Uveal Melanoma: Epidemiologic Aspects

Singh, Nakul; Bergman, Louise; Seregard, Stefan; Singh, Arun D.

doi:10.1007/978-3-642-54255-8_6

Cited by 42 publications

(46 citation statements)

References 75 publications

(65 reference statements)

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“…It is the most common primary intraocular malignancy in adults and occurs almost exclusively in Caucasians, with an incidence of approximately 5-7/million/year in certain European populations [2]. In the USA, it represents about 5% of all melanoma diagnoses [1,3]. Uveal melanoma tends to recur in approximately 50% of the cases despite successful therapy of the primary tumor, in particular those whose tumors have certain risk factors for metastasis, such as large tumor size, ciliary body location, epithelioid cell morphology, high mitotic count and chromosomal abnormalities (e.g., chromosome 3 loss, 8q gain) [4].…”

Section: Aimmentioning

confidence: 99%

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

et al. 2017

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Aim:To compare PD-L1 expression between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). Materials & methods: A total of 295 MCM and 78 MUM specimens were analyzed for tumor cell PD-L1 expression. Additionally, 91 MCM and 45 MUM specimens were analyzed for PD-1 expression on tumor-infiltrating lymphocytes. Results: A total of 77/295 (26.1%) MCM specimens expressed PD-L1 as compared to 4/78 (5.1%) MUM specimens (p < 0.0001). PD-1 expression on tumor-infiltrating lymphocytes was greater in MCM (73.6%; 67/91) than in MUM (51.1%; 23/45), respectively (p = 0.009). Conclusion: Significant differences exist in PD-L1 expression between MCM and MUM. The lower PD-L1 expression in MUM may provide a rationale for failure of PD-1 inhibitor therapy and suggests that immune evasion in this disease may occur via alternative mechanisms. Uveal melanoma originates from melanocytes in the choroid, ciliary body and iris of the eye [1]. It is the most common primary intraocular malignancy in adults and occurs almost exclusively in Caucasians, with an incidence of approximately 5-7/million/year in certain European populations [2]. In the USA, it represents about 5% of all melanoma diagnoses [1,3]. Uveal melanoma tends to recur in approximately 50% of the cases despite successful therapy of the primary tumor, in particular those whose tumors have certain risk factors for metastasis, such as large tumor size, ciliary body location, epithelioid cell morphology, high mitotic count and chromosomal abnormalities (e.g., chromosome 3 loss, 8q gain) [4]. Compared with cutaneous melanoma, uveal melanoma is characterized by its distinct genetic profile and clinical presentation, where most metastases are detected in the liver [5][6][7][8][9][10]. Once uveal melanoma metastasizes, prognosis is poor because metastatic uveal melanoma (MUM) tends to be widespread within the liver and only surgically resectable in some cases [11,12]. Therefore, there is an unmet need for investigating effective systemic therapies.Systemic immunotherapy with checkpoint inhibitors has vastly improved the treatment of metastatic cutaneous melanoma (MCM), leading to long-term durable responses [13,14]. MUM patients are often treated with immune checkpoint inhibitors identical to those used in the treatment of MCM (anti-programmed death-1 [PD-1] and anti-CTLA4 [Cytotoxic T-lymphocyte-associated protein 4] antibodies), either as monotherapy or in combination. Contrary to MCM, MUM demonstrates a poor response to these immune checkpoint blockades [15] (Table 1) [16][17][18][19][20][21][22][23] One of the mechanisms by which tumors evade the immune system is through upregulation and expression of PD-L1 protein on their surface. PD-L1 on tumor cells interacts with PD-1 receptor expressed on activated T cells, leading to T-cell exhaustion, anergy and ultimately, immune response abandonment [24,25]. Inhibition of the PD-1/PD-L1 interaction is the mechanism by which anti-PD-1 antibodies induce T-cell activation and antitumor effect.We evaluated the express...

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Section: Aimmentioning

confidence: 99%

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

et al. 2017

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“…Most arise from melanocytes within the uveal tract, which consists of the iris, ciliary body, and choroid of the eye (1). This type of melanoma has a very high tendency to metastasize to the liver (2). As opposed to cutaneus melanoma, BRAF and RAS mutations are absent or extremely rare in uveal melanoma (3).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells

Ambrosini¹,

Khanin

Schwartz

2014

Molecular Cancer Therapeutics

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The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK inhibitor-resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK inhibitor-resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease. Mol Cancer Ther; 13(8); 2073-80. Ó2014 AACR.

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“…[1][2][3][4][5][6][7] É importante referir que o melanoma intraocular (também designado melanoma da úvea) é considerado uma identidade diferente do melanoma cutâneo e da conjuntiva. O primeiro tem origem nos melanócitos da mesoderme e metastiza por via hemática, em contraste com o tumor da pele e mucosas que tem origem na ectoderme e metastiza, preferencialmente, por via linfática.…”

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Melanoma da Coroideia

et al. 2017

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INTRODUÇÃOO melanoma primário pode afetar diversas estruturas oculares, desde a pálpebra, conjuntiva, úvea (coroideia, corpo ciliar e íris) e muito raramente a órbita, sendo responsável por cerca de 3% -5% de todos os melanomas. [1][2][3][4][5][6][7] É importante referir que o melanoma intraocular (também designado melanoma da úvea) é considerado uma identidade diferente do melanoma cutâneo e da conjuntiva. O primeiro tem origem nos melanócitos da mesoderme e metastiza por via hemática, em contraste com o tumor da pele e mucosas que tem origem na ectoderme e metastiza, preferencialmente, por via linfática. 4É sobre o melanoma primário da coroideia, que corresponde a 85% dos melanomas oculares, que incide este trabalho de revisão. Em comparação com o melanoma da íris, apresenta pior prognóstico e melhor que o melanoma do corpo ciliar. 1,4,6Epidemiologia e fatores de risco O melanoma da coroideia é o tumor intraocular maligno primário mais comum no adulto, e o segundo tipo de melanoma primário mais frequente, imediatamente após o melanoma cutâneo. Estima-se uma incidência anual de aproximadamente 4 -10 casos por 1 milhão de habitantes. 1,2,3,6,[8][9][10] É mais frequente na sexta década de vida e, ao contrário do que se observa na maioria das neoplasias, a sua incidência parece decrescer em idades mais avançadas. Distribui-se igualmente em ambos os sexos, com predileção por indivíduos de pele e olhos claros. 1,4,7,11Acredita-se que a maioria dos melanomas da coroideia se desenvolva a partir de nevus pré-existentes, embora o crescimento de novo também possa ocorrer.Outros factores de risco são a melanocitose congéni-ta ocular e óculo-dérmica, síndrome de nevus displásico e neurofibromatose tipo 1. Não há evidência científica consistente quanto ao papel da radiação ultravioleta, ao contrário do que ocorre nos casos de melanoma da pele e mucosas. 4,5,7,8,[11][12][13] Apresentação clínicaAs manifestações clínicas são inespecíficas e não contribuem para o diagnóstico, sendo muitas vezes um achado acidental num exame oftalmológico de rotina.Numa fase inicial os doentes são assintomáticos, mas quando o tumor atinge grandes dimensões ou se localiza próximo ao nervo óptico ou mácula, pode causar queixas de baixa visão, miodesópsias e fotópsias. A dor é rara e um sintoma sugestivo de mau prognóstico. 4,5,7,10,11,13 Ao exame oftalmológico, o melanoma da coroideia apresenta-se como uma lesão elevada subretiniana, geralmente única e unilateral, com uma coloração que varia de amelanocítica (15% -20%) a pigmentada castanho-acinzentada, sendo raramente preto escuro. Tem uma conformação nodular (75%) (Fig. 1), em cogumelo (20%) (Fig. 2) ou difusa (5%). Subjacente ao tumor é possível observar alterações do epitélio pigmentado da retina como atrofia,

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Uveal Melanoma: Epidemiologic Aspects

Cited by 42 publications

References 75 publications

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

Overexpression of DDX43 Mediates MEK Inhibitor Resistance through RAS Upregulation in Uveal Melanoma Cells

Melanoma da Coroideia

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