Citations

A 68-year-old man with a history of keratoconus was referred for evaluation of a choroidal lesion in his left eye. Fundus autofluorescence demonstrated hyperautofluorescence in a leopard-spotting pattern. What would you do next?

Purpose: To review clinical presentations of periocular sebaceous carcinoma (SC) and introduce standardized nomenclature for multicentric and multifocal disease presentation. Methods: A comprehensive PubMed/Medline search was conducted to identify all articles reporting periocular multicentric or multifocal SC presentations. The authors also highlight an additional case of SC presenting with 2 clinically distinct tumor foci and complete secondary invasion of the lacrimal gland. Results: This review summarizes clinical presentations of periocular SC exhibiting discrete foci of microinvasion reported in the literature. Discrete microinvasion was associated with high rates of misdiagnosis (80%), simultaneous involvement of both upper and lower eyelids (80%), pagetoid spread (80%), multinodular growth (33%), local tumor spread (60%), previous eyelid manipulation (40%), and local recurrence (40%). Eyelid multifocality with clinically discrete nodules (42%) was associated with more advanced disease including orbital extension and regional invasion (80%). Conclusions: Despite previous reported associations with poorer outcomes, there is no consensus in the definition or nomenclature for discrete microinvasive or clinical disease presentations in periocular SC. The authors recommend defining multicentric disease as discrete foci of microinvasive tumor with basement membrane disruption and multifocal disease as discrete clinically evident nodules involving both the upper and lower eyelids. Differentiating between discrete microinvasive (multicentric) and clinically nodular (multifocal) disease may improve risk stratification to most accurately identify patients who require more aggressive management and surveillance.

To determine the frequency, characteristics, and clinical course of ophthalmic side effects associated with systemic BRAF inhibitor therapy. Medical records of patients taking BRAF inhibitors for the treatment of systemic malignances at Mayo Clinic, Rochester from 01/01/2010 to 08/30/2021, were retrospectively reviewed. Of 901 patients, 14 (1.6%) patients experienced an ophthalmic side effect. Mean age at presentation of the side effect was 60 years (median 59, range 50–80) and 11 (79%) were male. The most common side effect was uveitis in 7 (50%) patients, followed by dry eye in 4 (29%) patients, and central serous chorioretinopathy in 2 (14%) patients, with singular cases of cranial nerve VI palsy and conjunctival edema. A comparison between individual BRAF inhibitors (vemurafenib vs. dabrafenib vs. encorafenib) revealed that patients taking encorafenib had a shorter interval to any ophthalmic adverse event (mean 55.6 vs. 9.8 vs. 4.0 months, p = 0.03) and were the only patients to experience documented dry eye syndrome (DES) in this series. Outcomes were known in 13 (93%) patients, and ophthalmic adverse effects resolved or were controlled without discontinuing therapy in 10 (77%). Uveitis was successfully treated with topical corticosteroids in 4 patients, while 3 patients with refractory uveitis (2 with panuveitis and 1 with unspecified uveitis) required discontinuation of BRAF inhibitor therapy. Ophthalmic adverse events related to systemic BRAF inhibitor use are rare, with estimated frequency of 1.6%. Most events can be treated with local ophthalmic therapy. BRAF inhibitors provide life-saving therapy, and their discontinuation should be avoided.

Abstract Background: Uveal melanoma (UM) is a rare tumor of the eye which is biologically distinct from cutaneous melanoma (CM) and carries a poor prognosis once metastatic. We aimed to examine a multi-omics profile of UM as compared to CM. Methods: A total of 277 UM and 1,297 CM metastatic or primary samples were analyzed using next-generation sequencing (NextSeq, 592 genes and WES, NovaSeq, >700 genes) and whole transcriptome sequencing (WTS; NovaSeq) (Caris Life Sciences). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cutoff >10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. T- cell inflamed score was calculated using gene expression data. Pathway gene enrichment analysis using WTS data was performed using GSEA. Biostatistical significance was determined using chi-square/Fisher-Exact or Wilcoxon rank sum test and adjusted for multiple comparisons. Results: For all cases (primary and metastatic), UM compared to CM had a higher rate of GNAQ/11 (93.8% vs. 2.1% p≤0.001), SF3B1 (20.4% vs 3% p≤0.001), and BAP1 (52.9% vs. 1.5% p≤0.001) mutations. UM also had higher levels of MYC (7% vs 0.9% p≤0.001), NCOA2 (3.1% vs 0.1% p≤0.001), and RUNX1T1 genomic amplifications (2.3% vs 0.2% p≤0.001). Assessing only samples of liver metastases, UM was shown to have higher abundance of M2 macrophages (P≤0.0001) and less abundance of M1 macrophages(P≤0.0001), monocytes(P≤0.0001), CD4 T-cells(P≤0.0001), and regulatory T-cells (p = 0.0003) as compared to CM. GSEA comparison between liver metastases of UM and CM samples showed G2M checkpoint (NES score, 1.60 p≤0.0001) and E2F targets (NES score, 1.58 p=0.002) to be higher in metastatic CM. When comparing T-cell inflamed, intermediate, and non-inflamed tumors from any site, CM or UM, the average Z scores for both G2M and E2F were highest for inflamed and lowest for non-inflamed, P≤0.0001. A similar trend of higher Z score was seen for TMB high vs TMB low tumors, p≤0.0001. Conclusions: UM and CM are characterized by significantly different genomic and transcriptomic alterations, and cellular composition of TME. Further understanding of these characteristics may lead to better treatment strategies for metastatic UM. Citation Format: Justin C. Moser, Yusra F. Shao, Joanne Xiu, Yasmine Baca, Takami Sato, Lauren A. Dalvin, Sourat Darabi, Michael Korn, Burton Eisenberg, Geoff Gibney, Evidio Domingo-Musibay, Gino In, Dave Hoon, Michael S. Gordon. Multi-omics and immune cell profiling of metastatic uveal melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 50.

Purpose: The purpose of this study was to describe an exceedingly rare presentation of secondary vitreoretinal involvement by the uncommon entity “indolent T-cell lymphoproliferative disorder of the gastrointestinal tract” and illustrate the utility of fluorescence in situ hybridization for diagnosis. Methods: This is a case report. Results: A 57-year-old woman with presumed iritis on chronic topical prednisolone acetate presented with increased vitreous opacities in the right eye. She had a history of biopsy-confirmed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach and duodenum, JAK2-rearrangement positive, controlled on maintenance oral methotrexate. Vitreous biopsy was unremarkable with small CD3-positive and CD4-positive and CD20-negative lymphocytes, along with histiocytes and fibroblasts. Immunostains showed CD4 positivity, and fluorescence in situ hybridization revealed a JAK2 gene rearrangement, consistent with the patient's previously diagnosed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Intravitreal methotrexate injections were started in the right eye. MRI of the brain and lumbar puncture with cytology, MYD88, IL10, and flow cytometry performed at the time of right eye vitreoretinal lymphoma diagnosis revealed no evidence of central nervous system lymphoma, but subsequent bone marrow biopsy demonstrated 5% involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, JAK2-rearrangement positive, with a lung nodule on PET computed tomography. She returned 4 months later with fatigue, night sweats, and blurry vision in the left eye with vitreous and anterior chamber cellular infiltration and retinal vasculitis. Conclusion: T-cell vitreoretinal lymphoma is rare, and diagnosis can be challenging. Despite inconclusive cytology in this case, interphase fluorescence in situ hybridization detected a JAK2 gene rearrangement, which confirmed the involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and prompted appropriate treatment and workup for recurrent systemic or central nervous system lymphoma.

Melanocytoma is a benign tumor with histologic similarity to oculodermal melanocytosis, which can undergo malignant transformation in rare cases. Melanocytoma more commonly involves the optic disc, and few cases of orbital melanocytoma have been reported. Primary orbital melanoma is a rare malignancy known to arise from pigmentary conditions, although there is little information on this tumor arising from melanocytoma. The authors present a case of malignant transformation of orbital melanocytoma in the setting of ipsilateral oculodermal melanocytosis. This case illustrates histopathologic features associated with malignant transformation and highlights the significance of GNAQ, BAP1, and specific intrachromosomal alterations occurring in oculodermal melanocytosis and melanocytoma. The molecular markers observed in this case are of interest as they have overlap with those present in uveal melanoma. This case demonstrates a timeline of genetic and molecular alterations occurring in the malignant transformation of orbital melanocytoma.

Abstract Background The coronavirus disease 2019 pandemic has significantly impacted medical education, notably the mandate for all residency programs to implement virtual (rather than in-person) residency interviews. Understanding residency applicants' perceptions and approach to this novel virtual interview season will be beneficial as potential future interview formats are considered. Objective The aim of this study was to examine perceptions of the 2020 to 2021 ophthalmology residency match applicants regarding the virtual interview season prior to the start of the interview season. Patients and Methods Ophthalmology residency applicants during the 2020 to 2021 cycle were invited to complete the survey between October 20 and 29, 2020. Respondent demographic information, perceived importance of various application details in a normal versus virtual interview season, strengths and limitations of virtual interviews, and preferences for optimal virtual interview format were obtained. Results There were 337 survey respondents, with at least 50% of the survey completed by 190 applicants (56%). Of these, 73% of respondents applied to more than 60 ophthalmology residency programs, and 78% felt that the evaluation of candidates would be impacted by the virtual interview format. Regardless of interview format, United States Medical Licensing Examination Step 1 score and letters of recommendation were perceived to be the two most important factors related to matching at an applicant's top ranked programs. The primary limitation of a virtual interview season was the inability to experience a program's culture in person, while largest strength was cost savings. Conclusion The ophthalmology residency match is a competitive process made potentially more complex by a novel virtual interview format. A detailed postcycle analysis will be important to optimize future interview seasons.