A Review of Pediatric Ophthalmic Tumors.

Tumors of the eye, orbit, and ocular adnexa can arise in the pediatric population. These entities can be both vision- and life-threatening and may be associated with systemic disease. Given their relative rarity, pediatricians must be aware of these conditions and understand what findings warrant immediate referral to an ophthalmologist for initiation of further testing. We aimed to review these conditions and highlight clinical features to promote awareness and expedite diagnosis. Tumors are subdivided into the following categories for review: anterior tumors of the eyelid and ocular surface, orbital tumors, and intraocular tumors.

Schimmelpenning-Feuerstein-Mims syndrome with orbital choristoma and KRAS mutation: a current review and novel case report.

INTRODUCTION: Schimmelpenning-Feurstein-Mims Syndrome (SFMS) is a rare neurocutaneous disorder. Herein, we describe a novel case and review the phenotypic spectrum and molecular findings of SFMS from an ophthalmology perspective. METHODS: Clinical case including presentation, management, pathology, and genetic analysis is described. A literature search on Schimmelpenning-Feuerstein-Mims and its synonyms, Linear nevus sebaceous syndrome, Organoid nevus syndrome, Jadassohn nevus phacomatosis, and Solomon syndrome, was conducted. An updated review and description of published cases with identified genetic mutations are described. RESULTS: A 13-year-old boy with SFMS presented with acute right eye pain and an enlarging orbital mass. Excisional biopsy of the mass revealed an orbital choristoma. Genetic analysis of the orbital tumor confirmed a KRAS c.35 G>A, p.G12D mutation. A literature search revealed 19 cases of SFMS with mutations in the RAS-pathway. KRAS, HRAS, and NRAS mutations were identified in 74%, 21%, and 5% of patients, respectively. Ophthalmic pathology was seen in 83% of patients. Systemic findings varied and involved the skin, central nervous system, and eyes most commonly. DISCUSSION: SFMS, a rare neurocutaneous disorder, results from postzygotic mosaic mutations in the RAS/MAPK pathway. Patients present with various systemic findings and ophthalmic manifestations occur in most cases. This is the first case description of a KRAS mutation identified in an orbital choristoma in SFMS. The disease is described under various names in the literature, and we propose that all syndromic cases with mosaic RAS mutations be reported under the eponym, SFMS.

Ophthalmologic Findings in Pediatric Erdheim-Chester Disease: A Literature Review With a Novel Case Report.

PURPOSE: The authors aim to describe the ophthalmologic manifestations of pediatric Erdheim-Chester disease (ECD). METHODS: The authors describe a novel case of ECD presenting as isolated bilateral proptosis in a child and provide a comprehensive review of the documented pediatric cases to observe overall trends and ophthalmic manifestations of disease. Twenty pediatric cases were identified in the literature. RESULTS: The mean age at presentation was 9.6 years (1.8-17 years) with a mean time of symptom presentation to diagnosis of 1.6 years (0-6 years). Nine patients (45%) had ophthalmic involvement at diagnosis, 4 who presented with ophthalmic complaints: 3 with observable proptosis and 1 with diplopia. Other ophthalmic abnormalities included eyelid findings of a maculopapular rash with central atrophy on the eyelids and bilateral xanthelasmas, neuro-ophthalmologic findings of a right hemifacial palsy accompanied by bilateral optic atrophy and diplopia, and imaging findings of orbital bone and enhancing chiasmal lesions. No intraocular involvement was described, and visual acuity was not reported in most cases. CONCLUSIONS: Ophthalmic involvement occurs in almost half of documented pediatric cases. Typically presenting with other symptoms, the case highlights that isolated exophthalmos may be the only clinical sign, and ECD should be included in the differential diagnosis of bilateral exophthalmos in children. Ophthalmologists may be the first to evaluate these patients, and a high index of suspicion and an understanding of the varied clinical, radiographic, pathologic, and molecular findings are critical for prompt diagnosis and treatment of this unusual disease.

Ultrasound Verification of Plaque Brachytherapy Placement in Patients Treated for Primary Uveal Melanoma: A Single-Center Experience.

Introduction: Proper plaque positioning is essential for effective episcleral plaque brachytherapy and can be verified using ultrasound. In this study, we show our center's protocol for intraoperative ultrasound verification of plaque placement and present our single-center local recurrence data in patients with primary UM involving the choroid and/or ciliary body. We also indicate our center's distance metastasis rate for patients presenting with primary UM. Methods: All patients who presented to our institution with UM of the choroid and/or ciliary body between May 2017 and March 2022 and treated with plaque brachytherapy were enrolled. Endpoints include the 24-month local recurrence-free rate (primary) and 24-month metastasis rate (secondary), both estimated using the Kaplan-Meier method (KM). Results: Local Recurrence: 176 patients met the study criteria with median follow-up of 23.2 months. The 24-month recurrence-free probability for this cohort was estimated at 99.1% (95% confidence interval: 0.974-1.00). Metastatic Recurrence: 136 of these patients underwent at least one follow-up surveillance scan. The 24-month metastasis-free survival probability in our cohort was estimated at 87% (95% confidence interval: 81-94%). Conclusions: We show improved local control utilizing ultrasound verification compared to historical controls who received TTT and brachytherapy without intraoperative ultrasound confirmation.

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.

A case of sight threatening complications from topical 1% 5-fluorouracil in the treatment of ocular surface squamous neoplasia.

PURPOSE: 1% topical 5-fluorouracil (5-FU) is a treatment for ocular surface squamous neoplasia (OSSN) due to its effectiveness, low cost, and tolerable side effect profile. To our knowledge there is no reported sight-threatening corneal complication of 1% 5-FU for the treatment of OSSN. OBSERVATIONS: We report a 78 year-old man with bilateral conjunctival intraepithelial neoplasia (CIN) who developed bilateral corneoscleral ulceration and corneal perforation of the left eye after 1% 5-FU topical treatment. CONCLUSIONS AND IMPORTANCE: Our case report describes serious potential complications of 1% 5-FU, reviews possible risk factors associated with poor outcomes, and discusses our treatment approach.

Two cases of von Hippel-Lindau syndrome-associated retinal hemangioblastoma treated with belzutifan.

PURPOSE: To describe two cases of retinal hemangioblastoma (RH) regression following treatment with belzutifan in patients with von Hippel-Lindau (VHL) syndrome. METHODS: Clinical information was extracted from the charts and tumor imaging of two patients with VHL-associated RH. RESULTS: In case 1, a 40-year-old man was treated with belzutifan for spine hemangioblastomas after diagnosis of a 2.0x2.0x1.3 mm left eye RH temporal to the macula associated with intraretinal edema, subretinal fluid, and mild retinal traction. In case 2, a 66-year-old woman presented with a right eye 2.0x1.5x1.3 mm juxtapapillary lesion with subretinal fluid, intraretinal fluid, and nasal traction, and a 4.0x3.5x1.1 mm inferior mid-periphery lesion with subretinal fluid, intraretinal fluid, and active exudation. She was treated for 2.5 years with belzutifan for renal cell carcinoma on the National Institutes of Health trial. The patient in case 1 demonstrated a 10% reduction in largest tumor diameter and 8% reduction in thickness, along with improving subretinal fluid, intraretinal edema, and retinal traction, after 4 weeks of treatment. After 2.5 years of treatment, the patient in case 2 demonstrated similar margins of her now fibrotic-appearing juxtapapillary lesion with a 45% reduction in thickness, along with resolved subretinal fluid and greatly improved intraretinal fluid and traction. The inferior lesion demonstrated 12.5% reduction in largest diameter, 36% reduction in thickness, and was without active subretinal fluid or exudation. Neither patient demonstrated new lesions while on-treatment. CONCLUSION: Belzutifan is a promising treatment for RH with the potential for both rapid and sustained tumor regression.

Targeted Neoadjuvant Intra-arterial Chemotherapy in Lacrimal Gland Adenoid Cystic Carcinoma: A Histological Correlation Using Apoptotic Tumor Markers.

Neoadjuvant intra-arterial cytoreductive chemotherapy is used for the treatment of lacrimal gland adenoid cystic carcinomas (ACC) to improve outcomes in this condition with an otherwise dismal prognosis. We share our experience in the management of an advanced case of ACC using a novel, highly targeted intra-arterial cytoreductive chemotherapy delivery technique involving both the internal and external carotid circulation, with an attempt to correlate the effect histologically. Refinement of the chemotherapy delivery using the tumor's vascular anatomy and appropriate blood vessel selection may lead to future globe sparing procedures without compromising survival.

Response criteria for intraocular retinoblastoma: RB-RECIST.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

Post-Brachytherapy Pigment Dispersion in Uveal Melanoma.

We report delayed intravitreal pigment dispersion following Iodine-125 plaque brachytherapy, without evidence of tumor recurrence, in 4 patients treated for choroidal melanoma. These patients were treated with Iodine-125 plaque brachytherapy, with or without transpupillary thermotherapy, and were followed clinically and using ancillary investigations for signs of tumor recurrence. All 4 patients were noted to develop pigment dispersion - it was detected on the surface of the retina (2 patients), diffusely in the vitreous (1 patient), or both (1 patient). Follow-up ranged from 70 to 343 months (mean 165 months; median 124 months) post-treatment with plaque brachytherapy, throughout which the location and amount of pigment remained grossly unchanged. None of the patients developed tumor recurrence or metastasis. We conclude that post-brachytherapy pigment dispersion is an unusual but known complication in the treatment of uveal melanoma. Close surveillance to rule out tumor recurrence and metastasis may be a reasonable line of management.

Vitreous Metastasis in a Case of Metastatic Breast Cancer.

A 35-year-old female with a history of metastatic breast cancer (BC) presented with unilateral blurred vision and floaters over 6 weeks. Examination findings showed vitreous opacities and a vasculitis concerning for an infectious process. Diagnostic vitrectomy revealed no infectious cause, but rather metastatic cells in the vitreous, with no obvious retinal or choroidal metastatic focus. In this report we illustrate a case of vitreous metastasis in a patient with metastatic BC, highlighting the importance of recognizing this rare entity which can mimic an inflammatory or infectious process. Novel to this report is the use of modern wide-field retinal imaging, spectral-domain optical coherence tomography, and a surgical video to document the findings of this disease entity.

Primary Episcleral Melanoma Consistent with Uveal Melanoma Mutations Treated by Excision and Gamma Knife Stereotactic Radiosurgery.

Ocular melanocytosis has traditionally been associated with increased risk of developing uveal melanoma; however, rarely primary episcleral melanoma has been reported in the literature. Herein, we present the third case of primary episcleral melanoma treated by complete excision and cryotherapy. In contrast to previous cases, we obtained molecular genetic testing which revealed a GNA-11 mutation, and gene expression profiling resulted in a Class 2 PRAME positive tumor diagnosis. These two tests which have never been performed on previous cases, support lineage similar to uveal melanoma. In addition, we are the first case to report treatment of the surgical bed and surrounding orbital tissue with Gamma Knife stereotactic radiotherapy to both treat residual tissue and decrease risk of recurrence.

Conjunctival Melanoma: Current Treatments and Future Options.

Conjunctival melanoma is a rare tumor of the conjunctival epithelium with a heterogenous clinical presentation and a propensity for regional and distant metastatic spread. Guidelines for the treatment of local conjunctival melanoma are well-established, but there are no standard efficacious therapies for metastatic disease. Given that conjunctival melanoma is genetically similar to cutaneous melanoma and mucosal melanomas, targeted therapies effective in the treatment of these diseases, such as BRAF inhibitors and KIT inhibitors, may be effective in the treatment of patients with metastatic conjunctival melanoma. Other targeted small-molecule drugs in the drug development pipeline for the treatment of more prevalent melanomas could also be applicable to conjunctival melanoma. Furthermore, systemic immunotherapy treatments that are now a mainstay in the treatment of cutaneous melanoma, such as programmed cell death-1 and cytotoxic T lymphocyte-associated antigen-4 inhibitors, could also stand to benefit patients with metastatic conjunctival melanoma. Limited case reports provide clues about the effectiveness of both targeted small-molecule inhibitors and immunotherapy in patients with advanced local and metastatic conjunctival melanoma and give credence to the argument that conjunctival melanoma patients should be included in major trials studying new therapies in both cutaneous and mucosal melanomas where applicable.

A case of bilateral acute depigmentation of the Iris in one of two identical twins.

BACKGROUND: Bilateral Acute Depigmentation of the Iris (BADI) is a condition which was first described in a case series from Turkey by Tugal-Tutkin and Urgancioglu in (Graefes Arch Clin Exp Ophthalmol 244:742-6, 2006). The condition is characterized by bilateral acute depigmentation and discoloration of the iris stroma, pigment dispersion, and deposition of pigment in the angle. In our case we report a patient who developed BADI after receiving pitcher plant extract injections for chronic migraine, while her identical twin sister has normal iris architecture and pigmentation and never received any pitcher plant injections. CASE PRESENTATION: Patient is a 41-year-old female with history of pitcher plant extract injections to her face for chronic migraine, who later developed bilateral depigmentation of the iris. She did not have any signs of anterior segment uveitis or iridocyclitis. She has an identical twin sister who maintained normal iris pigmentation during the entire course. CONCLUSIONS: Bilateral Acute depigmentation of the is a recently discovered condition described in the literature in Turkish patients (Tugal-Tutkun and Urgancioglu, Graefes Arch Clin Exp Ophthalmol 244:742-6, 2006; Tugal-Tutkun et al., Ophthalmology 116(8):1552-7, 2009). This condition affects mainly young females and is characterized by acute bilateral stromal depigmentation, without other pathologic ocular findings. These patients usually maintain normal vision and do not develop significant glaucoma from pigment collecting in the anterior chamber angle. This condition can be mistaken for Fuchs' heterochromic iridocyclitis, pigment dispersion syndrome, pseudoexfoliation syndrome, and viral iridocyclitis. This is the first reported case in North America and is important for differentiation from the above pathologies. Our patient had a history of pitcher plant extract injections to the face but it is unclear if this is associated with our patient's development of BADI. As awareness of this condition progresses, a possible etiology may be elucidated.

A Potential Role For Apparent Diffusion Coefficient in the Diagnosis of Trilateral Retinoblastoma.

We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (>1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.

Experimentally Observed Cherenkov Light Generation in the Eye During Radiation Therapy.

PURPOSE: Patients have reported sensations of seeing light flashes during radiation therapy, even with their eyes closed. These observations have been attributed to either direct excitation of retinal pigments or generation of Cherenkov light inside the eye. Both in vivo human and ex vivo animal eye imaging was used to confirm light intensity and spectra to determine its origin and overall observability. METHODS AND MATERIALS: A time-gated and intensified camera was used to capture light exiting the eye of a patient undergoing stereotactic radiosurgery in real time, thereby verifying the detectability of light through the pupil. These data were compared with follow-up mechanistic imaging of ex vivo animal eyes with thin radiation beams to evaluate emission spectra and signal intensity variation with anatomic depth. Angular dependency of light emission from the eye was also measured. RESULTS: Patient imaging showed that light generation in the eye during radiation therapy can be captured with a signal-to-noise ratio of 68. Irradiation of ex vivo eye samples confirmed that the spectrum matched that of Cherenkov emission and that signal intensity was largely homogeneous throughout the entire eye, from the cornea to the retina, with a slight maximum near 10 mm depth. Observation of the signal external to the eye was possible through the pupil from 0° to 90°, with a detected emission near 2500 photons per millisecond (during peak emission of the ON cycle of the pulsed delivery), which is over 2 orders of magnitude higher than the visible detection threshold. CONCLUSIONS: By quantifying the spectra and magnitude of the signal, we now have direct experimental observations that Cherenkov light is generated in the eye during radiation therapy and can contribute to perceived light flashes. Furthermore, this technique can be used to further study and measure phosphenes in the radiation therapy clinic.

Two Uveal Melanomas in One Eye: A Choroidal Nevus Giving Rise to a Melanoma in an Eye with a Separate Large Choroidal Melanoma.

Multifocal uveal melanomas are extremely rare. In this case report, we describe a patient with 2 independent uveal melanomas in the same eye. A 52-year-old woman presented with a large choroidal melanoma and a smaller ciliary body mass, clinically thought to be a nevus, in her left eye. Enucleated specimen showed 2 primary lesions that were anatomically separate. Lesion 1 was a melanoma and lesion 2 was a melanoma arising centrally from a nevus. Both lesions harbored GNAQ mutations. This patient had no family history of uveal melanomas or signs of ocular melanocytosis and was negative for the BAP1 mutation. This case demonstrates how multifocal uveal melanomas can arise in patients who lack genetic predisposition for the disease. Furthermore, this case is one of the few that have shown, histopathologically, a small focus of malignant cells developing from a benign population within a nevus, which highlights the importance of closely monitoring nevi for signs of malignancy.