Time trends in the incidence of conjunctival melanoma in Sweden

Triay, Eugenio; Bergman, Louise; Nilsson, Bo; All-Ericsson, Charlotta; Seregard, Stefan

doi:10.1136/bjo.2009.157933

Cited by 115 publications

(91 citation statements)

References 14 publications

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“…Uveal melanoma exhibits mutations in GNAQ and GNA11, whereas skin melanoma and CM typically possess BRAF and NRAS mutations. 11,12 In addition, the incidence of CM is increasing, 1,[13][14][15] which is similar to the increasing frequency observed in skin melanoma.Primary cutaneous melanomas develop spontaneously in the skin of hepatocyte growth factor (HGF)-cyclin dependent kinase 4 …”

supporting

confidence: 58%

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

Schlereth

Iden

Mescher

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Conjunctival melanoma (CM) is an ocular surface tumor that can lead to fatal metastases. Patients developing, tumor-associated lymphangiogenesis have a significantly increased risk of metastatic disease, because tumor spread primarily occurs via lymphatic vessels to the draining lymph node. Here, we describe a novel immune-competent mouse model of CM that displays tumor-associated lymphangiogenesis with development of metastatic tumors.METHODS. C57BL/6N mice received C57BL/6N-derived dermal melanoma cells (hepatocyte growth factor [HGF] cyclin dependent kinase-4 [Cdk4]þ) or B16F10 via subconjunctival injection. A clinical score quantified primary tumor growth and metastases were identified by macroscopic examination of the draining lymph nodes, lung, and spleen. Confirmation of tumors and metastases was achieved by immunohistochemical staining for markers of pigmented cells (tyrosinase related protein-2 [TRP2]) and S-100, and of cell proliferation (Ki67). The intra-and peritumoral CD31þ blood and lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1)þ lymphatic vessels were quantified immunohistochemically.RESULTS. All mice rapidly developed aggressive TRP2þ, S100þ, and Ki67þ CM. Metastatic tumors were found in the lymph node (9%) and lung (6%) of HGF-Cdk4 R24C -treated mice and in the spleen (8%) and lung (17%) of B16F10-treated mice. The amount of peri-and intratumoral blood vessels was significantly increased compared with lymphatic vessels.CONCLUSIONS. This CM model in immune-competent animals offers new possibilities to study the pathobiology of tumor growth, invasion, and mechanisms of metastatic tumor spread, and provides a robust model to explore new immune-based and antilymphangiogenic treatment modalities of this malignancy.Keywords: conjunctival melanoma, mouse model, (lymph)-angiogenesis, ocular melanoma, B16F10, hepatocyte growth factor, metastasis C onjunctival melanoma (CM) is the second most common malignancy of the ocular surface. The current treatment of primary CM is complete surgical removal of the tumor combined with adjuvant therapy in terms of radio-, cryo-, topical chemo-, and/or immunotherapy. However, even though surgical specimens indicate intact tumor-negative margins and apparent tumor removal, CM patients still display an unusually high rate of local recurrence (36%-62% of patients [1][2][3][4][5][6] ). Tumor recurrence coincides with a high risk for the development of metastases, which occurs in 12% to 25% of patients. [1][2][3] Metastatic tumors in CM patients are typically first detected in the lymph nodes draining the tumor-containing eye, indicating the primary route of tumor cell dissemination occurs via the lymphatic vessels. In support of this, we previously demonstrated that lymphangiogenesis is associated with the transition of premalignant precursors into CM.7 Moreover, the extent of lymphatic vessels within CM coincided with an increased risk of local recurrence, lymphatic spread of tumor cells, and development of metastatic disease. [8][9][10] Melanomas ar...

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supporting

confidence: 58%

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

Schlereth

Iden

Mescher

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Conjunctival melanoma accounts for 5% to 10% of all ocular melanomas (8). The population incidence is 0.2 to 0.8 per million (9)(10)(11)(12)(13) with studies reporting an increase in incidence (9,12,14). It occurs more commonly in Caucasian populations and in middleaged and elderly individuals (13).…”

Section: Introductionmentioning

confidence: 99%

Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

Griewank

Westekemper

Murali

et al. 2013

Clinical Cancer Research

183

157

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Purpose: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas.Experimental Design: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples.Results: BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma.Conclusions: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents.

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“…1 Over the past decades, its incidence has increased worldwide. [2][3][4] The current treatment of choice for primary CM is wide surgical excision, combined with brachytherapy, cryotherapy, and topical chemotherapy (e.g., mitomycin C). However, effective targeted therapies have not yet been developed to treat this malignancy 5 ; CM's high recurrence rate is associated with metastasis and poor prognosis.…”

mentioning

confidence: 99%

Evaluation of (fli:GFP) Casper Zebrafish Embryos as a Model for Human Conjunctival Melanoma

Pontes

Groenewoud

Cao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Pontes KCS, Groenewoud A, Cao J, Ataide LMS, Snaar-Jagalska E, Jager MJ. Evaluation of (fli:GFP) Casper zebrafish embryos as a model for human conjunctival melanoma. Invest Ophthalmol Vis Sci. 2017;58:6065-6071. DOI:10.1167/iovs.17-22023 PURPOSE. Conjunctival melanoma (CM) is a rare malignant disease that can lead to recurrences and metastases. There is a lack of effective treatments for the metastases, and we set out to develop a new animal model to test potential therapies. Zebrafish are being used as a model for many diseases, and our goal was to test whether this animal could be used to study CM. METHODS.Three human CM cell lines (CRMM-1 and CM2005.1, which both harbor a B-RAF mutation, and CRMM-2, which has an N-RAS mutation) were injected into the yolk sac, around the eye, and into the duct of Cuvier of transgenic (fli:GFP) Casper zebrafish embryos. Fluorescent and confocal images were taken to assess the phenotype and the behavior of engrafted cells and to test the effect of Vemurafenib as a treatment against CM.RESULTS. While the cells that had been injected inside the yolk sac died and those injected around the eye sporadically went into the circulation, the cells that had been injected into the duct of Cuvier colonized the zebrafish: cells from all three cell lines proliferated and disseminated to the eyes, where they formed clusters, and to the tail, where we noticed extravasation and micrometastases. Vemurafenib, a potent agent for treatment of B-RAF V600E-positive melanoma, inhibited outgrowth of CRMM-1 and CM2005.1 cells in a mutation-dependent way.CONCLUSIONS. The (fli:GFP) Casper zebrafish embryo can be used as an efficient animal model to study metastatic behavior of human CM cells and warrants further testing of drug efficacy to aid care of CM patients.

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Time trends in the incidence of conjunctival melanoma in Sweden

Cited by 115 publications

References 14 publications

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice

Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

Evaluation of (fli:GFP) Casper Zebrafish Embryos as a Model for Human Conjunctival Melanoma

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