Developments in the management of uveal melanoma

Uveal melanomas threaten visual loss, enucleation, and death from metastatic disease. Most patients present because of symptoms, but failures of detection and diagnosis still occur commonly. Treatments aimed at avoiding enucleation include: plaque, proton beam or stereotactic radiotherapy; trans-scleral or trans-retinal local resection; and transpupillary thermotherapy. Increasingly, different modalities are being used in combination. The ocular outcomes are related to tumour size, location, spread and cell type. Metastatic disease occurs in many patients and is related to factors such as tumour dimensions, ciliary body involvement, cell type, extravascular matrix patterns and cytogenetics. Abnormalities related to chromosomes 3, 6 and 8 are strongly related to tumour behaviour, for the first time enabling survival probability to be estimated with a high degree of reliability in an individual patient. This enables high-risk individuals to be targeted for screening while providing reassurance to those with a minimal chance of developing metastatic disease. Such targeting would allow selection of patients for adjuvant systemic therapy, should a suitable treatment become available, and would also facilitate the evaluation of such treatment by increasing the statistical power of any randomized prospective study. The high mortality in patients with monosomy 3 melanoma suggests that in these patients ocular treatment is only palliative. Cytogenetic studies suggest that some melanomas may never develop any metastatic potential and if these impressions are confirmed by further studies, then in these patients the main priority of treatment would be to conserve vision.     

Regional chemotherapy for uveal melanoma liver metastases

Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma (UM). Compared with systemic chemotherapy, regional chemotherapy has similar efficacy and fewer systemic adverse effects. Regional chemotherapy for UM liver metastases includes hepatic artery infusion (HAI), transarterial chemoembolization (TACE), and isolated hepatic perfusion (IHP). In this review, we aim to examine the efficacy of regional chemotherapy and compare HAI, TACE, and IHP in terms of overall survival (OS). The three approaches showed no obvious difference in OS results.     

Current management of uveal melanoma: A review

Uveal melanoma is the most frequent primary intraocular cancer in adulthood and is mostly localised to the choroid. It can be treated using radiation therapy, laser therapy, local resection and enucleation, with the best results achieved by combining these procedures. However, up to half of patients develop metastatic disease. There are no efficacious treatment methods for patients in advanced stage or with metastasis. In recent years, several novel treatment modalities aimed at improving tumour control and reducing adverse events have emerged. This review summarises current clinical treatment methods and new therapeutic perspectives for uveal melanoma.     

MAPK通路中肿瘤转移抑制基因对葡萄膜黑色素瘤侵袭能力的影响

丝裂原活化蛋白激酶(MAPK)通路是进化上高度保守的信号通路,它将细胞外信号转化为细胞增生信号传递到细胞核,具有调控细胞的生长、分化、凋亡、基因表达的功能。MAPK信号通路的正常活化与某些肿瘤转移抑制基因的调控有关。在葡萄膜黑色素瘤中存在着nm23、RKIP、MKK4等肿瘤转移抑制基因异常表达所导致的MAPK通路信号传导异常,这种分子信号通路的异常变化对葡萄膜黑色素瘤的侵袭和转移能力有着重要的影响。     

葡萄膜恶性黑色素瘤中血管内皮生长因子水平与肿瘤转移的关系

目的：分析葡萄膜恶性黑色素瘤患者血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)的表达水平是否与葡萄膜恶性黑色素瘤的转移和预后有关。

方法：采用ELISA法检测葡萄膜恶性黑色素瘤患者和正常对照组中外周血VEGF水平,并采用RT-PCR和Western-blot检测葡萄膜恶性黑色素瘤患者肿瘤组织中VEGF mRNA和VEGF蛋白表达水平。对葡萄膜恶性黑色素瘤患者进行随访,用Kaplan-Meier法分析基线VEGF水平与患者术后转移的关系。

结果：葡萄膜恶性黑色素瘤患者外周血VEGF水平较健康者升高。就诊时肿瘤发生转移的患者VEGF mRNA和VEGF蛋白表达水平均较未发生转移的患者升高。在随访过程中,血清VEGF≥700pg/mL的患者,肿瘤发生转移的风险较高。

结论：葡萄膜恶性黑色素瘤患者中VEGF的表达水平与葡萄膜恶性黑色素瘤的转移密切相关。     

Congenital uveal malignant melanoma: a case report

CASE REPORT: We present a case of congenital choroidal mass in a male infant with multiple cutaneous pigmented lesions. Enucleation performed in the first weeks of life confirmed the diagnosis of diffuse uveal malignant melanoma with extraocular extension. The patient was also treated with 5 cycles of chemotherapy. He subsequently developed cutaneous and ocular pigmented lesions, including 2 choroidal nevi located within the posterior pole and a benign conjunctival lesion in the opposite eye, in addition to malignant melanoma of the skin. COMMENTS: At 10 years follow-up, the child is clinically well with no evidence of further malignancy. We believe this represents the fourth case ever reported in the literature and the longest follow-up of a congenital malignant melanoma originating within the eye.     

Treatment of metastatic uveal melanoma: Review and recommendations

This article reviews the published clinical responses of metastatic uveal melanoma and metastatic cutaneous melanoma with visceral involvement to current therapeutic protocols. Despite isolated patient responses to systemic treatment, no effective treatment currently exists for metastatic uveal melanoma. However, several new approaches involving interferons and interleukin and combination chemotherapy have shown some activity against metastatic cutaneous melanoma. The effectiveness against metastatic uveal melanomas has not been determined. A new approach to intrahepatic administration of chemotherapy also warrants further evaluation because of the high incidence of hepatic involvement with metastatic uveal melanoma. When an effective systemic treatment is found, early administration as an adjuvant to primary treatment may provide the best strategy for control of systemic spread.     

Detection of extrascleral extension in uveal melanoma with histopathological correlation

Purpose: Uveal melanoma is the most common primary intraocular malignancy. Extrascleral extension (ESE) is rare, but associated with an increased rate of orbital recurrence and an overall poor prognosis. Clinical studies show low rates when compared with histological studies. Due to the prognostic importance of ESE, we sought to compare our clinical, intraoperative, and histological detection rates.

Design: A retrospective cross-sectional case series.

Methods: A list of eyes enucleated for uveal melanoma was compiled from the admissions records of the London Ocular Oncology Service during the 28-month period, i.e. January 2010–April 2012. The surgical and clinical notes of patients with histopathology proven ESE were reviewed to determine when it was first diagnosed or suspected. The subsequent management of these cases is discussed.

Results: A total of 16 out of 174 (9%) eyes had histologically proven ESE. Eight of 16 cases were detected preoperatively at clinical examination, including the use of ocular ultrasound, 3 of 16 were discovered intra-operatively, and 5 of 16 deemed microscopic ESE, were first detected on histological examination. Seven of 7 (100%) of cases with anterior ESE were detected clinically by slit lamp biomicroscopy, while only 1 out of 9 (11%) of cases with posterior ESE was detected preoperatively with ultrasound.

Conclusions: Slit lamp biomicroscopy is sensitive for detecting anterior ESE. Most posterior ESE is microscopic, but macroscopic posterior ESE may also be missed by B-scan ocular ultrasound. Orbital surgeons should be suspicious of clinically undetected posterior ESE, and consider adjuvant orbital radiotherapy in cases with macroscopic ESE.     

Ocular and oculodermal melanocytosis associated with uveal melanoma

Fifteen patients with ocular or oculodermal melanocytosis were found after reviewing 1210 cases of histologically proven uveal melanomas. The melanoma in each of these patients developed in the eye affected with ocular or oculodermal melanocytosis and not in the unaffected eye. In the one case of bilateral involvement with oculodermal melanocytosis, the patient developed the melanoma in the eye more affected with melanocytosis. In the only case of partial ocular melanocytosis, the melanoma developed in a sector of the eye affected with melanocytosis. A comparison of the prevalence of ocular or oculodermal melanocytosis in patients with uveal melanoma with the prevalence of ocular or oculodermal melanocytosis in the general population, implies that there is an increased incidence of uveal melanomas in patients with ocular or oculodermal melanocytosis.     

Expression of haematogenous and lymphogenous chemokine receptors and their ligands on uveal melanoma in association with liver metastasis

Purpose: Chemokine receptors and their ligands are involved in a number of cell processes, including normal cell trafficking as well as metastasis in cancer. During metastasis, they are thought to play a role in determining cancer cell distribution and target organs. The aim of this study was to examine the expression of the chemokine receptors CXCR4, CCR7 and CCR10 as well as their respective chemokine ligands (CXCL12, CCL19, CCL27) in human uveal melanomas. Methods: Seventy formalin‐fixed paraffin‐embedded uveal melanoma specimens from patients treated in 1996–1997 were examined using immunohistochemistry and evaluated using an immune reactive score (IRS). Results: The chemokine receptors CXCR4, CCR7 and CCR10 were primarily expressed in the cytoplasm of uveal melanoma cells, with CXCR4 (average IRS 8.2) and CCR7 (average IRS 5.7) showing the strongest expression, respectively. The chemokine ligand CCL19 demonstrated a moderate expression (average IRS 5.3), whereas the expression of receptor CCR10 (average IRS of 3.4), ligand CCL27 (average IRS 2.5) and ligand CXCL12 (average IRS 0.6) by uveal melanoma cells was low. A significant association between liver metastases and chemokine expression was found for CCR7 expression (p = 0.037) only. Comparison of liver metastasis and choroid uveal melanoma (35.3%, n = 12 of 34) versus ciliary body involvement (72.7%, n = 8 of 11) was significant (p = 0.030). Conclusion: Chemokine receptors are more strongly expressed on uveal melanoma cells than their ligands. Our results show new aspects of the metastatic process in uveal melanoma.     

葡萄膜恶性黑色素瘤转移相关的非编码RNA表达谱及竞争性内源RNA调控网络分析

目的:利用生物信息学方法分析与葡萄膜恶性黑色素瘤转移相关的非编码RNA,以及它们作为竞争性内源RNA的作用机制.方法:从癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库下载80例葡萄膜恶性黑色素瘤患者的RNA测序数据和临床资料,采用edgeR算法分析转移与非转移患者组织中差异表达(dif...     

The electro-oculogram as an aid in the diagnosis of uveal melanoma

The electro-oculogram (EOG) in the 64 patients with a melanoma of the choroid or ciliary body was compared to the EOG in 11 patients with choroidal metastasis, 11 patients with choroidal naevi and 27 patients with a rhegmatogenous retinal detachment. Using the Dt and the Lp/Dt-ratio, 87.5% of the melanomas could be diagnosed correctly whereas choroidal naevus and retinal detachment were diagnosed correctly in 72.7% and 70.4% of the cases respectively. Choroidal metastases never were classified correctly. Accompanying retinal detachment, tumour volume or a break through Bruch's membrane had no influence on the EOG in the melanoma patients. An important advantage of the method is that it can be used irrespective of the condition of the other eye. Combined with ophthalmoscopy, ultrasonography and fluorescein-angiography the EOG can be an additional aid in the differential diagnosis of malignant melanoma of the choroid and ciliary body.     

Whole-body fluorine-18 fluordeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in staging of advanced uveal melanoma

Fluorine-18 fluordeoxyglucose positron emission tomography (FDG-PET) is an useful tool in diagnosing and monitoring of malignant cutaneous melanoma. However, the feasibility and usefulness of FDG-PET in uveal melanoma is not yet established. We present a patient with suspected advanced uveal melanoma who underwent combined FDG-PET/computed tomography (CT) for staging. FDG-PET/CT images demonstrated vital intraocular tumor. Anatomical assignment of the malignancy to the choroid was possible by means of the coregistered computed tomography. Furthermore, PET revealed an unknown otherwise undetected vital liver metastasis. We conclude that combined FDG-PET/CT has potential to further improve staging and therapy planning in patients with advanced uveal melanoma.     

葡萄膜黑色素瘤单体型3号染色体的检测：荧光原位杂交与多重连接依赖式探针扩增的比较

目的 比较荧光原位杂交（FISH）和多重连接依赖式探针扩增（MLPA）两种方法对于检测葡萄膜黑色素瘤的3号染色体异常的效能。设计 实验研究。研究对象 北京同仁医院2019年行眼球摘除治疗的33例葡萄膜黑色素瘤患者的眼球标本。方法 分析33例患者的临床组织病理学特征。对摘除后行福尔马林固定石蜡包埋（FFPE）的眼球标本中的肿瘤组织采用FISH和MLPA两种方法分别检测3号染色体的拷贝数并进行比较,并对单体型3号染色体与临床组织病理特征做相关性分析。主要指标 3号染色体拷贝数,年龄,性别,肿瘤位置,肿瘤最大基底径,肿瘤细胞类型。结果 33例葡萄膜黑色素瘤患者的肿瘤组织通过FISH和MLPA两种方法检测到单体型3号染色体的比例分别为33.3%和36.4%,其中1例患者FISH检测为二倍体型3号染色体,但MLPA检测为单体型3号染色体。FISH和MLPA两种方法检测的总体符合率为97.0%。单体型3号染色体的比例在肿瘤侵犯睫状体组为66.7%（6/9例）,而在肿瘤未侵犯睫状体组仅为25.0%（6/24例）（P=0.044）。单体型3号染色体的比例在上皮样细胞型组为50.0%（8/16例）,而在非上皮样细胞型组为23.5%（4/17例）（P=0.157）。结论 葡萄膜黑色素瘤为单体型3号染色体者占36.4%。FISH和MLPA均可在葡萄膜黑色素瘤的FFPE样本中完成3号染色体异常的检测,MLPA检测的敏感性较FISH略高。     

巩膜敷贴放射治疗后葡萄膜黑色素瘤的退行及其与预后的关系

葡萄膜黑色素瘤是成年人眼内最常见的恶性肿瘤.巩膜敷贴放射治疗是葡萄膜黑色素瘤临床保留眼球的主要治疗方式,能有效控制肿瘤生长,但放疗后肿瘤退行反应异质性明显.有研究提出巩膜敷贴放疗后肿瘤退行速度可作为巩膜敷贴放射治疗预后因素,退行速度越快预后越差.一些学者研究发现,肿瘤初始高度、3号染色体单体化、GEP分型与巩膜敷贴放疗...     

Clinicopathologic correlations in eyes enucleated after uveal melanoma resection with positive surgical margins

We identified three eyes that had undergone enucleation after transscleral resection of uveal melanoma. Two enucleated eyes with microscopically positive margins of resection exhibited no evidence of residual melanoma and these patients were alive without metastasis with at least four years' follow-up. One eye with a transected melanoma contained residual melanoma and that patient died with metastatic melanoma to the liver three years after enucleation. There appear to be at least two general types of positive surgical margins of resection of uveal melanoma: microscopically positive margins and macroscopically positive (transected) margins of resection.     

Evolving systemic targeted therapy strategies in uveal melanoma and implications for ophthalmic management: a review

Uveal melanoma (UM) is the most common primary ocular tumour in adults. Despite good local control of the primary tumour with current methods, survival after the development of metastasis has remained poor over the last 30 years. After cutaneous melanoma, UM is the most common type of melanoma, and an ongoing debate exists regarding whether these conditions should be considered separate entities, particularly in the context of targeted therapy, where many of the initial trials for patients with metatatic cutaneous melanoma excluded metastatic UM. This paper will review the recent and ongoing investigations designed to validate systemic targeted therapy and immunotherapy in patients with metastatic UM and suggests ways in which these developments may affect management of UM by ophthalmologists in the near future.