Metastatic Conjunctival Melanoma Research Articles

Case report: Drug-induced vitiligo during treatment with BRAF/MEK inhibitors in a patient with metastatic conjunctival melanoma.

Autoimmune side effects can be detected during the use of BRAF/MEK inhibitor. Although its frequency, mechanism and importance are not known exactly, there are cases reported in the literature. We report a case of drug-induced vitiligo in a patient with metastatic conjunctival malignant melanoma who was treated with BRAF/MEK inhibition therapy. In the case, vitiligo was controlled with topical treatments. Follow-up process of the patient has been continuing with no progression on month 12 of the current treatment. Although ICI-related autoimmune side effects and vitiligo have been described more frequently, vitiligo may also occur secondary to BRAK/MEK inhibition. This case also points out that cutaneous toxicity is manageable with no delay in treatment thanks to collaboration of dermatologists and oncologists.

Update on Immune Checkpoint Inhibitors for Conjunctival Melanoma.

The management of conjunctival melanoma is challenging due to the more frequent local recurrence and metastasis compared to other conjunctival neoplasms. Locally advanced conjunctival melanoma may require an orbital exenteration, and treatment options for metastatic conjunctival melanoma have been limited until recently. This review aims to provide comprehensive updates on immunotherapy for conjunctival melanoma, focusing on immune checkpoint inhibitors. We reviewed the available literature on the use of immunotherapy for the treatment of conjunctival melanoma. Systemic immunotherapy, particularly with checkpoint inhibitors, has recently been reported to have improved outcomes for patients with conjunctival melanoma. Immune checkpoint inhibitors that are currently approved by the US Food and Drug Administration for melanoma include anti-PD-1 (nivolumab and pembrolizumab), anti-PDL-1 (avelumab and atezolizumab), and anti-CTLA-4 inhibitors (ipilimumab). Most recent reports described using immune checkpoint inhibitors in patients with locally advanced conjunctival melanoma in an attempt to avoid orbital exenteration or in patients with metastatic conjunctival melanoma.Although the current data are limited to case reports and small case series, eye care providers should be aware of the potential role of immunotherapy for patients with locally advanced, recurrent, or metastatic conjunctival melanoma.

Genetic characterization of advanced conjunctival melanoma and response to systemic treatment

BackgroundConjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts. MethodsIn this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined. ResultsGenetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively. ConclusionsOur findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.

Immune Checkpoint Inhibitor Therapy as an Eye-Preserving Treatment for Locally Advanced Conjunctival Melanoma.

The authors present 2 patients with locally advanced conjunctival melanoma for whom definitive surgery would mean an orbital exenteration with its associated inherent total visual loss and major facial disfigurement. Instead both patients were treated with immune checkpoint inhibitor therapy. In 1 patient neoadjuvant pembrolizumab was used for approximately 12 months and the patient experienced near-total clinical resolution of the conjunctival melanoma. Multiple surgical biopsies of very small residual pigmentation showed pigmented macrophages and a complete pathologic response. In the second patient who presented with a locally advanced and metastatic conjunctival melanoma, significant shrinkage of conjunctival mass was observed after treatment with a combination of ipilimumab and nivolumab for 5 months, and this allowed preservation of the eye and ocular function.

Conjunctival Melanoma: Current Treatments and Future Options.

Conjunctival melanoma is a rare tumor of the conjunctival epithelium with a heterogenous clinical presentation and a propensity for regional and distant metastatic spread. Guidelines for the treatment of local conjunctival melanoma are well-established, but there are no standard efficacious therapies for metastatic disease. Given that conjunctival melanoma is genetically similar to cutaneous melanoma and mucosal melanomas, targeted therapies effective in the treatment of these diseases, such as BRAF inhibitors and KIT inhibitors, may be effective in the treatment of patients with metastatic conjunctival melanoma. Other targeted small-molecule drugs in the drug development pipeline for the treatment of more prevalent melanomas could also be applicable to conjunctival melanoma. Furthermore, systemic immunotherapy treatments that are now a mainstay in the treatment of cutaneous melanoma, such as programmed cell death-1 and cytotoxic T lymphocyte-associated antigen-4 inhibitors, could also stand to benefit patients with metastatic conjunctival melanoma. Limited case reports provide clues about the effectiveness of both targeted small-molecule inhibitors and immunotherapy in patients with advanced local and metastatic conjunctival melanoma and give credence to the argument that conjunctival melanoma patients should be included in major trials studying new therapies in both cutaneous and mucosal melanomas where applicable.

Global microRNA profiling of metastatic conjunctival melanoma.

This study aimed to investigate the microRNA (miRNA) profile in primary tumors from conjunctival melanoma with and without subsequent metastatic spread along with their coupled distant metastases to identify miRNAs likely to be involved in metastatic progression. This observational study included 13 patients with metastatic conjunctival melanoma (follow-up: 1-39 years) treated at a Danish referral center. Twenty-five patients with nonmetastatic conjunctival melanoma (follow-up: 5-17 years) were included for comparison. Global miRNA profiling was performed with the Affymetrix GeneChip 4.1 microarray. Taqman qPCR arrays were used for validation. Significant differentially expressed miRNAs were defined as having a false discovery rate of less than 0.05. Primary conjunctival melanoma with and without subsequent metastatic spread clustered separately according to miRNA expression, and 15 miRNAs were found to have significant differential expression. Six miRNAs (hsa-miR-4528, hsa-miR-1270, hsa-miR-1290, hsa-mir-548f-4, hsa-mir-4278, and hsa-miR-34a-3p) were downregulated and nine miRNAs were upregulated (hsa-mir-575, hsa-miR-527, hsa-miR-518a-5p, hsa-miR-6759-5p, hsa-miR-8078, hsa-mir-4501, hsa-mir-622, hsa-mir-4698, and hsa-mir-4654) in primary conjunctival melanoma with subsequent metastatic spread. A comparison of primary conjunctival melanoma with their pair-matched metastases identified six significant differentially expressed miRNAs (hsa-miR-1246 and hsa-miR-302d-5p, hsa-mir-6084, hsa-miR-184, hsa-mir-658, and hsa-mir-4427). qPCR confirmed downregulation of hsa-miR-184 in the distant metastases when compared with the corresponding primary tumor. Primary conjunctival melanoma with and without subsequent metastatic spread separated clearly on the miRNA level when profiled with microarray-based methods. qPCR was able to replicate expression levels of one miRNA (hsa-miR-184) that was downregulated in metastases when compared with corresponding primary tumors.

Checkpoint inhibition immunotherapy for advanced local and systemic conjunctival melanoma: a clinical case series

BackgroundHerein, we describe the use of systemic immunotherapy for both locally advanced and metastatic conjunctival melanoma. Current treatments for advanced conjunctival melanoma typically result in poor local control leading to disfiguring orbital exenteration surgery. Locoregional spread of conjunctival malignant melanoma typically requires pre-auricular and cervical lymph node dissection with post-operative adjuvant radiation therapy. In addition, classic systemic chemotherapy has been unsuccessful in the treatment of metastatic disease.MethodsThis is a retrospectively analyzed clinical case series of 5 patients with biopsy proven conjunctival melanoma who were treated with checkpoint inhibition therapy. Of these, 3 patients were treated for residual ocular disease present after failing multiple local therapies and refusing orbital exenteration surgery and two (with local ocular control) for metastatic conjunctival melanoma. Both those with locally advanced disease and patients with metastatic disease received an anti-PD1 agent in combination with another immunotherapeutic agent. All 5 were given multiple cycles of systemic anti-PD1 therapy, 1 was initially treated with single agent ipilimumab (3 mg/kg) prior to approval of anti-PD1 agents and two received interferon eye drops. As part of each ophthalmic examination, photographs of all conjunctival and eyelid surfaces were obtained. Systemic evaluations involved initial staging scans as well as periodic re-imaging.ResultsAll cases have shown responses. Of the 2 complete responses, 1 was a patient with systemic disease. No patients developed ocular toxicity or loss of vision. However, systemic adverse effects included adrenal insufficiency, Grade-III colitis, Grade-II dermatitis, Grade-II hepatotoxicity and Grade-II pneumonitis.ConclusionsThis report suggests that systemic immunotherapy with or without topical interferon is effective in treatment of malignant melanoma of the conjunctiva. Therefore, it can be considered for patients with advanced local conjunctival melanoma, those who refuse orbital exenteration surgery and those with systemic metastasis.

Immunotherapy With Programmed Cell Death 1 Inhibitors for 5 Patients With Conjunctival Melanoma

ImportanceConjunctival melanoma has the potential for regional lymphatic and distant metastasis. There is an urgent need for effective treatment for patients with metastatic or locally advanced conjunctival melanoma.ObjectiveTo describe the use of immune checkpoint inhibitors for the treatment of conjunctival melanoma in 5 adult patients.Design, Setting, and ParticipantsA retrospective review was conducted of the medical records of 5 patients with conjunctival melanoma who were treated with immune checkpoint inhibitors from March 6, 2013, to July 7, 2017.Main Outcomes and MeasuresResponse to treatment and disease-free survival.ResultsOf the 5 patients (4 women and 1 man) with metastatic conjunctival melanoma, 4 were treated with a programmed cell death 1 (PD-1) inhibitor, nivolumab, and had a complete response to treatment with no evidence of disease at 1, 7, 9, and 36 months after completing treatment. One patient with metastatic conjunctival melanoma was treated with another PD-1 inhibitor, pembrolizumab, and had stable metastases during the first 6 months of treatment. Later disease progression resulted in treatment cessation after 11 months and switching to another therapy. Two patients treated with nivolumab developed autoimmune colitis that necessitated stopping the immunotherapy; these patients subsequently were managed with systemic corticosteroids or infliximab.Conclusions and RelevanceThis case series report suggests that anti–PD-1 therapy can be used to treat metastatic conjunctival melanoma. Longer follow-up is needed to determine the long-term disease-free survival. Future studies might assess the potential for immune checkpoint inhibitors to obviate the need for orbital exenteration in selected patients with locally advanced disease.

NF1 mutations in conjunctival melanoma

BackgroundConjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood.MethodsA large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis.ResultsFrequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33%). Recurrent activating mutations were also identified in BRAF (n = 16, 25%) and RAS genes (n = 12, 19%; 11 NRAS and 1 KRAS).ConclusionsSimilar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma

Novel Adjuvant Therapy for Ocular Melanoma

Background Malignant melanoma is the most common cancer of the eye in adults that originates either in the intra-ocular uveal tract or extra-ocular conjunctiva. Although the primary tumor can be treated successfully, no effective therapy for both metastatic conjunctival and uveal melanoma currently exits. Tumor-associated lymphangiogenesis and immune cell infiltration play a pivotal role in the development and therapeutic targeting of metastases. Project description Here, we provide an overview of current translational research on lymphangiogenesis and its therapeutic inhibition as well as modulation of immune cell infiltration by passive and active immunotherapy in melanoma of the eye. Specifically, our previous and ongoing work on lymphangiogenesis and immune cells in ocular melanoma within the clinical research unit FOR 2240 "(Lymph)Angiogenesis and Cellular Immunity in Inflammatory Diseases of the Eye" is summarized. Conclusions Translational research on the modulation of tumor-associated lymphangiogenesis and immune cell infiltration could provide novel targets for adjuvant therapy in melanoma of the eye.

Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy.

PurposeConjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro.Methods131 conjunctival lesions obtained from 129 patients were collected. The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry. We studied cell proliferation, phosphorylation, cell cycling and apoptosis in three CM cell lines using two BRAF inhibitors (Vemurafenib and Dabrafenib), a MEK inhibitor (MEK162) and an AKT inhibitor (MK2206).ResultsThe BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM). Nuclear and cytoplasmic p-ERK and p-AKT were expressed in all conjunctival lesions. Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death. MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines.ConclusionERK and AKT are constitutively activated in conjunctival nevi, PAM and melanoma. While BRAF inhibitors prohibited cell growth, they were not always cytotoxic. Combining MEK and AKT inhibitors led to more growth inhibition and cell death in CM cells. The combination may benefit patients suffering from metastatic conjunctival melanoma.

Palindromic Rheumatism-Like Migratory Non-Erosive Seronegative Polyarthritis in a Patient With Metastatic Conjunctival Malignant Melanoma.

©2016 Turkish League Against Rheumatism. All rights reserved. Malignant melanoma of the conjunctiva is an extremely rare extraocular neoplasm. Local recurrence and metastases of this malignancy have been well documented in the literature,1,2 but there does not seem to be any information regarding cases of paraneoplastic polyarthritis arising from this metastatic malignancy. Herein, we describe the case of a patient with palindromic rheumatism (PR)-like migratory non-erosive seronegative polyarthritis in conjunction with metastatic conjunctival malignant melanoma.

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

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. C57BL/6N mice received C57BL/6N-derived dermal melanoma cells (hepatocyte growth factor [HGF] cyclin dependent kinase-4 [Cdk4]+) 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 CD31+ blood and lymphatic vessel endothelium hyaluronan receptor-1 (LYVE-1)+ lymphatic vessels were quantified immunohistochemically. All mice rapidly developed aggressive TRP2+, S100+, and Ki67+ 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. 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.

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

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. 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. 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. 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.

RUNX2 expression in conjunctival melanocytic proliferations

AbstractPurpose Amplification of RUNX2 (6p21.2), a transcription factor involved in bone formation and in tumor progression of prostate and breast cancer, has previously been identified in 76% (16/21) of primary conjunctival melanoma and in 100% (4/4) of metastatic conjunctival melanoma. The aim of this study was to investigate RUNX2 expression at the protein level in a panel of conjunctival melanocytic proliferationsMethods Expression of RUNX2 was assessed by immunohistochemistry in 26 conjunctival naevi (14 compound naevi, 11 subepithelial naevi and 1 cellular blue naevus), 13 PAM (9 PAM with atypia) and 25 conjunctival melanoma. Statistical analysis was performed with JUMP 8,0 software. Expression was regarded as negative if less than 10% of the tumor cells expressed RUNX2. Examination was independently assessed by two observers.Results RUNX2 was found in 3 naevi (11,5 %), in one PAM with atypia (7,6%) and in 5 melanoma (20 %) without significant variation between the 3 groups. In the melanoma group, there was no correlation between RUNX2 expression and TNM category, depth of invasion, proliferation index (Ki67), local lymphatic invasion and the presence of metastasis. There was however a significant correlation between RUNX2 expression and death (p=0,0191).Conclusion RUNX2 is expressed in a limited number of conjunctival melanocytic proliferations without significant differential expression between benign and malignant lesions. The biological significance of RUNX2 in conjunctival melanoma tumor progression requires further functional investigations.

Whole-body 18 FDG PET/CT imaging for lymph node and metastatic staging of conjunctival melanoma

Aim:To evaluate 18-fluoro-2-deoxyglucose (FDG) whole-body positron emission tomography/computed radiographic tomography (PET/CT) for lymph node and metastatic staging of patients with conjunctival melanoma.Methods:Fourteen patients with T3 (n = 13) and T4...

Topical mitomycin chemotherapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: 12 years’ experience

To report 12-year follow-up experience with topical mitomycin chemotherapy for diffuse and multifocal primary acquired melanosis (PAM) with atypia and conjunctival melanoma. Interventional case series of 16 patients. Mitomycin was a primary treatment for residual epithelial disease in ten patients (eight with PAM with atypia and two with conjunctival melanoma) and as an adjuvant to excision and cryotherapy in six with conjunctival malignant melanoma. Primary treatments consisted of mitomycin 0.04% qid for 28 days (two 14-day cycles) and for 7 consecutive days as adjuvant therapy. Patients were followed for both local recurrence and metastatic disease. Sixteen patients were followed for a mean 81 months (range 13-144 months) after treatment. All tumors responded to chemotherapy. Recurrence was noted in eight (three adjuvant and five primary treatment patients). Three underwent orbital exenteration. The remaining five were treated conservatively. The mean time to recurrence was 36.9 months. The short-term mitomycin-related complications included transient keratoconjunctivitis (n=14), severe keratoconjunctivitis (n=1) and one corneal abrasion with scar formation. The long-term complications included pannus (n=2) and corneal haze (n=1). Visual acuity was maintained within two lines in 14 patients (including measurements just prior to exenteration). Three patients died, one of metastatic conjunctival melanoma. Conjunctival melanoma and PAM responded to mitomycin 0.04% topical chemotherapy; subepithelial nests appeared resistant to treatment. Treatment-related complications were acceptable. In this series, as primary and adjuvant therapy, topical mitomycin yielded an overall recurrence rate of 50%.

Conjunctival Melanoma: The Role of Conservative Surgery and Radiotherapy in Regional Metastatic Disease

To evaluate prognostic factors and determine the role of conservative surgery and radiotherapy in managing metastatic conjunctival malignant melanoma (MM) involving preauricular/submandibular lymph nodes. A retrospective analysis (1990-2003) of clinical and histopathologic data from 12 patients presenting with regional metastases after failed local treatment for conjunctival MM. Patients received a common, multispecialty, conservative management approach: wide local excision, topical cryotherapy or radiotherapy to conjunctival MM (orbital exenteration for more advanced local disease), lumpectomy, and adjuvant "ring" radiotherapy of regional metastases, with chemotherapy for distant metastases. Median age at primary diagnosis was 51 (range 28-86) years with equal sex predilection. Six of the 12 patients had primary tumors of the bulbar conjunctiva; the remainder arose in the palpebral conjunctiva, the caruncle, or the fornix. Of 11 originating in primary acquired melanosis (PAM), 2 were amelanotic. Epithelioid tumor cells were noted histologically in seven of eight specimens in which cell type could be determined. Eight tumors metastasised to preauricular nodes, three to submandibular and one to both, with a median interval of 23 (range 12-108) months after primary diagnosis. After conservative surgery and "ring irradiation," 7 of 12 patients remained free of regional nodal relapse at median interval of 16 (range 3-126) months. Five patients developed regional nodal recurrence at median interval of 11 (range 6-13) months, 3 of whom were within radiotherapy portals. Eight patients developed distant metastasis at median interval of 44 (range 22-138) months. Eleven patients had tumor-related death. The mean Kaplan-Meier adjusted survival time after primary diagnosis was 76 months with death ensuing postregional metastasis within a median 18 (range 4-127) months. The sole survivor's follow-up duration was 56 months. Locoregional metastasis after treatment for conjunctival MM is associated with a poor prognosis. Both epithelioid tumor cells and PAM are associated with disseminating disease and poorer outcome. Literature review has failed to demonstrate advantages of mutilating radical surgery over a conservative approach in this rare disease.