Tumor Shape-Specific Brachytherapy Implants by 3D-Printing, Precision Radioactivity Painting, and Biomedical Imaging.

In brachytherapy (BT), or internal radiation therapy, cancer is treated by radioactive implants. For instance, episcleral plaques (EPs) for the treatment of uveal melanoma, are designed according to generic population approximations. However, more personalized implants can enhance treatment precision through better adjustment of dose profiles to the contours of cancerous tissues. An original approach integrating biomedical imaging, 3D printing, radioactivity painting, and biomedical imaging, is developed as a workflow for the development of tumor shape-specific BT implants. First, computer-aided design plans of EP are prepared according to guidelines prescribed by the Collaborative Ocular Melanoma Study protocol. Polyetheretherketone (PEEK), a high-performance polymer suitable for permanent implants, is used to 3D-print plaques and the geometrical accuracy of the printed design is evaluated by imaging. The possibility to modulate the dose distribution in a tridimensional manner is demonstrated by painting the inner surfaces of the EPs with radioactive 103Pd, followed by dose profile measurements. The possibility to modulate dose distributions generated by these 3D-printed plaques through radioactivity painting is therefore confirmed. Ex vivo surgical tests on human eyeballs are performed as an assessment of manipulation ease. Overall, this work provides a solution for the fabrication of tumor-specific radioactive implants requiring higher dose precision.

Choroidal melanocytic lesions in children: focal aggregates and melanocytosis.

PURPOSE: To investigate prevalence and age of onset of choroidal melanocytic lesions (other than nevi) in pediatric patients. METHODS: The pooled data of participants 6 months to 18 years of age in the Sydney Paediatric Eye Disease Study, the Sydney Myopia Study, and the Sydney Adolescent Vascular Eye Disease Study were reviewed retrospectively to identify children with choroidal melanocytic lesions. The clinical features and prevalence by age were assessed. RESULTS: From the pooled sample of 5,533 unique children, 39 cases of focal melanocytic aggregates and 22 cases of choroidal melanocytosis were identified, with overall prevalence of 0.70% and 0.40%, respectively. There was a statistically significant trend toward increased prevalence with increasing age. Both focal melanocytic aggregates and choroidal melanocytosis tended to be bilateral (100% and 86% respectively), brown in color, and temporally located in all cases. Amelanotic variants were not identified. Focal melanocytic aggregates were small (0.15-0.5 mm), whereas choroidal melanocytosis varied in size (5.0-20 mm). All focal melanocytic aggregates were characteristically located 4-5 mm temporal to the center of the fovea and were associated with linear nervelike (11 [28%]) or tortuous vessel like structures (10 [26%]). CONCLUSIONS: In this study, pooled data from large population studies revealed morphologic patterns of choroidal melanocytic lesions, other than nevus, that correlate with described clinical appearance in adults. The association of focal melanocytic aggregates with nervelike structures supports their embryologic origin along the migration path of uveal melanocytes.

Choroidal nevi in children: prevalence, age of onset, and progression.

PURPOSE: To determine the age of onset and prevalence of choroidal nevi in children. METHODS: In this cross-sectional study, the fundus photographs of a pooled sample of children 6 months to 18 years of age with 6-year longitudinal follow-up who participated in the Sydney Paediatric Eye Disease Study, Sydney Myopia Study, and the Sydney Adolescent Vascular Eye Disease Study were reviewed. Prevalence by age, clinical features, and longitudinal follow-up assessment was undertaken. RESULTS: Of 5,533 children (7,059 examinations), 48 children with a choroidal nevus were identified. Prevalence increased with age: <6 years, 0.47%; 6 years, 0.63%; 12 years, 1.06%; 18 years, 1.79%. Nevus was unilateral in all cases (100%), and the majority were melanotic (46, 96%). Most (36 [75%]) were irregular in shape, with ill-defined margins (45 [94%]). All identified nevi were posterior to the equator. All nevi were small, with the average largest basal diameter of 1.6 mm (range, 0.5-3.2) and were not associated with secondary changes (drusen, orange pigment, subretinal fluid). The majority (18/31 [58%]) of nevi remained stable, with 5 of 31 (16%) demonstrating subtle growth (minimum of 600 µm). Four new-onset nevi were documented. Malignant transformation was not observed in any of the nevi. CONCLUSIONS: In our study cohort, the prevalence of choroidal nevi increased with age up to 18 years. The distribution and prevalence of choroidal melanocytic lesions reported herein can be used for designing population-based studies in children that incorporate emerging imaging technologies.

Ocular surface squamous neoplasia: outcomes following primary excision with 2 mm margin and cryotherapy.

PURPOSE: To assess margins and the rate of local recurrence of ocular surface squamous neoplasia after excision with a 2 mm margin and cryotherapy at a single ophthalmic oncology center. OUTCOME MEASURES: (1) Conjunctival margin were assessed as positive, negative, or indeterminate margins. (2) Feasibility of repair without a graft. (3) Local recurrence. METHODS: Retrospective chart review of histologically proven conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma cases that underwent excision with a 2 mm margin and cryotherapy. RESULTS: Eighty cases met inclusion criteria for the quantitative analysis. The margin was positive in six cases (7.5%), four of which were treated with post-op topical immunotherapy/chemotherapy. Of the six positive margin cases, there was one recurrence which occurred in the patient who did not receive post-op topical adjuvant therapy, however resolved after starting topical treatment. Conjunctival repair without use of a graft was feasible in 74 (93%) cases with a mean basal diameter of 6.4 mm. Total number of local recurrence was seen in three cases (4%), which were successfully treated with adjuvant topical treatment (one positive margin case, one indeterminate margin case) or repeat resection followed by episcleral plaque brachytherapy (one negative margin case). CONCLUSION: Excision with 2 mm margin of OSSN is not associated with high rates of positive surgical margins. Even those with positive margins, when treated with adjuvant topical therapy did not develop recurrence. While achieving low rates of local recurrence, the conjunctiva is conserved, thereby minimizing the need for amniotic membrane or free conjunctival grafts for conjunctival repair.

Histopathologic Patterns of Recurrent Choroidal Melanoma Following I-125 Plaque Brachytherapy.

PURPOSE: Histologic correlation of clinical patterns of recurrent choroidal melanoma following I-125 plaque brachytherapy was performed to identify pathologic mechanisms of recurrence. METHODS: We reviewed 7 cases of recurrent choroidal melanoma following I-125 plaque brachytherapy managed with enucleation. Clinical characteristics included tumor dimensions, radiation dose, time to local recurrence, and clinical pattern of recurrence. Histopathology (hematoxylin and eosin and periodic acid - Schiff) and immunohistochemistry (Ki-67, CD-163, HMB45, and SOX10) were performed. RESULTS: Mean follow-up time and time to local recurrence were 42 and 21 months after brachytherapy, respectively. Tumor recurrences were described clinically as marginal in 43%, diffuse in 29%, and extraocular extension (EOE) in 29%. Eighty-six percent were classified as mixed cell type and 14% were epithelioid type. Tumor zonation (histologic demarcation between zones of recurrent and nonrecurrent tumor cells by immunohistochemistry) was present in marginal and EOE cases (n = 6) and absent in the diffuse cases (n = 2). Ki-67 proliferative index was higher in marginal and EOE recurrences, while diffuse cases showed uniform -Ki-67 staining. CD-163 staining was found to be greater in nonrecurrent tumor. HMB45 correlated with SOX10 with a greater staining in recurrent tumor. CONCLUSION: Our observations provide a correlation between histopathologic and clinical patterns of local recurrence of choroidal melanoma after brachytherapy.

Fine-needle aspiration biopsy for suspected uveal metastases.

OBJECTIVE: One indication of fine-needle aspiration biopsy (FNAB) is the diagnostic confirmatory of a clinical suspicion of uveal metastasis. We analyzed our experience in this clinical setting to assess the effectiveness of FNAB technique. DESIGN: Retrospective study. PARTICIPANTS: 28 patients (28 eyes) underwent FNAB biopsy. METHODS: Aspirates were performed using 25-gauge needle and were classified into the following categories: positive, atypical, negative, or nondiagnostic. The electronic medical records provided all clinical data. Subsequent clinical course was considered as the diagnostic standard. RESULTS: Subsequent clinical course was metastatic tumour in 19 cases (68%) and nonmetastatic tumour in other 9 cases, considered as the diagnostic standard. Cytological interpretations for metastases were positive in 19 cases (68%), atypical in 2 cases (7%), negative in 4 cases (14%), and nondiagnostic in 3 cases (11%). The metastasis-positive cases included 9 adenocarcinoma, 3 uveal lymphoma, 3 small cell carcinomas, 3 non-small cell carcinomas, and 1 metastatic paraganglioma. Both of the atypical cases were suggestive for non-Hodgkin lymphoma. The 4 negative cases for metastases included 2 true negative cases, and 2 false negative aspirates that subsequently proved to be metastatic adenocarcinoma. The 3 nondiagnostic cases included 1 schwannoma, 1 low-grade uveal non-Hodgkin lymphoma, and 1 metastatic adenocarcinoma. The overall sensitivity for FNAB was 87.5%, with a specificity of 100%. CONCLUSIONS: FNAB of suspected uveal metastases is a reliable diagnostic technique.

Case Report: Primary Orbital Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) of the orbit is almost uniformly the result of local invasion from a cutaneous primary, extension by perineural invasion, or the result of metastasis. This is owed to the lack of native squamous epithelium in the orbit. After review of the literature, to date, only 6 reports of 8 patients with primary orbital SCC exist. Of those cases, only 2 reported non-apical orbital SCC. There are 2 reports of orbital SCC after retina surgery with proposed transplanted conjunctival epithelium and subsequent malignant transformation of a conjunctival cyst. The initial signs and symptoms can be vague and lead to delay in diagnosis. We present a case of primary orbital SCC and discuss the workup, imaging, and multidisciplinary management of this rare condition.

Conjunctival Squamous Neoplasia: Staging and Initial Treatment.

PURPOSE: To evaluate the clinical relevance of the American Joint Committee on Cancer (AJCC) classification in the initial management of squamous neoplasia of the conjunctiva. METHODS: This retrospective study enrolled 95 histopathologically proven cases of treatment-naive conjunctival squamous neoplasia. Tumors were classified into 4 histological groups: conjunctival intraepithelial neoplasia (CIN) with mild dysplasia (grade 1/3), moderate dysplasia (grade 2/3), severe dysplasia (grade 3/3 or carcinoma in situ), and invasive squamous cell carcinoma (SCC). Clinical findings such as tumor location, largest basal diameter, growth pattern, and adjacent structures involved were recorded. RESULTS: CIN was observed in 74 cases (78%), and SCC was noted in 21 cases (22%). Based on the AJCC classification, all the 74 cases of CIN were classified as Tis (tumor in situ). Among the invasive SCC, there were 3 T1 tumors, 2 T2 tumors, and 16 T3 tumors. Complete excision with or without adjuvant therapy was selected as initial treatment in 80% of cases (76/95). Two cases of SCC with scleral invasion were treated using brachytherapy. CONCLUSIONS: The AJCC stage does not correlate with the initial treatment of CIN. The AJCC T3 category should be reviewed to differentiate diffuse SCCs with broad surface extension from tumors with deep scleral invasion.

Radiation Retinopathy 47 Years following Brachytherapy for Retinoblastoma.

A 50-year-old female who had undergone enucleation in the left eye and brachytherapy in the right eye for retinoblastoma at the age of 2 years was diagnosed with nonproliferation radiation retinopathy 47 years following the initial treatment. The patient had noticed black spots in her vision (scotomas) that interfered with reading. New onset of microaneurysms and lipid exudation threatening the foveola was noted on examination of the right eye. Initial visual acuity (VA) was 20/25. Optical coherence tomography showed no evidence of macular edema, but parafoveal lipid exudation was present. On fluorescein angiography, no sign of neovascularization or macular ischemia was observed. Direct focal treatment of microaneurysms was performed to prevent progression of the radiation retinopathy and vision loss. At 18 months' follow-up following focal laser, VA remained stable at 20/25 and there was a regression of the retinopathy.

Linear nevus sebaceous syndrome presenting as circumscribed choroidal hemangioma.

A 4-year-old female with a unilateral circumscribed choroidal hemangioma and secondary total exudative retinal detachment. A nasal skin scar-like lesion incised to confirm a histopathologic diagnosis of linear nevus sebaceous. Further imaging disclosed asymmetry of the lateral ventricle frontal horns, suggestive of the diagnosis of linear nevus sebaceous syndrome. The choroidal hemangioma was treated with I-125 episcleral brachytherapy (apical dose of 45 Gy). At 6 months post-radiation, the tumor showed regression with total resolution of exudative retinal detachment.

Liver Imaging Techniques: Recognition of Uveal Melanoma Metastases.

BACKGROUND: The liver is the most common site for metastases of several primary malignancies including uveal melanoma. METHODS: Review of imaging characteristics of incidental common benign liver lesions including hepatic cyst, hemangioma, focal nodular hyperplasia, and hepatic adenoma and contrasting them with uveal melanoma metastases. RESULTS: Benign hepatic lesions may be cystic or, if solid, relatively stable in size over time. For hepatic lesions larger than 10 mm in size, characteristic imaging features typically allow for confident diagnosis. When lesions are small (less than 10 mm), definitive characterization can be difficult. Moreover, lesions smaller than 10 mm can be difficult to biopsy under ultrasound or computed tomography (CT) guidance, and short-term follow-up will often be useful to assess for stability or progression. Overall, magnetic resonance imaging is more specific than CT scan and at least as sensitive as CT for detecting uveal melanoma liver metastases. CONCLUSIONS: New multiple enhancing solid liver lesions should raise suspicion of uveal melanoma liver metastases. Discussion of challenging cases with the radiologist may be beneficial, as pertinent information such as size, location, and molecular prognostication status of the primary tumor can guide radiological interpretation of hepatic lesions.

Ocular/adnexal lymphoma: dissimilar to systemic lymphoma.

Ocular adnexal lymphoma and intraocular lymphoma, whether occurring simultaneously or sequentially, are often similar to associated systemic lymphoma. We describe 4 cases of ocular adnexal lymphoma or intraocular lymphoma with a dissimilar systemic lymphoma. Two of the cases represent Richter transformation of chronic lymphocytic leukemia/small-cell lymphoma into diffuse large B-cell lymphoma. In the third patient, conjunctival extranodal marginal zone lymphoma developed following treatment for Hodgkin lymphoma. The fourth patient had a remote history of systemic diffuse large B-cell lymphoma with a subsequent diagnosis of orbital extranodal marginal zone lymphoma. Clinical-pathological correlation is reported for all cases in addition to pertinent review of the literature.

Iodine-125 Brachytherapy for Uveal Melanoma: A Systematic Review of Radiation Dose.

AIM: To investigate whether lower radiation doses may yield similar outcome measures to those from the COMS trial. METHODS: A literature review of English language articles was performed using the PubMed database of the U.S. National Library of Medicine and the Cochrane Central Register of Controlled Trials using the following keywords: uveal melanoma, choroidal melanoma, primary uveal malignant melanoma, iodine-125 brachytherapy, local recurrence, local treatment failure, and local tumor control. The relationships between study local recurrence rate and median dosage were tested by linear regression, with each study weighted by the number of patients included. RESULTS: Fifteen retrospective and prospective studies were selected for systematic review (2,662 patients). Ranges of reported mean or median radiation dose to tumor apex were 62.5-104.0 Gy. Local recurrence rates ranged from 0 to 24%. A 1.0-Gy increase in the average study dose was associated with a 0.14% decrease in local recurrence rate, which was not statistically significant (p value 0.336). CONCLUSION: The gold standard empirically derived 85.0-Gy radiation dose for the treatment of uveal melanoma could be tested in a randomized study.

Reactive Retinal Astrocytic Tumor (Focal Nodular Gliosis): Report of the Clinical Spectrum of 3 Cases.

PURPOSE: To report 3 cases providing insight into clinical progression of reactive retinal astrocytic tumor. METHODS: The clinical, imaging, and when available, the cytologic features of 3 cases of reactive retinal astrocytic tumor (focal nodular gliosis) were reviewed. RESULTS: A 6-year-old female, a 49-year-old man, and a 39-year-old man each developed a white retinal mass associated with laser photocoagulation, lattice degeneration, and treatment of a presumed vascular tumor, respectively. All tumors were white, circumscribed retinal masses that tended to be associated with exudation and either initially or eventually minimal vascularity. CONCLUSION: Reactive retinal astrocytic tumor can be observed in response to a degenerative, inflammatory, or ischemic retinal insult. Such tumors may progress after therapeutic intervention.

Local Failure After Episcleral Brachytherapy for Posterior Uveal Melanoma: Patterns, Risk Factors, and Management.

PURPOSE: To evaluate the patterns, the risk factors, and the management of recurrence following brachytherapy in patients with posterior uveal melanoma, given that an understanding of the recurrence patterns can improve early recognition and management of local treatment failure in such patients. DESIGN: Retrospective cohort study. METHODS: Setting: Multispecialty tertiary care center. PARTICIPANTS: A total of 375 eyes treated with episcleral brachytherapy for posterior uveal melanoma from January 2004 to December 2014. Exclusion criteria included inadequate follow-up (<1 year) and previous radiation therapy. Main Outcomes and Measures: Local control rate and time to recurrence were the primary endpoints. Kaplan-Meier estimation and Cox proportional hazards models were conducted to identify risk factors for recurrence. RESULTS: Twenty-one patients (5.6%) experienced recurrence (follow-up range 12-156 months; median 47 months). The median time to recurrence was 18 months (range 4-156 months). Five-year estimated local recurrence rate was 6.6%. The majority (90.5%) of the recurrences occurred within the first 5 years. The predominant site of recurrence was at the tumor margin (12 patients, 57.1%). Univariate analysis identified 3 statistically significant recurrence risk factors: advanced age, largest basal diameter, and the use of adjuvant transpupillary thermotherapy (TTT). Recurrent tumors were managed by repeat brachytherapy, TTT, or enucleation. CONCLUSIONS: Local recurrences following brachytherapy are uncommon 5 years after episcleral brachytherapy. Follow-up intervals can be adjusted to reflect time to recurrence. Most of the eyes with recurrent tumor can be salvaged by conservative methods.