements of the tumor thickness and tumor base. It defines which of the four previously designated size groups the tumor fits into: T1, T2, T3, or T4 (TABLE 1). The staging process involves the categorization results and information regarding lymph nodes (N) and metastasis (M) to define which of the four anatomical stages the tumor fits into: I, II, III, or IV (TABLE 2). The present article sought to explore the predictive value of the AJCC’s anatomical stage classification system for metastasis and death by posterior uveal melanoma. Based on data from the Ocular Oncology Service at the Wills Eye Hospital, 7731 patients with a diagnosis of ciliary body or choroidal melanoma between 1970 and 2008 were considered. There was adequate tumor information regarding all patients, which enabled retrospective classification of uveal melanoma using AJCC categorization (7 th edition). Basal diameter was estimated using binocular indirect ophthalmoscopy and ultrasonography, and tumor thickness was measured using ultrasonography. Various treatment options were used with these patients, including laser photocoagulation, transpupillary thermotherapy, plaque radiotherapy, local resection, enucleation, and exenteration. Furthermore, systemic monitoring and screening for metastasis were performed. Out of the 7731 patients, 2767 (36%), 3735 (48%), 1220 (16%), and 9 (<1%) were classified as having stage I, II, III, and IV tumors, respectively. Following data analysis, it was estimated that, of the patients with 10 and 20 years of follow-up, the respective probability of metastasis was 12% and 20% for stage I patients, 29% and 44% for stage II patients, 61% and 73% for stage III patients (p < 0.001), and 100% among stage IV patients after 1 year of follow-up. Meanwhile, the respective estimates of melanoma-related death at 10 and 20 years after diagnosis were 6% and 8% for stage I patients, 15% and 24% for stage II patients, 39% and 53% for stage III patients, and 100% among stage IV patients after 1 year of follow-up (p < 0.001). The predictive factors for metastatic disease and death in cases of stage I melanoma include a large tumor base and an increase in tumor thickness. Aging, increase in tumor thickness, a large tumor base, tumor pigmentation, a mushroom configuration, and associated subretinal fluid were predictive factors among stage II patients. Stage III factors included not only the abovementioned factors but also an inferior tumor location. A recent publication by the AJCC Ophthalmic Oncology Task Force mentioned a study using a cohort of 3809 patients from 10 international ocular oncology centers. The estimates of metastasis-free survival 10 years after diagnosis were found to be 94% (stage I), 78% (stage II), and 56% (stage III). Thus, the analysis of 7731 patients with posterior uveal melanoma revealed the AJCC’s clinical classification to be predictive of metastatic disease. Briefly, this classification may be used to select patients at high risk for metastasis for treatment protocols that focus on the prevention of metastatic events. Furthermore, it shows the importance of early detection and disease management.

The prognostic effect of American Joint Committee on Cancer staging and genetic status in patients with choroidal and ciliary body melanoma.

To evaluate the prognostic effect of a combination of American Joint Committee on Cancer (AJCC) staging (7th edition) and genetic status in patients with posterior uveal melanoma. A consecutive cohort of 153 patients with posterior uveal melanoma treated at Copenhagen University Hospital from January 1, 2009 through December 31, 2012 was followed until October 2014. Survival, AJCC stage, and cytogenetic data were registered. The AJCC stage was available for all patients, and cytogenetic information for chromosomes 3 and 8 was available for 139 patients. The individual and joint prognostic effects of AJCC staging and cytogenetic changes were evaluated by cumulative incidence curves and Cox proportional hazard models. An overall 5-year survival rate of 62% (95% confidence interval [CI]: 0.50-0.73) was observed. A normal genetic status of chromosomes 3 and 8, as found in 42 patients (30%), minimized the additional prognostic effect of AJCC staging. The frequency of tumors with normal genetic status decreased with increasing AJCC stage. Both AJCC stage III (hazard ratio [HR]: 11.0, 95% CI: 1.4-85.6) and abnormal copy number of chromosomes 3 (HR: 6.3, 95% CI: 1.4-28.3) and 8 (HR: 2.8, 95% CI: 1.03-7.8) were identified as significant predictors of a poor prognosis in the multivariate Cox regression analysis. Identification of a normal genetic status of chromosomes 3 and 8 minimized the prognostic effect of AJCC staging, while a combination of genetic status and AJCC staging provided the most accurate prediction of survival in patients with an abnormal chromosomal status.

Management of Posterior Uveal Melanoma: Past, Present, and Future: The 2014 Charles L. Schepens Lecture

To review the management of ciliary body and choroidal melanoma (posterior uveal melanoma [PUM]) over the last century with an emphasis on changing concepts. Retrospective review. Review of personal experience over 40 years and pertinent literature on management of PUM. Diagnosis and therapy for PUM. Patient survival. In the early 1900s, most patients presented with a large symptomatic melanoma that necessitated enucleation, and the systemic prognosis was poor. In the 1970s, controversy erupted regarding the role of enucleation for PUM. Some authorities advocated prompt enucleation, and others proposed that enucleation promoted metastasis, known as the "Zimmerman hypothesis." Others recommended observation, withholding treatment until tumor growth was documented. During the 1970s, there was a trend toward eye-saving procedures, including laser photocoagulation, surgical removal of tumor, and techniques of radiotherapy. Despite local treatment success, systemic prognosis remained guarded with approximately 40% mortality overall. However, there was convincing evidence that smaller tumors offered a significantly better prognosis. Currently, there is a movement toward earlier identification and treatment of small melanomas using clinical factors predictive of malignant potential, in keeping with similar philosophy regarding other cancers. Further understanding of melanoma cytogenetics and molecular pathways have helped to recognize patients at risk for metastasis. At-risk patients are offered systemic therapeutic trials to prevent metastasis. We anticipate that the future management of PUM will focus on detection of clinical and imaging clues for earliest diagnosis, prompt local tumor treatment, and systemic targeted therapies for microscopic metastasis or prevention of metastasis. Personalized evaluation of patient-specific melanoma molecular pathway signature could allow for therapeutic intervention at a site specific to the pathway abnormality that leads to the development of melanoma. Management of PUM has made major strides over the past century from the days of enucleation for massive, fatal tumor to early detection of smallest tumors with a more favorable prognosis. Current and future targeted specific tumor pathway interruption using systemic agents could improve survival.