Extraocular Invasion Research Articles

Single-cell transcriptomics enable the characterization of local extension in retinoblastoma

Retinoblastoma (RB) is the most prevalent ocular tumor of childhood, and its extraocular invasion significantly increases the risk of metastasis. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing on four RB samples (two from intraocular and two from extraocular RB patients), and integrate public datasets of five normal retina samples, four intraocular samples, and three extraocular RB samples to characterize RB local extension at the single-cell level. A total of 128,454 qualified cells are obtained in nine major cell types. Copy number variation inference reveals chromosome 6p amplification in cells derived from extraocular RB samples. In cellular heterogeneity analysis, we identified 10, 8, and 7 cell subpopulations in cone precursor like cells, retinoma like cells, and MKI67+ photoreceptorness decreased (MKI67+ PhrD) cells, respectively. A high expression level of SOX4 was detected in cells from extraocular samples, especially in MKI67+ PhrD cells, which was verified in additional clinical RB samples. These results suggest that SOX4 might drive RB local extension. Our study presents a single-cell transcriptomic landscape of intraocular and extraocular RB samples, improving our understanding of RB local extension at the single-cell resolution and providing potential therapeutic targets for RB patients.

Diagnostic utility of immunohistochemistry in concordance with mRNA analysis of PRAME in the stratification of high-risk uveal melanoma patients.

Existing clinical indicators for metastatic risk classification and patient treatment of uveal melanoma (UM) in the Asian population are limited. Preferentially expressed antigen in melanoma (PRAME) has gained attention in the prognosis of cancers and considered as a potential biomarker in many tumors including UM. Therefore, this study investigated the expression of PRAME and its association with loss of nuclear BAP1 (nBAP1) as well as its correlation with clinicopathological parameters and patient outcome. Immunohistochemical expression of PRAME and BAP1 proteins were assessed in 66 prospective cases of UM. mRNA expression level was measured by quantitative real-time PCR. Kaplan-Meier curves and Cox proportional hazard models were used to analyze the correlation of protein expression with clinicopathological parameters, metastasis-free survival and overall survival. Nuclear PRAME (nPRAME) expression and loss of nBAP1 were observed in 24 and 62% cases, respectively. PRAME mRNA expression level was found to be upregulated in 64% (7/11) of metastatic patients. mRNA and immunoexpression of nPRAME were statistically significant with many clinicopathological high-risk factors. On univariate and multivariate analyses, high mitotic activity, extraocular invasion and presence of nPRAME expression were statistically significant (p < 0.05). On Kaplan-Meier survival analysis, patients expressing PRAME had significantly reduced metastasis-free survival (MFS) and overall survival (OS). MFS and OS were also reduced in patients expressing PRAME along with loss of nBAP1. Our data show that nPRAME expression, in combination with loss of nBAP1, could be a useful predictive biomarker in the therapeutic management of UM patients at high risk.

Successful treatment of ciliary body medulloepithelioma with intraocular melphalan chemotherapy: a case report

BackgroundIntraocular medulloepithelioma is commonly treated with primary enucleation. Conservative treatment options include brachytherapy, local resection and/or cryotherapy in selected cases. We report for the first time the use of targeted chemotherapy to treat a ciliary body medulloepithelioma with aqueous and vitreous seeding.Case presentationA 17-month-old boy with a diagnosis of ciliary body medulloepithelioma with concomitant seeding and neovascular glaucoma in the right eye was seen for a second opinion after parental refusal of enucleation. Examination under anesthesia showed multiple free-floating cysts in the pupillary area associated with iris neovascularization and a subluxated and notched lens. Ultrasound biomicroscopy revealed a partially cystic mass adjacent to the ciliary body between the 5 and 9 o’clock meridians as well as multiple nodules in the posterior chamber invading the anterior vitreous inferiorly. Fluorescein angiography demonstrated peripheral retinal ischemia. Left eye was unremarkable. Diagnosis of intraocular medulloepithelioma with no extraocular invasion was confirmed and conservative treatment initiated with combined intracameral and intravitreal melphalan injections given according to the previously described safety-enhanced technique. Ciliary tumor and seeding totally regressed after a total of 3 combined intracameral (total dose 8.1 μg) and intravitreal (total dose 70 μg) melphalan injections given every 7–10 days. Ischemic retina was treated with cryoablation as necessary. Three years later, ab interno trabeculotomy followed by 360° gonioscopy-assisted transluminal trabeculotomy 6 months later was performed for uncontrolled intraocular pressure despite antihypertensive drugs combined to cyclophotocoagulation and 7 intravitreal anti-VEGF injections for recurrent iris neovascularization. Cataract was removed at the same operative time. The child has remained disease- and metastasis-free at a 5-year follow-up since the last melphalan injection (25-month follow-up after the combined lensectomy-trabeculotomy) with a controlled intraocular pressure under topical quadritherapy and a best corrected Snellen visual acuity of 0.08.ConclusionsWe report for the first time complete regression of a non-infiltrating ciliary body medulloepithelioma with seeding achieved with only a small number of intracameral and intravitreal melphalan injections. Concomitant secondary neovascular glaucoma and cataract needed appropriate management to allow long-term eye and vision preservation.

Associations among Socioeconomic Factors, Lag Time, and High-Risk Histopathologic Features in Eyes Primarily Enucleated for Retinoblastoma

ABSTRACTPurpose/Aim: To determine the associations among socioeconomic factors, delay in management, and high-risk histopathologic features in eyes primarily enucleated for retinoblastoma.Materials and Methods: A single-site survey was conducted from January 2016 through January 2018. Eyes primarily enucleated for unilateral retinoblastoma were reviewed for the presence of high-risk histopathologic features. Information on clinical characteristics, socioeconomic factors, and lag time were collected during hospitalization.Results: Of the 138 children analyzed, 60 (43.5%) carried high-risk histopathologic features. Compared to children with a standard risk, those with a high risk had a longer median lag time before treatment (21.5 vs 15.0 days, P = .007), but their overall lag time (54.0 vs 50.0 days, P = .062) and delay in the initial visit (7.0 vs 10.0 days, P = .782) were comparable. Logistic regression analysis showed that children with a lag time ≥ 30 days were at a significantly higher risk of extraocular invasion (odds ratio [OR] = 2.38 and 95% confidence interval [CI] = 1.08–5.37 for treatment delay; OR = 2.12 and 95% CI = 1.01–4.62 for overall delay). Neither high-risk histopathologic features nor lag time was associated with any demographic or major socioeconomic factors, including sex, age at diagnosis or enucleation, ethnicity, household income, parents’ education level, medical insurance coverage, and left-behind status.Conclusions: For children with advanced unilateral retinoblastoma, there is no statistical difference in overall lag time between standard and high-risk groups. Major socioeconomic parameters have little impact on the delay and histopathologic outcomes, thus implying that children with varied socioeconomic status may be at a similar risk of advanced tumor invasion.

Analysis of high-risk histopathologic features of 482 primarily enucleated retinoblastomas

Objective: To evaluate the high-risk histopathologic features of retinoblastoma eyes enucleated as primary treatment. Methods: Retrospective case series study. An analysis was carried out on the high-risk histopathologic features of 482 primarily enucleated retinoblastoma eyes in Beijing Tongren Eye Center during December 2011 and December 2016. The high-risk histopathologic features included post lamina cribrosa invasion, massive choroidal invasion, anterior segment invasion and extraocular invasion. According to the neovascularization of iris (NVI) in the tissue specimen, the patients were divided into the NVI positive group and negative group. The rates of high-risk histopathologic features in the NVI positive group and negative group were analyzed using the chi-square test. Results: Among 482 children with retinoblastoma, 280 (58.1%) were males and 202 (41.9%) were females. The median age at enucleation surgery was 24 months (range, 1-84 months). Of the 482 primarily enucleated eyes, 184 (38.2%) were classified as high-risk histopathologic features, including 148 (30.7%) with post lamina cribrosa invasion, 15 (3.1%) with optic nerve transection invasion, 66 (13.7%) with massive choroidal invasion, 35 (7.3%) with anterior segment invasion, and 5 (1.0%) with extraocular invasion. NVI was detected in 257 (53.3%) cases and there was a significant relation between high-risk histopathologic features and NVI. The rate of high-risk histopathologic features was significantly higher in the NVI positive group (123 cases, 47.9%) than the NVI negative group (61 cases, 27.1%) (χ(2)=21.883, P=0.001). The rate of post lamina cribrosa invasion was significantly higher in the NVI positive group (110 cases, 42.8%) than the NVI negative group (38 cases, 16.9%) (χ(2)=37.860, P=0.001). Conclusions: In this large sample of patients, about 1/3 of retinoblastoma eyes has high-risk histopathologic features. The NVI positive retinoblastoma is more likely to have high-risk histopathologic features or post lamina cribrosa invasion than the NVI negative retinoblastoma. (Chin J Ophthalmol, 2018, 54: 782-786).

Retinoblastoma and retinocytoma (retinoma)

Retinoblastomas are extremely rare withabout half of the cases being hereditary eye neoplasms in young children. They show highly proliferative, CRX-positive undifferentiated tumour cells (occasionally forming rosettes). Staging is performed according to the pTNM classification and the International Retinoblastoma Staging System (IRSS). The diagnostic basis for systemic administration of chemotherapy and/or radiation is postlaminar optic nerve invasion, massive choroidal tumour infiltration, scleral invasion or even extraocular invasion. In cases that are difficult to diagnose, immunohistochemical stains (CRX and Ki67) may be very helpful. Retinocytomas (retinomas)completely lackundifferentiated tumour cell areas, showan exclusive photoreceptor differentiation and an exceptionally low Ki67 index.

The clinical characteristics and survival rate of the patients with extraocular retinoblastoma

Objective To observe the clinical characteristics and survival rate of the patients with extraocular retinoblastoma (RB). Methods This is a retrospective case analysis. From November 2003 to May 2015, 38 eyes of 31 patients with RB in the extra-ocular stage from 213 RB patients were enrolled in this study. There were 18 males and 13 females. Bilateral lesions were observed in 7 patients and unilateral lesions were observed in 24 patients.19 patients were diagnosed at less than 2 years old, 10 patients at 2 to 5 years old, and 2 patients at age over 5 years old. First visit time was less than 1 month in 12 patients, from 1 to 3 months in 15 patients, over 3 months to 6 months in 4 patients. Medical history and family history were record at the first visit. All patients underwent orbital CT, MRI, double color Doppler imaging and wide angle digital retinal imaging system. CT and (or) MRI examination detected tumor extraocular invasion. Histopathological examination showed that there were tumor cells invasion of the scleral, optic nerve root and optic nerve. Chemotherapy was done after surgery. In the extra-ocular stage, 3 to 6 rounds of intensive chemotherapy combined with orbital radiotherapy were done. The average follow-up period was (25.5±4.5) months after treatment. The cumulative survival rate was observed after 6 months, 1 and 5 years after treatment, and the relationship between the initial age, time, sex, single eye, tumor and survival time of the patients was analyzed. Results The extraocular RB accounted 14.55% of all RB patients in this study. There is no family history of RB, no special history. There were 15 patients with leukocoria and yellow-white reflection in the pupil; 5 patients with lacrimation, swelling, photophobia and exophthalmos; 11 patients with strabismus. The cumulative survival rate at 6 months, 1, 5 years after treatment was (78.0±9.0)%, (62.0±11.0)%, (57.0±11.0)% respectively. The average survival time was (53.9±7.8) months; the cumulative survival rate was (59.3±11.3)%. When the age of first visit was less than 1 month, 1 - 3 months, 3 - 6 months, the median survival time was 78, 15 and 18 months respectively, the cumulative survival rate was 100.0%, (40.0±21.9)% and (25.0±21.7)%, respectively. The survival time of the newly diagnosed patients at 1 month was more than at 1 to 6 months, and the difference was statistically significant (t=9.20, P<0.05). Conclusions 14.55% of all RB patients was extraocular RB in this study. One of the most common clinical manifestations is leukocoria at the first visit. The cumulative survival rate of extraocular RB is lower, while the survival rate of patients with the age of first visit time was less than 1 month is higher. Key words: Retinoblastoma/diagnosis; Retinoblastoma/mortality; Neoplasm metastasis; Survival rate

Clinical presentation and survival of retinoblastoma in Indian children

ObjectiveTo study the clinical presentation and survival among Indian children with retinoblastoma (RB) and to determine factors predictive of poor outcome.MethodsA retrospective review of children newly diagnosed with RB at...

Neoadjuvant/adjuvant treatment of high-risk retinoblastoma: a report from the German Retinoblastoma Referral Centre

BackgroundRetinoblastoma can extend beyond the structures of the eye, where cells can enter the bloodstream and cause metastases. Various types of protocols for adjuvant treatment risk-adapted according to histopathological risk...

An aggressive small choroidal melanoma

AbstractPurpose To describe a small non diffuse choroidal melanoma with extraocular extension.Methods Case‐reportResults We describe the case of a 50year‐old patient presenting with visual loss and metamorphopsia. Fundus examination revealed a suprapapillary trilobular choroidal mass with inhomogenous pigmentation and lipofuscin. The optic nerve was slightly oedematous. On fluorescein angiography, the lesion revealed pin‐points and exsudation. Ultrasound sonography (20Mhz) showed a peripapillary lesion of 3mm thickness. MRI was performed and confirmed the diagnosis of choroidal melanoma. No extraocular extension was seen on MRI or ultrasound imaging. Because of optic nerve oedema we decided to perform an enucleation. On pathology, the lesion measured 9mm diameter and 3mm thickness. It was mostly composed of epithelioïd cells and it showed scleral, perineural , optic nerve and periocular soft tissue invasion. Complementary orbital radiotherapy was performed. Until now, after one year follow‐up, the patient has shown no metastasis or local recurrence.Conclusion Extraocular invasion in a small thickness non diffuse choroidal melanoma is rare. In times of eye‐sparing choroidal melanoma treatment, the ophthalmologist should not forget the possibility of extra‐ocular involvement, even in small tumors.

Invasion and metastasis of human retinoblastoma

Children with retinoblastoma (RB) typically survive their cancer due to advances in early diagnosis and treatment. Extraocular invasion and metastasis, and secondary malignant tumor carry a very high mortality rate. Prerequisites for metastasis include tumor initiating capacity, altered cellular adhesion and cell motility, resistance to extracellular death signals and disruption of the basement membrane and extracellular matrix. All those changes can be determined by the cell of origin and the genetic instability of the tumor, responding to the multiple layers of pressure such as hypoxia, from the tumor microenvironment or niche. The interaction between tumor cells and the tumor stroma is regulated by several metastasissuppressor proteins and microRNA. This knowledge has important implications for our understanding and the treatment of extraocular spreading of RB. Key words: Retinoblastoma/prevention & control; Retinoblastoma/pathophysiology; Neoplasm metastasis; Editorial

Retinoblastoma in Taiwan: Survival Rate and Prognostic Factors

The mortality rate of patients with retinoblastoma still varies in developing countries, and data for Asia and Taiwan are relatively scarce. In this retrospective study, we aimed to describe the survival characteristics and prognostic factors of 54 retinoblastoma cases diagnosed at the Taipei Veterans General Hospital between 1982 and 2004. From medical records, we retrospectively analyzed the data of 54 consecutive children diagnosed in our hospital between 1982 and 2004 as having retinoblastoma. Data on sex, laterality, age at diagnosis, presenting signs, family history, duration of symptoms, lag time for treatment, spread of tumor, treatment mode, and survival time were collected. Seventy-five percent of the cases were unilateral and 25% of the cases were bilateral. The mean patient age at the time of diagnosis was 26.3 months. The mean duration of symptoms was 2.96 months. After diagnosis, the mean lag time before treatment was 2.59 months. The most common presenting signs were leukocoria (71.4%), red, painful, or tearing eye (18.4%), strabismus (14.3%), and blurred vision (14.3%). Only 3 of 52 cases (5.8%) were familial. The most common sites of extraocular invasion included the central nervous system (seven cases) and the orbit (seven cases). In 13.7% of the cases, parents had refused the treatment suggested by the doctors. None of the patients developed a secondary neoplasm. The 5-year overall survival rate was 80.9% (unilateral, 88.1%; bilateral, 64.3%). The survival rate of patients with an interval between onset and treatment of <5 months was 90.9%, and that for an interval of >5 months was 60.9%. The survival rate of those with a lag time of <2.5 months was 90.0%, and that of those with one of >2.5 months was 31.3%. The survival rate of patients with intraocular and extraocular disease was 96.9% and 39.2%, respectively. Extraocular disease was an independent factor indicating a poor prognosis, determined by multivariate analysis. The mortality rate of patients with retinoblastoma is higher in Taiwan than in developed countries. The proportion of patients' parents refusing or delaying treatment in Taiwan is high. The factors for a poor prognosis were an interval between onset and treatment of >5 months, a lag time before treatment of >2.5 months, and extraocular disease. The duration of symptoms was not a prognostic factor. The only independent factor indicating a poor prognosis was extraocular disease.

Experimental malignant tumors from retinal pigment epithelium.

Malignant neoplasms of the retinal pigment epithelium (RPE) were produced by infecting pure cultures of hamster RPE in vitro with simian vacuolating virus 40, an oncogenic DNA virus. When transformed cells were injected subcutaneously into irradiated 4-week-old hamsters, neoplasms developed at the injection site within three weeks and subsequently killed the animals by generalized metastasis. These experimental tumors resembled morphologically some tumors seen in human eyes arising from the RPE. While extraocular invasion or metastasis of human RPE tumors has not been documented convincingly, this study demonstrates that under experimental conditions retinal pigment can give rise to tumors capable of invasion and metastasis and provides a model useful in distinguishing histologic characteristics of true malignant tumors of the RPE.