Clinical and genetic characteristics of retinoblastoma patients in a single center with four novel RB1 variants.

AIM: To assess the clinical and genetic characteristics of children diagnosed with retinoblastoma (RB) at Gazi University Faculty of Medicine's Department of Pediatric Oncology. METHODS: All cases diagnosed with RB and received treatment and follow-up in the Ophthalmology and Pediatric Oncology Department, October 2016 to May 2021 were evaluated retrospectively. The RB1 gene was analyzed by next-generation sequencing (NGS) technique in DNAs obtained from peripheral blood samples of the patients. RESULTS: This study included 53 cases with 67 RB-affected eyes during the study period. The mean age was 24.6 (median: 18.5, range: 3-151)mo. There were 15 (22.3%) Group D eyes and 39 (58.2%) Group E eyes. The RB1 gene was sequenced by the NGS method in 19 patients. Heterozygous RB1:NM_000321.3: c.54_76del (p.Glu19AlafsTer4) variant was detected in a 15-month-old female with bilateral RB. Heterozygous RB1:NM_000321.3: c.1814+3A>T variant was detected in a 5.5-month-old male with bilateral RB. The intronic RB1:NM_000321.3: c.1332+4A>G variant was detected in patient 14, a 13-month-old male with unilateral RB. The RB1:NM_000321.3: c.575_576del (p.Lys192SerfsTer10) variant was found in an 18-month-old female with an allele frequency of 37%. These variants have not been reported in the literature and mutation databases. CONCLUSION: Four novel variants are described and one of them is found in two different patients. This data is crucial for assessing prognosis. It serves as a guide for estimating the long-term risk of secondary malignancy as well as the short-term risk of developing additional malignancies in the same eye and the other eye.

Clinical characteristics and the treatment modalities of Graves' orbitopathy in a tertiary referral center in Turkey: changes over two decades.

PURPOSE: To evaluate the changes in demographics, clinical findings, and treatment modalities in Graves' orbitopathy (GO) patients at a tertiary referral center in Turkey over the last two decades. METHODS: The clinical data of 752 GO patients were evaluated retrospectively. Patients were divided into 2 groups according to the first ophthalmic examination date; Group 1(n:344) between January 1998 and December 2007 and Group 2(n:408) between January 2008 and December 2017. RESULTS: The number of nonsmokers was significantly higher in Group 2 (44.0 vs. 26.5%, p < 0.001). The time from the diagnosis of thyroid dysfunction and referral to our center was 32.4 months in Group 1 and 34.8 months in Group 2, (p = 0.166). The most common treatment of hyperthyroidism was antithyroid medications. Radioiodine ablation treatment rate was significantly lower in Group 2 (14.8 vs. 9.1%, p < 0.001). The time between the diagnosis of thyroid disease and orbital involvement was 22.0 vs. 26.6 months in Groups 1 and 2, respectively (p = 0.009). The time elapsed between the diagnosis of orbital disease and referral to our clinic was 21.0 months vs. 22.4 months in Group 1 and 2, respectively (p = 0.068). Orbital disease was most commonly mild, and inactive. Mild and moderate to severe GO and the mean Clinical Activity Score significantly increased, and the rate of sight-threatening disease and orbital decompression surgery significantly decreased in Group 2 (p = 0.042; p < 0.001, respectively). CONCLUSIONS: Mild and inactive orbital disease was the most common form of GO. The severity of GO is declining over the last two decades in Turkey.

The Final Diagnosis: Retinoblastoma or Pseudoretinoblastoma.

PURPOSE: To review the authors' experience in the diagnosis of retinoblastoma and to explore the frequency of intraocular conditions that mimic this malignancy according to patient age at presentation. METHODS: This was a retrospective observational study including 549 patients (769 eyes) who were referred for confirmation and/or management of retinoblastoma between October 1998 and June 2019 at a single tertiary center. A detailed ocular examination was done by the same ocular oncologist under general anesthesia for every patient. RESULTS: Of 549 patients referred for diagnostic confirmation or management of retinoblastoma, 393 (71.6%) patients were found to have retinoblastoma and 156 (28.4%) patients received the diagnosis of pseudoretinoblastoma. The mean patient age at presentation was 52.1 months, ranging from 1 to 276 months. The most common diagnoses among patients with pseudoretinoblastoma younger than 1 year were persistent fetal vasculature (PFV) (n = 19; 28.8%), Coats disease (n = 7; 10.6%), chorioretinal coloboma (n = 4; 6.1%), retinal dysplasia (n = 4; 6.1%), and retinal detachment (n = 4; 6.1%). In patients with pseudoretinoblastoma who were 1 to 5 years old, the most common diagnoses were Coats disease (n = 10; 25.6%), PFV (n = 7; 17.9%), and optic disc hypoplasia (n = 3; 7.7%). Patients older than 5 years were most likely to have Coats disease (n = 8; 15.7%), optic disc drusen (n = 5; 9.8%), retinopathy of prematurity (n = 4; 7.8%), and combined hamartoma (n = 4; 7.8%). CONCLUSIONS: This study shows that 28.4% of patients referred for suspicion or management of retinoblastoma were classified as having pseudoretinoblastoma. The most common conditions causing diagnostic confusion with retinoblastoma included PFV and Coats disease, similar to previous publications from both high-and low-income countries. [J Pediatr Ophthalmol Strabismus. 2021;58(3):161-167.].

Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the lacrimal drainage system in two pediatric patients.

Primary non-Hodgkin lymphoma (NHL) of lacrimal drainage system (LDS) is quite rare in children, but it is important to expedite early diagnosis in an effort to alter possible life-threatening disease since they are usually misdiagnosed as chronic dacryocystitis. In the literature, there are few examples of tumors of LDS in children. The authors herein report two pediatric cases of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) originating from lacrimal sac in an attempt to increase the knowledge about the clinical course of NHL of LDS. Considerable care must be taken since tumors of lacrimal drainage can mimic dacryocystitis clinically and macroscopically. Two patients both attended with painless swelling in the left lacrimal sac region and epiphora of the left eye. Orbital magnetic resonance imaging showed a tumoral lesion in the left lacrimal sac region and histopathological examination of excisional biopsy specimen demonstrated MALT lymphoma in both patients. The treatment regimen comprises lacrimal sac excision within the tumor, canalicular dacryocystorhinostomy (DCR) with bicanalicular silicone intubation (BSI) combined with chemotherapy and regional radiotherapy in one case, whereas the second case received only radiotherapy after canalicular DCR with BSI. Both of them maintained clinical remission along follow-up.

Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma.

PURPOSE: To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM). DESIGN: Retrospective cohort study. METHODS: The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint. RESULTS: GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10-8), largest basal tumor diameter (P = 2.5 × 10-6), PRAME status (P = 2.6 × 10-6), and TNM stage (P = 3.7 × 10-6). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10-14) was superior to an optimized TNM model (P = 1.3 × 10-5). CONCLUSIONS: In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.

Stereotactic Radiosurgery and Fractionated Stereotactic Radiation Therapy for the Treatment of Uveal Melanoma.

PURPOSE: To evaluate treatment results of stereotactic radiosurgery or fractionated stereotactic radiation therapy (SRS/FSRT) for uveal melanoma. METHODS AND MATERIALS: We retrospectively evaluated 181 patients with 182 uveal melanomas receiving SRS/FSRT between 2007 and 2013. Treatment was administered with CyberKnife. RESULTS: According to Collaborative Ocular Melanoma Study criteria, tumor size was small in 1%, medium in 49.5%, and large in 49.5% of the patients. Seventy-one tumors received <45 Gy, and 111 received ≥45 Gy. Median follow-up time was 24 months. Complete and partial response was observed in 8 and 104 eyes, respectively. The rate of 5-year overall survival was 98%, disease-free survival 57%, local recurrence-free survival 73%, distant metastasis-free survival 69%, and enucleation-free survival 73%. There was a significant correlation between tumor size and disease-free survival, SRS/FSRT dose and enucleation-free survival; and both were prognostic for local recurrence-free survival. Enucleation was performed in 41 eyes owing to progression in 26 and complications in 11. CONCLUSIONS: The radiation therapy dose is of great importance for local control and eye retention; the best treatment outcome was achieved using ≥45 Gy in 3 fractions.

Uveal Melanoma: Current Trends in Diagnosis and Management.

Uveal melanoma, which is the most common primary intraocular malignancy in adults, arises from melanocytes within the iris, ciliary body and choroid. The diagnosis is based principally on clinical examination of the tumor with biomicroscopy and indirect ophthalmoscopy and confirmed by diagnostic techniques such as ultrasonography, fundus fluorescein angiography and optical coherence tomography. The clinical diagnosis of posterior uveal melanomas can be made when the classical appearance of a pigmented dome-shaped mass is detected on dilated fundus exam. Uveal melanomas classically show low to medium reflectivity on A-scan ultrasonography and on B-scan ultrasonography the tumor appears as a hyperechoic, acoustically hollow intraocular mass. Management of a suspicious pigmented lesion is determined by its risk factors of transforming into a choroidal melanoma, such as documentation of growth, thickness greater than 2 mm, presence of subretinal fluid, symptoms and orange pigment, margin within 3 mm of the optic disc, and absence of halo and drusen. Advances in the diagnosis and local and systemic treatment of uveal melanoma have caused a shift from enucleation to eye-conserving treatment modalities including transpupillary thermotherapy and radiotherapy over the past few decades. Prognosis can be most accurately predicted by genetic profiling of fine needle aspiration biopsy of the tumor before the treatment, and high-risk patients can now be identified for clinical trials that may lead to target-based therapies for metastatic disease and adjuvant therapy which aims to prevent metastatic disease.

Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas.

BACKGROUND: We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas. In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter. RESULTS: Among 678 samples analyzed by qPCR, 498 (73.5%) were PRAME- and 180 (26.5%) were PRAME+. Class 1 tumors were more likely to be PRAME-, whereas Class 2 tumors were more likely to be PRAME+ (P < 0.0001). PRAME expression was associated with shorter time to metastasis and melanoma specific mortality in Class 2 tumors (P = 0.01 and P = 0.02, respectively). In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004). PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter. MATERIALS AND METHODS: Analyses included PRAME mRNA expression, Class 1 versus Class 2 status, chromosomal copy number, mutation status of BAP1, EIF1AX, GNA11, GNAQ and SF3B1, and genomic DNA methylation status. Analyses were performed on 555 de-identified samples from Castle Biosciences, 123 samples from our center, and 80 samples from the TCGA. CONCLUSIONS: PRAME is aberrantly hypomethylated and activated in Class 1 and Class 2 uveal melanomas and is associated with increased metastatic risk in both classes. Since PRAME has been successfully targeted for immunotherapy, it may prove to be a companion prognostic biomarker.

Orbital Extension of an Unsuspected Choroidal Melanoma Presumably through an Aqueous Tube Shunt.

AIMS: To report a patient with unrecognized small macular melanoma, who gradually developed neovascular glaucoma that was treated with an Ahmed valve. We presume that tumor cells gained access to the orbit through this aqueous drainage device. METHODS: The medical records pertaining to 5 different centers, the results of imaging studies, the clinical course of the patient and histopathological findings were retrospectively reviewed. RESULTS: A 61-year-old man presented with a blind and painful proptotic right eye. Retinal hemorrhage had been suspected 3 years earlier and followed accordingly thereafter. Yearly performed MRI studies demonstrated the steady growth of the hemorrhagic lesion/tumor. Meanwhile, he developed neovascular glaucoma first treated unsuccessfully with cyclocryotherapy then with implantation of an Ahmed valve. Right proptosis became evident within a year, and a final MRI study revealed a large retrobulbar mass. Orbital exenteration was performed and histopathological examination showed intraocular and orbital epithelioid cell melanoma. Tumor cells were also found within the reservoir of the Ahmed valve. The patient died of widespread metastases 1 year later. CONCLUSIONS: Ahmed valve implantation in an eye with unsuspected macular choroidal melanoma may ultimately be associated with extraocular extension and orbital tumor formation.

Intra-Arterial Chemotherapy for Retinoblastoma: A Single-Center Experience.

BACKGROUND: Studies conducted in recent years have reported promising results regarding the treatment of retinoblastoma with the intra-arterial use of melphalan. In the present study, we intended to report the results of intra-arterial chemotherapy with melphalan (IACT) in the treatment of newly diagnosed or relapsed-refractory retinoblastoma patients at the Department of Pediatric Oncology of Hacettepe University, Ankara, Turkey. MATERIALS AND METHODS: This was a retrospective study of patients with intraocular retinoblastoma who were treated with IACT from December 2011 to May 2014. A total of 56 eyes of 46 consecutive patients (30 males and 16 females) were included in the study. Forty-four eyes received systemic chemotherapy upon diagnosis (systemic chemotherapy group, SCG), and 12 eyes were those of newly diagnosed patients (primary intra-arterial melphalan group, PIAG). The choice of the IACT dose was based on age. Tumor control and globe salvage with IACT were analyzed. Complete blood counts were examined 7 days after the IACT for systemic toxicity. Ocular toxicities such as proptosis, eyelid edema, ocular motility, and retinal and optic atrophy were assessed by an ocular oncologist with regular ophthalmologic examinations. RESULTS: Enucleation was avoided overall in 66% (37/56) of the eyes, including 75% (9/12) in the PIAG and 64% (28/44) in the SCG patients. The 1-year enucleation-free survival rate was 56.7% at a median follow-up time of 11.9 months (range 0.27-27.6). IACT was administered in a total of 124 cycles (ranging from 1 to 7 cycles, mean 2.3). The responses were as follows: regression of the retinal tumor in 27 eyes and improvements in vitreous seeding in 5 of 15 eyes. The further treatment requirements after IACT were as follows: enucleation in 19 eyes (10 with vitreous seeding), radiotherapy in 3 eyes, systemic chemotherapy in 1 eye, and local therapy in 1 eye. No severe systemic side effects occurred. Transient swelling of the eyelids (22 patients), conjunctival chemosis (12 patients), upper eyelid ptosis (5 patients), redness over the frontal area (3 patients), limitation of ocular motility (3 patients) and mild proptosis (1 patient) were detected. Retinal pigment epithelial alterations (30 patients) and optic atrophy (3 patients) were seen in the late follow-up. CONCLUSIONS: Globe salvage and avoidance of radiotherapy may be achieved by IACT with limited toxicity. This treatment is efficient, repeatable and safe.

Total clinical regression of an orbital macrocystic lymphatic malformation following intralesional sodium tetradecyl sulphate injection.

Lymphatic malformations are usually managed by observation, although significant cosmetic abnormalities, compressive optic neuropathy, risk of amblyopia, exposure keratopathy, or elevated intraocular pressure mandate treatment. We report the case of a 10-year-old boy with a deep orbital macrocystic lymphatic malformation that was successfully treated with intralesional injection of sodium tetradecyl sulphate, a sclerozing agent mainly used in the treatment of small varicose veins in the lower extremity.

Adult orbital xanthogranulomas: clinical features and management.

PURPOSE: Adult-onset asthma with periocular xanthogranuloma and adult-onset xanthogranuloma are 2 rare subtypes of non-Langerhans cell histiocytic disorder and much remains unknown regarding optimal treatment. The authors describe their experience in the management of these 2 disease subtypes. METHODS: This is a retrospective case series with histopathologically proven orbital xanthogranuloma over a period of 12 years. Clinical, imaging, and histopathologic features; associated systemic conditions; treatment modality; and outcome during follow-up of 6 adult patients who had adult-onset asthma with periocular xanthogranuloma and adult-onset xanthogranuloma were reviewed. RESULTS: The age range was 29-75 years (median 56 years). The duration of symptoms and signs varied from 10 months to 9 years. All patients had bilateral and asymmetric involvement. Palpebral swelling with yellow discoloration and upper eyelid ptosis were the most common signs. Adult-onset asthma was present in 2 patients. Imaging studies demonstrated ill-defined infiltrative lesions involving the preseptal area, lacrimal glands, extraocular muscles, retrobulbar fat, and optic nerves. The median follow-up was 50 months. Complete regression of all clinical signs was obtained at 8 months, whereas imaging findings disappeared at 18 months with treatment. No recurrence was observed. CONCLUSIONS: Treatment consisting of debulking as much affected soft tissue as possible followed by a 3-day course of intravenous pulse methylprednisolone administration and then by oral prednisone for at least 6 months may provide adequate regression of the granulomas without recurrence and satisfactory cosmesis in patients with adult orbital xanthogranuloma with and without asthma.

Renal Carcinoid Tumor Metastatic to the Uvea, Medial Rectus Muscle, and the Contralateral Lacrimal Gland.

Renal carcinoid tumor is an exceedingly rare malignancy. A 57-year-old man with a renal carcinoid tumor discovered after metastasizing to intraocular and bilateral orbital structures is described. The patient presented with a blind painful OS and a right superotemporal subconjunctival mass. Imaging studies revealed a large left intraocular tumor, a mass in the left medial rectus muscle, and right lacrimal gland enlargement. The OS was enucleated, and incisional biopsies were performed from the other 2 lesions. Histopathological studies demonstrated metastatic neuroendocrine tumor with chromogranin and synaptophysin positivity. Systemic work up revealed a right renal mass and multiple hepatic metastatic lesions. Radical nephrectomy was performed, and octreotide, capecitabine, and temozolomide were administered. Removal of the primary tumor and the eye that had no prospect for useful vision and further treatment with octreotide, capecitabine, and temozolomide provided a disease progression-free period of 24 months and allowed the patient to function normally.

Genome-wide homozygosity mapping in families with leber congenital amaurosis identifies mutations in AIPL1 and RDH12 genes.

Leber congenital amaurosis (LCA) causes severe visual impairment and blindness very early in life. Mutant alleles of several genes acting in different pathways, of which all have critical roles for normal retinal function, were involved in LCA development. The purpose of this study was to use genome-wide genotyping to identify LCA-causing loci in two Turkish families. Genome-wide genotyping and haplotype analysis were performed for prioritization of candidate genes for mutation screening in families with LCA. Identified informative critical choromosomal regions obtained by homozygosity mapping from the families were searched for overlapping of any LCA causative genes. Corresponding clinical phenotypes of the patients with identified mutations were evaluated. In this study, two families were shown to be linked to two different LCA loci covering retinol dehydrogenase 12 (RDH12) and aryl-hydrocarbon-interacting protein-like1 (AIPL1) genes. Mutation screening revealed a novel p.Gln141* mutation in the AIPL1 gene and a previously described p.Thr49Met mutation in the RDH12 gene in a homozygous state. Our patients with the RDH12 mutation had the distinct macular coloboma sign, and the patient with the AIPL1 mutation developed microphthalmia and severe widespread retinal pigment epithelial atrophy, in contrast to previously reported cases. It is currently evident that mutation screening needs to be done in at least 18 genes known to be associated with LCA. Thus, homozygosity mapping is an alternative technique to improve the molecular diagnosis in LCA, which is a group of genetically and clinically heterogeneous diseases causing retinal degeneration. The patients without mutation in known genes may further be analyzed by using next-generation sequencing.

Optical coherence tomography characteristics of epi-iridic membrane in a child with recurrent hyphema and presumed juvenile xanthogranuloma.

We report a case of spontaneous hyphema in a 6-month-old girl with no history of trauma and no visible iris mass. Subtle green-blue heterochromia was noted in the right eye. The iris crypts in the right eye appeared flattened by a thin, transparent layer on the iris surface. Anterior segment optical coherence tomography (AS-OCT) disclosed a thin homogenous membrane overlying the entire iris surface in the right eye. Fluorescein angiography revealed diffuse hyperfluorescence without neovascularization. These features were suggestive of diffuse iris juvenile xanthogranuloma. Sub-Tenon's triamcinolone acetate plus topical corticosteroids eyedrops resolved the condition within 1 month.