Personalized Prognosis of Uveal Melanoma Based on Cytogenetic Profile in 1059 Patients over an 8-Year Period: The 2017 Harry S. Gradle Lecture.

PURPOSE: To determine the personalized rate of uveal melanoma-related metastasis on the basis of individual tumor cytogenetic profile. DESIGN: Retrospective case series. PARTICIPANTS: A total of 1059 patients with uveal melanoma. METHODS: Fine-needle aspiration biopsy (FNAB) for DNA amplification and whole genome array-based assay were performed for analysis of chromosomes 3, 6, and 8. MAIN OUTCOME MEASURES: Melanoma-related metastasis. RESULTS: The mean patient age was 57 years, and most were white (1026/1059, 97%). The melanoma involved the choroid (938/1059, 89%), ciliary body (85/1059, 8%), or iris (36/1059, 3%), with 19% being macular in location. The mean largest basal diameter was 11 mm (median, 12 mm; range, 3-24 mm), and mean thickness was 5 mm (median, 4 mm; range, 1-20 mm). On the basis of individual chromosomal mutations, risk for metastasis was increased for chromosome 3 partial monosomy (hazard ratio [HR], 2.84; P = 0.001), 3 complete monosomy (HR, 6.7, P < 0.001), 6q loss (HR, 3.1, P = 0.003), 8p loss (HR, 21.5, P < 0.001), and 8q gain (HR, 9.8, P < 0.001). Kaplan-Meier estimate for melanoma-related metastasis in 1, 3, 5, and 7 years for 3 partial monosomy was 1%, 5%, 14%, and 17%; for 3 complete monosomy was 3%, 19%, 28%, and 37%; for 6q loss was 8%, 23%, 49%, and 49%; for 8p loss was 8%, 29%, not estimable (NE), and NE; and for 8q gain was 6%, 21%, 35%, 48%, respectively. On the basis of personalized cytogenetic profiles, Kaplan-Meier estimates (1, 3, and 5 years) for melanoma-related metastasis for 3, 6, and 8 disomy (1%, 1%, 4% [HR, 1]) were low compared with the higher-risk combinations of 3 complete monosomy, 6p gain, and 8q gain (0%, 29%, 29% [HR, 10.6, P = 0.02]); 3 complete monosomy, 6 disomy, 8q gain, and 8p gain (14%, 14%, NE [HR, 18.3, P = 0.02]); 3 complete monosomy, 6 disomy, and 8q gain (8%, 27%, 39% [HR, 19.5, P < 0.001]); and 3 complete monosomy, 6 disomy, 8q gain, and 8p loss (3%, 28%, NE [HR, 31.6, P < 0.001]), respectively. CONCLUSIONS: Risk for melanoma-related metastasis strongly correlates with personalized cytogenetic profiles, with 5-year Kaplan-Meier estimates ranging from 4% with chromosomes 3, 6, and 8 disomy up to 39% for 3 complete monosomy, 6 disomy, and 8q gain.

Cytogenetic Abnormalities in Uveal Melanoma Based on Tumor Features and Size in 1059 Patients: The 2016 W. Richard Green Lecture.

PURPOSE: To determine the risks for altered cytogenetic profile based on melanoma features and size. DESIGN: Retrospective case series. PARTICIPANTS: A total of 1059 patients with uveal melanoma. METHODS: Fine-needle aspiration biopsy (FNAB) of tumor for DNA amplification and whole genome array-based assay. MAIN OUTCOME MEASURES: Risk for cytogenetic abnormalities based on features and size: small (≤3 mm thickness), medium (>3-<8 mm), and large (≥8 mm). RESULTS: Of 1059 patients with uveal melanoma sampled for status of chromosomes 3, 6, and 8, comparison (normal [disomy] chromosomes 3, 6, and 8 vs. any 3, 6, or 8 abnormality) revealed differences in mean age (55 vs. 58 years, P = 0.018), ocular melanocytosis (1% vs. 5%, P = 0.027), mean visual acuity (VA) (20/30 vs. 20/50, P = 0.011), poor VA (≤20/200) (9% vs. 15%, P = 0.041), ciliary body location (5% vs. 11%, P < 0.001), extramacular location (73% vs. 87%, P < 0.001), increased mean distance to optic disc (3.3 vs. 5.0 mm, P < 0.001) and foveola (3.1 vs. 4.7 mm, P < 0.001), and increased mean basal diameter (9.8 vs. 12.6 mm, P < 0.001) and thickness (3.8 vs. 5.9 mm, P < 0.001). Tumors classified as small, medium, and large showed abnormalities with loss of disomy of chromosomes 3 (35%/52%/65%), 6 (15%/34%/51%), and 8 (19%/41%/69%), respectively. By comparison (medium/large vs. small melanoma), the odds ratio (OR) included complete monosomy 3 (3.09, P < 0.001), partial monosomy 3 (1.44, P = 0.053), 6p gain (3.78, P < 0.001), 6q gain (1.37, P = 0.537), 6p loss (2.52, P = 0.410), 6q loss (12.61, P < 0.001), 8p gain (6.16, P < 0.001), 8p loss (6.04, P < 0.001), and 8q gain (4.87, P < 0.001). For chromosome 3 monosomy, the OR was highest for ciliary body location (8.17, P < 0.001), tumor thickness ≥8 mm (2.70, P < 0.001), tumor base ≥10 mm (2.59, P < 0.001), and age ≥60 years (1.83, P < 0.001). For chromosome 8p loss, the OR was highest for ciliary body location (53.91, P = 0.008), ocular melanocytosis (3.95, P = 0.038), and thickness ≥8 mm (5.14, P < 0.001), whereas for 8q gain, the OR was highest for ciliary body location (102.87, P = 0.001), thickness >8 mm (4.44, P < 0.001), and ocular melanocytosis (2.75, P = 0.049). CONCLUSIONS: Increasing melanoma size demonstrates greater cytogenetic alterations. Alterations in chromosome 8 show unique correlation with melanocytosis. This suggests that prompt management of small melanoma might reduce chromosomal instability and could improve overall patient survival.

Role of pars plana vitrectomy and membrane peel in vitreomacular traction associated with retinal vasoproliferative tumors.

To report a case of retinal vasoproliferative tumor (VPT) with secondary epiretinal membrane (ERM) formation and vitreo-macular traction managed by pars plana vitrectomy (PPV) and membrane peel. A 29-year-old male was referred for management of decreased vision in the right eye (OD) for 1 week. Presenting visual acuity was 20/50 Snellen feet (ft) OD, and fundus examination showed an ERM associated with a reddish-yellow mass in the inferotemporal quadrant with overlying exudation, hemorrhage, and subretinal fluid consistent with VPT, and cryotherapy was recommended. Two months later, there was complete tumor regression, but there was decreased vision from progressive vitreomacular traction to 20/400 ft. PPV with combined ERM and internal limiting membrane (ILM) peel were performed with resolution of vitreomacular traction and improvement of visual acuity to 20/50 ft at 6 months. PPV with combined ERM and ILM peel is effective for vision loss secondary to ERM and vitreomacular traction associated with retinal VPT.

Indocyanine Green-Enhanced Transpupillary Thermotherapy for Retinoblastoma: Analysis of 42 Tumors.

PURPOSE: To evaluate the efficacy of indocyanine green-enhanced transpupillary thermotherapy (ICG-TTT) for retinoblastoma that shows suboptimal response to conventional treatments. METHODS: A single center, retrospective chart review. The technique involved ICG infusion (range: 0.3 to 0.5 mg/kg) 1 minute prior to applying TTT using the indirect ophthalmoscope technique with a spot size of 1.2 mm. RESULTS: There were 42 retinoblastomas in 30 eyes of 21 patients treated with ICG-TTT. The reasons for ICG enhancement included suboptimal response to standard TTT (n = 31, 74%), recurrence after standard TTT (n = 3, 7%), or minimally pigmented fundus with poor standard TTT uptake (n = 8, 19%). The mean patient age at treatment was 12 months (median: 11.6 months, range: 3 to 31 months). The mean tumor base was 3.5 mm (median: 3 mm), mean tumor thickness was 2.5 mm (median; 2 mm), mean distance to the foveola was 2.6 mm (median: 3 mm), and mean distance to the optic disc was 2.2 mm (median: 0.75 mm). Treatment parameters included a spot size of 1.2 mm, mean power of 760 mW (median: 800 mW, range: 400 to 1,200 mW), and mean duration of 4 minutes (median: 4 minutes, range: 0.5 to 14 minutes). Following a median of 2 sessions (range: 1 to 5 sessions) of ICG-TTT, 33 (79%) tumors demonstrated complete regression. The mean tumor thickness postoperatively was 1.7 mm. Two (5%) tumors showed minimal regression after ICG-TTT. During a mean follow-up of 46 months (median: 33 months), tumor recurrence after ICG-TTT developed in 7 (17%) cases at a mean interval of 7 months. Local complications of ICG-TTT included focal paraxial cataract (n = 2, 7%), iris atrophy (n = 1, 3%), and transient retinal hemorrhage (n = 2, 7%). Systemic problems included ICG allergy (n = 1, 5%). Overall, tumor control and globe salvage was achieved in all 30 (100%) eyes. There were no metastatic events. CONCLUSIONS: ICG-TTT is an effective alternative for reti-noblastoma control, particularly for small tumors that show suboptimal response to standard

Sebaceous Carcinoma of the Ocular Region: The 2014 Professor Winifred Mao Lecture.

Sebaceous carcinoma is a malignancy arising in the periocular region that can lead to blindness and tumor-related metastases. This study is a review of published literature and personal experience. This malignancy can arise from the sebaceous units in the tarsus (meibomian glands), in association with the cilia (Zeis glands), in the brow, and in the caruncle. There is a tendency for diffuse intraepithelial growth (pagetoid spread) that can be clinically invisible. Detection before lymph node metastasis is critical. This malignancy often masquerades as chronic unilateral conjunctivitis or blepharitis, typically in older patients. Management includes a 2-step approach with step 1 focused on eyelid and conjunctival map biopsies to determine the full extent of solid deep tumor and pagetoid spread. After complete review of all biopsies, step 2 is performed using local resection for all deep tumor, cryotherapy to pagetoid disease, and reconstruction. In most cases, the posterior lamella of eyelid is sacrificed with tumor removal, whereas the anterior lamella of the eyelid can be saved. After removal and cryotherapy, immediate reconstruction, using clean instruments, with buccal membrane graft for the posterior lamella and skin flap for the anterior lamella, is developed. For persistent or recurrent pagetoid disease, cryotherapy, topical mitomycin C, or plaque radiotherapy is provided. Exenteration is sometimes necessary. Sebaceous carcinoma, if detected early, can be managed with carefully planned map biopsy to determine tumor extent, followed by local resection, cryotherapy, and eyelid reconstruction. Orbital exenteration is occasionally necessary.

Juvenile Xanthogranuloma Involving the Eye and Ocular Adnexa: Tumor Control, Visual Outcomes, and Globe Salvage in 30 Patients.

PURPOSE: To report clinical features and treatment outcomes of ocular juvenile xanthogranuloma (JXG). DESIGN: Retrospective case series. PARTICIPANTS: There were 32 tumors in 31 eyes of 30 patients with ocular JXG. METHODS: Review of medical records. MAIN OUTCOME MEASURES: Tumor control, intraocular pressure (IOP), and visual acuity. RESULTS: The mean patient age at presentation was 51 months (median, 15 months; range, 1-443 months). Eye redness (12/30, 40%) and hyphema (4/30, 13%) were the most common presenting symptoms. Cutaneous JXG was concurrently present in 3 patients (3/30, 10%), and spinal JXG was present in 1 patient (1/30, 3%). The ocular tissue affected by JXG included the iris (21/31, 68%), conjunctiva (6/31, 19%), eyelid (2/31, 6%), choroid (2/31, 6%), and orbit (1/31, 3%). Those with iris JXG presented at a median age of 13 months compared with 30 months for those with conjunctival JXG. In the iris JXG group, mean IOP was 19 mmHg (median, 18 mmHg; range, 11-30 mmHg) and hyphema was noted in 8 eyes (8/21, 38%). The iris tumor was nodular (16/21, 76%) or diffuse (5/21, 24%). Fine-needle aspiration biopsy was used in 10 cases and confirmed JXG cytologically in all cases. The iris lesion was treated with topical (18/21, 86%) and/or periocular (4/21, 19%) corticosteroids. The eyelid, conjunctiva, and orbital JXG were treated with excisional biopsy in 5 patients (5/9, 56%), topical corticosteroids in 2 patients (2/9, 22%), and observation in 2 patients (2/9, 22%). Of 28 patients with a mean follow-up of 15 months (median, 6 months; range, 1-68 months), tumor regression was achieved in all cases, without recurrence. Two patients were lost to follow-up. Upon follow-up of the iris JXG group, visual acuity was stable or improved (18/19 patients, 95%) and IOP was controlled long-term without medication (14/21 patients, 74%). No eyes were managed with enucleation. CONCLUSIONS: Ocular JXG preferentially affects the iris and is often isolated without cutaneous involvement. Iris JXG responds to topical or periocular corticosteroids, often with stabilization or improvement of vision and IOP.

Review of spectral domain enhanced depth imaging optical coherence tomography of tumors of the choroid.

BACKGROUND: Spectral domain enhanced depth imaging optical coherence tomography (EDI-OCT) can provide anatomic localization of intraocular tumors. AIMS: The aim was to identify topographical and intrinsic patterns of choroidal tumors on EDI-OCT. SETTINGS AND DESIGN: Retrospective review. MATERIALS AND METHODS: Analysis of published reports and personal observations using office based EDI-OCT. RESULTS: Using EDI-OCT, choroidal nevus displayed a smooth, dome-shaped topography with overlying retinal pigment epithelium alterations, drusen, and occasional subretinal cleft demonstrating photoreceptor loss. Small choroidal melanoma showed smooth, moderately dome-shaped topography, commonly with overlying shallow subretinal fluid that often depicted "shaggy" photoreceptors. Choroidal metastasis showed a minimally "lumpy, bumpy" surface topography and with overlying subretinal fluid and shaggy photoreceptors. Choroidal hemangioma showed a smooth, dome-shaped topography, with expansion of the affected small, medium, and large choroidal vessels. Choroidal lymphoma showed varying topography with increasing tumor thickness as "flat, rippled, or undulating (seasick)" surface. Choroidal osteoma displayed a smooth undulating surface with visible intralesional horizontal lines suggestive of bone lamellae and occasional horizontal and vertical tubules with intralesional "spongy" flecks. Choroidal melanocytosis appeared as uniformly thickened choroid with increased stromal density surrounding the normal choroidal vascular structures. CONCLUSIONS: Enhanced depth imaging-OCT can depict characteristic patterns that are suggestive of various choroidal tumors.

Review of spectral domain-enhanced depth imaging optical coherence tomography of tumors of the retina and retinal pigment epithelium in children and adults.

BACKGROUND: Spectral domain (SD) enhanced depth imaging optical coherence tomography (EDI-OCT) is a useful tool for anatomic, cross-sectional imaging of retinal conditions. AIMS: The aim was to identify characteristic patterns of retinal and retinal pigment epithelial tumors on EDI-OCT in children and adults. SETTINGS AND DESIGN: Retrospective review. MATERIALS AND METHODS: Analysis of published reports and personal observations using office-based EDI-OCT for adults and portable hand-held SD OCT for infants and children. RESULTS: Using EDI-OCT, retinal tumors such as small retinoblastoma, astrocytic hamartoma, and hemangioblastoma arose abruptly from the retina, immediately adjacent to normal retina. Small exophytic retinoblastoma and retinal hemangioblastoma showed the full-thickness, homogeneous retinal disorganization with surrounding normal retina "draping" over the margins. Retinoblastoma occasionally had intralesional cavities and surrounding subretinal fluid. Hemangioblastoma often had adjacent intraretinal edema and subretinal fluid. Astrocytic hamartoma arose within the nerve fiber layer and sometimes with a "moth-eaten" or cavitary appearance. Retinal pigment epithelial (RPE) lesions such as congenital hypertrophy of RPE appeared flat with shadowing, occasional subretinal cleft, and abrupt photoreceptor loss. Congenital simple hamartoma showed an abrupt elevation from the inner retina with crisp, dark posterior shadowing. Combined hamartoma of the retina/RPE showed vitreoretinal traction causing "sawtooth mini-peak" or gently "maxi-peak" folding of the retina. RPE adenoma often produces remote macular edema or epiretinal membrane and the tumor has an irregular, "rugged" surface with deep shadowing. CONCLUSIONS: Enhanced depth imaging optical coherence tomography shows characteristic patterns that are suggestive of certain retinal and RPE tumors.

CLASSIFICATION OF SCLEROCHOROIDAL CALCIFICATION BASED ON ENHANCED DEPTH IMAGING OPTICAL COHERENCE TOMOGRAPHY "MOUNTAIN-LIKE" FEATURES.

PURPOSE: To describe distinct enhanced depth optical coherence tomography patterns of sclerochoroidal calcification and their correlation to clinical features. METHODS: Retrospective chart review of 67 eyes of 46 patients with spectral domain optical coherence tomography imaging. RESULTS: The mean patient age at diagnosis was 68 years. There were 20 (43%) men and 26 (57%) women of white (n = 45, 98%) or Hispanic (n = 1, 2%) heritage. The most prominent sclerochoroidal calcification lesions were located in the superotemporal quadrant (n = 57, 85%) between the temporal arcades and the equator (n = 58, 87%). On enhanced depth optical coherence tomography, the sclerochoroidal calcification was located within the sclera in all cases and the inner surface topography assumed specific "mountain-like" patterns, including flat (Type 1) (n = 9) at median thickness of 1.2 mm, rolling (Type 2) (n = 28) at 1.4 mm thickness, rocky-rolling (Type 3) (n = 21) at 2.1 mm thickness, and table mountain (Type 4) (n = 9) at a thickness of 1.9 mm. The retinal layers were undisturbed in flat lesions, and outer retinal abnormalities were found in all other types. A comparison of the 4 types revealed that Type 3 lesions were thickest (P < 0.001), showing abnormalities in the retinal pigment epithelium, ellipsoid region, and external limiting membrane most commonly (P < 0.05) and demonstrating the most dramatic thinning of the overlying choroid (P < 0.01) and retina (P < 0.05). Type 4 lesions showed greatest basal diameter (P < 0.01) and least outer retinal abnormalities (P < 0.05) or choroid thinning (P < 0.05). CONCLUSION: In this report, enhanced depth optical coherence tomography has demonstrated that sclerochoroidal calcification is a scleral-based disease and can be classified based on four "mountain-like" topographic patterns, associated with variable effects on the choroid and retina.

Sclerochoroidal calcification: clinical features, outcomes, and relationship with hypercalcemia and parathyroid adenoma in 179 eyes.

PURPOSE: To describe the clinical features and long-term ophthalmic and systemic findings in patients with sclerochoroidal calcification (SCC). METHODS: Retrospective non-interventional clinical chart review of 179 eyes of 118 patients with SCC to evaluate for the relationship of SCC with systemic calcium metabolic abnormalities. RESULTS: The mean patient age at diagnosis was 69 years. There were 47 (40%) men and 71 (60%) women of Caucasian (n = 116, 98%) and Hispanic (n = 2, 2%) heritage. The condition was unilateral in 57 patients (48%) and bilateral in 61 (52%), with a mean of 1.6 lesions per eye (range, 1-7 lesions per eye). The referring diagnosis was choroidal nevus (n = 23, 20%), melanoma (n = 15, 13%), lymphoma (n = 12, 10%), metastasis (n = 6, 5%), osteoma (n = 4, 3%), SCC (n = 6, 5%), and no diagnosis (n = 51, 43%). Of 277 SCC lesions, the most common location was superotemporal quadrant (n = 191, 69%). The largest lesion per eye demonstrated mean basal diameter of 3.6 mm and thickness of 1.8 mm, with yellow or white color (n = 150 lesions, 84%) and located superiorly (n = 105, 61%) at the retinal vascular arcade or near the equator (n = 161, 94%). The lesion demonstrated overlying focal choroidal atrophy (n = 63, 35%) and retinal pigment epithelium atrophy (n = 88, 49%). There was no case of subretinal fluid, hemorrhage, or choroidal neovascular membrane. At mean 4 years follow up, there was no lesion enlargement, decalcification, or related subretinal fluid/hemorrhage, choroidal neovascularization, or vision loss. Ocular treatment was not necessary in any case. Systemic outcomes revealed hyperparathyroidism (n = 9/33, 27%) with parathyroid adenoma (n = 5/33, 15%), Bartter syndrome (n = 1/53, 2%), or Gitelman syndrome (n = 6/53, 11%). CONCLUSIONS: Sclerochoroidal calcification is a stable deposition of calcium in the sclera that, unlike choroidal osteoma, has minimal risk for vision loss. All patients with SCC should be evaluated for underlying systemic calcium disorders, especially parathyroid and renal metabolic conditions.

Intravitreal chemotherapy provides control for massive vitreous seeding from retinoblastoma.

Treatment of vitreous seeds in retinoblastoma is challenging because of relatively poor chemotherapeutic drug penetration by standard intravenous or intra-arterial routes. Intravitreal monotherapy with melphalan is effective but has a narrow therapeutic window. The authors describe a case of massive vitreous seeding successfully controlled after combination intravitreal chemotherapy using melphalan and topotecan with preserved anatomic outcome.