MRI Features for Identifying MYCN-amplified RB1 Wild-type Retinoblastoma.

Background MYCN-amplified RB1 wild-type (MYCNARB1+/+) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCNARB1+/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCNARB1+/+ retinoblastoma and age-matched children with RB1-/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing (RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCNARB1+/+ retinoblastoma and 88 control children with RB1-/- retinoblastoma. Children in the MYCNARB1+/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1-/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCNARB1+/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCNARB1+/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCNARB1+/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

Longitudinal Detection of Radiation-Induced Peripapillary and Macular Retinal Capillary Ischemia Using OCT Angiography.

PURPOSE: To study longitudinal changes in retinal capillary circulation in eyes treated with iodine 125 (I125) plaque brachytherapy for uveal melanoma using OCT angiography (OCTA). DESIGN: Longitudinal prospective study of 21 patients undergoing treatment for uveal melanoma with I125 plaque brachytherapy. Eyes with melanoma were imaged with OCTA before treatment and at 12-month intervals until 2 years after brachytherapy. PARTICIPANTS: After institutional review board approval, participants were enrolled prospectively from an academic ocular oncology clinic. METHODS: Peripapillary (4.5 × 4.5-mm) and macular (3 × 3-mm) OCTA scans were acquired with AngioVue (Optovue, Inc, Fremont, CA). MAIN OUTCOME MEASURES: The peripapillary nerve fiber layer plexus capillary density (NFLP_CD), macular superficial vascular complex vessel density (mSVC_VD), and foveal avascular zone (FAZ) area were calculated. RESULTS: Before treatment, no significant difference was found in the NFLP_CD, mSVC_VD, or FAZ area between eyes with melanoma and normal fellow eyes. By 24 months, 11 eyes had developed clinical signs of radiation retinopathy, radiation optic neuropathy, or both. In treated eyes, the NFLP_CD (48.4±4.1%) was reduced at 12 months (46.7±5.0%; P = 0.04, Wilcoxon signed-rank test) and 24 months (44.5±6.1%; P < 0.001). Similarly, the mSVC_VD (48.4 2±3.6%) was reduced in treated eyes at 12 months (43.5±5.9%; P = 0.01) and 24 months (37.4±9.1%; P < 0.001). The FAZ area (0.26±0.11 mm2) increased in treated eyes at 12 months (0.35±0.22 mm2; P = 0.009) and 24 months (0.81±1.03 mm2; P = 0.001). When only eyes with clinically evident radiation changes were evaluated, the changes in NFLP_CD, mSVC_VD, and FAZ area were more pronounced. OCT angiography measurements correlated with both radiation dose and visual acuity. The mSVC_VD measured at 12 months was found to predict the development of clinically apparent radiation retinopathy within 1 year. CONCLUSIONS: OCT angiography demonstrated early emergence of peripapillary and macular capillary vasculature changes after I125 plaque brachytherapy. OCT angiography provided a quantitative measurement of retinal capillary changes associated with ischemia that correlated with visual acuity and radiation dose and may predict future development of radiation-induced retinal toxicity.

Characterization of corneal deposition keratopathy in the setting of blood cell dyscrasia and a minimally invasive technique to clear the cornea in a single case.

PURPOSE: To report 3 cases of corneal protein deposition occurring in association with systemic disease, with one case demonstrating a novel technique for clearing corneal deposits. OBSERVATIONS: Three patients presented with corneal deposits associated with systemic disease. Corneal involvement was noted prior to diagnosis of systemic disease in two patients, leading to subsequent diagnosis of multiple myeloma or monoclonal gammopathy of undetermined significance. OCT revealed protein deposition at various corneal levels, including at different stromal depths in the two cases of multiple myeloma. A novel technique of posterior endothelial scraping was performed in one case with deep stromal deposits, leading to significant corneal clearing. CONCLUSIONS AND IMPORTANCE: This case series demonstrates that recognition of corneal deposits may precede the diagnosis of systemic disease. It incorporates the use of anterior segment OCT to characterize corneal deposits, and demonstrates a novel surgical technique for clearing certain types corneal deposits.

Metastases and death rates after primary enucleation of unilateral retinoblastoma in the USA 2007-2017.

BACKGROUND/AIMS: Enucleation for retinoblastoma is performed less often in the past decade due to increasingly widespread alternative therapies, but enucleation remains an important option. There is a paucity of reports on the current incidence of metastases and metastatic deaths in unilateral retinoblastoma from US centres. METHODS: Retrospective chart review at five tertiary retinoblastoma centres in the USA for unilateral retinoblastoma patients treated with primary enucleation, 2007-2017, with >1 year of follow-up or treatment failure. RESULTS: Among 228 patients (228 eyes), there were nine metastases (3.9%) and four deaths (1.7%). The Kaplan-Meier estimate at 5 years for metastasis-free survival was 96% (95% CI, 94% to 99 %), and for overall survival was 98% (95% CI 96% to 100%). All metastases were evident within 12 months. Histopathology revealed higher risk pathology (postlaminar optic nerve and/or massive choroidal invasion) in 62 of 228 eyes (27%). Of these higher risk eyes, 39 received adjuvant chemotherapy. There were four subsequent metastases in this higher risk pathology with adjuvant chemotherapy group, with three deaths. Of the nine overall with metastases, seven (78%) showed higher risk pathology. All metastatic patients were classified as Reese-Ellsworth V and International Classification of Retinoblastoma Groups D or E. Initial metastases presented as orbital invasion in seven of nine cases. CONCLUSIONS: Primary enucleation for unilateral retinoblastoma results in a low rate of metastatic death, but is still associated with a 3.9% chance of metastases within a year of enucleation. Most but not all patients who developed metastases had higher risk histopathological findings.

Quantitative OCT Angiography Evaluation of Peripapillary Retinal Circulation after Plaque Brachytherapy.

OBJECTIVE: To study peripapillary retinal capillary circulation in eyes treated with I-125 plaque brachytherapy for uveal melanoma using optical coherence tomography angiography (OCTA). DESIGN: Cross-sectional study of 10 subjects imaged with OCTA prior to uveal melanoma treatment and 15 subjects imaged after development of radiation retinopathy and/or optic neuropathy. PARTICIPANTS: Following IRB approval, subjects were enrolled from an academic ocular oncology clinical practice. All subjects had uveal melanoma in one eye and treatment with I-125 plaque brachytherapy was planned or had previously taken place. Patients with low vision at baseline and uncontrolled hypertension were excluded. In the post-treatment group, seven subjects were male and eight were female; age range 38 to 81 years. Visual acuities in the irradiated eyes ranged from 20/20 to counting fingers. Visual acuities in the untreated fellow eyes were 20/25 or better. METHODS: Peripapillary retinal capillary circulation was measured by OCTA (Optovue, Inc). 4.5×4.5 mm optic disc scans were obtained. 10 subjects were imaged prior to brachytherapy treatment and 15 subjects were imaged after development of clinically apparent radiation retinopathy and/or radiation optic neuropathy post-brachytherapy. MAIN OUTCOME MEASURES: The relationship of the peripapillary retinal capillary density (PPCD) as measured by OCTA to the calculated dose to the optic nerve (D50, the dose to 50% of the disc) and the LogMAR vision was evaluated. RESULTS: No significant difference was seen in the PPCD as measured by OCTA when comparing the eye with melanoma to the fellow eye prior to brachytherapy; however the PPCD was significantly lower in treated eyes (52.9% +/- 22.4%) than in fellow eyes that did not receive radiation (73.3% +/- 13.7%, p = 0.004). There was an inverse linear correlation between D50 and the PPCD (Pearson's; r= -0.528, P=0.043) and between visual acuity and the PPCD (Pearson's; r= -0.564, P=0.028). CONCLUSIONS: Among patients with clinically apparent radiation retinopathy and/or radiation optic neuropathy, PPCD was lower in the treated eye and correlated with the radiation dose to the optic nerve and the visual acuity. OCTA provides a measure of capillary changes following radiation, and may serve as a quantitative endpoint to address visual prognosis.

Uveal Melanoma with Histopathologic Intratumoral Heterogeneity Associated with Gene Expression Profile Discordance.

PURPOSE: To report a case of intratumoral gene expression profile discordance in a malignant uveal melanoma, associated with intratumoral heterogeneity based upon histopathologic features. METHODS: The clinical history, fundus findings, imaging and histopathologic features, and DecisionDx-UM gene expression profile results (Castle Biosciences, Inc., Phoenix, AZ, USA) of the tumor were reviewed. RESULTS: A trans-retinal fine-needle aspiration biopsy was performed for a thin, pigmented choroidal tumor in a 33-year-old man. Cells obtained from this biopsy were tested using the DecisionDx-UM gene expression profile test and the tumor was classified as class 1A. Cytology confirmed melanoma. The patient subsequently elected to undergo enucleation. On microscopic examination of the globe, the tumor was composed primarily of spindle B cells, but had a focal area composed of epithelioid cells. This portion of the tumor was subsequently tested and demonstrated a class 1B gene expression profile. CONCLUSION: Intratumoral discordance in gene expression profile results has been described in uveal melanomas. Here we demonstrate that this discordance may be associated in some cases with intratumoral heterogeneity based upon histopathologic features.

CLINICOPATHOLOGIC CORRELATION OF RETINAL ANGIOMATOUS PROLIFERATION TREATED WITH RANIBIZUMAB.

PURPOSE: To describe histopathologic features of an eye with retinal angiomatous proliferation (RAP) secondary to age-related macular degeneration treated with serial ranibizumab injections and to correlate these findings with spectral domain optical coherence tomography. METHODS: Histopathologic features from serial sections through the globe of a 93-year-old man with age-related macular degeneration were studied and compared with spectral domain optical coherence tomography images obtained 7 weeks before his death. RESULTS: The pathologic correlate of ranibizumab-treated RAP was a circumscribed, branching paucicellular vascular complex extending from the inner plexiform layer to Bruch membrane. The histopathologic findings corresponded to an area of hyperreflectivity on spectral domain optical coherence tomography imaging, substantiating the reported tomographic appearance of RAP lesions. A frank anastomosis with choroidal or retinal vasculature was not seen in this treated RAP lesion. There was a lack of retinal pigment epithelium underlying the lesion in an area of retinal pigment epithelium detachment. The elastic portion of Bruch membrane appeared intact. Treatment with ranibizumab over an extended period of time may have been associated with a loss of cellularity of the RAP lesion. CONCLUSION: In a patient with ARMD extensively treated with ranibizumab, color fundus photography, fluorescein angiography and SD-OCT images of RAP correlated histopathologically with a paucicellular intraretinal vascular complex.

Transmission of Donor-Derived Breast Carcinoma as a Recurrent Mass in a Keratolimbal Allograft.

PURPOSE: To report a case of local transmission of invasive lobular carcinoma from a donor to a recipient in a keratolimbal allograft after cessation of systemic immunosuppressive therapy. METHODS: This is a case report including the clinicopathologic findings. Sections of the donor breast tumor and recipient conjunctival lesions were stained with hematoxylin and eosin. Immunohistochemical studies were performed using pancytokeratin, CK7, CK20, CAM 5.2, CD138, TTF1, estrogen receptor, progesterone receptor, GATA-3, GCDFP-15, and mammaglobin. Polymerase chain reaction-based DNA profiling of tumor cells was performed. RESULTS: Histopathologic examination revealed an infiltrate of atypical cells with large hyperchromatic nuclei consistent with carcinoma. Immunohistochemical analysis showed pancytokeratin, CK7, CAM 5.2, GATA-3, and estrogen receptor positivity and progesterone receptor absence, consistent with the previously determined phenotype of the donor's breast carcinoma. Results of polymerase chain reaction analysis were also consistent with the donor's tumor. After reduced dosing of tacrolimus and mycophenolate mofetil, 2 limbal tumors occurred in the recipient. The immunosuppressive treatment had been stopped completely before the appearance of the third lesion. The recipient had no history of malignancy, and she had routine screenings for breast cancer. CONCLUSIONS: We report a case of donor-derived breast carcinoma in a keratolimbal allograft recipient. The grafted tissue harbored donor-derived tumor cells for more than 4 years after surgery even after systemic immunosuppression was discontinued. Although no similar reports of tumor transfer could be found in the literature, this case suggests the need for increased stringency in donor selection and heightened surveillance for such tumor transmission.