Иммуногистохимический анализ экспрессии белка PRAME как прогностический фактор у больных увеальной меланомой

The study objective is to analyze the prognostic significance of PRAME protein expression in patients with uveal melanoma using immunohistochemical assay.Materials and methods. A total of 30 patients with uveal melanoma were examined and treated. The average age of patients at the time of treatment was 51.3 ± 11.8 years. In all cases, enucleation was performed according to the indications. A routine clinical-morphological, molecular-genetic, and immunohistochemical assay study was performed (n = 29). The immunohistochemical study was performed using antibodies to PRAME (clone 6H8, dilution 1: 50). The median follow-up period was 86.3 ± 2.9 months.Results. Of the 29 samples studied, staining was determined in 16, which was 55.2 %. Weak intensity of 1+ staining (from 10 to 20 % of tumor cells) was detected in 7 uveal melanoma samples, medium intensity of 2+ (from 10 to 20 % of tumor cells) – also in 7, and strong intensity of 3+ (30 % of tumor cells) – in 2 tumor samples. When assessing the seven-year survival, the cumulative survival rate in the group without PRAME expression was 0.857, while in the group with PRAME expression it was significantly lower and amounted to 0.357 (p = 0.0001). The PRAME protein expression was significantly correlated with the epithelioid cell type of the tumor (p = 0.041) and with the total and partial monosomy of chromosome 3 (p = 0.013).Conclusion. This paper presents the world’s first study of the prognostic significance of PRAME protein expression by immunohistochemical analysis in patients with uveal melanoma. A significant association of PRAME-positive patients with an unfavorable vital prognosis was shown.Цель исследования – анализ прогностической значимости экспрессии белка PRAME у пациентов с увеальной меланомой с помощью иммуногистохимического исследования.Материалы и методы. Были обследованы и пролечены 30 пациентов с увеальной меланомой, которым с марта по декабрь 2012 г. проведена терапия в стационаре Национального медицинского исследовательского центра глазных болезней им. Гельмгольца Минздрава России. Средний возраст больных на момент исследования составил 51,3 ± 11,8 года. Во всех случаях по показаниям выполнена энуклеация. Проведены рутинное клиникоморфологическое, молекулярно-генетическое и иммуногистохимическое исследования (n = 29). Иммуногистохимическое исследование выполнено с использованием антител к PRAME (клон 6Н8, разведение 1 : 50). Медиана наблюдения составила 86,3 ± 2,9 мес.Результаты. Из 29 исследованных образцов увеальной меланомы окрашивание определено в 16 (55,2 %). Слабая интенсивность окрашивания 1+ (от 10 до 20 % опухолевых клеток) выявлена в 7 образцах, средняя интенсивность 2+ (от 10 до 20 % опухолевых клеток) – также в 7, сильная интенсивность 3+ (30 % опухолевых клеток) – в 2 образцах. При оценке 7-летней выживаемости накопленная доля выживших в группе без экспрессии PRAME составила 0,857, в то время как в группе с наличием экспрессии PRAME она была значимо ниже и составила 0,357 (p = 0,0001). Показана значимая взаимосвязь экспрессии белка PRAME, эпителиоидноклеточного типа опухоли (p = 0,041) и полной и частичной моносомии хромосомы 3 (p = 0,013).Заключение. В настоящей работе представлено первое в мировой практике исследование прогностической значимости экспрессии белка PRAME методом иммуногистохимического анализа у пациентов с увеальной меланомой. PRAME-положительный статус опухоли значимо ассоциирован с неблагоприятным витальным прогнозом

Patients presenting with metastases: stage IV uveal melanoma, an international study

Objective To analyse ocular and systemic findings of patients presenting with systemic metastasis. Methods and analysis It is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases. Results Of 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1-T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category. Conclusions Though higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.Ophthalmic researc

The Pediatric Choroidal and Ciliary Body Melanoma Study A Survey by the European Ophthalmic Oncology Group

Purpose: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. Design: Retrospective, multicenter observational study. Participants: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. Methods: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. Main Outcome Measures: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. Results: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. Conclusions: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups. (C) 2016 by the American Academy of Ophthalmology.Peer reviewe

The quality of life monitoring in patients with uveal melanoma at diagnosis and 12 months after treatment

Purpose. The purpose of the study was the quality of life monitoring in patients with uveal melanoma (UM) depending on age and treatment type during the first year follow-up.Material and methods. The study included 123 patients with primary UM aged from 17 to 82 years. Depending on the age the patients were divided into three groups: group I (17 to 25 years), II (27 to 59 years), III (60 to 82 years), and each group was divided into subgroups depending on the treatment type (eye-preserving or enucleation). As tools for the quality of life assessment the questionnaires SF-36 and VF-14 were used.Results. Statistically significant differences in quality of life (QOL) were obtained comparing the responses of patients after laser treatment, radiation therapy and enucleation. The QOL indices of UM patients 12 months after the start of treatment in the basic group and the group of eye-preserving treatment were significantly higher compared with indices during the initial survey. Among the patients after enucleation occurred an opposite situation. In the subjective assessment a statistically significant difference of visual acuity of the diseased eye was revealed in patients after the laser and radiation therapy. Statistically significant differences in the degree of binocular vision alteration depending on the type of treatment were not determined in patients of the groups I and II. In the group III a significantly better outcome was obtained in patients after eyepreserving treatment compared with patients after enucleation.Conclusion. Thus, our study determined that the choice of treatment type was a fundamental factor affecting changes in QOL of UM patients 12 months after the treatment. Hence, a timely UM diagnosis, allowing the use of the eye-preserving treatment is the key to success in the improvement of quality of life for UM patients

An Analysis of Long-Term Quality of Life Changes in Uveal Melanoma Patients Depending on Age and Treatment Type

We analyze long-term changes of quality of life (QOL) in uvealmelanoma patients, depending on age and treatment type. The study involved 100 patients (28 males and 72 females) aged 11 to 79. The patients were divided in three age groups: group I (25 years or younger), II (26-59 years), III (over 60 years), each group being further subdivided into subgroups depending on the treatment type - eye-preserving therapy (laser or brachytherapy) and enucleation. We used the general type questionnaire SF-36 for oncological patients. For each patient, the survey was taken once, 18 to 72 months after treatment start. The follow-up start median was 30 months for group 1 and 48 months for groups 2 and 3. It could be revealed that over the whole set of patients, the mean values of QOL parameters are no worse than the similar parameters in healthy population. No statistically significant differences in QOL parameters of patients from Groups 1 and 2 were revealed between those receiving eye-preserving or enucleation (p > 0.05). In group 3 statistically significant differences were found in the scales of physical and emotional functioning (p = 0.014, p = 0.001). Middle-aged and elderly patients who received laser treatment demonstrated a higher QOL level as compared to patients of the same age categories who received brachytherapy. In particular, group 2 patients revealed statistically significant differences in the scales of general health (GH, p = 0.012) and vitality (VT, p = 0.03), whereas the patients of group 3 showed similar differences in the scales of GH (p = 0.043), physical functioning (p = 0.005), bodily pain (BP, p = 0.003) and VT (p = 0,048). The lowest levels of QOL were identified in elderly patients after enucleation, and the best results were achieved in patients after laser treatment in all age groups // Russian Ophthalmological Journal, 2016; 1: 56-61

Quality of life factors in young patients with uveal melanoma after surgical treatment

Purpose: to characterize the quality of life (QOL) of young patients with uveal melanoma (UM) after surgical treatment. Materials and methods. 23 patients with UM aged 11 to 25 (mean age 21±4,1 years, 11 females, 12 males) were surveyed on the issue. Of these, 17 people received eye-preserving treatment while 6 patients underwent enucleation. The survey, taken 9-110 months (Me=36) after treatment start, used a generic 36-Item Short-Form Health Survey (SF-36) for cancer patients. Results. The average values of QOL parameters in young UM patients exceed those of healthy people in the population in most scales of the questionnaire. The patient’s sex and treatment type had no effect on the QOL, which was found to improve after eye-preserving treatment during the first year. Statistically significant differences were obtained for scales GH (p=0,043), FF (p=0,042), VT (p=0,043) and PH (p = 0,039). Conclusions. The obtained results testify to high adaptive capacities of UM patients as regards their physical and emotional state caused by eye cancer // Russian Ophthalmological Journal, 2016; 3: 61-5 doi: 10.21516/2072-0076-2016-9-3-61-65

Indications for enucleation after uveal melanoma brachytherapy

Purpose: to analyze indications for enucleation in uveal melanoma (UM) patients after brachytherapy (BT). Material and methods. 52 patients with UM (31 females and 21 males) aged 25 to 74 years (mean age 53.2 ± 12.3) underwent an enucleation after a previously administered BT. Tumor sizes before BT were 6.1 ± 2.1 (1.2-11) mm in thickness and 13.0 ±2.9 (6-19) mm in diameter. Immediately before enucleation, they were 5.3 ± 3.4 (1-17) mm and 12.4 ± 3.6 (5-20) mm respectively. The time span between BT and enucleation varied from 2 to 103 months (median, 25 months). 40 patients (77 %) had choroidal localization of UM (of these,16 had juxtapapillary localization), 10 patients (19.2 %) had ciliochoroidal localization, and 2 patients (3.8 %) had UM in the anterior areas of the eye (iris and ciliary body). Results. In more than a half of the patients (30 patients, or 58 %) tumor regrowth was detected 5-96 months after BT. The second frequent cause for enucleation was neovascular glaucoma found in 21 patients (40 %). Extraocular extension of UM, identified in 12 patients (23 %), took place 3-82 months after BT and turned out to be the third complication as far as frequency of occurrence is concerned. Conclusion. Tumor regrowth remained to be the main cause for secondary enucleation in UM patients after BT. As a matter of fact, complications that can require immediate enucleationmay develop at any time after BT (although the peak falls upon the first 2 years after BT. This fact confirms the need of lifelong follow-up of such patients. Hence, unfounded extension of indications for BT may result in ineffective prolongation of local treatment, a number of radiation complications requiring immediate secondary surgical treatment // Russian Ophthalmological Journal, 2016; 4: 46-51. doi: 10.21516/2072-0076-2016-9-4-46-51

Scleral necrosis after brachytherapy of uveal melanoma and methods of its elimination

Purpose: To analyze the results of scleroplastic operations aimed at eliminating radiation necrosis of the sclera in patients who underwent brachytherapy (BT) of uveal melanoma (UM) using a variety of plastic materials. Material and methods. The paper presents the results of treatment of 19 patients aged 32 to 67 years with radiation necrosis of the sclera after BT of UM. Scleroplasty was carried out 3 to 33 months (the median being 15 months) after brachytherapy using cadaveric sclera (13 patients), alloplant from the dura mater (3 patients) and synthetic ophthalmic material (4 patients). Results. On the whole, the materials and methods used for scleroplasty are effective and most cases save the patient’s eye (17 of 19 eyes have been saved)., However, they are imperfect, which requires that new materials and new methods of eliminating post-radiation defects of the sclera be elaborated and introduced into clinical practice. Conclusion. When planning and performing sclero plasty, strict individual approachs required. The operations have to be performed only in specialized ophthalmic hospitals in cases, of clear indications to uveal melanoma radiotherapy. Preventive measures should always be taken with regard to patients with a risk of necrosis, which will help reduce the frequency and severity of radiation sclera necrosis // Russian Ophthalmological Journal, 2017; 1: 43-8. doi: 10.21516/2072-0076-2017-10-1-43-48

Long-term survival of uveal melanoma patients after enucleation, depending on molecular genetic aberrations

Rationale: In the recent years molecular genetic prognostic factors are becoming very important for predicting the course of uveal melanoma (UM). In clinical practice, molecular genetic methods are used to identify patients with a high risk of metastases.Aim: To determine the survival of UM patients after enucleation, depending on molecular genetic aberrations.Materials and methods: Thirty (30) patients with UM aged from 23 to 83 years were examined and treated. In all cases, enucleation was performed. The removed eyes underwent morphological and molecular genetic and cytogenetic analysis (loss of heterozygocity on chromosomes 1, 3 and 8, methylation of the RASSF1A gene, mutations in GNAQ/11 genes, polymorphism of the ABCB1 gene). The median follow-up was 61 months.Results: The cumulative 3-year survival of the UM patients was 77.8 ± 8.0%, and the 5-year survival 63.0 ± 9.0%. The mean survival time was 52.8 ± 3.9 months. The patients with chromosome 3 monosomy showed significantly lower 5-year survival rates than the patients with partial monosomy and without loss of heterozygocity in chromosome 3 (log-rank test, χ2 = 14.111, p = 0.001). The loss of heterozygocity on chromosomes 1 and 8, the methylation of the RASSF1A gene, the mutations in GNAQ/11 genes, and the polymorphism of the ABCB1 gene were not associated with poorer vital prognosis.Conclusion: Molecular genetic aberrations play an important role in predicting the course of the tumor process and determining the risk of hematogenous metastasizing in UM patients. The significant role of chromosome 3 monosomy has been proved. Due to the relatively small cohort (30 patients) and the time factor (analysis of 5-year survival), the role of other molecular genetic changes has not been confirmed, which requires an assessment of not only genetic, but also clinical, echographic and morphological prognostic factors

Intraocular Medulloepitheliomae (Clinical Case Series)

Purpose. Retrospective analysis of clinical, instrumental, cytological and pathological features of intraocular medulloepithelioma based on our own experience in the period from 2005 to 2018. Patients and Methods. For a specified period of time in the department of ocular oncology and radiology in Moscow Helmholtz Research Institute of Eye Diseases we examined 9 patients aged from 1 to 44 years (5 men and 4 women), with a confirmed histological diagnosis of intraocular medulloepithelioma (medulloblastoma).  The average age of patients in assessing vital status was 15.8 ± 13.5 years, the average age at the time of  making the diagnosis “intraocular neoplasm” was 9.5 ± 11 years. All patients underwent a comprehensive clinical and instrumental ophthalmologic examination, which included visometry, tonometry, perimetry, biomicroscopy, ophthalmoscopy, Doppler ultrasound (ACUSON, USA), as well as general physical examination. Analysis of the initial status (before hospitalization) was carried out retrospectively according to the data of outpatient records. In one case, iridocyclosclerectomy was performed, in eight cases — enucleation of the affected eye followed by histopathological examination, as well as analysis of long-term results of treatment. Results. A detailed analysis of nine clinical cases is presented, including typical clinical features, echographic signs of a meduloepithelioma (heterogeneous structure of the tumor, anechoic inclusions (cysts) in the  thickness of the tumor) are presented. According to the localization, we observed the tumor of the ciliary body (n = 3), the ciliary body and iris (n = 2), the retina (n = 1), the retina, the choroid and the optic nerve disc (n = 1), the ciliary body and the choroid (n = 1) and the choroid with invasion in extraocular muscles and optic nerve (n = 1). In 8 cases, enucleation was performed, one case was preceded by an iridectomy and a fine- needle aspiration biopsy. One patient underwent local conservative treatment (iridocyclosclerectomy) in the  presence of a tumor of the ciliary body and iris. Pathological and cytological features of the tumor were presented. 8 of 9 patients were alive and had no signs of metastases. One patient died 3 years after treatment.  Conclusions. Despite the relative rarity, medulloepithelioma should be included in the differential-diagnostic series in patients with suspected retinoblastoma, non-pigmented uveal melanoma, adenocarcinoma of the  retinal pigment epithelium, and other rare intraocular neoplasms